STANDARDS OF MEDICAL CARE IN DIABETES—2017

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JANUARY 2017

STANDARDS OF MEDICAL CARE IN DIABETES—2017

ISSN 0149-5992

American Diabetes Association Standards of Medical Care in Diabetesd2017

January 2017 Volume 40, Supplement 1

[T]he simple word Care may suffice to express [the journal’s] philosophical mission. The new journal is designed to promote better patient care by serving the expanded needs of all health professionals committed to the care of patients with diabetes. As such, the American Diabetes Association views Diabetes Care as a reaffirmation of Francis Weld Peabody’s contention that “the secret of the care of the patient is in caring for the patient.” —Norbert Freinkel, Diabetes Care, January-February 1978 EDITOR IN CHIEF

William T. Cefalu, MD ASSOCIATE EDITORS

EDITORIAL BOARD

George Bakris, MD Lawrence Blonde, MD, FACP Andrew J.M. Boulton, MD David D’Alessio, MD Mary de Groot, PhD Eddie L. Greene, MD Frank B. Hu, MD, MPH, PhD Steven E. Kahn, MB, ChB Derek LeRoith, MD, PhD Robert G. Moses, MD Stephen Rich, PhD Matthew C. Riddle, MD Julio Rosenstock, MD William V. Tamborlane, MD Katie Weinger, EdD, RN Judith Wylie-Rosett, EdD, RD

Nicola Abate, MD Vanita R. Aroda, MD Geremia Bolli, MD John B. Buse, MD, PhD Robert J. Chilton, DO, FACC, FAHA Kenneth Cusi, MD, FACP, FACE Paresh Dandona, MD, PhD J. Hans DeVries, MD, PhD Ele Ferrannini, MD Franco Folli, MD, PhD Meredith A. Hawkins, MD, MS Richard Hellman, MD Norbett Hermanns, PhD, MSc George S. Jeha, MD Irl B. Hirsch, MD, MACP Lee M. Kaplan, MD, PhD M. Sue Kirkman, MD Ildiko Lingvay, MD, MPH, MSCS Harold David McIntyre, MD, FRACP AMERICAN DIABETES ASSOCIATION OFFICERS CHAIR OF THE BOARD

David A. DeMarco, PhD PRESIDENT, MEDICINE & SCIENCE

Alvin C. Powers, MD PRESIDENT, HEALTH CARE & EDUCATION

Brenda Montgomery, RN, MSHS, CDE SECRETARY/TREASURER

Umesh Verma CHIEF EXECUTIVE OFFICER

Kevin L. Hagan

The mission of the American Diabetes Association is to prevent and cure diabetes and to improve the lives of all people affected by diabetes.

Maureen Monaghan, PhD, CDE Kristen J. Nadeau, MD, MS Kwame Osei, MD Kevin A. Peterson, MD, MPH, FRCS(Ed), FAAFP Jonathan Q. Purnell, MD Peter Reaven, MD Ravi Retnakaran, MD, MSc, FRCPC Helena Wachslicht Rodbard, MD Elizabeth Seaquist, MD Guntram Schernthaner, MD David J. Schneider, MD Norbert Stefan, MD Jan S. Ulbrecht, MB, BS Joseph Wolfsdorf, MD, BCh Tien Yin Wong, MBBS, FRCSE, FRANZCO, MPH, PhD Bernard Zinman, CM, MD, FRCPC, FACP

Diabetes Care is a journal for the health care practitioner that is intended to increase knowledge, stimulate research, and promote better management of people with diabetes. To achieve these goals, the journal publishes original research on human studies in the following categories: Clinical Care/Education/Nutrition/ Psychosocial Research, Epidemiology/Health Services Research, Emerging Technologies and Therapeutics, Pathophysiology/Complications, and Cardiovascular and Metabolic Risk. The journal also publishes ADA statements, consensus reports, clinically relevant review articles, letters to the editor, and health/medical news or points of view. Topics covered are of interest to clinically oriented physicians, researchers, epidemiologists, psychologists, diabetes educators, and other health professionals. More information about the journal can be found online at care.diabetesjournals.org. Copyright © 2017 by the American Diabetes Association, Inc. All rights reserved. Printed in the USA. Requests for permission to reuse content should be sent to Copyright Clearance Center at www.copyright.com or 222 Rosewood Dr., Danvers, MA 01923; phone: (978) 750-8400; fax: (978) 646-8600. Requests for permission to translate should be sent to Permissions Editor, American Diabetes Association, at [email protected] The American Diabetes Association reserves the right to reject any advertisement for any reason, which need not be disclosed to the party submitting the advertisement. Commercial reprint orders should be directed to Sheridan Content Services, (800) 635-7181, ext. 8065. Single issues of Diabetes Care can be ordered by calling toll-free (800) 232-3472, 8:30 A.M. to 5:00 P.M. EST, Monday through Friday. Outside the United States, call (703) 549-1500. Rates: $75 in the United States, $95 in Canada and Mexico, and $125 for all other countries.

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Diabetes Care is available online at care.diabetesjournals.org. Please call the numbers listed above, e-mail [email protected], or visit the online journal for more information about submitting manuscripts, publication charges, ordering reprints, subscribing to the journal, becoming an ADA member, advertising, permission to reuse content, and the journal’s publication policies. Periodicals postage paid at Alexandria, VA, and additional mailing offices.

AMERICAN DIABETES ASSOCIATION PERSONNEL AND CONTACTS VICE PRESIDENT, PUBLISHER

EDITORIAL CONTENT MANAGER

Michael Eisenstein

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January 2017 Volume 40, Supplement 1

Standards of Medical Care in Diabetes—2017 S1 S3 S4 S6

Introduction Professional Practice Committee Standards of Medical Care in Diabetes—2017: Summary of Revisions 1. Promoting Health and Reducing Disparities in Populations Diabetes and Population Health Tailoring Treatment to Reduce Disparities

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S33

S48

S99

6. Glycemic Targets

S105

S114

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S120

14. Diabetes Care in the Hospital Hospital Care Delivery Standards Glycemic Targets in Hospitalized Patients Bedside Blood Glucose Monitoring Antihyperglycemic Agents in Hospitalized Patients Hypoglycemia Medical Nutrition Therapy in the Hospital Self-management in the Hospital Standards for Special Situations Transition From the Acute Care Setting Preventing Admissions and Readmissions

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8. Pharmacologic Approaches to Glycemic Treatment Pharmacologic Therapy for Type 1 Diabetes Pharmacologic Therapy for Type 2 Diabetes

13. Management of Diabetes in Pregnancy Diabetes in Pregnancy Preconception Counseling Glycemic Targets in Pregnancy Management of Gestational Diabetes Mellitus Management of Preexisting Type 1 Diabetes and Type 2 Diabetes in Pregnancy Postpartum Care Pregnancy and Drug Considerations

7. Obesity Management for the Treatment of Type 2 Diabetes Assessment Diet, Physical Activity, and Behavioral Therapy Pharmacotherapy Metabolic Surgery

12. Children and Adolescents Type 1 Diabetes Type 2 Diabetes Transition From Pediatric to Adult Care

Assessment of Glycemic Control A1C Testing A1C Goals Hypoglycemia Intercurrent Illness S57

11. Older Adults Neurocognitive Function Hypoglycemia Treatment Goals Pharmacologic Therapy Treatment in Skilled Nursing Facilities and Nursing Homes End-of-Life Care

5. Prevention or Delay of Type 2 Diabetes Lifestyle Interventions Pharmacologic Interventions Prevention of Cardiovascular Disease Diabetes Self-management Education and Support

10. Microvascular Complications and Foot Care Diabetic Kidney Disease Diabetic Retinopathy Neuropathy Foot Care

4. Lifestyle Management Diabetes Self-management Education and Support Nutrition Therapy Physical Activity Smoking Cessation: Tobacco and e-Cigarettes Psychosocial Issues

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3. Comprehensive Medical Evaluation and Assessment of Comorbidities Patient-Centered Collaborative Care Comprehensive Medical Evaluation Assessment of Comorbidities

9. Cardiovascular Disease and Risk Management Hypertension/Blood Pressure Control Lipid Management Antiplatelet Agents Coronary Heart Disease

2. Classification and Diagnosis of Diabetes Classification Diagnostic Tests for Diabetes Categories of Increased Risk for Diabetes (Prediabetes) Type 1 Diabetes Type 2 Diabetes Gestational Diabetes Mellitus Monogenic Diabetes Syndromes Cystic Fibrosis–Related Diabetes Posttransplantation Diabetes Mellitus

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15. Diabetes Advocacy Advocacy Position Statements

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Professional Practice Committee Disclosures

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Index

This issue is freely accessible online at care.diabetesjournals.org. Keep up with the latest information for Diabetes Care and other ADA titles via Facebook (/ADAJournals) and Twitter (@ADA_Journals).

Diabetes Care Volume 40, Supplement 1, January 2017

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INTRODUCTION

Introduction Diabetes Care 2017;40(Suppl. 1):S1–S2 | DOI: 10.2337/dc17-S001 Diabetes is a complex, chronic illness requiring continuous medical care with multifactorial risk-reduction strategies beyond glycemic control. Ongoing patient self-management education and support are critical to preventing acute complications and reducing the risk of long-term complications. Significant evidence exists that supports a range of interventions to improve diabetes outcomes. The American Diabetes Association’s (ADA’s) “Standards of Medical Care in Diabetes,” referred to as the “Standards of Care,” is intended to provide clinicians, patients, researchers, payers, and other interested individuals with the components of diabetes care, general treatment goals, and tools to evaluate the quality of care. The Standards of Care recommendations are not intended to preclude clinical judgment and must be applied in the context of excellent clinical care, with adjustments for individual preferences, comorbidities, and other patient factors. For more detailed information about management of diabetes, please refer to Medical Management of Type 1 Diabetes (1) and Medical Management of Type 2 Diabetes (2). The recommendations include screening, diagnostic, and therapeutic actions that are known or believed to favorably affect health outcomes of patients with diabetes. Many of these interventions have also been shown to be cost-effective (3). The ADA strives to improve and update the Standards of Care to ensure that clinicians, health plans, and policymakers can continue to rely on them as the most authoritative and current guidelines for diabetes care. ADA STANDARDS, STATEMENTS, AND REPORTS

The ADA has been actively involved in the development and dissemination of diabetes care standards, guidelines, and related documents for over 25 years.

ADA’s clinical practice recommendations are viewed as important resources for health care professionals who care for people with diabetes. ADA’s Standards of Care, position statements, and scientific statements undergo a formal review process by ADA’s Professional Practice Committee (PPC) and the Board of Directors. Readers who wish to comment on the 2017 Standards of Care are invited to do so at http://professional.diabetes .org/SOC. Standards of Care

Standards of Care: ADA position statement that provides key clinical practice recommendations. The PPC performs an extensive literature search and updates the Standards of Care annually based on the quality of new evidence. ADA Position Statement

A position statement is an official ADA point of view or belief that contains clinical or research recommendations. Position statements are issued on scientific or medical issues related to diabetes. They are published in the ADA journals and other scientific/medical publications. ADA position statements are typically based on a systematic review or other review of published literature. Position statements undergo a formal review process. They are updated every 5 years or as needed. ADA Scientific Statement

A scientific statement is an official ADA point of view or belief that may or may not contain clinical or research recommendations. Scientific statements contain scholarly synopsis of a topic related to diabetes. Workgroup reports fall into this category. Scientific statements are published in the ADA journals and other scientific/medical publications, as appropriate. Scientific statements also undergo a formal review process.

Consensus Report

A consensus report contains a comprehensive examination by an expert panel (i.e., consensus panel) of a scientific or medical issue related to diabetes. A consensus report is not an ADA position and represents expert opinion only. The category may also include task force and expert committee reports. The need for a consensus report arises when clinicians or scientists desire guidance on a subject for which the evidence is contradictory or incomplete. A consensus report is developed following a consensus conference where the controversial issue is extensively discussed. The report represents the panel’s collective analysis, evaluation, and opinion at that point in time based in part on the conference proceedings. A consensus report does not undergo a formal ADA review process. GRADING OF SCIENTIFIC EVIDENCE

Since the ADA first began publishing practice guidelines, there has been considerable evolution in the evaluation of scientific evidence and in the development of evidence-based guidelines. In 2002, the ADA developed a classification system to grade the quality of scientific evidence supporting ADA recommendations for all new and revised ADA position statements. A recent analysis of the evidence cited in the Standards of Care found steady improvement in quality over the past 10 years, with the 2014 Standards of Care for the first time having the majority of bulleted recommendations supported by A- or B-level evidence (4). A grading system (Table 1) developed by the ADA and modeled after existing methods was used to clarify and codify the evidence that forms the basis for the recommendations. ADA recommendations are assigned ratings of A, B, or C, depending on the quality

“Standards of Medical Care in Diabetes” was originally approved in 1988. Most recent review/revision: December 2015. © 2017 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.

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Introduction

Diabetes Care Volume 40, Supplement 1, January 2017

Table 1—ADA evidence-grading system for “Standards of Medical Care in Diabetes” Level of evidence

Description

A

Clear evidence from well-conducted, generalizable randomized controlled trials that are adequately powered, including c Evidence from a well-conducted multicenter trial c Evidence from a meta-analysis that incorporated quality ratings in the analysis Compelling nonexperimental evidence, i.e., “all or none” rule developed by the Centre for Evidence-Based Medicine at the University of Oxford Supportive evidence from well-conducted randomized controlled trials that are adequately powered, including c Evidence from a well-conducted trial at one or more institutions c Evidence from a meta-analysis that incorporated quality ratings in the analysis

B

Supportive evidence from well-conducted cohort studies c Evidence from a well-conducted prospective cohort study or registry c Evidence from a well-conducted meta-analysis of cohort studies Supportive evidence from a well-conducted case-control study

C

Supportive evidence from poorly controlled or uncontrolled studies c Evidence from randomized clinical trials with one or more major or three or more minor methodological flaws that could invalidate the results c Evidence from observational studies with high potential for bias (such as case series with comparison with historical controls) c Evidence from case series or case reports Conflicting evidence with the weight of evidence supporting the recommendation

E

Expert consensus or clinical experience

of evidence. Expert opinion E is a separate category for recommendations in which there is no evidence from clinical trials, in which clinical trials may be impractical, or in which there is conflicting evidence. Recommendations with an A rating are based on large well-designed clinical trials or well-done meta-analyses.

Generally, these recommendations have the best chance of improving outcomes when applied to the population to which they are appropriate. Recommendations with lower levels of evidence may be equally important but are not as well supported. Of course, evidence is only one component of

clinical decision making. Clinicians care for patients, not populations; guidelines must always be interpreted with the individual patient in mind. Individual circumstances, such as comorbid and coexisting diseases, age, education, disability, and, above all, patients’ values and preferences, must be considered and may lead to different treatment targets and strategies. Furthermore, conventional evidence hierarchies, such as the one adapted by the ADA, may miss nuances important in diabetes care. For example, although there is excellent evidence from clinical trials supporting the importance of achieving multiple risk factor control, the optimal way to achieve this result is less clear. It is difficult to assess each component of such a complex intervention. References 1. American Diabetes Association. Medical Management of Type 1 Diabetes. 6th ed. Kaufman FR, Ed. Alexandria, VA, American Diabetes Association, 2012 2. American Diabetes Association. Medical Management of Type 2 Diabetes. 7th ed. Burant CF, Young LA, Eds. Alexandria, VA, American Diabetes Association, 2012 3. Li R, Zhang P, Barker LE, Chowdhury FM, Zhang X. Cost-effectiveness of interventions to prevent and control diabetes mellitus: a systematic review. Diabetes Care 2010;33:1872– 1894 4. Grant RW, Kirkman MS. Trends in the evidence level for the American Diabetes Association’s “Standards of Medical Care in Diabetes” from 2005 to 2014. Diabetes Care 2015;38:6–8

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Professional Practice Committee Diabetes Care 2017;40(Suppl. 1):S3 | DOI: 10.2337/dc17-S002 The Professional Practice Committee (PPC) of the American Diabetes Association (ADA) is responsible for the “Standards of Medical Care in Diabetes” position statement, referred to as the “Standards of Care.” The PPC is a multidisciplinary expert committee comprised of physicians, diabetes educators, registered dietitians, and others who have expertise in a range of areas, including adult and pediatric endocrinology, epidemiology, public health, lipid research, hypertension, preconception planning, and pregnancy care. Appointment to the PPC is based on excellence in clinical practice and research. Although the primary role of the PPC is to review and update the Standards of Care, it is also responsible for overseeing the review and revision of ADA’s position statements and scientific statements. The ADA adheres to the Institute of Medicine Standards for Developing Trustworthy Clinical Practice Guidelines. All members of the PPC are required to disclose potential conflicts of interest with industry and/or other relevant organizations. These disclosures are discussed at the onset of each Standards of Care revision meeting. Members of the committee, their employer, and their disclosed conflicts of interest are listed in the “Professional Practice Committee Disclosures” table (see p. S130). For the current revision, PPC members systematically searched MEDLINE for

human studies related to each section and published since 1 January 2016. Recommendations were revised based on new evidence or, in some cases, to clarify the prior recommendation or match the strength of the wording to the strength of the evidence. A table linking the changes in recommendations to new evidence can be reviewed at http://professional .diabetes.org/SOC. As for all position statements, the Standards of Care position statement was approved by the Executive Committee of ADA’s Board of Directors, which includes health care professionals, scientists, and lay people. Feedback from the larger clinical community was valuable for the 2017 revision of the Standards of Care. Readers who wish to comment on the 2017 Standards of Care are invited to do so at http://professional.diabetes.org/SOC. The ADA funds development of the Standards of Care and all ADA position statements out of its general revenues and does not use industry support for these purposes. The PPC would like to thank the following individuals who provided their expertise in reviewing and/or consulting with the committee: Conor J. Best, MD; William T. Cefalu, MD; Mary de Groot, PhD; Gary D. Hack, DDS; Silvio E. Inzucchi, MD; Meghan Jardine, MS, MBA, RD, LD, CDE; Victor R. Lavis, MD; Mark E. Molitch, MD; Antoinette Moran, MD;

Matt Petersen; Sean Petrie; Louis H. Philipson, MD, PhD; Margaret A. Powers, PhD, RD, CDE; Desmond Schatz, MD; Philip R. Schauer, MD; Sonali N. Thosani, MD; and Guillermo E. Umpierrez, MD. Members of the PPC William H. Herman, MD, MPH (Co-Chair) Rita R. Kalyani, MD, MHS, FACP (Co-Chair)* Andrea L. Cherrington, MD, MPH Donald R. Coustan, MD Ian de Boer, MD, MS Robert James Dudl, MD Hope Feldman, CRNP, FNP-BC Hermes J. Florez, MD, PhD, MPH* Suneil Koliwad, MD, PhD* Melinda Maryniuk, MEd, RD, CDE Joshua J. Neumiller, PharmD, CDE, FASCP* Joseph Wolfsdorf, MB, BCh *Subgroup leaders ADA Staff Erika Gebel Berg, PhD (Corresponding author: [email protected]) Sheri Colberg-Ochs, PhD Alicia H. McAuliffe-Fogarty, PhD, CPsychol Sacha Uelmen, RDN, CDE Robert E. Ratner, MD, FACP, FACE

© 2017 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.

PROFESSIONAL PRACTICE COMMITTEE

Diabetes Care Volume 40, Supplement 1, January 2017

SUMMARY OF REVISIONS

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Diabetes Care Volume 40, Supplement 1, January 2017

Standards of Medical Care in Diabetesd2017: Summary of Revisions Diabetes Care 2017;40(Suppl. 1):S4–S5 | DOI: 10.2337/dc17-S003 GENERAL CHANGES

In light of the American Diabetes Association’s (ADA’s) new position statement on psychosocial care in the treatment of diabetes, the “Standards of Medical Care in Diabetes,” referred to as the “Standards of Care,” has been updated to address psychosocial issues in all aspects of care including self-management, mental health, communication, complications, comorbidities, and life-stage considerations. Although levels of evidence for several recommendations have been updated, these changes are not addressed below as the clinical recommendations have remained the same. Changes in evidence level from, for example, E to C are not noted below. The 2017 Standards of Care contains, in addition to many minor changes that clarify recommendations or reflect new evidence, the following more substantive revisions. SECTION CHANGES Section 1. Promoting Health and Reducing Disparities in Populations

This section was renamed and now focuses on improving outcomes and reducing disparities in populations with diabetes. Recommendations were added to assess patients’ social context as well as refer to local community resources and provide self-management support. Section 2. Classification and Diagnosis of Diabetes

The section was updated to include a new consensus on the staging of type 1 diabetes (Table 2.1) and a discussion of a proposed unifying diabetes classification scheme that focuses on b-cell dysfunction and disease stage as indicated by glucose status. Language was added to clarify screening and testing for diabetes. Screening

approaches were described, and Fig. 2.1 was included to provide an example of a validated tool to screen for prediabetes and previously undiagnosed type 2 diabetes. Due to recent data, delivering a baby weighing 9 lb or more is no longer listed as an independent risk factor for the development of prediabetes and type 2 diabetes. A section was added that discusses recent evidence on screening for diabetes in dental practices. The recommendation to test women with gestational diabetes mellitus for persistent diabetes was changed from 6–12 weeks’ postpartum to 4–12 weeks’ postpartum to allow the test to be scheduled just before the standard 6-week postpartum obstetrical checkup so that the results can be discussed with the patient at that time of the visit or to allow the test to be rescheduled at the visit if the patient did not get the test. Additional detail was added to the section on monogenic diabetes syndromes, and a new table was added (Table 2.7) describing the most common forms of monogenic diabetes. A new section was added on posttransplantation diabetes mellitus. Section 3. Comprehensive Medical Evaluation and Assessment of Comorbidities

This new section, including components of the 2016 section “Foundations of Care and Comprehensive Medical Evaluation,” highlights the importance of assessing comorbidities in the context of a patient-centered comprehensive medical evaluation. A new discussion of the goals of providerpatient communication is included. The Standards of Care now recommends the assessment of sleep pattern and duration as part of the comprehensive

medical evaluation based on emerging evidence suggesting a relationship between sleep quality and glycemic control. An expanded list of diabetes comorbidities now includes autoimmune diseases, HIV, anxiety disorders, depression, disordered eating behavior, and serious mental illness. Section 4. Lifestyle Management

This section, previously entitled “Foundations of Care and Comprehensive Medical Evaluation,” was refocused on lifestyle management. The recommendation for nutrition therapy in people prescribed flexible insulin therapy was updated to include fat and protein counting in addition to carbohydrate counting for some patients to reflect evidence that these dietary factors influence insulin dosing and blood glucose levels. Based on new evidence of glycemic benefits, the Standards of Care now recommends that prolonged sitting be interrupted every 30 min with short bouts of physical activity. A recommendation was added to highlight the importance of balance and flexibility training in older adults. A new section and table provide information on situations that might warrant referral to a mental health provider. Section 5. Prevention or Delay of Type 2 Diabetes

To help providers identify those patients who would benefit from prevention efforts, new text was added emphasizing the importance of screening for prediabetes using an assessment tool or informal assessment of risk factors and performing a diagnostic test when appropriate. To reflect new evidence showing an association between B12 deficiency and long-term metformin use, a recommendation was added to consider periodic

© 2017 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.

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measurement of B12 levels and supplementation as needed. Section 6. Glycemic Targets

Based on recommendations from the International Hypoglycaemia Study Group, serious, clinically significant hypoglycemia is now defined as glucose ,54 mg/dL (3.0 mmol/L), while the glucose alert value is defined as #70 mg/dL (3.9 mmol/L) (Table 6.3). Clinical implications are discussed. Section 7. Obesity Management for the Treatment of Type 2 Diabetes

To be consistent with other ADA position statements and to reinforce the role of surgery in the treatment of type 2 diabetes, bariatric surgery is now referred to as metabolic surgery. To reflect the results of an international workgroup report endorsed by the ADA and many other organizations, recommendations regarding metabolic surgery have been substantially changed, including those related to BMI thresholds for surgical candidacy (Table 7.1), mental health assessment, and appropriate surgical venues. Section 8. Pharmacologic Approaches to Glycemic Treatment

The title of this section was changed from “Approaches to Glycemic Treatment” to “Pharmacologic Approaches to Glycemic Treatment” to reinforce that the section focuses on pharmacologic therapy alone. Lifestyle management and obesity management are discussed in separate chapters. To reflect new evidence showing an association between B12 deficiency and longterm metformin use, a recommendation was added to consider periodic measurement of B12 levels and supplementation as needed. A section was added describing the role of newly available biosimilar insulins in diabetes care. Based on the results of two large clinical trials, a recommendation was added to consider empagliflozin or liraglutide in patients with established cardiovascular disease to reduce the risk of mortality. Figure 8.1, antihyperglycemic therapy in type 2 diabetes, was updated to acknowledge the high cost of insulin.

Summary of Revisions

The algorithm for the use of combination injectable therapy in patients with type 2 diabetes (Fig. 8.2) has been changed to reflect studies demonstrating the noninferiority of basal insulin plus glucagonlike peptide 1 receptor agonist versus basal insulin plus rapid-acting insulin versus two daily injections of premixed insulin, as well as studies demonstrating the noninferiority of multiple dose premixed insulin regimens versus basal-bolus therapy. Due to concerns about the affordability of antihyperglycemic agents, new tables were added showing the median costs of noninsulin agents (Table 8.2) and insulins (Table 8.3). Section 9. Cardiovascular Disease and Risk Management

To better align with existing data, the hypertension treatment recommendation for diabetes now suggests that, for patients without albuminuria, any of the four classes of blood pressure medications (ACE inhibitors, angiotensin receptor blockers, thiazide-like diuretics, or dihydropyridine calcium channel blockers) that have shown beneficial cardiovascular outcomes may be used. To optimize maternal health without risking fetal harm, the recommendation for the treatment of pregnant patients with diabetes and chronic hypertension was changed to suggest a blood pressure target of 120–160/80–105 mmHg. A section was added describing the cardiovascular outcome trials that demonstrated benefits of empagliflozin and liraglutide in certain high-risk patients with diabetes. Section 10. Microvascular Complications and Foot Care

A recommendation was added to highlight the importance of provider communication regarding the increased risk of retinopathy in women with preexisting type 1 or type 2 diabetes who are planning pregnancy or who are pregnant. The section now includes specific recommendations for the treatment of neuropathic pain. A new recommendation highlights the benefits of specialized therapeutic

footwear for patients at high risk for foot problems. Section 12. Children and Adolescents

Additional recommendations highlight the importance of assessment and referral for psychosocial issues in youth. Due to the risk of malformations associated with unplanned pregnancies and poor metabolic control, a new recommendation was added encouraging preconception counseling starting at puberty for all girls of childbearing potential. To address diagnostic challenges associated with the current obesity epidemic, a discussion was added about distinguishing between type 1 and type 2 diabetes in youth. A section was added describing recent nonrandomized studies of metabolic surgery for the treatment of obese adolescents with type 2 diabetes. Section 13. Management of Diabetes in Pregnancy

Insulin was emphasized as the treatment of choice in pregnancy based on concerns about the concentration of metformin on the fetal side of the placenta and glyburide levels in cord blood. Based on available data, preprandial self-monitoring of blood glucose was deemphasized in the management of diabetes in pregnancy. In the interest of simplicity, fasting and postprandial targets for pregnant women with gestational diabetes mellitus and preexisting diabetes were unified. Section 14. Diabetes Care in the Hospital

This section was reorganized for clarity. A treatment recommendation was updated to clarify that either basal insulin or basal plus bolus correctional insulin may be used in the treatment of noncritically ill patients with diabetes in a hospital setting, but not sliding scale alone. The recommendations for insulin dosing for enteral/parenteral feedings were expanded to provide greater detail on insulin type, timing, dosage, correctional, and nutritional considerations.

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Diabetes Care Volume 40, Supplement 1, January 2017

1. Promoting Health and Reducing Disparities in Populations

American Diabetes Association

Diabetes Care 2017;40(Suppl. 1):S6–S10 | DOI: 10.2337/dc17-S004

Recommendations

1. PROMOTING HEALTH AND REDUCING DISPARITIES

c

c c

c

Treatment decisions should be timely, rely on evidence-based guidelines, and be made collaboratively with patients based on individual preferences, prognoses, and comorbidities. B Providers should consider the burden of treatment and self-efficacy of patients when recommending treatments. E Treatment plans should align with the Chronic Care Model, emphasizing productive interactions between a prepared proactive practice team and an informed activated patient. A When feasible, care systems should support team-based care, community involvement, patient registries, and decision support tools to meet patient needs. B

DIABETES AND POPULATION HEALTH

Clinical practice guidelines are key to improving population health; however, for optimal outcomes, diabetes care must be individualized for each patient. Thus, efforts to improve population health will require a combination of system-level and patient-level approaches. With such an integrated approach in mind, the American Diabetes Association (ADA) highlights the importance of patient-centered care, defined as care that is respectful of and responsive to individual patient preferences, needs, and values and ensuring that patient values guide all clinical decisions (1). Practice recommendations, whether based on evidence or expert opinion, are intended to guide an overall approach to care. The science and art of medicine come together when the clinician is faced with making treatment recommendations for a patient who may not meet the eligibility criteria used in the studies on which guidelines are based. Recognizing that one size does not fit all, the standards presented here provide guidance for when and how to adapt recommendations for an individual. Care Delivery Systems

Over the last 10 years, there has been steady improvement in the proportion of patients with diabetes who are treated with statins and who achieve recommended hemoglobin A1C (A1C), blood pressure, and LDL cholesterol levels (2). The mean A1C nationally among people with diabetes has declined from 7.6% (60 mmol/mol) in 1999–2002 to 7.2% (55 mmol/mol) in 2007–2010 based on the National Health and Nutrition Examination Survey (NHANES), with younger adults less likely to meet treatment targets than older adults (2). This has been accompanied by improvements in cardiovascular outcomes and has led to substantial reductions in end-stage microvascular complications. Nevertheless, 33–49% of patients still do not meet targets for glycemic, blood pressure, or cholesterol control, and only 14% meet targets for all three measures while also avoiding smoking (2). Evidence suggests that progress in cardiovascular risk factor control (particularly tobacco use) may be slowing (2,3). Certain segments of the population, such as young adults and patients with complex comorbidities, financial or other social hardships, and/or limited English proficiency, face particular challenges to goal-based care (4–6). Even after adjusting for these patient factors, the persistent variability in the quality of diabetes care across providers and practice settings indicates that substantial system-level improvements are still needed. Chronic Care Model

Numerous interventions to improve adherence to the recommended standards have been implemented. However, a major barrier to optimal care is a delivery

Suggested citation: American Diabetes Association. Promoting health and reducing disparities in populations. Sec. 1. In Standards of Medical Care in Diabetesd2017. Diabetes Care 2017; 40(Suppl. 1):S6–S10 © 2017 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals .org/content/license.

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system that is often fragmented, lacks clinical information capabilities, duplicates services, and is poorly designed for the coordinated delivery of chronic care. The Chronic Care Model (CCM) takes these factors into consideration, and is an effective framework for improving the quality of diabetes care (7). Six Core Elements. The CCM includes six core elements to optimize the care of patients with chronic disease:

1. Delivery system design (moving from a reactive to a proactive care delivery system where planned visits are coordinated through a teambased approach) 2. Self-management support 3. Decision support (basing care on evidence-based, effective care guidelines) 4. Clinical information systems (using registries that can provide patientspecific and population-based support to the care team) 5. Community resources and policies (identifying or developing resources to support healthy lifestyles) 6. Health systems (to create a qualityoriented culture) Redefining the roles of the health care delivery team and empowering patient self-management are fundamental to the successful implementation of the CCM (8). Collaborative, multidisciplinary teams are best suited to provide care for people with chronic conditions such as diabetes and to facilitate patients’ selfmanagement (9–11). Strategies for System-Level Improvement

Optimal diabetes management requires an organized, systematic approach and the involvement of a coordinated team of dedicated health care professionals working in an environment where patientcentered high-quality care is a priority (6). The National Diabetes Education Program (NDEP) maintains an online resource (www.betterdiabetescare.nih.gov) to help health care professionals to design and implement more effective health care delivery systems for those with diabetes. Three specific objectives, with references to literature outlining practical strategies to achieve each, are as follows. Objective 1: Optimize Provider and Team Behavior. The care team, which includes

the patient, should prioritize timely and appropriate intensification of lifestyle

Promoting Health and Reducing Disparities in Populations

and/or pharmacological therapy for patients who have not achieved the recommended metabolic targets (12–14). To inform this process, providers should routinely assess medication adherence. At a system level, “adequate” adherence is defined as 80% (calculated as the number of pills taken by the patient in a given time period divided by the number of pills prescribed by the physician in that same time period) (15). If adherence is 80% or above, then treatment intensification should be considered (e.g., up-titration). Additional strategies shown to improve care team behavior and thereby catalyze reductions in A1C, blood pressure, and/or LDL cholesterol include explicit and collaborative goal setting with patients (16,17); identifying and addressing language, numeracy, or cultural barriers to care (18–20); integrating evidence-based guidelines and clinical information tools into the process of care (21–23); soliciting performance feedback, setting reminders, and providing structured care (e.g., guidelines, formal case management, and patient education resources) (6); and incorporating care management teams including nurses, dietitians, pharmacists, and other providers (24,25). Objective 2: Support Patient Self-management.

Successful diabetes care requires a systematic approach to supporting patients’ behavior change efforts, including the following: 1. Healthy lifestyle choices (healthy eating, physical activity, tobacco cessation, weight management, and effective strategies for coping with stress) 2. Disease self-management (taking and managing medications and, when clinically appropriate, self-monitoring of glucose and blood pressure) 3. Prevention of diabetes complications (self-monitoring of foot health; active participation in screening for eye, foot, and renal complications; and immunizations) 4. Identification of self-management problems and development of strategies to solve those problems, including self-selected behavioral goal setting High-quality diabetes self-management education (DSME) has been shown to improve patient self-management,

satisfaction, and glucose outcomes. National DSME standards call for an integrated approach that includes clinical content and skills, behavioral strategies (goal setting, problem solving), and engagement with psychosocial concerns (26). In devising approaches to support disease self-management, it is notable that in 23% of cases, uncontrolled A1C, blood pressure, or lipids were associated with poor medication adherence (15). Barriers to adherence may include patient factors (remembering to obtain or take medications, fear, depression, or health beliefs), medication factors (complexity, multiple daily dosing, cost, or side effects), and system factors (inadequate follow-up or support). A patient-centered, nonjudgmental communication style can help providers to identify barriers to adherence as well as motivation for self-care (17). Nurse-directed interventions, home aides, diabetes education, and pharmacyderived interventions improved adherence but had a very small effect on outcomes, including metabolic control (27). Success in overcoming barriers to adherence may be achieved if the patient and provider agree on a targeted approach for a specific barrier (10). For example, simplifying a complex treatment regimen may improve adherence in those who identify complexity as a barrier. Objective 3: Change the Care System.

A characteristic of most successful care systems is making high-quality care an institutional priority (28). Changes that increase the quality of diabetes care include providing care on evidence-based guidelines (21); expanding the role of teams to implement more intensive disease management strategies (6,24,29); tracking medication adherence at a system level (15); redesigning the care process (30); implementing electronic health record tools (31,32); empowering and educating patients (33,34); removing financial barriers and reducing patient out-of-pocket costs for diabetes education, eye exams, self-monitoring of blood glucose, and necessary medications (6); assessing and addressing psychosocial issues (26,35); and identifying/developing/engaging community resources and public policy that support healthy lifestyles (36). Initiatives such as the Patient-Centered Medical Home show promise for improving

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outcomes by coordinating primary care and offering new opportunities for team-based chronic disease management (37). Additional strategies to improve diabetes care include reimbursement structures that, in contrast to visitbased billing, reward the provision of appropriate and high-quality care to achieve metabolic goals (38), and incentives that accommodate personalized care goals (6,39). TAILORING TREATMENT TO REDUCE DISPARITIES Recommendations c

c

c

Providers should assess social context, including potential food insecurity, housing stability, and financial barriers, and apply that information to treatment decisions. A Patients should be referred to local community resources when available. B Patients should be provided with selfmanagement support from lay health coaches, navigators, or community health workers when available. A

The causes of health disparities are complex and include societal issues such as institutional racism, discrimination, socioeconomic status, poor access to health care, education, and lack of health insurance. Social determinants of health can be defined as the economic, environmental, political, and social conditions in which people live, and are responsible for a major part of health inequality worldwide (40). Given the tremendous burden that obesity, unhealthy eating, physical inactivity, and smoking place on the health of patients with diabetes, efforts are needed to address and change the societal determinants of these problems (41). The ADA recognizes the association between social and environmental factors and the development of obesity and type 2 diabetes and has issued a call for research that seeks to better understand how these social determinants influence behaviors and how the relationships between these variables might be modified for the prevention and management of diabetes (42). Ethnic/Cultural/Sex Differences

Ethnic, cultural, and sex differences may affect diabetes prevalence and outcomes. Despite advances over the last several decades in medical knowledge

Diabetes Care Volume 40, Supplement 1, January 2017

around diabetes management, racial and ethnic minorities remain at higher risk for microvascular complications than nonminorities. Type 2 diabetes develops more frequently in women with prior gestational diabetes mellitus (43) and in certain racial/ethnic groups (African American, Native American, Hispanic/ Latino, and Asian American) (44). Women with diabetes are also at greater risk of coronary heart disease than men with diabetes (45). Access to Health Care

Socioeconomic and ethnic inequalities exist in the provision of health care to individuals with diabetes (46). For example, children with type 1 diabetes from racial/ethnic minority populations with lower socioeconomic status are at risk for poor metabolic control and poor emotional functioning (47). Significant racial differences and barriers exist in self-monitoring and outcomes (48). Lack of Health Insurance

Not having health insurance affects the processes and outcomes of diabetes care. Individuals without insurance coverage for blood glucose monitoring supplies have a 0.5% higher A1C than those with coverage (49). In a recent study of predominantly African American or Hispanic uninsured patients with diabetes, 50–60% had hypertension, but only 22– 37% had systolic blood pressure controlled by treatments to under 130 mmHg (50). The Affordable Care Act has improved access to health care; however, many remain without coverage (www.cdc.gov/nchs/ fastats/health-insurance.htm). System-Level Interventions

Eliminating disparities will require individualized, patient-centered, and culturally appropriate strategies as well as system-level interventions. Structured interventions that are developed for diverse populations and that integrate culture, language, finance, religion, and literacy and numeracy skills positively influence patient outcomes (51). All providers and health care systems are encouraged to use the National Quality Forum’s National Voluntary Consensus Standards for Ambulatory CaredMeasuring Healthcare Disparities (52). Community Support

Identification or development of resources to support healthy lifestyles is a core element of the CCM (7). Health

care community linkages are receiving increasing attention from the American Medical Association, the Agency for Healthcare Research and Quality, and others as a means of promoting translation of clinical recommendations for lifestyle modification in real-world settings (53). To overcome disparities, community health workers (54), peers (55,56), and lay leaders (57) may assist in the delivery of DSME and diabetes self-management support services (58), particularly in underserved communities. Strong social support leads to improved clinical outcomes, a reduction in psychosocial issues, and adoption of healthier lifestyles (59). Food Insecurity

Food insecurity (FI) is the unreliable availability of nutritious food and the inability to consistently obtain food without resorting to socially unacceptable practices. Over 14% (or one of every seven people in the U.S.) are food insecure. The rate is higher in some racial/ethnic minority groups including African American and Latino populations, in low-income households, and in homes headed by a single mother. FI may involve a tradeoff between purchasing more expensive nutritious food and less expensive energyand carbohydrate-dense processed foods, which may contribute to obesity. The risk for type 2 diabetes is increased twofold in those with FI (42). Therefore, in people with FI, interventions should focus on preventing diabetes. In those with diabetes and FI, the priority is mitigating the increased risk for uncontrolled hyperglycemia and severe hypoglycemia. Reasons for the increased risk of hyperglycemia include the steady consumption of inexpensive carbohydrate-rich processed foods, binge eating, financial constraints to the filling of diabetes medication prescriptions, and anxiety/depression leading to poor diabetes self-care behaviors. Hypoglycemia can occur as a result of inadequate or erratic carbohydrate consumption following administration of sulfonylureas or insulin. Providers should recognize that FI complicates diabetes management and seek local resources that can help patients and the parents of patients with diabetes to more regularly obtain nutritious food (60). Treatment Options

If using a sulfonylurea in patients with FI, glipizide may be considered due to its

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relatively short half-life. It can be taken immediately before meals, thus obviating the need to plan meals to an extent that may be unreachable for those with FI. For those needing insulin, short-acting insulin analogs, preferably delivered by a pen, may be used immediately after meal consumption, whenever food becomes available. While such insulin analogs may be costly, many pharmaceutical companies provide access to free medications through patient assistance programs. If short-acting insulin analogs are not options for those with FI who need insulin therapy, a relatively low dose of an ultra-long-acting insulin analog may be prescribed simply to prevent marked hyperglycemia, while recognizing that tight control may not be possible in such cases. Language Barriers

Diabetes is more common among nonEnglish speaking individuals in the U.S., as is FI. Therefore, it is important to consider screening for diabetes and FI in this population. Providers that care for nonEnglish speakers should develop or offer educational programs and materials in multiple languages with the specific goal of preventing diabetes and building diabetes awareness in people who cannot easily read or write in English. Homelessness

Homelessness often accompanies many barriers to diabetes self-management, including FI, literacy and numeracy deficiencies, lack of insurance, cognitive dysfunction, and mental health issues. Therefore, providers who care for homeless individuals should be well versed or have access to social workers to facilitate temporary housing for their patients as a means to prevent and control diabetes. Additionally, patients with diabetes who are homeless need secure places to keep their diabetes supplies and refrigerator access to properly store their insulin and have access to take it on a regular schedule. References 1. Institute of Medicine. Committee on Quality of Health Care in America. Crossing the quality chasm: a new health system for the 21st century [Internet], 2001. Washington, DC, The National Academies Press. Available from http://www.nap .edu/catalog/10027. Accessed 8 September 2016 2. Ali MK, Bullard KM, Saaddine JB, Cowie CC, Imperatore G, Gregg EW. Achievement of goals in U.S. diabetes care, 1999–2010. N Engl J Med 2013;368:1613–1624

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3. Wang J, Geiss LS, Cheng YJ, et al. Long-term and recent progress in blood pressure levels among U.S. adults with diagnosed diabetes, 1988-2008. Diabetes Care 2011;34:1579–1581 4. Kerr EA, Heisler M, Krein SL, et al. Beyond comorbidity counts: how do comorbidity type and severity influence diabetes patients’ treatment priorities and self-management? J Gen Intern Med 2007;22:1635–1640 5. Fernandez A, Schillinger D, Warton EM, et al. Language barriers, physician-patient language concordance, and glycemic control among insured Latinos with diabetes: the Diabetes Study of Northern California (DISTANCE). J Gen Intern Med 2011;26:170–176 6. TRIAD Study Group. Health systems, patients factors, and quality of care for diabetes: a synthesis of findings from the TRIAD study. Diabetes Care 2010;33:940–947 7. Stellefson M, Dipnarine K, Stopka C. The chronic care model and diabetes management in US primary care settings: a systematic review. Prev Chronic Dis 2013;10:E26 8. Coleman K, Austin BT, Brach C, Wagner EH. Evidence on the Chronic Care Model in the new millennium. Health Aff (Millwood) 2009;28:75–85 9. Piatt GA, Anderson RM, Brooks MM, et al. 3-year follow-up of clinical and behavioral improvements following a multifaceted diabetes care intervention: results of a randomized controlled trial. Diabetes Educ 2010;36:301–309 10. Katon WJ, Lin EH, Von Korff M, et al. Collaborative care for patients with depression and chronic illnesses. N Engl J Med 2010;363:2611–2620 11. Parchman ML, Zeber JE, Romero RR, Pugh JA. Risk of coronary artery disease in type 2 diabetes and the delivery of care consistent with the chronic care model in primary care settings: a STARNet study. Med Care 2007;45:1129–1134 12. Davidson MB. How our current medical care system fails people with diabetes: lack of timely, appropriate clinical decisions. Diabetes Care 2009;32:370–372 13. Selby JV, Uratsu CS, Fireman B, et al. Treatment intensification and risk factor control: toward more clinically relevant quality measures. Med Care 2009;47:395–402 14. Raebel MA, Ellis JL, Schroeder EB, et al. Intensification of antihyperglycemic therapy among patients with incident diabetes: a Surveillance Prevention and Management of Diabetes Mellitus (SUPREME-DM) study. Pharmacoepidemiol Drug Saf 2014;23:699–710 15. Raebel MA, Schmittdiel J, Karter AJ, Konieczny JL, Steiner JF. Standardizing terminology and definitions of medication adherence and persistence in research employing electronic databases. Med Care 2013;51(Suppl. 3):S11–S21 16. Grant RW, Pabon-Nau L, Ross KM, Youatt EJ, Pandiscio JC, Park ER. Diabetes oral medication initiation and intensification: patient views compared with current treatment guidelines. Diabetes Educ 2011;37:78–84 17. Tamha ne S, Rodriguez-G utierrez R, Hargraves I, Montori VM. Shared decision-making in diabetes care. Curr Diab Rep 2015;15:112 18. Schillinger D, Piette J, Grumbach K, et al. Closing the loop: physician communication with diabetic patients who have low health literacy. Arch Intern Med 2003;163:83–90 19. Rosal MC, Ockene IS, Restrepo A, et al. Randomized trial of a literacy-sensitive, culturally

tailored diabetes self-management intervention for low-income Latinos: Latinos en Control. Diabetes Care 2011;34:838–844 20. Osborn CY, Cavanaugh K, Wallston KA, et al. Health literacy explains racial disparities in diabetes medication adherence. J Health Commun 2011;16(Suppl. 3):268–278 21. O’Connor PJ, Bodkin NL, Fradkin J, et al. Diabetes performance measures: current status and future directions. Diabetes Care 2011;34: 1651–1659 22. Garg AX, Adhikari NK, McDonald H, et al. Effects of computerized clinical decision support systems on practitioner performance and patient outcomes: a systematic review. JAMA 2005;293:1223–1238 23. Smith SA, Shah ND, Bryant SC, et al.; Evidens Research Group. Chronic care model and shared care in diabetes: randomized trial of an electronic decision support system. Mayo Clin Proc 2008;83:747–757 24. Jaffe MG, Lee GA, Young JD, Sidney S, Go AS. Improved blood pressure control associated with a large-scale hypertension program. JAMA 2013;310:699–705 25. Stone RA, Rao RH, Sevick MA, et al. Active care management supported by home telemonitoring in veterans with type 2 diabetes: the DiaTel randomized controlled trial. Diabetes Care 2010;33:478–484 26. Powers MA, Bardsley J, Cypress M, et al. Diabetes self-management education and support in type 2 diabetes: a joint position statement of the American Diabetes Association, the American Association of Diabetes Educators, and the Academy of Nutrition and Dietetics. Diabetes Care 2015;38:1372–1382 27. Vermeire E, Wens J, Van Royen P, Biot Y, Hearnshaw H, Lindenmeyer A. Interventions for improving adherence to treatment recommendations in people with type 2 diabetes mellitus. Cochrane Database Syst Rev 2005;2:CD003638 28. Tricco AC, Ivers NM, Grimshaw JM, et al. Effectiveness of quality improvement strategies on the management of diabetes: a systematic review and meta-analysis. Lancet 2012;379: 2252–2261 29. Peikes D, Chen A, Schore J, Brown R. Effects of care coordination on hospitalization, quality of care, and health care expenditures among Medicare beneficiaries: 15 randomized trials. JAMA 2009;301:603–618 30. Feifer C, Nemeth L, Nietert PJ, et al. Different paths to high-quality care: three archetypes of top-performing practice sites. Ann Fam Med 2007;5:233–241 31. Reed M, Huang J, Graetz I, et al. Outpatient electronic health records and the clinical care and outcomes of patients with diabetes mellitus. Ann Intern Med 2012;157:482–489 32. Cebul RD, Love TE, Jain AK, Hebert CJ. Electronic health records and quality of diabetes care. N Engl J Med 2011;365:825–833 33. Battersby M, Von Korff M, Schaefer J, et al. Twelve evidence-based principles for implementing self-management support in primary care. Jt Comm J Qual Patient Saf 2010;36:561–570 34. Grant RW, Wald JS, Schnipper JL, et al. Practice-linked online personal health records for type 2 diabetes mellitus: a randomized controlled trial. Arch Intern Med 2008;168:1776– 1782

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35. Young-Hyman D, de Groot M, Hill-Briggs F, Gonzalez JS, Hood K, Peyrot M. Psychosocial care for people with diabetes: a position statement of the American Diabetes Association. Diabetes Care 2016;39:2126–2140 36. Pullen-Smith B, Carter-Edwards L, Leathers KH. Community health ambassadors: a model for engaging community leaders to promote better health in North Carolina. J Public Health Manag Pract 2008;14(Suppl.):S73–S81 37. Bojadzievski T, Gabbay RA. Patient-centered medical home and diabetes. Diabetes Care 2011; 34:1047–1053 38. RosenthalMB,CutlerDM,FederJ.TheACOrulesd striking the balance between participation and transformative potential. N Engl J Med 2011;365:e6 39. Washington AE, Lipstein SH. The PatientCentered Outcomes Research Institutedpromoting better information, decisions, and health. N Engl J Med 2011;365:e31 40. Commission on Social Determinants of Health. Closing the gap in a generation: health equity through action on the social determinants of health. Final report of the Commission on Social Determinants of Health. Geneva, World Health Organization. Available from http://apps.who.int/ iris/bitstream/10665/43943/1/9789241563703_eng .pdf. Accessed 18 November 2016 41. Jack L, Jack NH, Hayes SC. Social determinants of health in minority populations: a call for multidisciplinary approaches to eliminate diabetes-related health disparities. Diabetes Spectr 2012;25:9–13 42. Hill JO, Galloway JM, Goley A, et al. Scientific statement: socioecological determinants of prediabetes and type 2 diabetes. Diabetes Care 2013;36:2430–2439 43. Kim C, Newton KM, Knopp RH. Gestational diabetes and the incidence of type 2 diabetes: a systematic review. Diabetes Care 2002;25:1862–1868

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44. Hutchinson RN, Shin S. Systematic review of health disparities for cardiovascular diseases and associated factors among American Indian and Alaska Native populations. PLoS One 2014; 9:e80973 45. Peters SAE, Huxley RR, Woodward M. Diabetes as risk factor for incident coronary heart disease in women compared with men: a systematic review and meta-analysis of 64 cohorts including 858,507 individuals and 28,203 coronary events. Diabetologia 2014;57:1542–1551 46. Ricci-Cabello I, Ruiz-Pe´ rez I, Olry de Labry´ S. Do social inequalLima A, M´arquez-Calderon ities exist in terms of the prevention, diagnosis, treatment, control and monitoring of diabetes? A systematic review. Health Soc Care Community 2010;18:572–587 47. Borschuk AP, Everhart RS. Health disparities among youth with type 1 diabetes: a systematic review of the current literature. Fam Syst Health 2015;33:297–313 48. Campbell JA, Walker RJ, Smalls BL, Egede LE. Glucose control in diabetes: the impact of racial differences on monitoring and outcomes. Endocrine 2012;42:471–482 49. Bowker SL, Mitchell CG, Majumdar SR, Toth EL, Johnson JA. Lack of insurance coverage for testing supplies is associated with poorer glycemic control in patients with type 2 diabetes. CMAJ 2004;171:39–43 50. Baumann LC, Chang M-W, Hoebeke R. Clinical outcomes for low-income adults with hypertension and diabetes. Nurs Res 2002;51: 191–198 51. Zeh P, Sandhu HK, Cannaby AM, Sturt JA. The impact of culturally competent diabetes care interventions for improving diabetes-related outcomes in ethnic minority groups: a systematic review. Diabet Med 2012;29:1237–1252 52. National Quality Forum. National voluntary consensus standards for ambulatory cared

measuring healthcare disparities [Internet], 2008. Available from http://www.qualityforum .org/Publications/2008/03/National_Voluntary_ Consensus_Standards_for_Ambulatory_Care% E2%80%94Measuring_Healthcare_Disparities .aspx. Accessed 18 November 2016 53. Agency for Healthcare Research and Quality. Clinical-community linkages [Internet]. Available from http://www.ahrq.gov/professionals/ prevention-chronic-care/improve/community/ index.html. Accessed 10 October 2016 54. Shah M, Kaselitz E, Heisler M. The role of community health workers in diabetes: update on current literature. Curr Diab Rep 2013;13: 163–171 55. Heisler M, Vijan S, Makki F, Piette JD. Diabetes control with reciprocal peer support versus nurse care management: a randomized trial. Ann Intern Med 2010;153:507–515 56. Long JA, Jahnle EC, Richardson DM, Loewenstein G, Volpp KG. Peer mentoring and financial incentives to improve glucose control in African American veterans: a randomized trial. Ann Intern Med 2012;156:416–424 57. Foster G, Taylor SJ, Eldridge SE, Ramsay J, Griffiths CJ. Self-management education programmes by lay leaders for people with chronic conditions. Cochrane Database Syst Rev 2007;4: CD005108 58. Siminerio L, Ruppert KM, Gabbay RA. Who can provide diabetes self-management support in primary care? Findings from a randomized controlled trial. Diabetes Educ 2013;39:705–713 59. Strom JL, Egede LE. The impact of social support on outcomes in adult patients with type 2 diabetes: a systematic review. Curr Diab Rep 2012;12:769–781 60. Seligman HK, Schillinger D. Hunger and socioeconomic disparities in chronic disease. N Engl J Med 2010;363:6–9

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2. Classification and Diagnosis of Diabetes

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Diabetes Care 2017;40(Suppl. 1):S11–S24 | DOI: 10.2337/dc17-S005

CLASSIFICATION

Diabetes can be classified into the following general categories:

This section reviews most common forms of diabetes but is not comprehensive. For additional information, see the American Diabetes Association (ADA) position statement “Diagnosis and Classification of Diabetes Mellitus” (1). Type 1 diabetes and type 2 diabetes are heterogeneous diseases in which clinical presentation and disease progression may vary considerably. Classification is important for determining therapy, but some individuals cannot be clearly classified as having type 1 or type 2 diabetes at the time of diagnosis. The traditional paradigms of type 2 diabetes occurring only in adults and type 1 diabetes only in children are no longer accurate, as both diseases occur in both cohorts. Occasionally, patients with type 2 diabetes may present with diabetic ketoacidosis (DKA), particularly ethnic minorities (2). Children with type 1 diabetes typically present with the hallmark symptoms of polyuria/polydipsia, and approximately one-third present with DKA (3). The onset of type 1 diabetes may be more variable in adults, and they may not present with the classic symptoms seen in children. Although difficulties in distinguishing diabetes type may occur in all age-groups at onset, the true diagnosis becomes more obvious over time. In October 2015, the ADA, JDRF, the European Association for the Study of Diabetes, and the American Association of Clinical Endocrinologists convened the Differentiation of Diabetes by Pathophysiology, Natural History, and Prognosis Research Symposium (4). The goals of the symposium were to discuss the genetic and environmental determinants of type 1 and type 2 diabetes risk and progression, to determine appropriate therapeutic approaches based on disease pathophysiology and stage, and to define research gaps hindering a personalized approach to treatment. The experts agreed that in both type 1 and type 2 diabetes, various genetic and environmental factors can result in the progressive loss of b-cell mass and/or function that manifests clinically as hyperglycemia. Once hyperglycemia occurs, patients with all forms of diabetes are at risk for developing the same complications, although rates of progression may differ. They concluded that the identification of individualized therapies for diabetes in the future will require better characterization of the many paths to b-cell demise or dysfunction. Characterization of the underlying pathophysiology is much more developed in type 1 diabetes than in type 2 diabetes. It is now clear from studies of first-degree relatives of patients with type 1 diabetes that the persistent presence of two or

2. CLASSIFICATION AND DIAGNOSIS OF DIABETES

1. Type 1 diabetes (due to autoimmune b-cell destruction, usually leading to absolute insulin deficiency) 2. Type 2 diabetes (due to a progressive loss of b-cell insulin secretion frequently on the background of insulin resistance) 3. Gestational diabetes mellitus (GDM) (diabetes diagnosed in the second or third trimester of pregnancy that was not clearly overt diabetes prior to gestation) 4. Specific types of diabetes due to other causes, e.g., monogenic diabetes syndromes (such as neonatal diabetes and maturity-onset diabetes of the young [MODY]), diseases of the exocrine pancreas (such as cystic fibrosis), and drug- or chemical-induced diabetes (such as with glucocorticoid use, in the treatment of HIV/AIDS, or after organ transplantation)

Suggested citation: American Diabetes Association. Classification and diagnosis of diabetes. Sec. 2. In Standards of Medical Care in Diabetesd 2017. Diabetes Care 2017;40(Suppl. 1):S11–S24 © 2017 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals .org/content/license.

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Classification and Diagnosis of Diabetes

more autoantibodies is an almost certain predictor of clinical hyperglycemia and diabetes. The rate of progression is dependent on the age at first detection of antibody, number of antibodies, antibody specificity, and antibody titer. Glucose and A1C levels rise well before the clinical onset of diabetes, making diagnosis feasible well before the onset of DKA. Three distinct stages of type 1 diabetes can be identified (Table 2.1) and serve as a framework for future research and regulatory decision making (4,5). The paths to b-cell demise and dysfunction are less well defined in type 2 diabetes, but deficient b-cell insulin secretion frequently in the setting of insulin resistance appears to be the common denominator. Characterization of subtypes of this heterogeneous disorder have been developed and validated in Scandinavian and Northern European populations, but have not been confirmed in other ethnic and racial groups. Type 2 diabetes is primarily associated with insulin secretory defects related to inflammation and metabolic stress among other contributors including genetic factors. Future classification schemes for diabetes will likely focus on the pathophysiology of the underlying b-cell dysfunction and the stage of disease as indicated by glucose status (normal, impaired, or diabetes) (4). DIAGNOSTIC TESTS FOR DIABETES

Diabetes may be diagnosed based on plasma glucose criteria, either the fasting plasma glucose (FPG) or the 2-h plasma glucose (2-h PG) value after a 75-g oral glucose tolerance test (OGTT) or A1C criteria (1,6) (Table 2.2). FPG, 2-h PG after 75-g OGTT, and A1C are equally appropriate for diagnostic testing. It should be noted that the tests do not necessarily detect diabetes in the same individuals. The efficacy of

Diabetes Care Volume 40, Supplement 1, January 2017

interventions for primary prevention of type 2 diabetes (7,8) has primarily been demonstrated among individuals with impaired glucose tolerance (IGT), not for individuals with isolated impaired fasting glucose (IFG) or for those with prediabetes defined by A1C criteria. The same tests may be used to screen for and diagnose diabetes and to detect individuals with prediabetes. Diabetes may be identified anywhere along the spectrum of clinical scenarios: in seemingly low-risk individuals who happen to have glucose testing, in individuals tested based on diabetes risk assessment, and in symptomatic patients. Fasting and 2-Hour Plasma Glucose

The FPG and 2-h PG may be used to diagnose diabetes (Table 2.2). The concordance between the FPG and 2-h PG tests is imperfect, as is the concordance between A1C and either glucose-based test. Numerous studies have confirmed that, compared with FPG and A1C cut points, the 2-h PG value diagnoses more people with diabetes. A1C

The A1C test should be performed using a method that is certified by the NGSP (www.ngsp.org) and standardized or traceable to the Diabetes Control and Complications Trial (DCCT) reference assay. Although point-of-care A1C assays may be NGSP certified, proficiency testing is not mandated for performing the test, so use of point-of-care assays for diagnostic purposes is not recommended but may be considered in the future if proficiency testing is performed and documented. The A1C has several advantages compared with the FPG and OGTT, including greater convenience (fasting not required), greater preanalytical stability, and less day-to-day perturbations during stress and illness. However, these

advantages may be offset by the lower sensitivity of A1C at the designated cut point, greater cost, limited availability of A1C testing in certain regions of the developing world, and the imperfect correlation between A1C and average glucose in certain individuals. National Health and Nutrition Examination Survey (NHANES) data indicate that an A1C cut point of $6.5% (48 mmol/mol) identifies one-third fewer cases of undiagnosed diabetes than a fasting glucose cut point of $126 mg/dL (7.0 mmol/L) (9). When using A1C to diagnose diabetes, it is important to recognize that A1C is an indirect measure of average blood glucose levels and to take other factors into consideration that may impact hemoglobin glycation independently of glycemia including age, race/ethnicity, and anemia/ hemoglobinopathies. Age

The epidemiological studies that formed the basis for recommending A1C to diagnose diabetes included only adult populations. Therefore, it remains unclear if A1C and the same A1C cut point should be used to diagnose diabetes in children and adolescents (9,10). Race/Ethnicity

A1C levels may vary with race/ethnicity independently of glycemia (11,12). For example, African Americans may have higher A1C levels than non-Hispanic whites despite similar fasting and postglucose load glucose levels (13). Though there is some conflicting data, African Americans may also have higher levels of fructosamine and glycated albumin and lower levels of 1,5-anhydroglucitol, suggesting that their glycemic burden (particularly postprandially) may be higher (14,15). The association of A1C with risk for complications appears to be similar in African Americans and non-Hispanic whites (16).

Table 2.1—Staging of type 1 diabetes (4,5) Stage 1

Stage 2

Stage 3

Stage

c

Autoimmunity c Normoglycemia c Presymptomatic

c

Autoimmunity c Dysglycemia c Presymptomatic

c

Diagnostic criteria

c

c

c

c

c

c

Multiple autoantibodies No IGT or IFG

Multiple autoantibodies Dysglycemia: IFG and/or IGT c FPG 100–125 mg/dL (5.6–6.9 mmol/L) c 2-h PG 140–199 mg/dL (7.8–11.0 mmol/L) c A1C 5.7–6.4% (39–47 mmol/mol) or $10% increase in A1C

New-onset hyperglycemia c Symptomatic Clinical symptoms Diabetes by standard criteria

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Classification and Diagnosis of Diabetes

Table 2.2—Criteria for the diagnosis of diabetes FPG $126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 h.* OR 2-h PG $200 mg/dL (11.1 mmol/L) during an OGTT. The test should be performed as described by the WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.* OR A1C $6.5% (48 mmol/mol). The test should be performed in a laboratory using a method that is NGSP certified and standardized to the DCCT assay.* OR In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose $200 mg/dL (11.1 mmol/L). *In the absence of unequivocal hyperglycemia, results should be confirmed by repeat testing.

Hemoglobinopathies/Red Blood Cell Turnover

Interpreting A1C levels in the presence of certain hemoglobinopathies may be problematic. For patients with an abnormal hemoglobin but normal red blood cell turnover, such as those with the sickle cell trait, an A1C assay without interference from abnormal hemoglobins should be used. An updated list of interferences is available at www.ngsp .org/interf.asp. In conditions associated with increased red blood cell turnover, such as pregnancy (second and third trimesters), hemodialysis, recent blood loss or transfusion, or erythropoietin therapy, only blood glucose criteria should be used to diagnose diabetes. Confirming the Diagnosis

Unless there is a clear clinical diagnosis (e.g., patient in a hyperglycemic crisis or with classic symptoms of hyperglycemia and a random plasma glucose $200 mg/dL [11.1 mmol/L]), a second test is required for confirmation. It is recommended that the same test be repeated without delay using a new blood sample for confirmation because there will be a greater likelihood of concurrence. For example, if the A1C is 7.0% (53 mmol/mol) and a repeat result is 6.8% (51 mmol/mol), the diagnosis of diabetes is confirmed. If two different tests (such as A1C and FPG) are both above the diagnostic threshold, this also confirms the diagnosis. On the other hand, if a patient has discordant results from two different tests, then the test result that is above the diagnostic cut point should be repeated. The diagnosis is made on the basis of the confirmed test. For example, if a patient meets the diabetes criterion of the A1C (two results $6.5% [48 mmol/mol]) but not

FPG (,126 mg/dL [7.0 mmol/L]), that person should nevertheless be considered to have diabetes. Since all the tests have preanalytic and analytic variability, it is possible that an abnormal result (i.e., above the diagnostic threshold), when repeated, will produce a value below the diagnostic cut point. This scenario is likely for FPG and 2-h PG if the glucose samples remain at room temperature and are not centrifuged promptly. Because of the potential for preanalytic variability, it is critical that samples for plasma glucose be spun and separated immediately after they are drawn. If patients have test results near the margins of the diagnostic threshold, the health care professional should follow the patient closely and repeat the test in 3–6 months. CATEGORIES OF INCREASED RISK FOR DIABETES (PREDIABETES) Recommendations c

c

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Screening for prediabetes and risk for future diabetes with an informal assessment of risk factors or validated tools should be considered in asymptomatic adults. B Testing for prediabetes and risk for future diabetes in asymptomatic people should be considered in adults of any age who are overweight or obese (BMI $25 kg/m2 or $23 kg/m 2 in Asian Americans) and who have one or more additional risk factors for diabetes. B For all people, testing should begin at age 45 years. B If tests are normal, repeat testing carried out at a minimum of 3-year intervals is reasonable. C

c

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c

To test for prediabetes, fasting plasma glucose, 2-h plasma glucose after 75-g oral glucose tolerance test, and A1C are equally appropriate. B In patients with prediabetes, identify and, if appropriate, treat other cardiovascular disease risk factors. B Testing for prediabetes should be considered in children and adolescents who are overweight or obese and who have two or more additional risk factors for diabetes. E

Description

In 1997 and 2003, the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (17,18) recognized a group of individuals whose glucose levels did not meet the criteria for diabetes but were too high to be considered normal. “Prediabetes” is the term used for individuals with IFG and/or IGT and/or A1C 5.7–6.4% (39–47 mmol/mol). Prediabetes should not be viewed as a clinical entity in its own right but rather as an increased risk for diabetes (Table 2.3) and cardiovascular disease (CVD). Prediabetes is associated with obesity (especially abdominal or visceral obesity), dyslipidemia with high triglycerides and/or low HDL cholesterol, and hypertension. Diagnosis

The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (17,18) defined IFG as FPG levels between 100 and 125 mg/dL (between 5.6 and 6.9 mmol/L) and IGT as 2-h PG after 75-g OGTT levels between 140 and 199 mg/dL (between 7.8 and 11.0 mmol/L). It should be noted that the World Health Organization (WHO) and numerous other diabetes organizations define the IFG cutoff at 110 mg/dL (6.1 mmol/L). As with the glucose measures, several prospective studies that used A1C to predict the progression to diabetes as defined by A1C criteria demonstrated a strong, continuous association between A1C and subsequent diabetes. In a systematic review of 44,203 individuals from 16 cohort studies with a follow-up interval averaging 5.6 years (range 2.8– 12 years), those with A1C between 5.5 and 6.0% (between 37 and 42 mmol/mol)

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Table 2.3—Criteria for testing for diabetes or prediabetes in asymptomatic adults 1. Testing should be considered in overweight or obese (BMI $25 kg/m2 or $23 kg/m2 in Asian Americans) adults who have one or more of the following risk factors: c A1C $5.7% (39 mmol/mol), IGT, or IFG on previous testing c first-degree relative with diabetes c high-risk race/ethnicity (e.g., African American, Latino, Native American, Asian American, Pacific Islander) c women who were diagnosed with GDM c history of CVD c hypertension ($140/90 mmHg or on therapy for hypertension) c HDL cholesterol level ,35 mg/dL (0.90 mmol/L) and/or a triglyceride level .250 mg/dL (2.82 mmol/L) c women with polycystic ovary syndrome c physical inactivity c other clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosis nigricans).

and may serve as an indication for intervention in the setting of a clinical trial. Outcomes may include reversion of autoantibody status, prevention of glycemic progression within the normal or prediabetes range, prevention of clinical diabetes, or preservation of residual C-peptide secretion. A Diagnosis

2. For all patients, testing should begin at age 45 years. 3. If results are normal, testing should be repeated at a minimum of 3-year intervals, with consideration of more frequent testing depending on initial results (e.g., those with prediabetes should be tested yearly) and risk status.

had a substantially increased risk of diabetes (5-year incidence from 9 to 25%). An A1C range of 6.0–6.5% (42–48 mmol/mol) had a 5-year risk of developing diabetes between 25 and 50% and a relative risk 20 times higher compared with A1C of 5.0% (31 mmol/mol) (19). In a communitybased study of African American and non-Hispanic white adults without diabetes, baseline A1C was a stronger predictor of subsequent diabetes and cardiovascular events than fasting glucose (20). Other analyses suggest that A1C of 5.7% (39 mmol/mol) or higher is associated with a diabetes risk similar to that of the high-risk participants in the Diabetes Prevention Program (DPP) (21), and A1C at baseline was a strong predictor of the development of glucosedefined diabetes during the DPP and its follow-up (22). Hence, it is reasonable to consider an A1C range of 5.7–6.4% (39–47 mmol/mol) as identifying individuals with prediabetes. Similar to those with IFG and/or IGT, individuals with A1C of 5.7–6.4% (39– 47 mmol/mol) should be informed of their increased risk for diabetes and CVD and counseled about effective strategies to lower their risks (see Section 5 “Prevention or Delay of Type 2 Diabetes”). Similar to glucose measurements, the continuum of risk is curvilinear, so as A1C rises, the diabetes risk rises disproportionately (19). Aggressive interventions and vigilant follow-up should be pursued for those considered at very high risk (e.g., those with A1C .6.0% [42 mmol/mol]).

Table 2.4 summarizes the categories of prediabetes and Table 2.3 the criteria for prediabetes testing. The ADA diabetes risk test is an additional option for screening (Fig. 2.1). For recommendations regarding risk factors and screening for prediabetes, see pp. S17–S18 (“Screening and Testing for Type 2 Diabetes and Prediabetes in Asymptomatic Adults” and “Screening and Testing for Type 2 Diabetes and Prediabetes in Children and Adolescents”).

TYPE 1 DIABETES Recommendations c

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Blood glucose rather than A1C should be used to diagnose the acute onset of type 1 diabetes in individuals with symptoms of hyperglycemia. E Screening for type 1 diabetes with a panel of autoantibodies is currently recommended only in the setting of a research trial or in first-degree family members of a proband with type 1 diabetes. B Persistence of two or more autoantibodies predicts clinical diabetes

In a patient with classic symptoms, measurement of blood glucose is sufficient to diagnose diabetes (symptoms of hyperglycemia or hyperglycemic crisis plus a random plasma glucose $200 mg/dL [11.1 mmol/L]). In these cases, knowing the blood glucose level is critical because, in addition to confirming that symptoms are due to diabetes, it will inform management decisions. Some providers may also want to know the A1C to determine how long a patient has had hyperglycemia. Immune-Mediated Diabetes

This form, previously called “insulindependent diabetes” or “juvenile-onset diabetes,” accounts for 5–10% of diabetes and is due to cellular-mediated autoimmune destruction of the pancreatic b-cells. Autoimmune markers include islet cell autoantibodies and autoantibodies to GAD (GAD65), insulin, the tyrosine phosphatases IA-2 and IA-2b, and ZnT8. Type 1 diabetes is defined by the presence of one or more of these autoimmune markers. The disease has strong HLA associations, with linkage to the DQA and DQB genes. These HLA-DR/DQ alleles can be either predisposing or protective. The rate of b-cell destruction is quite variable, being rapid in some individuals (mainly infants and children) and slow in others (mainly adults). Children and adolescents may present with ketoacidosis as the first manifestation of the disease. Others have modest fasting hyperglycemia

Table 2.4—Categories of increased risk for diabetes (prediabetes)* FPG 100 mg/dL (5.6 mmol/L) to 125 mg/dL (6.9 mmol/L) (IFG) OR 2-h PG in the 75-g OGTT 140 mg/dL (7.8 mmol/L) to 199 mg/dL (11.0 mmol/L) (IGT) OR A1C 5.726.4% (39247 mmol/mol) *For all three tests, risk is continuous, extending below the lower limit of the range and becoming disproportionately greater at the higher end of the range.

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Classification and Diagnosis of Diabetes

Figure 2.1—ADA risk test.

that can rapidly change to severe hyperglycemia and/or ketoacidosis with infection or other stress. Adults may retain sufficient b-cell function to prevent

ketoacidosis for many years; such individuals eventually become dependent on insulin for survival and are at risk for ketoacidosis. At this latter stage of the

disease, there is little or no insulin secretion, as manifested by low or undetectable levels of plasma C-peptide. Immune-mediated diabetes commonly occurs in childhood

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and adolescence, but it can occur at any age, even in the 8th and 9th decades of life. Autoimmune destruction of b-cells has multiple genetic predispositions and is also related to environmental factors that are still poorly defined. Although patients are not typically obese when they present with type 1 diabetes, obesity should not preclude the diagnosis. Patients with type 1 diabetes are also prone to other autoimmune disorders such as Hashimoto thyroiditis, Graves disease, Addison disease, celiac disease, vitiligo, autoimmune hepatitis, myasthenia gravis, and pernicious anemia (see Section 3 “Comprehensive Medical Evaluation and Assessment of Comorbidities”). Idiopathic Type 1 Diabetes

Some forms of type 1 diabetes have no known etiologies. These patients have permanent insulinopenia and are prone to ketoacidosis, but have no evidence of b-cell autoimmunity. Although only a minority of patients with type 1 diabetes fall into this category, of those who do, most are of African or Asian ancestry. Individuals with this form of diabetes suffer from episodic ketoacidosis and exhibit varying degrees of insulin deficiency between episodes. This form of diabetes is strongly inherited and is not HLA associated. An absolute requirement for insulin replacement therapy in affected patients may be intermittent. Testing for Type 1 Diabetes Risk

The incidence and prevalence of type 1 diabetes is increasing (23). Patients with type 1 diabetes often present with acute symptoms of diabetes and markedly elevated blood glucose levels, and approximately one-third are diagnosed with life-threatening ketoacidosis (3). Several studies indicate that measuring islet autoantibodies in relatives of those with type 1 diabetes may identify individuals who are at risk for developing type 1 diabetes (5). Such testing, coupled with education about diabetes symptoms and close follow-up, may enable earlier identification of type 1 diabetes onset. A study reported the risk of progression to type 1 diabetes from the time of seroconversion to autoantibody positivity in three pediatric cohorts from Finland, Germany, and the U.S. Of the 585 children who developed more than two autoantibodies, nearly

Diabetes Care Volume 40, Supplement 1, January 2017

70% developed type 1 diabetes within 10 years and 84% within 15 years (24). These findings are highly significant because, while the German group was recruited from offspring of parents with type 1 diabetes, the Finnish and American groups were recruited from the general population. Remarkably, the findings in all three groups were the same, suggesting that the same sequence of events led to clinical disease in both “sporadic” and familial cases of type 1 diabetes. Indeed, the risk of type 1 diabetes increases as the number of relevant autoantibodies detected increases (25–27). Although there is currently a lack of accepted screening programs, one should consider referring relatives of those with type 1 diabetes for antibody testing for risk assessment in the setting of a clinical research study (http://www.diabetestrialnet .org). Widespread clinical testing of asymptomatic low-risk individuals is not currently recommended due to lack of approved therapeutic interventions. Individuals who test positive will be counseled about the risk of developing diabetes, diabetes symptoms, and DKA prevention. Numerous clinical studies are being conducted to test various methods of preventing type 1 diabetes in those with evidence of autoimmunity (www.clinicaltrials.gov). TYPE 2 DIABETES Recommendations c

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Screening for type 2 diabetes with an informal assessment of risk factors or validated tools should be considered in asymptomatic adults. B Testing for type 2 diabetes in asymptomatic people should be considered in adults of any age who are overweight or obese (BMI $25 kg/m2 or $23 kg/m2 in Asian Americans) and who have one or more additional risk factors for diabetes. B For all people, testing should begin at age 45 years. B If tests are normal, repeat testing carried out at a minimum of 3-year intervals is reasonable. C To test for type 2 diabetes, fasting plasma glucose, 2-h plasma glucose after 75-g oral glucose tolerance test, and A1C are equally appropriate. B In patients with diabetes, identify and treat other cardiovascular disease risk factors. B

c

Testing for type 2 diabetes should be considered in children and adolescents who are overweight or obese and who have two or more additional risk factors for diabetes. E

Description

Type 2 diabetes, previously referred to as “noninsulin-dependent diabetes” or “adult-onset diabetes,” accounts for 90–95% of all diabetes. This form encompasses individuals who have relative (rather than absolute) insulin deficiency and have peripheral insulin resistance. At least initially, and often throughout their lifetime, these individuals may not need insulin treatment to survive. There are various causes of type 2 diabetes. Although the specific etiologies are not known, autoimmune destruction of b-cells does not occur, and patients do not have any of the other known causes of diabetes. Most, but not all, patients with type 2 diabetes are overweight or obese. Excess weight itself causes some degree of insulin resistance. Patients who are not obese or overweight by traditional weight criteria may have an increased percentage of body fat distributed predominantly in the abdominal region. Ketoacidosis seldom occurs spontaneously in type 2 diabetes; when seen, it usually arises in association with the stress of another illness such as infection. Type 2 diabetes frequently goes undiagnosed for many years because hyperglycemia develops gradually and, at earlier stages, is often not severe enough for the patient to notice the classic diabetes symptoms. Nevertheless, even undiagnosed patients are at increased risk of developing macrovascular and microvascular complications. Whereas patients with type 2 diabetes may have insulin levels that appear normal or elevated, the higher blood glucose levels in these patients would be expected to result in even higher insulin values had their b-cell function been normal. Thus, insulin secretion is defective in these patients and insufficient to compensate for insulin resistance. Insulin resistance may improve with weight reduction and/or pharmacological treatment of hyperglycemia but is seldom restored to normal. The risk of developing type 2 diabetes increases with age, obesity, and lack of

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physical activity. It occurs more frequently in women with prior GDM, in those with hypertension or dyslipidemia, and in certain racial/ethnic subgroups (African American, American Indian, Hispanic/Latino, and Asian American). It is often associated with a strong genetic predisposition, more so than type 1 diabetes. However, the genetics of type 2 diabetes is poorly understood. In adults without traditional risk factors for type 2 diabetes and/or younger age, consider antibody testing for type 1 diabetes (i.e., GAD). Screening and Testing for Type 2 Diabetes and Prediabetes in Asymptomatic Adults

Screening for prediabetes and type 2 diabetes through an informal assessment of risk factors (Table 2.3) or with an assessment tool, such as the ADA risk test (Fig. 2.1), is recommended to guide providers on whether performing a diagnostic test (Table 2.2) is appropriate. Prediabetes and type 2 diabetes meet criteria for conditions in which early detection is appropriate. Both conditions are common and impose significant clinical and public health burdens. There is often a long presymptomatic phase before the diagnosis of type 2 diabetes. Simple tests to detect preclinical disease are readily available. The duration of glycemic burden is a strong predictor of adverse outcomes. There are effective interventions that prevent progression from prediabetes to diabetes (see Section 5 “Prevention or Delay of Type 2 Diabetes”) and reduce the risk of diabetes complications (see Section 9 “Cardiovascular Disease and Risk Management” and Section 10 “Microvascular Complications and Foot Care”). Approximately one-quarter of people with diabetes in the U.S. and nearly half of Asian and Hispanic Americans with diabetes are undiagnosed (28). Although screening of asymptomatic individuals to identify those with prediabetes or diabetes might seem reasonable, rigorous clinical trials to prove the effectiveness of such screening have not been conducted and are unlikely to occur. A large European randomized controlled trial compared the impact of screening for diabetes and intensive multifactorial intervention with that of screening and routine care (29). General practice patients between the ages of

Classification and Diagnosis of Diabetes

40 and 69 years were screened for diabetes and randomly assigned by practice to intensive treatment of multiple risk factors or routine diabetes care. After 5.3 years of follow-up, CVD risk factors were modestly but significantly improved with intensive treatment compared with routine care, but the incidence of first CVD events or mortality was not significantly different between the groups (29). The excellent care provided to patients in the routine care group and the lack of an unscreened control arm limited the authors’ ability to determine whether screening and early treatment improved outcomes compared with no screening and later treatment after clinical diagnoses. Computer simulation modeling studies suggest that major benefits are likely to accrue from the early diagnosis and treatment of hyperglycemia and cardiovascular risk factors in type 2 diabetes (30); moreover, screening, beginning at age 30 or 45 years and independent of risk factors, may be cost-effective (,$11,000 per quality-adjusted life-year gained) (31). Additional considerations regarding testing for type 2 diabetes and prediabetes in asymptomatic patients include the following. Age

Screening recommendations for diabetes in asymptomatic adults are listed in Table 2.3. Age is a major risk factor for diabetes. Testing should begin at age 45 years for all patients. Screening should be considered in overweight or obese adults of any age with one or more risk factors for diabetes. BMI and Ethnicity

In general, BMI $25 kg/m2 is a risk factor for diabetes. Data and recommendations from the ADA position statement “BMI Cut Points to Identify At-Risk Asian Americans for Type 2 Diabetes Screening” (32,33) suggest that the BMI cut point should be lower for the Asian American population. The BMI cut points fall consistently between 23 and 24 kg/m2 (sensitivity of 80%) for nearly all Asian American subgroups (with levels slightly lower for Japanese Americans). This makes a rounded cut point of 23 kg/m2 practical. In determining a single BMI cut point, it is important to balance sensitivity and specificity so as to provide a valuable screening tool without

numerous false positives. An argument can be made to push the BMI cut point to lower than 23 kg/m2 in favor of increased sensitivity; however, this would lead to an unacceptably low specificity (13.1%). Data from the WHO also suggest that a BMI of $23 kg/m2 should be used to define increased risk in Asian Americans (34). The finding that half of diabetes in Asian Americans is undiagnosed suggests that testing is not occurring at lower BMI thresholds (28). Evidence also suggests that other populations may benefit from lower BMI cut points. For example, in a large multiethnic cohort study, for an equivalent incidence rate of diabetes, a BMI of 30 kg/m2 in non-Hispanic whites was equivalent to a BMI of 26 kg/m2 in African Americans (35). Medications

Certain medications, such as glucocorticoids, thiazide diuretics, and atypical antipsychotics (36), are known to increase the risk of diabetes and should be considered when deciding whether to screen. Testing Interval

The appropriate interval between screening tests is not known (37). The rationale for the 3-year interval is that with this interval, the number of falsepositive tests that require confirmatory testing will be reduced and individuals with false-negative tests will be retested before substantial time elapses and complications develop (37). Community Screening

Ideally, testing should be carried out within a health care setting because of the need for follow-up and treatment. Community screening outside a health care setting is not recommended because people with positive tests may not seek, or have access to, appropriate follow-up testing and care. Community testing may also be poorly targeted; i.e., it may fail to reach the groups most at risk and inappropriately test those at very low risk or even those who have already been diagnosed (38). Screening in Dental Practices

Because periodontal disease is associated with diabetes, the utility of chairside screening and referral to primary care as a means to improve the diagnosis of prediabetes and diabetes has been explored (39–41), with one study estimating that 30% of patients $30 years

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of age seen in general dental practices had dysglycemia (41). Further research is needed to demonstrate the feasibility, effectiveness, and cost-effectiveness of screening in this setting. Screening and Testing for Type 2 Diabetes and Prediabetes in Children and Adolescents

In the last decade, the incidence and prevalence of type 2 diabetes in adolescents has increased dramatically, especially in racial and ethnic minority populations (23). Recent studies question the validity of A1C in the pediatric population, especially among certain ethnicities, and suggest OGTT or FPG as more suitable diagnostic tests (42). However, many of these studies do not recognize that diabetes diagnostic criteria are based on long-term health outcomes, and validations are not currently available in the pediatric population (43). The ADA acknowledges the limited data supporting A1C for diagnosing type 2 diabetes in children and adolescents. Although A1C is not recommended for diagnosis of diabetes in children with cystic fibrosis or symptoms suggestive of acute onset of type 1 diabetes and only A1C assays without interference are appropriate for children with hemoglobinopathies, the ADA continues to recommend A1C for diagnosis of type 2 diabetes in this cohort (44,45). The modified recommendations of the ADA consensus report “Type 2 Diabetes in Children and Adolescents” are summarized in Table 2.5 (46). GESTATIONAL DIABETES MELLITUS Recommendations c

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Test for undiagnosed diabetes at the first prenatal visit in those with risk factors, using standard diagnostic criteria. B Test for gestational diabetes mellitus at 24–28 weeks of gestation in pregnant women not previously known to have diabetes. A Test women with gestational diabetes mellitus for persistent diabetes at 4–12 weeks’ postpartum, using the oral glucose tolerance test and clinically appropriate nonpregnancy diagnostic criteria. E Women with a history of gestational diabetes mellitus should

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Table 2.5—Testing for type 2 diabetes or prediabetes in asymptomatic children* (46) Criteria c Overweight (BMI .85th percentile for age and sex, weight for height .85th percentile, or weight .120% of ideal for height) Plus any two of the following risk factors: c Family history of type 2 diabetes in first- or second-degree relative c Race/ethnicity (Native American, African American, Latino, Asian American, Pacific Islander) c Signs of insulin resistance or conditions associated with insulin resistance (acanthosis nigricans, hypertension, dyslipidemia, polycystic ovary syndrome, or small-forgestational-age birth weight) c Maternal history of diabetes or GDM during the child’s gestation Age of initiation: age 10 years or at onset of puberty, if puberty occurs at a younger age Frequency: every 3 years *Persons aged #18 years.

c

have lifelong screening for the development of diabetes or prediabetes at least every 3 years. B Women with a history of gestational diabetes mellitus found to have prediabetes should receive intensive lifestyle interventions or metformin to prevent diabetes. A

Definition

For many years, GDM was defined as any degree of glucose intolerance that was first recognized during pregnancy (17), regardless of whether the condition may have predated the pregnancy or persisted after the pregnancy. This definition facilitated a uniform strategy for detection and classification of GDM, but it was limited by imprecision. The ongoing epidemic of obesity and diabetes has led to more type 2 diabetes in women of childbearing age, with an increase in the number of pregnant women with undiagnosed type 2 diabetes (47). Because of the number of pregnant women with undiagnosed type 2 diabetes, it is reasonable to test women with risk factors for type 2 diabetes (Table 2.3) at their initial prenatal visit, using standard diagnostic criteria (Table 2.2). Women diagnosed with diabetes in the first trimester should be classified as having preexisting pregestational diabetes (type 2 diabetes or, very rarely, type 1 diabetes). GDM is diabetes that is first diagnosed in the second or third trimester of pregnancy that is not clearly either preexisting type 1 or type 2 diabetes (see Section 13 “Management of Diabetes in Pregnancy”). The International Association of the Diabetes and Pregnancy Study Groups (IADPSG) GDM diagnostic criteria for the 75-g

OGTT were not derived from data in the first half of pregnancy, so the diagnosis of GDM in early pregnancy by either FPG or OGTT values is not evidence based (48). Diagnosis

GDM carries risks for the mother and neonate. Not all adverse outcomes are of equal clinical importance. The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study (49), a large-scale multinational cohort study completed by more than 23,000 pregnant women, demonstrated that risk of adverse maternal, fetal, and neonatal outcomes continuously increased as a function of maternal glycemia at 24–28 weeks, even within ranges previously considered normal for pregnancy. For most complications, there was no threshold for risk. These results have led to careful reconsideration of the diagnostic criteria for GDM. GDM diagnosis (Table 2.6) can be accomplished with either of two strategies: 1. “One-step” 75-g OGTT or 2. “Two-step” approach with a 50-g (nonfasting) screen followed by a 100-g OGTT for those who screen positive Different diagnostic criteria will identify different degrees of maternal hyperglycemia and maternal/fetal risk, leading some experts to debate, and disagree on, optimal strategies for the diagnosis of GDM. One-Step Strategy

In the 2011 Standards of Care (50), the ADA for the first time recommended that all pregnant women not known to have prior diabetes undergo a 75-g

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Classification and Diagnosis of Diabetes

Table 2.6—Screening for and diagnosis of GDM One-step strategy Perform a 75-g OGTT, with plasma glucose measurement when patient is fasting and at 1 and 2 h, at 24228 weeks of gestation in women not previously diagnosed with overt diabetes. The OGTT should be performed in the morning after an overnight fast of at least 8 h. The diagnosis of GDM is made when any of the following plasma glucose values are met or exceeded: c Fasting: 92 mg/dL (5.1 mmol/L) c 1 h: 180 mg/dL (10.0 mmol/L) c 2 h: 153 mg/dL (8.5 mmol/L) Two-step strategy Step 1: Perform a 50-g GLT (nonfasting), with plasma glucose measurement at 1 h, at 24–28 weeks of gestation in women not previously diagnosed with overt diabetes. If the plasma glucose level measured 1 h after the load is $130 mg/dL, 135 mg/dL, or 140 mg/dL* (7.2 mmol/L, 7.5 mmol/L, or 7.8 mmol/L), proceed to a 100-g OGTT. Step 2: The 100-g OGTT should be performed when the patient is fasting. The diagnosis of GDM is made if at least two of the following four plasma glucose levels (measured fasting and 1 h, 2 h, 3 h after the OGTT) are met or exceeded: Carpenter/Coustan (59) c

Fasting c1h c2h c3h

95 mg/dL (5.3 mmol/L) 180 mg/dL (10.0 mmol/L) 155 mg/dL (8.6 mmol/L) 140 mg/dL (7.8 mmol/L)

or

NDDG (60) 105 mg/dL (5.8 mmol/L) 190 mg/dL (10.6 mmol/L) 165 mg/dL (9.2 mmol/L) 145 mg/dL (8.0 mmol/L)

NDDG, National Diabetes Data Group. *The ACOG recommends either 135 mg/dL (7.5 mmol/L) or 140 mg/dL (7.8 mmol/L). A systematic review determined that a cutoff of 130 mg/dL (7.2 mmol/L) was more sensitive but less specific than 140 mg/dL (7.8 mmol/L) (55).

OGTT at 24–28 weeks of gestation, based on a recommendation of the IADPSG (51). The IADPSG defined diagnostic cut points for GDM as the average fasting, 1-h, and 2-h plasma glucose values in the HAPO study at which odds for adverse outcomes reached 1.75 times the estimated odds of these outcomes at the mean fasting, 1-h, and 2-h PG levels of the study population. This one-step strategy was anticipated to significantly increase the incidence of GDM (from 5–6% to 15–20%), primarily because only one abnormal value, not two, became sufficient to make the diagnosis. The ADA recognized that the anticipated increase in the incidence of GDM would have a substantial impact on costs and medical infrastructure needs and had the potential to “medicalize” pregnancies previously categorized as normal. Nevertheless, the ADA recommended these changes in diagnostic criteria with the intent of optimizing gestational outcomes because these criteria were the only ones based on pregnancy outcomes rather than end points such as prediction of subsequent maternal diabetes. The expected benefits to the offspring are inferred from intervention trials that focused on women with lower levels of hyperglycemia than identified using

older GDM diagnostic criteria. Those trials found modest benefits including reduced rates of large-for-gestational-age births and preeclampsia (52,53). It is important to note that 80–90% of women being treated for mild GDM in two randomized controlled trials could be managed with lifestyle therapy alone. The OGTT glucose cutoffs in these two trials overlapped with the thresholds recommended by the IADPSG, and in one trial (53), the 2-h PG threshold (140 mg/dL [7.8 mmol/L]) was lower than the cutoff recommended by the IADPSG (153 mg/dL [8.5 mmol/L]). No randomized controlled trials of identifying and treating GDM using the IADPSG criteria versus older criteria have been published to date. Data are also lacking on how the treatment of lower levels of hyperglycemia affects a mother’s future risk for the development of type 2 diabetes and her offspring’s risk for obesity, diabetes, and other metabolic disorders. Additional well-designed clinical studies are needed to determine the optimal intensity of monitoring and treatment of women with GDM diagnosed by the one-step strategy. Two-Step Strategy

In 2013, the National Institutes of Health (NIH) convened a consensus development conference to consider diagnostic

criteria for diagnosing GDM (54). The 15-member panel had representatives from obstetrics/gynecology, maternalfetal medicine, pediatrics, diabetes research, biostatistics, and other related fields. The panel recommended a twostep approach to screening that used a 1-h 50-g glucose load test (GLT) followed by a 3-h 100-g OGTT for those who screened positive. Commonly used cutoffs for the 1-h 50-g GLT include 130, 135, and 140 mg/dL (7.2, 7.5, and 7.8 mmol/L). The American College of Obstetricians and Gynecologists (ACOG) recommends either 135 or 140 mg/dL (45). A systematic review for the U.S. Preventive Services Task Force compared GLT cutoffs of 130 mg/dL (7.2 mmol/L) and 140 mg/dL (7.8 mmol/L) (55). The higher cutoff yielded sensitivity of 70–88% and specificity of 69–89%, while the lower cutoff was 88–99% sensitive and 66–77% specific. Data regarding a cutoff of 135 mg/dL are limited. As for other screening tests, choice of a cutoff is based upon the tradeoff between sensitivity and specificity. The use of A1C at 24–28 weeks as a screening test for GDM does not function as well as the GLT (56). Key factors cited by the NIH panel in their decision-making process were the lack of clinical trial data demonstrating the benefits of the one-step strategy and the potential negative consequences of identifying a large group of women with GDM, including medicalization of pregnancy with increased health care utilization and costs. Moreover, screening with a 50-g GLT does not require fasting and is therefore easier to accomplish for many women. Treatment of higher threshold maternal hyperglycemia, as identified by the two-step approach, reduces rates of neonatal macrosomia, large-for-gestational-age births (57), and shoulder dystocia, without increasing small-for-gestational-age births. ACOG updated its guidelines in 2013 and supported the two-step approach (58). The ACOG recommends either of two sets of diagnostic thresholds for the 3-h 100-g OGTT (59,60). Each is based on different mathematical conversions of the original recommended thresholds, which used whole blood and nonenzymatic methods for glucose determination. A recent secondary analysis of data from a randomized clinical trial of identification and treatment of

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mild GDM (61) demonstrated that treatment was similarly beneficial in patients meeting only the lower thresholds (59) and in those meeting only the higher thresholds (60). If the two-step approach is used, it would appear advantageous to use the lower diagnostic thresholds as shown in Step 2 in Table 2.6. Future Considerations

The conflicting recommendations from expert groups underscore the fact that there are data to support each strategy. A cost-benefit estimation comparing the two strategies concluded that the onestep approach is cost-effective only if patients with GDM receive postdelivery counseling and care to prevent type 2 diabetes (62). The decision of which strategy to implement must therefore be made based on the relative values placed on factors that have yet to be measured (e.g., willingness to change practice based on correlation studies rather than intervention trial results, available infrastructure, and importance of cost considerations). As the IADPSG criteria (“one-step strategy”) have been adopted internationally, further evidence has emerged to support improved pregnancy outcomes with cost savings (63) and may be the preferred approach. Data comparing population-wide outcomes with one-step versus two-step approaches have been inconsistent to date (64,65). In addition, pregnancies complicated by GDM per the IADPSG criteria, but not recognized as such, have comparable outcomes to pregnancies diagnosed as GDM by the more stringent two-step criteria (66,67). There remains strong consensus that establishing a uniform approach to diagnosing GDM will benefit patients, caregivers, and policymakers. Longer-term outcome studies are currently under way. MONOGENIC DIABETES SYNDROMES Recommendations c

c

All children diagnosed with diabetes in the first 6 months of life should have immediate genetic testing for neonatal diabetes. A Children and adults, diagnosed in early adulthood, who have diabetes not characteristic of type 1 or type 2 diabetes that occurs in successive generations (suggestive of an autosomal dominant pattern of

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c

inheritance) should have genetic testing for maturity-onset diabetes of the young. A In both instances, consultation with a center specializing in diabetes genetics is recommended to understand the significance of these mutations and how best to approach further evaluation, treatment, and genetic counseling. E

Monogenic defects that cause b-cell dysfunction, such as neonatal diabetes and MODY, represent a small fraction of patients with diabetes (,5%). Table 2.7 describes the most common causes of monogenic diabetes. For a comprehensive list of causes, see Genetic Diagnosis of Endocrine Disorders (68). Neonatal Diabetes

Diabetes occurring under 6 months of age is termed “neonatal” or “congenital” diabetes, and about 80–85% of cases can be found to have an underlying monogenic cause (69). Neonatal diabetes occurs much less often after 6 months of age, whereas autoimmune type 1 diabetes rarely occurs before 6 months of age. Neonatal diabetes can either be transient or permanent. Transient diabetes is most often due to overexpression of genes on chromosome 6q24, is recurrent in about half of cases, and may be treatable with medications other than insulin. Permanent neonatal diabetes is most commonly due to autosomal dominant mutations in the genes encoding the Kir6.2 subunit (KCNJ11) and SUR1 subunit (ABCC8) of the b-cell KATP channel. Correct diagnosis has critical implications because most patients with KATP-related neonatal diabetes will exhibit improved glycemic control when treated with high-dose oral sulfonylureas instead of insulin. Insulin gene (INS) mutations are the second most common cause of permanent neonatal diabetes, and, while treatment presently is intensive insulin management, there are important genetic considerations as most of the mutations that cause diabetes are dominantly inherited. Maturity-Onset Diabetes of the Young

MODY is frequently characterized by onset of hyperglycemia at an early age (classically before age 25 years, although diagnosis may occur at older

ages). MODY is characterized by impaired insulin secretion with minimal or no defects in insulin action (in the absence of coexistent obesity). It is inherited in an autosomal dominant pattern with abnormalities in at least 13 genes on different chromosomes identified to date. The most commonly reported forms are GCKMODY (MODY2), HNF1A-MODY (MODY3), and HNF4A-MODY (MODY1). Clinically, patients with GCK-MODY exhibit mild, stable, fasting hyperglycemia and do not require antihyperglycemic therapy except sometimes during pregnancy. Patients with HNF1A- or HNF4A-MODY usually respond well to low doses of sulfonylureas, which are considered first-line therapy. Mutations or deletions in HNF1B are associated with renal cysts and uterine malformations (renal cysts and diabetes [RCAD] syndrome). Other extremely rare forms of MODY have been reported to involve other transcription factor genes including PDX1 (IPF1) and NEUROD1. Diagnosis

A diagnosis of one of the three most common forms of MODY including GCKMODY, HNF1A-MODY, and HNF4A-MODY allows for more cost-effective therapy (no therapy for GCK-MODY; sulfonylureas as first-line therapy for HNF1A-MODY and HNF4A-MODY). Additionally, diagnosis can lead to identification of other affected family members. A diagnosis of MODY should be considered in individuals who have atypical diabetes and multiple family members with diabetes not characteristic of type 1 or type 2 diabetes, although admittedly “atypical diabetes” is becoming increasingly difficult to precisely define in the absence of a definitive set of tests for either type of diabetes. In most cases, the presence of autoantibodies for type 1 diabetes precludes further testing for monogenic diabetes, but the presence of autoantibodies in patients with monogenic diabetes has been reported (70). Individuals in whom monogenic diabetes is suspected should be referred to a specialist for further evaluation if available, and consultation is available from several centers. Readily available commercial genetic testing following the criteria listed below now enables a cost-effective (71), often cost-saving, genetic diagnosis that is increasingly supported by health insurance. It

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Table 2.7—Most common causes of monogenic diabetes (68) Gene

Inheritance

Clinical features

GCK

AD

HNF1A

AD

HNF4A

AD

HNF1B

AD

GCK-MODY: stable, nonprogressive elevated fasting blood glucose; typically does not require treatment; microvascular complications are rare; small rise in 2-h PG level on OGTT (,54 mg/dL [3 mmol/L]) HNF1A-MODY: progressive insulin secretory defect with presentation in adolescence or early adulthood; lowered renal threshold for glucosuria; large rise in 2-h PG level on OGTT (.90 mg/dL [5 mmol/L]); sensitive to sulfonylureas HNF4A-MODY: progressive insulin secretory defect with presentation in adolescence or early adulthood; may have large birth weight and transient neonatal hypoglycemia; sensitive to sulfonylureas HNF1B-MODY: developmental renal disease (typically cystic); genitourinary abnormalities; atrophy of the pancreas; hyperuricemia; gout

KCNJ11

AD

INS ABCC8

AD AD

6q24 (PLAGL1, HYMA1)

AD for paternal duplications

GATA6

AD

EIF2AK3

AR

FOXP3

X-linked

MODY

Neonatal diabetes Permanent or transient: IUGR; possible developmental delay and seizures; responsive to sulfonylureas Permanent: IUGR; insulin requiring Transient or permanent: IUGR; rarely developmental delay; responsive to sulfonylureas Transient: IUGR; macroglossia; umbilical hernia; mechanisms include UPD6, paternal duplication or maternal methylation defect; may be treatable with medications other than insulin Permanent: pancreatic hypoplasia; cardiac malformations; pancreatic exocrine insufficiency; insulin requiring Permanent: Wolcott-Rallison syndrome: epiphyseal dysplasia; pancreatic exocrine insufficiency; insulin requiring Permanent: immunodysregulation, polyendocrinopathy, enteropathy X-linked (IPEX) syndrome: autoimmune diabetes; autoimmune thyroid disease; exfoliative dermatitis; insulin requiring

AD, autosomal dominant; AR, autosomal recessive; IUGR, intrauterine growth restriction.

is critical to correctly diagnose one of the monogenic forms of diabetes because these patients may be incorrectly diagnosed with type 1 or type 2 diabetes, leading to suboptimal, even potentially harmful, treatment regimens and delays in diagnosing other family members (72). The information is especially critical for GCK-MODY mutations where multiple studies have shown that no complications ensue in the absence of glucose-lowering therapy (73). Genetic counseling is recommended to ensure that affected individuals understand the patterns of inheritance and the importance of a correct diagnosis. The diagnosis of monogenic diabetes should be considered in children and adults diagnosed with diabetes in early adulthood with the following findings: ○



Diabetes diagnosed within the first 6 months of life (with occasional cases presenting later, mostly INS and ABCC8 mutations) (69,74) Diabetes without typical features of type 1 or type 2 diabetes (negative diabetes–associated autoantibodies; nonobese, lacking other metabolic

features, especially with strong family history of diabetes) Stable, mild fasting hyperglycemia (100–150 mg/dL [5.5–8.5 mmol/L]), stable A1C between 5.6 and 7.6% (between 38 and 60 mmol/mol), especially if nonobese



CYSTIC FIBROSIS–RELATED DIABETES Recommendations c

c

c

c

Annual screening for cystic fibrosis– related diabetes with oral glucose tolerance test should begin by age 10 years in all patients with cystic fibrosis not previously diagnosed with cystic fibrosis–related diabetes. B A1C as a screening test for cystic fibrosis–related diabetes is not recommended. B Patients with cystic fibrosis–related diabetes should be treated with insulin to attain individualized glycemic goals. A Beginning 5 years after the diagnosis of cystic fibrosis–related diabetes, annual monitoring for complications of diabetes is recommended. E

Cystic fibrosis–related diabetes (CFRD) is the most common comorbidity in people with cystic fibrosis, occurring in about 20% of adolescents and 40–50% of adults. Diabetes in this population, compared with individuals with type 1 or type 2 diabetes, is associated with worse nutritional status, more severe inflammatory lung disease, and greater mortality. Insulin insufficiency is the primary defect in CFRD. Genetically determined b-cell function and insulin resistance associated with infection and inflammation may also contribute to the development of CFRD. Milder abnormalities of glucose tolerance are even more common and occur at earlier ages than CFRD. Whether individuals with IGT should be treated with insulin replacement has not currently been determined. Although screening for diabetes before the age of 10 years can identify risk for progression to CFRD in those with abnormal glucose tolerance, no benefit has been established with respect to weight, height, BMI, or lung function. Continuous glucose monitoring may be more sensitive than OGTT to detect risk for progression to CFRD; however, evidence linking continuous glucose

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monitoring results to long-term outcomes is lacking, and its use is not recommended for screening (75). CFRD mortality has significantly decreased over time, and the gap in mortality between cystic fibrosis patients with and without diabetes has considerably narrowed (76). There are limited clinical trial data on therapy for CFRD. The largest study compared three regimens: premeal insulin aspart, repaglinide, or oral placebo in cystic fibrosis patients with diabetes or abnormal glucose tolerance. Participants all had weight loss in the year preceding treatment; however, in the insulin-treated group, this pattern was reversed, and patients gained 0.39 (6 0.21) BMI units (P 5 0.02). The repaglinide-treated group had initial weight gain, but this was not sustained by 6 months. The placebo group continued to lose weight (77). Insulin remains the most widely used therapy for CFRD (78). Recommendations for the clinical management of CFRD can be found in the ADA position statement “Clinical Care Guidelines for Cystic Fibrosis–Related Diabetes: A Position Statement of the American Diabetes Association and a Clinical Practice Guideline of the Cystic Fibrosis Foundation, Endorsed by the Pediatric Endocrine Society” (79). POSTTRANSPLANTATION DIABETES MELLITUS Recommendations c

c

c

Patients should be screened after organ transplantation for hyperglycemia, with a formal diagnosis of posttransplantation diabetes mellitus being best made once a patient is stable on an immunosuppressive regimen and in the absence of an acute infection. E The oral glucose tolerance test is the preferred test to make a diagnosis of posttransplantation diabetes mellitus. B Immunosuppressive regimens shown to provide the best outcomes for patient and graft survival should be used, irrespective of posttransplantation diabetes mellitus risk. E

Several terms are used in the literature to describe the presence of diabetes following organ transplantation. “Newonset diabetes after transplantation” (NODAT) is one such designation that

Diabetes Care Volume 40, Supplement 1, January 2017

describes individuals who develop new-onset diabetes following transplant. NODAT excludes patients with pretransplant diabetes that was undiagnosed as well as posttransplant hyperglycemia that resolves by the time of discharge (80). Another term, “posttransplantation diabetes mellitus” (PTDM) (80), describes the presence of diabetes in the posttransplant setting irrespective of the timing of diabetes onset. Hyperglycemia is very common during the early posttransplant period, with ;90% of kidney allograft recipients exhibiting hyperglycemia in the first few weeks following transplant (80,81). In most cases, such stress or steroidinduced hyperglycemia resolves by the time of discharge. Risk factors for PTDM include both general diabetes risks (such as age, family history of diabetes, etc.) as well as transplant-specific factors, such as use of immunosuppressant agents. Whereas posttransplantation hyperglycemia is an important risk factor for subsequent PTDM, a formal diagnosis of PTDM is optimally made once the patient is stable on maintenance immunosuppression and in the absence of acute infection. The OGTT is considered the gold standard test for the diagnosis of PTDM (80,82–84). However, screening patients using fasting glucose and/or A1C can identify high-risk patients requiring further assessment and may reduce the number of overall OGTTs required (85). There is currently a lack of clinical data examining the use of antidiabetes agents in the setting of PTDM to inform specific recommendations for use in this population. Although the use of immunosuppressive therapies is a major contributor to the development of PTDM, the risks of transplant rejection outweigh the risks of PTDM and the role of the diabetes care provider is to treat hyperglycemia appropriately regardless of the type of immunosuppression (80). References 1. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2014;37(Suppl. 1):S81–S90 2. Newton CA, Raskin P. Diabetic ketoacidosis in type 1 and type 2 diabetes mellitus: clinical and biochemical differences. Arch Intern Med 2004;164:1925–1931 3. Dabelea D, Rewers A, Stafford JM, et al.; SEARCH for Diabetes in Youth Study Group. Trends in the prevalence of ketoacidosis at

diabetes diagnosis: the Search for Diabetes in Youth Study. Pediatrics 2014;133:e938–e945 4. Skyler JS, Bakris GL, Bonifacio E, et al. Differentiation of diabetes by pathophysiology, natural history, and prognosis. Diabetes. 15 December 2016 [Epub ahead of print]. DOI: 10.2337/db16-0806 5. Insel RA, Dunne JL, Atkinson MA, et al. Staging presymptomatic type 1 diabetes: a scientific statement of JDRF, the Endocrine Society, and the American Diabetes Association. Diabetes Care 2015;38:1964–1974 6. International Expert Committee. International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care 2009;32:1327–1334 7. Knowler WC, Barrett-Connor E, Fowler SE, et al.; Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393–403 8. Tuomilehto J, Lindstr¨om J, Eriksson JG, et al.; Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001;344:1343–1350 9. Cowie CC, Rust KF, Byrd-Holt DD, et al. Prevalence of diabetes and high risk for diabetes using A1C criteria in the U.S. population in 1988–2006. Diabetes Care 2010;33:562–568 10. Nowicka P, Santoro N, Liu H, et al. Utility of hemoglobin A1c for diagnosing prediabetes and diabetes in obese children and adolescents. Diabetes Care 2011;34:1306–1311 11. Ziemer DC, Kolm P, Weintraub WS, et al. Glucose-independent, black-white differences in hemoglobin A1c levels: a cross-sectional analysis of 2 studies. Ann Intern Med 2010;152:770–777 12. Kumar PR, Bhansali A, Ravikiran M, et al. Utility of glycated hemoglobin in diagnosing type 2 diabetes mellitus: a community-based study. J Clin Endocrinol Metab 2010;95:2832–2835 13. Herman WH, Ma Y, Uwaifo G, et al.; Diabetes Prevention Program Research Group. Differences in A1C by race and ethnicity among patients with impaired glucose tolerance in the Diabetes Prevention Program. Diabetes Care 2007;30:2453–2457 14. Carson AP, Munter P, Selvin E, et al. Do glycemic marker levels vary by race? Differing results from a cross-sectional analysis of individuals with and without diagnosed diabetes. BMJ Open Diabetes Res Care 2016;4:e000213 15. Herman WH, Dungan KM, Wolffenbuttel BH, et al. Racial and ethnic differences in mean plasma glucose, hemoglobin A1c, and 1,5-anhydroglucitol in over 2000 patients with type 2 diabetes. J Clin Endocrinol Metab 2009;94:1689–1694 16. Selvin E, Rawlings AM, Bergenstal RM, Coresh J, Brancati FL. No racial differences in the association of glycated hemoglobin with kidney disease and cardiovascular outcomes. Diabetes Care 2013;36:2995–3001 17. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997;20:1183–1197 18. Genuth S, Alberti KG, Bennett P, et al.; Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care 2003;26: 3160–3167

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19. Zhang X, Gregg EW, Williamson DF, et al. A1C level and future risk of diabetes: a systematic review. Diabetes Care 2010;33:1665–1673 20. Selvin E, Steffes MW, Zhu H, et al. Glycated hemoglobin, diabetes, and cardiovascular risk in nondiabetic adults. N Engl J Med 2010;362:800– 811 21. Ackermann RT, Cheng YJ, Williamson DF, Gregg EW. Identifying adults at high risk for diabetes and cardiovascular disease using hemoglobin A1c National Health and Nutrition Examination Survey 2005–2006. Am J Prev Med 2011;40:11–17 22. Diabetes Prevention Program Research Group. HbA1c as a predictor of diabetes and as an outcome in the diabetes prevention program: a randomized clinical trial. Diabetes Care 2015;38:51–58 23. Dabelea D, Mayer-Davis EJ, Saydah S, et al.; SEARCH for Diabetes in Youth Study. Prevalence of type 1 and type 2 diabetes among children and adolescents from 2001 to 2009. JAMA 2014; 311:1778–1786 24. Ziegler AG, Rewers M, Simell O, et al. Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA 2013;309:2473–2479 25. Sosenko JM, Skyler JS, Palmer JP, et al.; Type 1 Diabetes TrialNet Study Group; Diabetes Prevention Trial–Type 1 Study Group. The prediction of type 1 diabetes by multiple autoantibody levels and their incorporation into an autoantibody risk score in relatives of type 1 diabetic patients. Diabetes Care 2013;36: 2615–2620 26. Steck AK, Vehik K, Bonifacio E, et al.; TEDDY Study Group. Predictors of progression from the appearance of islet autoantibodies to early childhood diabetes: The Environmental Determinants of Diabetes in the Young (TEDDY). Diabetes Care 2015;38:808–813 27. Orban T, Sosenko JM, Cuthbertson D, et al.; Diabetes Prevention Trial–Type 1 Study Group. Pancreatic islet autoantibodies as predictors of type 1 diabetes in the Diabetes Prevention Trial–Type 1. Diabetes Care 2009;32:2269–2274 28. Menke A, Casagrande S, Geiss L, Cowie CC. Prevalence of and trends in diabetes among adults in the United States, 1988–2012. JAMA 2015;314:1021–1029 29. Griffin SJ, Borch-Johnsen K, Davies MJ, et al. Effect of early intensive multifactorial therapy on 5-year cardiovascular outcomes in individuals with type 2 diabetes detected by screening (ADDITION-Europe): a cluster-randomised trial. Lancet 2011;378:156–167 30. Herman WH, Ye W, Griffin SJ, et al. Early detection and treatment of type 2 diabetes reduce cardiovascular morbidity and mortality: a simulation of the results of the Anglo-DanishDutch study of intensive treatment in people with screen-detected diabetes in primary care (ADDITION-Europe). Diabetes Care 2015;38: 1449–1455 31. Kahn R, Alperin P, Eddy D, et al. Age at initiation and frequency of screening to detect type 2 diabetes: a cost-effectiveness analysis. Lancet 2010;375:1365–1374 32. Araneta MR, Kanaya A, Hsu WC, et al. Optimum BMI cut points to screen Asian Americans for type 2 diabetes. Diabetes Care 2015; 38:814–820

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33. Hsu WC, Araneta MRG, Kanaya AM, Chiang JL, Fujimoto W. BMI cut points to identify at-risk Asian Americans for type 2 diabetes screening. Diabetes Care 2015;38:150–158 34. WHO Expert Consultation. Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet 2004;363:157–163 35. Chiu M, Austin PC, Manuel DG, Shah BR, Tu JV. Deriving ethnic-specific BMI cutoff points for assessing diabetes risk. Diabetes Care 2011;34: 1741–1748 36. Erickson SC, Le L, Zakharyan A, et al. Newonset treatment-dependent diabetes mellitus and hyperlipidemia associated with atypical antipsychotic use in older adults without schizophrenia or bipolar disorder. J Am Geriatr Soc 2012;60:474–479 37. Johnson SL, Tabaei BP, Herman WH. The efficacy and cost of alternative strategies for systematic screening for type 2 diabetes in the U.S. population 45-74 years of age. Diabetes Care 2005;28:307–311 38. Tabaei BP, Burke R, Constance A, et al. Community-based screening for diabetes in Michigan. Diabetes Care 2003;26:668–670 39. Lalla E, Kunzel C, Burkett S, Cheng B, Lamster IB. Identification of unrecognized diabetes and pre-diabetes in a dental setting. J Dent Res 2011;90:855–860 40. Lalla E, Cheng B, Kunzel C, Burkett S, Lamster IB. Dental findings and identification of undiagnosed hyperglycemia. J Dent Res 2013;92:888–892 41. Herman WH, Taylor GW, Jacobson JJ, Burke R, Brown MB. Screening for prediabetes and type 2 diabetes in dental offices. J Public Health Dent 2015;75:175–182 42. Buse JB, Kaufman FR, Linder B, Hirst K, El Ghormli L, Willi S; HEALTHY Study Group. Diabetes screening with hemoglobin A1c versus fasting plasma glucose in a multiethnic middle-school cohort. Diabetes Care 2013;36:429–435 43. Kapadia C, Zeitler P; Drugs and Therapeutics Committee of the Pediatric Endocrine Society. Hemoglobin A1c measurement for the diagnosis of type 2 diabetes in children. Int J Pediatr Endocrinol 2012;2012:31 44. Kester LM, Hey H, Hannon TS. Using hemoglobin A1c for prediabetes and diabetes diagnosis in adolescents: can adult recommendations be upheld for pediatric use? J Adolesc Health 2012;50:321–323 45. Wu E-L, Kazzi NG, Lee JM. Cost-effectiveness of screening strategies for identifying pediatric diabetes mellitus and dysglycemia. JAMA Pediatr 2013;167:32–39 46. American Diabetes Association. Type 2 diabetes in children and adolescents. Diabetes Care 2000;23:381–389 47. Lawrence JM, Contreras R, Chen W, Sacks DA. Trends in the prevalence of preexisting diabetes and gestational diabetes mellitus among a racially/ethnically diverse population of pregnant women, 1999–2005. Diabetes Care 2008;31:899–904 48. McIntyre HD, Sacks DA, Barbour LA, et al. Issues with the diagnosis and classification of hyperglycemia in early pregnancy. Diabetes Care 2016;39:53–54 49. Metzger BE, Lowe LP, Dyer AR, et al.; HAPO Study Cooperative Research Group. Hyperglycemia

and adverse pregnancy outcomes. N Engl J Med 2008;358:1991–2002 50. American Diabetes Association. Standards of medical care in diabetesd2011. Diabetes Care 2011;34(Suppl. 1):S11–S61 51. Metzger BE, Gabbe SG, Persson B, et al.; International Association of Diabetes and Pregnancy Study Groups Consensus Panel. International Association of Diabetes and Pregnancy Study Groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care 2010;33:676–682 52. Landon MB, Spong CY, Thom E, et al.; Eunice Kennedy Shriver National Institute of Child Health and Human Development MaternalFetal Medicine Units Network. A multicenter, randomized trial of treatment for mild gestational diabetes. N Engl J Med 2009;361:1339–1348 53. Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeffries WS, Robinson JS; Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS) Trial Group. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med 2005;352:2477–2486 54. Vandorsten JP, Dodson WC, Espeland MA, et al. NIH consensus development conference: diagnosing gestational diabetes mellitus. NIH Consens State Sci Statements 2013;29:1–31 55. Donovan L, Hartling L, Muise M, Guthrie A, Vandermeer B, Dryden DM. Screening tests for gestational diabetes: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 2013;159:115–122 56. Khalafallah A, Phuah E, Al-Barazan AM, et al. Glycosylated haemoglobin for screening and diagnosis of gestational diabetes mellitus. BMJ Open 2016;6:e011059 57. Horvath K, Koch K, Jeitler K, et al. Effects of treatment in women with gestational diabetes mellitus: systematic review and meta-analysis. BMJ 2010;340:c1395 58. Committee on Practice BulletinsdObstetrics. Practice Bulletin No. 137: gestational diabetes mellitus. Obstet Gynecol 2013;122:406–416 59. Carpenter MW, Coustan DR. Criteria for screening tests for gestational diabetes. Am J Obstet Gynecol 1982;144:768–773 60. National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 1979;28:1039–1057 61. Harper LM, Mele L, Landon MB, et al.; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network. Carpenter-Coustan compared with National Diabetes Data Group criteria for diagnosing gestational diabetes. Obstet Gynecol 2016;127: 893–898 62. Werner EF, Pettker CM, Zuckerwise L, et al. Screening for gestational diabetes mellitus: are the criteria proposed by the International Association of the Diabetes and Pregnancy Study Groups cost-effective? Diabetes Care 2012;35: 529–535 ´ MJ, et al. Intro63. Duran A, S´aenz S, Torrejon duction of IADPSG criteria for the screening and diagnosis of gestational diabetes mellitus results in improved pregnancy outcomes at a lower cost in a large cohort of pregnant women: the St. Carlos Gestational Diabetes Study. Diabetes Care 2014;37:2442–2450

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64. Wei Y, Yang H, Zhu W, et al. International Association of Diabetes and Pregnancy Study Group criteria is suitable for gestational diabetes mellitus diagnosis: further evidence from China. Chin Med J (Engl) 2014;127:3553–3556 65. Feldman RK, Tieu RS, Yasumura L. Gestational diabetes screening: the International Association of the Diabetes and Pregnancy Study Groups compared with Carpenter-Coustan screening. Obstet Gynecol 2016;127:10–17 66. Ethridge JK Jr, Catalano PM, Waters TP. Perinatal outcomes associated with the diagnosis of gestational diabetes made by the International Association of the Diabetes and Pregnancy Study Groups criteria. Obstet Gynecol 2014;124: 571–578 67. Mayo K, Melamed N, Vandenberghe H, Berger H. The impact of adoption of the International Association of Diabetes in Pregnancy Study Group criteria for the screening and diagnosis of gestational diabetes. Am J Obstet Gynecol 2015;212:224.e1–224.e9 68. Carmody D, Støy J, Greeley SA, Bell GI, Philipson LH. A clinical guide to monogenic diabetes. In Genetic Diagnosis of Endocrine Disorders. 2nd ed. Weiss RE, Refetoff S, Eds. Philadelphia, PA, Elsevier, 2016 69. De Franco E, Flanagan SE, Houghton JAL, et al. The effect of early, comprehensive genomic testing on clinical care in neonatal diabetes: an international cohort study. Lancet 2015;386: 957–963 70. Urbanova´ J, Rypa´ cˇkova´ B, Procha´ zkova´ Z, et al. Positivity for islet cell autoantibodies in patients with monogenic diabetes is associated

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with later diabetes onset and higher HbA1c level. Diabet Med 2014;31:466–471 71. Naylor RN, John PM, Winn AN, et al. Costeffectiveness of MODY genetic testing: translating genomic advances into practical health applications. Diabetes Care 2014;37:202–209 72. Hattersley A, Bruining J, Shield J, Njolstad P, Donaghue KC. The diagnosis and management of monogenic diabetes in children and adolescents. Pediatr Diabetes 2009;10(Suppl. 12):33–42 73. Rubio-Cabezas O, Hattersley AT, Njølstad PR, et al.; International Society for Pediatric and Adolescent Diabetes. ISPAD Clinical Practice Consensus Guidelines 2014. The diagnosis and management of monogenic diabetes in children and adolescents. Pediatr Diabetes 2014;15 (Suppl. 20):47–64 74. Greeley SAW, Naylor RN, Philipson LH, Bell GI. Neonatal diabetes: an expanding list of genes allows for improved diagnosis and treatment. Curr Diab Rep 2011;11:519–532 75. Ode KL, Moran A. New insights into cystic fibrosis-related diabetes in children. Lancet Diabetes Endocrinol 2013;1:52–58 76. Moran A, Dunitz J, Nathan B, Saeed A, Holme B, Thomas W. Cystic fibrosis-related diabetes: current trends in prevalence, incidence, and mortality. Diabetes Care 2009;32:1626–1631 77. Moran A, Pekow P, Grover P, et al.; Cystic Fibrosis Related Diabetes Therapy Study Group. Insulin therapy to improve BMI in cystic fibrosisrelated diabetes without fasting hyperglycemia: results of the Cystic Fibrosis Related Diabetes Therapy Trial. Diabetes Care 2009;32:1783– 1788

78. Onady GM, Stolfi A. Insulin and oral agents for managing cystic fibrosis-related diabetes. Cochrane Database Syst Rev 2016;4:CD004730 79. Moran A, Brunzell C, Cohen RC, et al.; CFRD Guidelines Committee. Clinical care guidelines for cystic fibrosis–related diabetes: a position statement of the American Diabetes Association and a clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society. Diabetes Care 2010;33:2697–2708 80. Sharif A, Hecking M, de Vries APJ, et al. Proceedings from an international consensus meeting on posttransplantation diabetes mellitus: recommendations and future directions. Am J Transplant 2014;14:1992–2000 81. Ramirez SC, Maaske J, Kim Y, et al. The association between glycemic control and clinical outcomes after kidney transplantation. Endocr Pract 2014;20:894–900 82. Sharif A, Moore RH, Baboolal K. The use of oral glucose tolerance tests to risk stratify for new-onset diabetes after transplantation: an underdiagnosed phenomenon. Transplantation 2006;82:1667–1672 83. Hecking M, Werzowa J, Haidinger M, et al. Novel views on new-onset diabetes after transplantation: development, prevention and treatment. Nephrol Dial Transplant 2013;28:550–566 84. Hecking M, Kainz A, Werzowa J, et al. Glucose metabolism after renal transplantation. Diabetes Care 2013;36:2763–2771 85. Valderhaug TG, Jenssen T, Hartmann A, et al. Fasting plasma glucose and glycosylated hemoglobin in the screening for diabetes mellitus after renal transplantation. Transplantation 2009;88:429–434

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3. Comprehensive Medical Evaluation and Assessment of Comorbidities

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Diabetes Care 2017;40(Suppl. 1):S25–S32 | DOI: 10.2337/dc17-S006

PATIENT-CENTERED COLLABORATIVE CARE Recommendation

A patient-centered communication style that uses active listening, elicits patient preferences and beliefs, and assesses literacy, numeracy, and potential barriers to care should be used to optimize patient health outcomes and health-related quality of life. B

A successful medical evaluation depends on beneficial interactions between the patient and the care team. The Chronic Care Model (1–3) (see Section 1 “Promoting Health and Reducing Disparities in Populations”) is a patient-centered approach to care that requires a close working relationship between the patient and clinicians involved in treatment planning. People with diabetes should receive health care from a team that may include physicians, nurse practitioners, physician assistants, nurses, dietitians, exercise specialists, pharmacists, dentists, podiatrists, and mental health professionals. Individuals with diabetes must assume an active role in their care. The patient, family or support persons, physician, and health care team should formulate the management plan, which includes lifestyle management (see Section 4 “Lifestyle Management”). Treatment goals and plans should be created with the patients based on their individual preferences, values, and goals. The management plan should take into account the patient’s age, cognitive abilities, school/work schedule and conditions, health beliefs, support systems, eating patterns, physical activity, social situation, financial concerns, cultural factors, literacy and numeracy (mathematical literacy) skills, diabetes complications, comorbidities, health priorities, other medical conditions, preferences for care, and life expectancy. Various strategies and techniques should be used to support patients’ self-management efforts, including providing education on problem-solving skills for all aspects of diabetes management. Provider communications with patients/families should acknowledge that multiple factors impact glycemic management, but also emphasize that collaboratively developed treatment plans and a healthy lifestyle can significantly improve disease outcomes and well-being (4–7). Thus, the goal of provider-patient communication is to establish a collaborative relationship and to assess and address self-management barriers without blaming patients for “noncompliance” or “nonadherence” when the outcomes of self-management are not optimal (8). The familiar terms “noncompliance” and “nonadherence” denote a passive, obedient role for a person with diabetes in “following doctor’s orders” that is at odds with the active role people with diabetes take in directing the day-to-day decision making, planning, monitoring, evaluation, and problem-solving involved in diabetes self-management. Using a nonjudgmental approach that normalizes periodic lapses in self-management may help minimize patients’ resistance to reporting problems with self-management. Empathizing and using active listening techniques, such as open-ended questions, reflective statements, and summarizing what the patient said can help facilitate communication. Patients’ perceptions about their own ability, or selfefficacy, to self-manage diabetes are one important psychosocial factor related to improved diabetes self-management and treatment outcomes in diabetes

MEDICAL EVALUATION AND COMORBIDITIES

c

Suggested citation: American Diabetes Association. Comprehensive medical evaluation and assessment of comorbidities. Sec. 3. In Standards of Medical Care in Diabetesd2017. Diabetes Care 2017;40(Suppl. 1):S25–S32 © 2017 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals .org/content/license.

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(9–13) and should be a target of ongoing assessment, patient education, and treatment planning.

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and implementing an approach to glycemic control with the patient is a part, not the sole goal, of care. Immunization

COMPREHENSIVE MEDICAL EVALUATION

Recommendations c

Recommendations

A complete medical evaluation should be performed at the initial visit to c c c

c

c

Confirm the diagnosis and classify diabetes. B Detect diabetes complications and potential comorbid conditions. E Review previous treatment and risk factor control in patients with established diabetes. E Begin patient engagement in the formulation of a care management plan. B Develop a plan for continuing care. B

The comprehensive medical evaluation (Table 3.1) includes the initial and ongoing evaluations, assessment of complications, psychosocial assessment, management of comorbid conditions, and engagement of the patient throughout the process. The goal is to provide the health care team information to optimally support a patient. In addition to the medical history, physical examination, and laboratory tests, providers should assess diabetes self-management behaviors, nutrition, and psychosocial health (see Section 4 “Lifestyle Management”) and give guidance on routine immunizations. Consider the assessment of sleep pattern and duration; a recent meta-analysis found that poor sleep quality, short sleep, and long sleep were associated with higher A1C in people with type 2 diabetes (14). Lifestyle management and psychosocial care are the cornerstones of diabetes management. Patients should be referred for diabetes self-management education (DSME), diabetes self-management support (DSMS), medical nutrition therapy (MNT), and psychosocial/emotional health concerns if indicated. Patients should receive recommended preventive care services (e.g., immunizations, cancer screening, etc.); smoking cessation counseling; and ophthalmological, dental, and podiatric referrals. Additional referrals should be arranged as necessary (Table 3.2). Clinicians should ensure that individuals with diabetes are appropriately screened for complications and comorbidities. Discussing

c

c

c

c

Provide routine vaccinations for children and adults with diabetes according to age-related recommendations. C Annual vaccination against influenza is recommended for all persons with diabetes $6 months of age. C Vaccination against pneumonia is recommended for all people with diabetes 2 through 64 years of age with pneumococcal polysaccharide vaccine (PPSV23). At age $65 years, administer the pneumococcal conjugate vaccine (PCV13) at least 1 year after vaccination with PPSV23, followed by another dose of vaccine PPSV23 at least 1 year after PCV13 and at least 5 years after the last dose of PPSV23. C Administer 3-dose series of hepatitis B vaccine to unvaccinated adults with diabetes who are age 19–59 years. C Consider administering 3-dose series of hepatitis B vaccine to unvaccinated adults with diabetes who are age $60 years. C

As for the general population, all children and adults with diabetes should receive vaccinations (15,16) according to agespecific recommendations. The child and adolescent vaccination schedule is available at http://www.cdc.gov/vaccines/ schedules/hcp/imz/child-adolescent.html, and the adult vaccination schedule is available at http://www.cdc.gov/vaccines/ schedules/hcp/imz/adult.html. The Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) recommends influenza and pneumococcal vaccines for individuals with diabetes (http:// www.cdc.gov/vaccines/schedules).

Pneumococcal Pneumonia

Like influenza, pneumococcal pneumonia is a common, preventable disease. People with diabetes may be at increased risk for the bacteremic form of pneumococcal infection and have been reported to have a high risk of nosocomial bacteremia, with a mortality rate as high as 50% (18). All patients with diabetes 2 years of age and older should receive the pneumococcal polysaccharide vaccine (PPSV23). There is sufficient evidence to support that adults with diabetes ,65 years of age have appropriate serologic and clinical responses to these vaccinations (19). The American Diabetes Association (ADA) endorses recommendations from the CDC ACIP that all adults 65 years of age or older receive a dose of pneumococcal conjugate vaccine (PCV13) followed by a dose of PPSV23 at least 1 year later (and at least 5 years after their previous PPSV23 dose). Hepatitis B

Compared with the general population, people with type 1 or type 2 diabetes have higher rates of hepatitis B. This may be due to contact with infected blood or through improper equipment use (glucose monitoring devices or infected needles). Because of the higher likelihood of transmission, hepatitis B vaccine is recommended for adults with diabetes. ASSESSMENT OF COMORBIDITIES

Besides assessing diabetes-related complications, clinicians and their patients need to be aware of common comorbidities that affect people with diabetes and may complicate management (20–24). Diabetes comorbidities are conditions that affect people with diabetes more often than agematched people without diabetes. The list below includes many of the common comorbidities observed in patients with diabetes but is not necessarily inclusive of all the conditions that have been reported. Autoimmune Diseases Recommendation c

Influenza

Influenza is a common, preventable infectious disease associated with high mortality and morbidity in vulnerable populations including the young and the elderly and people with chronic diseases. In a case-control study, the influenza vaccine was found to reduce diabetes-related hospital admission by as much as 79% during flu epidemics (17).

Consider screening patients with type 1 diabetes for autoimmune thyroid disease and celiac disease soon after diagnosis. E

People with type 1 diabetes are at increased risk for other autoimmune diseases including thyroid disease, primary adrenal insufficiency, celiac disease, autoimmune gastritis, autoimmune hepatitis, dermatomyositis, and myasthenia gravis

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Comprehensive Medical Evaluation and Assessment of Comorbidities

Table 3.1—Components of the comprehensive diabetes medical evaluation* Medical history c Age and characteristics of onset of diabetes (e.g., diabetic ketoacidosis, asymptomatic laboratory finding) c Eating patterns, nutritional status, weight history, sleep behaviors (pattern and duration), and physical activity habits; nutrition education and behavioral support history and needs c Complementary and alternative medicine use c Presence of common comorbidities and dental disease c Screen for depression, anxiety, and disordered eating using validated and appropriate measures** c Screen for diabetes distress using validated and appropriate measures** c Screen for psychosocial problems and other barriers to diabetes self-management, such as limited financial, logistical, and support resources c History of tobacco use, alcohol consumption, and substance use c Diabetes education, self-management, and support history and needs c Review of previous treatment regimens and response to therapy (A1C records) c Assess medication-taking behaviors and barriers to medication adherence c Results of glucose monitoring and patient’s use of data c Diabetic ketoacidosis frequency, severity, and cause c Hypoglycemia episodes, awareness, and frequency and causes c History of increased blood pressure, abnormal lipids c Microvascular complications: retinopathy, nephropathy, and neuropathy (sensory, including history of foot lesions; autonomic, including sexual dysfunction and gastroparesis) c Macrovascular complications: coronary heart disease, cerebrovascular disease, and peripheral arterial disease c For women with childbearing capacity, review contraception and preconception planning Physical examination c Height, weight, and BMI; growth and pubertal development in children and adolescents c Blood pressure determination, including orthostatic measurements when indicated c Fundoscopic examination c Thyroid palpation c Skin examination (e.g., for acanthosis nigricans, insulin injection or infusion set insertion sites) c Comprehensive foot examination ○ Inspection ○ Palpation of dorsalis pedis and posterior tibial pulses ○ Presence/absence of patellar and Achilles reflexes ○ Determination of proprioception, vibration, and monofilament sensation Laboratory evaluation c A1C, if the results are not available within the past 3 months c If not performed/available within the past year ○ Fasting lipid profile, including total, LDL, and HDL cholesterol and triglycerides, as needed ○ Liver function tests ○ Spot urinary albumin–to–creatinine ratio ○ Serum creatinine and estimated glomerular filtration rate ○ Thyroid-stimulating hormone in patients with type 1 diabetes *The comprehensive medical evaluation should ideally be done on the initial visit, although different components can be done as appropriate on follow-up visits. **Refer to the ADA position statement “Psychosocial Care for People With Diabetes” for additional details on diabetes-specific screening measures (65).

(25,26). Type 1 diabetes may also occur with other autoimmune diseases in the context of specific genetic disorders or polyglandular autoimmune syndromes (27). In autoimmune diseases, the immune system fails to maintain self-tolerance to specific peptides within target organs. It is likely that many factors trigger autoimmune disease; however, common triggering factors are known for only some autoimmune conditions (i.e., gliadin peptides in celiac disease) (see Section 12 “Children and Adolescents”). Cancer

Diabetes is associated with increased risk of cancers of the liver, pancreas, endometrium, colon/rectum, breast, and bladder (28). The association may result from

shared risk factors between type 2 diabetes and cancer (older age, obesity, and physical inactivity) but may also be due to diabetesrelated factors (29), such as underlying disease physiology or diabetes treatments, although evidence for these links is scarce. Patients with diabetes should be encouraged to undergo recommended ageand sex-appropriate cancer screenings and to reduce their modifiable cancer risk factors (obesity, physical inactivity, and smoking). Cognitive Impairment/Dementia Recommendation c

In people with cognitive impairment/ dementia, intensive glucose control cannot be expected to remediate deficits. Treatment should

be tailored to avoid significant hypoglycemia. B Diabetes is associated with a significantly increased risk and rate of cognitive decline and an increased risk of

Table 3.2—Referrals for initial care management c Eye care professional for annual dilated eye exam c Family planning for women of reproductive age c Registered dietitian for MNT c DSME/DSMS c Dentist for comprehensive dental and periodontal examination c Mental health professional, if indicated

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dementia (30,31). A recent meta-analysis of prospective observational studies in people with diabetes showed a 73% increased risk of all types of dementia, a 56% increased risk of Alzheimer dementia, and 127% increased risk of vascular dementia compared with individuals without diabetes (32). The reverse is also true: people with Alzheimer dementia are more likely to develop diabetes than people without Alzheimer dementia. In a 15-year prospective study of community-dwelling people .60 years of age, the presence of diabetes at baseline significantly increased the age- and sexadjusted incidence of all-cause dementia, Alzheimer disease, and vascular dementia compared with rates in those with normal glucose tolerance (33).

Cochrane review found insufficient evidence to recommend any dietary change for the prevention or treatment of cognitive dysfunction (40).

Hyperglycemia

Fatty Liver Disease

In those with type 2 diabetes, the degree and duration of hyperglycemia are related to dementia. More rapid cognitive decline is associated with both increased A1C and longer duration of diabetes (34). The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study found that each 1% higher A1C level was associated with lower cognitive function in individuals with type 2 diabetes (35). However, the ACCORD study found no difference in cognitive outcomes in participants randomly assigned to intensive and standard glycemic control, supporting the recommendation that intensive glucose control should not be advised for the improvement of cognitive function in individuals with type 2 diabetes (36). Hypoglycemia

In type 2 diabetes, severe hypoglycemia is associated with reduced cognitive function, and those with poor cognitive function have more severe hypoglycemia. In a long-term study of older patients with type 2 diabetes, individuals with one or more recorded episode of severe hypoglycemia had a stepwise increase in risk of dementia (37). Likewise, the ACCORD trial found that as cognitive function decreased, the risk of severe hypoglycemia increased (38). Tailoring glycemic therapy may help to prevent hypoglycemia in individuals with cognitive dysfunction. Nutrition

In one study, adherence to the Mediterranean diet correlated with improved cognitive function (39). However, a recent

Statins

A systematic review has reported that data do not support an adverse effect of statins on cognition (41). The U.S. Food and Drug Administration (FDA) postmarketing surveillance databases have also revealed a low reporting rate for cognitive-related adverse events, including cognitive dysfunction or dementia, with statin therapy, similar to rates seen with other commonly prescribed cardiovascular medications (41). Therefore fear of cognitive decline should not be a barrier to statin use in individuals with diabetes and a high risk for cardiovascular disease.

general population and include vitamin D supplementation. For patients with type 2 diabetes with fracture risk factors, thiazolidinediones (48) and sodium– glucose cotransporter 2 inhibitors (49) should be used with caution. Hearing Impairment

Hearing impairment, both in high-frequency and low/mid-frequency ranges, is more common in people with diabetes than in those without, perhaps due to neuropathy and/or vascular disease. In a National Health and Nutrition Examination Survey (NHANES) analysis, hearing impairment was about twice as prevalent in people with diabetes compared with those without, after adjusting for age and other risk factors for hearing impairment (50). HIV

Elevations of hepatic transaminase concentrations are associated with higher BMI, waist circumference, and triglyceride levels and lower HDL cholesterol levels. In a prospective analysis, diabetes was significantly associated with incident nonalcoholic chronic liver disease and with hepatocellular carcinoma (42). Interventions that improve metabolic abnormalities in patients with diabetes (weight loss, glycemic control, and treatment with specific drugs for hyperglycemia or dyslipidemia) are also beneficial for fatty liver disease (43,44). Fractures

Age-specific hip fracture risk is significantly increased in people with both type 1 (relative risk 6.3) and type 2 (relative risk 1.7) diabetes in both sexes (45). Type 1 diabetes is associated with osteoporosis, but in type 2 diabetes, an increased risk of hip fracture is seen despite higher bone mineral density (BMD) (46). In three large observational studies of older adults, femoral neck BMD T score and the World Health Organization Fracture Risk Assessment Tool (FRAX) score were associated with hip and nonspine fractures. Fracture risk was higher in participants with diabetes compared with those without diabetes for a given T score and age for a given FRAX score (47). Providers should assess fracture history and risk factors in older patients with diabetes and recommend measurement of BMD if appropriate for the patient’s age and sex. Fracture prevention strategies for people with diabetes are the same as for the

Recommendation c

Patients with HIV should be screened for diabetes and prediabetes with a fasting glucose level every 6– 12 months before starting antiretroviral therapy and 3 months after starting or changing antiretroviral therapy. If initial screening results are normal, checking fasting glucose every year is advised. If prediabetes is detected, continue to measure fasting glucose levels every 3–6 months to monitor for progression to diabetes. E

Diabetes risk is increased with certain protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs). New-onset diabetes is estimated to occur in more than 5% of patients infected with HIV on PIs, whereas more than 15% may have prediabetes (51). PIs are associated with insulin resistance and may also lead to apoptosis of pancreatic b-cells. NRTIs also affect fat distribution (both lipohypertrophy and lipoatrophy), which is associated with insulin resistance. Individuals with HIV are at higher risk for developing prediabetes and diabetes on antiretroviral (ARV) therapies, so a screening protocol is recommended (52). The A1C test underestimates glycemia in people with HIV and is not recommended for diagnosis and may present challenges for monitoring (53). In those with prediabetes, weight loss through healthy nutrition and physical activity may reduce the progression toward diabetes. Among patients with HIV and diabetes,

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preventive health care using an approach similar to that used in patients without HIV is critical to reduce the risks of microvascular and macrovascular complications. For patients with HIV and ARV-associated hyperglycemia, it may be appropriate to consider discontinuing the problematic ARV agents if safe and effective alternatives are available (54). Before making ARV substitutions, carefully consider the possible effect on HIV virological control and the potential adverse effects of new ARV agents. In some cases, antihyperglycemic agents may still be necessary.

Comprehensive Medical Evaluation and Assessment of Comorbidities

diagnoses are considerably more common in people with diabetes than for those without the disease (64). Symptoms, both clinical and subclinical, that interfere with the person’s ability to carry out diabetes self-management must be addressed. Diabetes distress is addressed in Section 4 “Lifestyle Management,” as this state is very common and distinct from a psychological disorder (65). Anxiety Disorders Recommendations c

Low Testosterone in Men

Mean levels of testosterone are lower in men with diabetes compared with agematched men without diabetes, but obesity is a major confounder (55). Treatment in asymptomatic men is controversial. The evidence that testosterone replacement affects outcomes is mixed, and recent guidelines do not recommend testing or treating men without symptoms (56). Obstructive Sleep Apnea

Age-adjusted rates of obstructive sleep apnea, a risk factor for cardiovascular disease, are significantly higher (4- to 10-fold) with obesity, especially with central obesity (57). The prevalence of obstructive sleep apnea in the population with type 2 diabetes may be as high as 23%, and the prevalence of any sleep disordered breathing may be as high as 58% (58,59). In obese participants enrolled in the Action for Health in Diabetes (Look AHEAD) trial, it exceeded 80% (60). Sleep apnea treatment (lifestyle modification, continuous positive airway pressure, oral appliances, and surgery) significantly improves quality of life and blood pressure control. The evidence for a treatment effect on glycemic control is mixed (61). Periodontal Disease

Periodontal disease is more severe, and may be more prevalent, in patients with diabetes than in those without (62,63). Current evidence suggests that periodontal disease adversely affects diabetes outcomes, although evidence for treatment benefits remains controversial (24). Psychosocial/Emotional Disorders

Prevalence of clinically significant psychopathology in people with diabetes ranges across diagnostic categories, and some

c

Consider screening for anxiety in people exhibiting anxiety or worries regarding diabetes complications, insulin injections or infusion, taking medications, and/or hypoglycemia that interfere with self-management behaviors and those who express fear, dread, or irrational thoughts and/or show anxiety symptoms such as avoidance behaviors, excessive repetitive behaviors, or social withdrawal. Refer for treatment if anxiety is present. B Persons with hypoglycemic unawareness, which can co-occur with fear of hypoglycemia, should be treated using blood glucose awareness training (or other evidence-based similar intervention) to help re-establish awareness of hypoglycemia and reduce fear of hyperglycemia. A

Anxiety symptoms and diagnosable disorders (e.g., generalized anxiety disorder, body dysmorphic disorder, obsessivecompulsive disorder, specific phobias, and posttraumatic stress disorder) are common in people with diabetes (66). The Behavioral Risk Factor Surveillance System (BRFSS) estimated the lifetime prevalence of generalized anxiety disorder to be 19.5% in people with either type 1 or type 2 diabetes (67). Common diabetes-specific concerns include fears related to hyperglycemia (68,69), not meeting blood glucose targets (66), and insulin injections or infusion (70). Onset of complications presents another critical point when anxiety can occur (71). People with diabetes who exhibit excessive diabetes self-management behaviors well beyond what is prescribed or needed to achieve glycemic targets may be experiencing symptoms of obsessive-compulsive disorder (72).

General anxiety is a predictor of injectionrelated anxiety and associated with fear of hypoglycemia (69,73). Fear of hypoglycemia and hypoglycemia unawareness often co-occur, and interventions aimed at treating one often benefit both (74). Fear of hypoglycemia may explain avoidance of behaviors associated with lowering glucose such as increasing insulin doses or frequency of monitoring. If fear of hypoglycemia is identified and a person does not have symptoms of hypoglycemia, a structured program, blood glucose awareness training, delivered in routine clinical practice, can improve A1C, reduce the rate of severe hypoglycemia, and restore hypoglycemia awareness (75,76). Depression Recommendations c

c

c

Providers should consider annual screening of all patients with diabetes, especially those with a selfreported history of depression, for depressive symptoms with ageappropriate depression screening measures, recognizing that further evaluation will be necessary for individuals who have a positive screen. B Beginning at diagnosis of complications or when there are significant changes in medical status, consider assessment for depression. B Referrals for treatment of depression should be made to mental health providers with experience using cognitive behavioral therapy, interpersonal therapy, or other evidence-based treatment approaches in conjunction with collaborative care with the patient’s diabetes treatment team. A

History of depression, current depression, and antidepressant medication use are risk factors for the development of type 2 diabetes, especially if the individual has other risk factors such as obesity and family history of type 2 diabetes (77–79). Elevated depressive symptoms and depressive disorders affect one in four patients with type 1 or type 2 diabetes (80). Thus, routine screening for depressive symptoms is indicated in this high-risk population including people with prediabetes (particularly those who are overweight), type 1 or type 2 diabetes, gestational diabetes mellitus and

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postpartum diabetes. Regardless of diabetes type, women have significantly higher rates of depression than men (81). Routine monitoring with patientappropriate validated measures can help to identify if referral is warranted. Remission of depressive symptoms or disorder in adult patients suggests the need for ongoing monitoring of depression recurrence within the context of routine care (77). Integrating mental and physical health care can improve outcomes. When a patient is in psychological therapy (talk therapy), the mental health provider should be incorporated into the diabetes treatment team (82). Disordered Eating Behavior

When evaluating symptoms of disordered or disrupted eating in people with diabetes, etiology and motivation for the behavior should be considered (85,91). Adjunctive medication such as glucagon-like peptide 1 receptor agonists (92) may help individuals to not only meet glycemic targets but also to regulate hunger and food intake, thus having the potential to reduce uncontrollable hunger and bulimic symptoms. Serious Mental Illness Recommendations c

c

Recommendations c

c

Providers should consider reevaluating the treatment regimen of people with diabetes who present with symptoms of disordered eating behavior, an eating disorder, or disrupted patterns of eating. B Consider screening for disordered or disrupted eating using validated screening measures when hyperglycemia and weight loss are unexplained based on self-reported behaviors related to medication dosing, meal plan, and physical activity. In addition, a review of the medical regimen is recommended to identify potential treatment-related effects on hunger/caloric intake. B

Estimated prevalence of disordered eating behaviors and diagnosable eating disorders in people with diabetes varies (83–85). For people with type 1 diabetes, insulin omission causing glycosuria in order to lose weight is the most commonly reported disordered eating behavior (86,87); in people with type 2 diabetes, bingeing (excessive food intake with an accompanying sense of loss of control) is most commonly reported. For people with type 2 diabetes treated with insulin, intentional omission is also frequently reported (88). People with diabetes and diagnosable eating disorders have high rates of comorbid psychiatric disorders (89). People with type 1 diabetes and eating disorders have high rates of diabetes distress and fear of hypoglycemia (90).

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c

Annually screen people who are prescribed atypical antipsychotic medications for prediabetes or diabetes. B If a second-generation antipsychotic medication is prescribed for adolescents or adults with diabetes, changes in weight, glycemic control, and cholesterol levels should be carefully monitored and the treatment regimen should be reassessed. C Incorporate monitoring of diabetes self-care activities into treatment goals in people with diabetes and serious mental illness. B

Studies of individuals with serious mental illness, particularly schizophrenia and other thought disorders, show significantly increased rates of type 2 diabetes (93). People with schizophrenia should be monitored for type 2 diabetes because of the known comorbidity. Disordered thinking and judgment can be expected to make it difficult to engage in behaviors that reduce risk factors for type 2 diabetes, such as restrained eating for weight management. Coordinated management of diabetes or prediabetes and serious mental illness is recommended to achieve diabetes treatment targets. In addition, those taking second-generation (atypical) antipsychotics such as olanzapine require greater monitoring because of an increase in risk of type 2 diabetes associated with this medication (94). References 1. Stellefson M, Dipnarine K, Stopka C. The Chronic Care Model and diabetes management in US primary care settings: a systematic review. Prev Chronic Dis 2013;10:E26 2. Coleman K, Austin BT, Brach C, Wagner EH. Evidence on the Chronic Care Model in the new millennium. Health Aff (Millwood) 2009; 28:75–85

3. Gabbay RA, Bailit MH, Mauger DT, Wagner EH, Siminerio L. Multipayer patient-centered medical home implementation guided by the Chronic Care Model. Jt Comm J Qual Patient Saf 2011;37:265–273 4. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352:837–853 5. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulindependent diabetes mellitus. N Engl J Med 1993; 329:977–986 6. Lachin JM, Genuth S, Nathan DM, Zinman B, Rutledge BN; DCCT/EDIC Research Group. Effect of glycemic exposure on the risk of microvascular complications in the Diabetes Control and Complications Trialdrevisited. Diabetes 2008; 57:995–1001 7. White NH, Cleary PA, Dahms W, Goldstein D, Malone J, Tamborlane WV; Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Research Group. Beneficial effects of intensive therapy of diabetes during adolescence: outcomes after the conclusion of the Diabetes Control and Complications Trial (DCCT). J Pediatr 2001;139:804–812 8. Anderson RM, Funnell MM. Compliance and adherence are dysfunctional concepts in diabetes care. Diabetes Educ 2000;26:597–604 9. Sarkar U, Fisher L, Schillinger D. Is self-efficacy associated with diabetes self-management across race/ethnicity and health literacy? Diabetes Care 2006;29:823–829 10. King DK, Glasgow RE, Toobert DJ, et al. Self-efficacy, problem solving, and socialenvironmental support are associated with diabetes self-management behaviors. Diabetes Care 2010;33:751–753 11. Nouwen A, Urquhart Law G, Hussain S, McGovern S, Napier H. Comparison of the role of self-efficacy and illness representations in relation to dietary self-care and diabetes distress in adolescents with type 1 diabetes. Psychol Health 2009;24:1071–1084 12. Beckerle CM, Lavin MA. Association of selfefficacy and self-care with glycemic control in diabetes. Diabetes Spectr 2013;26:172–178 13. Iannotti RJ, Schneider S, Nansel TR, et al. Self-efficacy, outcome expectations, and diabetes self-management in adolescents with type 1 diabetes. J Dev Behav Pediatr 2006;27:98–105 14. Lee SWH, Ng KY, Chin WK. The impact of sleep amount and sleep quality on glycemic control in type 2 diabetes: a systematic review and meta-analysis. Sleep Med Rev 2016;S10870792(16)00017-4 15. Strikas RA; Centers for Disease Control and Prevention (CDC); Advisory Committee on Immunization Practices (ACIP); ACIP Child/ Adolescent Immunization Work Group. Advisory committee on immunization practices recommended immunization schedules for persons aged 0 through 18 yearsdUnited States, 2015. MMWR Morb Mortal Wkly Rep 2015;64:93–94 16. Kim DK, Bridges CB, Harriman KH; Centers for Disease Control and Prevention (CDC);

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Advisory Committee on Immunization Practices (ACIP); ACIP Adult Immunization Work Group. Advisory Committee on Immunization Practices recommended immunization schedule for adults aged 19 years or olderdUnited States, 2015. MMWR Morb Mortal Wkly Rep 2015;64:91–92 17. Colquhoun AJ, Nicholson KG, Botha JL, Raymond NT. Effectiveness of influenza vaccine in reducing hospital admissions in people with diabetes. Epidemiol Infect 1997;119:335–341 18. Smith SA, Poland GA. Use of influenza and pneumococcal vaccines in people with diabetes. Diabetes Care 2000;23:95–108 19. Feery BJ, Hartman LJ, Hampson AW, Proietto J. Influenza immunization in adults with diabetes mellitus. Diabetes Care 1983;6: 475–478 20. Selvin E, Coresh J, Brancati FL. The burden and treatment of diabetes in elderly individuals in the U.S. Diabetes Care 2006;29:2415–2419 21. Grant RW, Ashburner JM, Hong CS, Chang Y, Barry MJ, Atlas SJ. Defining patient complexity from the primary care physician’s perspective: a cohort study. Ann Intern Med 2011;155:797– 804 22. Tinetti ME, Fried TR, Boyd CM. Designing health care for the most common chronic conditiondmultimorbidity. JAMA 2012;307: 2493–2494 23. Sudore RL, Karter AJ, Huang ES, et al. Symptom burden of adults with type 2 diabetes across the disease course: Diabetes & Aging Study. J Gen Intern Med 2012;27: 1674–1681 24. Borgnakke WS, Yl o¨ stalo PV, Taylor GW, Genco RJ. Effect of periodontal disease on diabetes: systematic review of epidemiologic observational evidence. J Periodontol 2013; 84(Suppl.):S135–S152 25. Triolo TM, Armstrong TK, McFann K, et al. Additional autoimmune disease found in 33% of patients at type 1 diabetes onset. Diabetes Care 2011;34:1211–1213 26. Hughes JW, Riddlesworth TD, DiMeglio LA, Miller KM, Rickels MR, McGill JB; T1D Exchange Clinic Network. Autoimmune diseases in children and adults with type 1 diabetes from the T1D Exchange Clinic Registry. J Clin Endocrinol Metab 2016; jc20162478 27. Eisenbarth GS, Gottlieb PA. Autoimmune polyendocrine syndromes. N Engl J Med 2004; 350:2068–2079 28. Suh S, Kim K-W. Diabetes and cancer: is diabetes causally related to cancer? Diabetes Metab J 2011;35:193–198 29. Giovannucci E, Harlan DM, Archer MC, et al. Diabetes and cancer: a consensus report. Diabetes Care 2010;33:1674–1685 30. Cukierman T, Gerstein HC, Williamson JD. Cognitive decline and dementia in diabetesdsystematic overview of prospective observational studies. Diabetologia 2005;48:2460–2469 31. Biessels GJ, Staekenborg S, Brunner E, Brayne C, Scheltens P. Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol 2006;5:64–74 32. Gudala K, Bansal D, Schifano F, Bhansali A. Diabetes mellitus and risk of dementia: a metaanalysis of prospective observational studies. J Diabetes Investig 2013;4:640–650 33. Ohara T, Doi Y, Ninomiya T, et al. Glucose tolerance status and risk of dementia in the

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community: the Hisayama study. Neurology 2011;77:1126–1134 34. Rawlings AM, Sharrett AR, Schneider AL, et al. Diabetes in midlife and cognitive change over 20 years: a cohort study. Ann Intern Med 2014;161:785–793 35. Cukierman-Yaffe T, Gerstein HC, Williamson JD, et al.; Action to Control Cardiovascular Risk in Diabetes-Memory in Diabetes (ACCORD-MIND) Investigators. Relationship between baseline glycemic control and cognitive function in individuals with type 2 diabetes and other cardiovascular risk factors: the Action to Control Cardiovascular Risk in Diabetes-Memory in Diabetes (ACCORDMIND) trial. Diabetes Care 2009;32:221–226 36. Launer LJ, Miller ME, Williamson JD, et al.; ACCORD MIND Investigators. Effects of intensive glucose lowering on brain structure and function in people with type 2 diabetes (ACCORD MIND): a randomised open-label substudy. Lancet Neurol 2011;10:969–977 37. Whitmer RA, Karter AJ, Yaffe K, Quesenberry CP Jr, Selby JV. Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus. JAMA 2009;301:1565–1572 38. Punthakee Z, Miller ME, Launer LJ, et al.; ACCORD Group of Investigators; ACCORDMIND Investigators. Poor cognitive function and risk of severe hypoglycemia in type 2 diabetes: post hoc epidemiologic analysis of the ACCORD trial. Diabetes Care 2012;35:787–793 39. Scarmeas N, Stern Y, Mayeux R, Manly JJ, Schupf N, Luchsinger JA. Mediterranean diet and mild cognitive impairment. Arch Neurol 2009;66:216–225 40. Ooi CP, Loke SC, Yassin Z, Hamid T-A. Carbohydrates for improving the cognitive performance of independent-living older adults with normal cognition or mild cognitive impairment. Cochrane Database Syst Rev 2011;4:CD007220 41. Richardson K, Schoen M, French B, et al. Statins and cognitive function: a systematic review. Ann Intern Med 2013;159:688–697 42. El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 2004;126:460–468 43. American Gastroenterological Association. American Gastroenterological Association medical position statement: nonalcoholic fatty liver disease. Gastroenterology 2002;123:1702–1704 44. Cusi K, Orsak B, Bril F, et al. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial. Ann Intern Med 2016;165:305–315 45. Janghorbani M, Van Dam RM, Willett WC, Hu FB. Systematic review of type 1 and type 2 diabetes mellitus and risk of fracture. Am J Epidemiol 2007;166:495–505 46. Vestergaard P. Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetesda meta-analysis. Osteoporos Int 2007;18:427–444 47. Schwartz AV, Vittinghoff E, Bauer DC, et al.; Study of Osteoporotic Fractures (SOF) Research Group; Osteoporotic Fractures in Men (MrOS) Research Group; Health, Aging, and Body Composition (Health ABC) Research Group. Association of BMD and FRAX score with risk of fracture in older adults with type 2 diabetes. JAMA 2011; 305:2184–2192

48. Kahn SE, Zinman B, Lachin JM, et al.; Diabetes Outcome Progression Trial (ADOPT) Study Group. Rosiglitazone-associated fractures in type 2 diabetes: an analysis from A Diabetes Outcome Progression Trial (ADOPT). Diabetes Care 2008;31:845–851 49. Taylor SI, Blau JE, Rother KI. Possible adverse effects of SGLT2 inhibitors on bone. Lancet Diabetes Endocrinol 2015;3:8–10 50. Bainbridge KE, Hoffman HJ, Cowie CC. Diabetes and hearing impairment in the United States: audiometric evidence from the National Health and Nutrition Examination Survey, 1999 to 2004. Ann Intern Med 2008;149:1–10 51. Monroe AK, Glesby MJ, Brown TT. Diagnosing and managing diabetes in HIV-infected patients: current concepts. Clin Infect Dis 2015;60: 453–462 52. Schambelan M, Benson CA, Carr A, et al. Management of metabolic complications associated with antiretroviral therapy for HIV-1 infection: recommendations of an International AIDS Society-USA panel. J Acquir Immune Defic Syndr 2002;31:257–275 53. Kim PS, Woods C, Georgoff P, et al. A1C underestimates glycemia in HIV infection. Diabetes Care 2009;32:1591–1593 54. Wohl DA, McComsey G, Tebas P, et al. Current concepts in the diagnosis and management of metabolic complications of HIV infection and its therapy. Clin Infect Dis 2006;43:645–653 55. Dhindsa S, Miller MG, McWhirter CL, et al. Testosterone concentrations in diabetic and nondiabetic obese men. Diabetes Care 2010; 33:1186–1192 56. Bhasin S, Cunningham GR, Hayes FJ, et al.; Task Force, Endocrine Society. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010;95: 2536–2559 57. Li C, Ford ES, Zhao G, Croft JB, Balluz LS, Mokdad AH. Prevalence of self-reported clinically diagnosed sleep apnea according to obesity status in men and women: National Health and Nutrition Examination Survey, 2005–2006. Prev Med 2010;51:18–23 58. West SD, Nicoll DJ, Stradling JR. Prevalence of obstructive sleep apnoea in men with type 2 diabetes. Thorax 2006;61:945–950 59. Resnick HE, Redline S, Shahar E, et al.; Sleep Heart Health Study. Diabetes and sleep disturbances: findings from the Sleep Heart Health Study. Diabetes Care 2003;26:702–709 60. Foster GD, Sanders MH, Millman R, et al.; Sleep AHEAD Research Group. Obstructive sleep apnea among obese patients with type 2 diabetes. Diabetes Care 2009;32:1017–1019 61. Shaw JE, Punjabi NM, Wilding JP, Alberti KG, Zimmet PZ; International Diabetes Federation Taskforce on Epidemiology and Prevention. Sleep-disordered breathing and type 2 diabetes: a report from the International Diabetes Federation Taskforce on Epidemiology and Prevention. Diabetes Res Clin Pract 2008;81:2–12 62. Khader YS, Dauod AS, El-Qaderi SS, Alkafajei A, Batayha WQ. Periodontal status of diabetics compared with nondiabetics: a meta-analysis. J Diabetes Complications 2006;20:59–68 63. Casanova L, Hughes FJ, Preshaw PM. Diabetes and periodontal disease: a two-way relationship. Br Dent J 2014;217:433–437

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64. de Groot M, Golden SH, Wagner J. Psychological conditions in adults with diabetes. Am Psychol 2016;71:552–562 65. Young-Hyman D, de Groot M, Hill-Briggs F, Gonzalez JS, Hood K, Peyrot M. Psychosocial care for people with diabetes: a position statement of the American Diabetes Association. Diabetes Care 2016;39:2126–2140 66. Smith KJ, B´eland M, Clyde M, et al. Association of diabetes with anxiety: a systematic review and meta-analysis. J Psychosom Res 2013; 74:89–99 67. Li C, Barker L, Ford ES, Zhang X, Strine TW, Mokdad AH. Diabetes and anxiety in US adults: findings from the 2006 Behavioral Risk Factor Surveillance System. Diabet Med 2008;25:878–881 68. Cox DJ, Irvine A, Gonder-Frederick L, Nowacek G, Butterfield J. Fear of hypoglycemia: quantification, validation, and utilization. Diabetes Care 1987;10:617–621 69. Wild D, von Maltzahn R, Brohan E, Christensen T, Clauson P, Gonder-Frederick L. A critical review of the literature on fear of hypoglycemia in diabetes: implications for diabetes management and patient education. Patient Educ Couns 2007;68:10–15 70. Zambanini A, Newson RB, Maisey M, Feher MD. Injection related anxiety in insulin-treated diabetes. Diabetes Res Clin Pract 1999;46:239–246 71. Young-Hyman D, Peyrot M. Psychosocial Care for People with Diabetes. Alexandria, VA, American Diabetes Association, 2012 72. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders [Internet], 2013. 5th ed. Available from http:// psychiatryonline.org/doi/book/10.1176/appi .books.9780890425596. Accessed 29 September 2016 73. Mitsonis C, Dimopoulos N, Psarra V. Clinical implications of anxiety in diabetes: a critical review of the evidence base. Eur Psychiatry 2009;24:S526 74. Yeoh E, Choudhary P, Nwokolo M, Ayis S, Amiel SA. Interventions that restore awareness

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of hypoglycemia in adults with type 1 diabetes: a systematic review and meta-analysis. Diabetes Care 2015;38:1592–1609 75. Cox DJ, Gonder-Frederick L, Polonsky W, Schlundt D, Kovatchev B, Clarke W. Blood glucose awareness training (BGAT-2): longterm benefits. Diabetes Care 2001;24:637– 642 76. Gonder-Frederick LA, Schmidt KM, Vajda KA, et al. Psychometric properties of the Hypoglycemia Fear Survey-II for adults with type 1 diabetes. Diabetes Care 2011;34:801–806 77. Lustman PJ, Griffith LS, Clouse RE. Depression in adults with diabetes. Results of 5-yr follow-up study. Diabetes Care 1988;11:605–612 78. de Groot M, Crick KA, Long M, Saha C, Shubrook JH. Lifetime duration of depressive disorders in patients with type 2 diabetes. Diabetes Care. 2016;12:2174–2181 79. Rubin RR, Ma Y, Marrero DG, et al.; Diabetes Prevention Program Research Group. Elevated depression symptoms, antidepressant medicine use, and risk of developing diabetes during the Diabetes Prevention Program. Diabetes Care 2008;31:420–426 80. Anderson RJ, Freedland KE, Clouse RE, Lustman PJ. The prevalence of comorbid depression in adults with diabetes: a meta-analysis. Diabetes Care 2001;24:1069–1078 81. Clouse RE, Lustman PJ, Freedland KE, Griffith LS, McGill JB, Carney RM. Depression and coronary heart disease in women with diabetes. Psychosom Med 2003;65:376–383 82. Katon WJ, Lin EHB, Von Korff M, et al. Collaborative care for patients with depression and chronic illnesses. N Engl J Med 2010;363:2611–2620 83. Pinhas-Hamiel O, Hamiel U, Levy-Shraga Y. Eating disorders in adolescents with type 1 diabetes: challenges in diagnosis and treatment. World J Diabetes 2015;6:517–526 84. Papelbaum M, Appolin´ario JC, Moreira R de O, Ellinger VC, Kupfer R, Coutinho WF. Prevalence of eating disorders and psychiatric comorbidity in a

clinical sample of type 2 diabetes mellitus patients. Rev Bras Psiquiatr 2005;27:135–138 85. Young-Hyman DL, Davis CL. Disordered eating behavior in individuals with diabetes: importance of context, evaluation, and classification. Diabetes Care 2010;33:683–689 86. Pinhas-Hamiel O, Hamiel U, Greenfield Y, et al. Detecting intentional insulin omission for weight loss in girls with type 1 diabetes mellitus. Int J Eat Disord 2013;46:819–825 87. Goebel-Fabbri AE, Fikkan J, Franko DL, Pearson K, Anderson BJ, Weinger K. Insulin restriction and associated morbidity and mortality in women with type 1 diabetes. Diabetes Care 2008;31:415–419 88. Weinger K, Beverly EA. Barriers to achieving glycemic targets: who omits insulin and why? Diabetes Care 2010;33:450–452 89. Hudson JI, Hiripi E, Pope HG Jr, Kessler RC. The prevalence and correlates of eating disorders in the National Comorbidity Survey Replication. Biol Psychiatry 2007;61:348–358 90. Martyn-Nemeth P, Quinn L, Hacker E, Park H, Kujath AS. Diabetes distress may adversely affect the eating styles of women with type 1 diabetes. Acta Diabetol 2014;51:683–686 91. Peterson CM, Fischer S, Young-Hyman D. Topical review: a comprehensive risk model for disordered eating in youth with type 1 diabetes. J Pediatr Psychol 2015;40:385–390 92. Garber AJ. Novel GLP-1 receptor agonists for diabetes. Expert Opin Investig Drugs 2012; 21:45–57 93. Suvisaari J, Per¨al¨a J, Saarni SI, et al. Type 2 diabetes among persons with schizophrenia and other psychotic disorders in a general population survey. Eur Arch Psychiatry Clin Neurosci 2008; 258:129–136 94. Koro CE, Fedder DO, L’Italien GJ, et al. Assessment of independent effect of olanzapine and risperidone on risk of diabetes among patients with schizophrenia: population based nested case-control study. BMJ 2002;325:243

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4. Lifestyle Management

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Diabetes Care 2017;40(Suppl. 1):S33–S43 | DOI: 10.2337/dc17-S007

Lifestyle management is a fundamental aspect of diabetes care and includes diabetes self-management education (DSME), diabetes self-management support (DSMS), nutrition therapy, physical activity, smoking cessation counseling, and psychosocial care. Patients and care providers should focus together on how to optimize lifestyle from the time of the initial comprehensive medical evaluation, throughout all subsequent evaluations and follow-up, and during the assessment of complications and management of comorbid conditions in order to enhance diabetes care. DIABETES SELF-MANAGEMENT EDUCATION AND SUPPORT 4. LIFESTYLE MANAGEMENT

Recommendations c

c

c

c

c

In accordance with the national standards for diabetes self-management education and support, all people with diabetes should participate in diabetes self-management education to facilitate the knowledge, skills, and ability necessary for diabetes self-care and in diabetes self-management support to assist with implementing and sustaining skills and behaviors needed for ongoing self-management, both at diagnosis and as needed thereafter. B Effective self-management and improved clinical outcomes, health status, and quality of life are key goals of diabetes self-management education and support that should be measured and monitored as part of routine care. C Diabetes self-management education and support should be patient centered, respectful, and responsive to individual patient preferences, needs, and values and should help guide clinical decisions. A Diabetes self-management education and support programs have the necessary elements in their curricula to delay or prevent the development of type 2 diabetes. Diabetes self-management education and support programs should therefore be able to tailor their content when prevention of diabetes is the desired goal. B Because diabetes self-management education and support can improve outcomes and reduce costs B, diabetes self-management education and support should be adequately reimbursed by third-party payers. E

DSME and DSMS programs facilitate the knowledge, skills, and abilities necessary for optimal diabetes self-care and incorporate the needs, goals, and life experiences of the person with diabetes. The overall objectives of DSME and DSMS are to support informed decision making, self-care behaviors, problem solving, and active collaboration with the health care team to improve clinical outcomes, health status, and quality of life in a cost-effective manner (1). Providers should consider the burden of treatment and the patient’s level of confidence/selfefficacy for management behaviors as well as the level of social and family support when providing DSME or DSMS. Monitor patient performance of selfmanagement behaviors as well as psychosocial factors impacting the person’s self-management. DSME and DSMS, and the current national standards guiding them (1,2), are based on evidence of their benefits. Specifically, DSME helps people with diabetes to identify and implement effective self-management strategies and cope with diabetes at the four critical time points (described below) (1). Ongoing DSMS helps people with diabetes to maintain effective self-management throughout a lifetime of diabetes as they face new challenges and as advances in treatment become available (3).

Suggested citation: American Diabetes Association. Lifestyle management. Sec. 4. In Standards of Medical Care in Diabetesd2017. Diabetes Care 2017;40(Suppl. 1):S33–S43 © 2017 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals .org/content/license.

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Four critical time points have been defined when the need for DSME and DSMS should be evaluated by the medical care provider and/or multidisciplinary team, with referrals made as needed (1): 1. At diagnosis 2. Annually for assessment of education, nutrition, and emotional needs 3.When new complicating factors (health conditions, physical limitations, emotional factors, or basic living needs) arise that influence self-management 4. When transitions in care occur DSME focuses on supporting patient empowerment by providing people with diabetes the tools to make informed self-management decisions (4). Diabetes care has shifted to an approach that is more patient centered and places the person with diabetes and his or her family at the center of the care model, working in collaboration with health care professionals. Patient-centered care is respectful of and responsive to individual patient preferences, needs, and values. It ensures that patient values guide all decision making (5). Evidence for the Benefits

Studies have found that DSME is associated with improved diabetes knowledge and self-care behaviors (2), lower A1C (6–9), lower self-reported weight (10,11), improved quality of life (8,12), healthy coping (13,14), and reduced health care costs (15,16). Better outcomes were reported for DSME interventions that were over 10 h in total duration, included followup with DSMS (3,17), were culturally (18,19) and age appropriate (20,21), were tailored to individual needs and preferences, and addressed psychosocial issues and incorporated behavioral strategies (4,13,22,23). Individual and group approaches are effective (11,24). Emerging evidence is pointing to the benefit of Internet-based DSME programs for diabetes prevention and the management of type 2 diabetes (25,26). There is growing evidence for the role of community health workers (27), as well as peer (27–29) and lay (30) leaders, in providing ongoing support. DSME is associated with an increased use of primary care and preventive services (15,31,32) and less frequent use of acute care and inpatient hospital services (10). Patients who participate in DSME are more likely to follow best practice treatment recommendations, particularly among the Medicare population,

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and have lower Medicare and insurance claim costs (16,31). Despite these benefits, reports indicate that only 5–7% of individuals eligible for DSME through Medicare or a private insurance plan actually receive it (33,34). This low participation may be due to lack of referral or other identified barriers such as logistical issues (timing, costs) and the lack of a perceived benefit (35). Thus, alternative and innovative models of DSME delivery need to be explored and evaluated.

patterns containing nutrient-dense, highquality foods with less focus on specific nutrients. The Mediterranean (45), Dietary Approaches to Stop Hypertension (DASH) (46,47), and plant-based diets (48) are all examples of healthful eating patterns. See Table 4.1 for specific nutrition recommendations. For complete discussion and references, see the ADA position statement “Nutrition Therapy Recommendations for the Management of Adults With Diabetes” (37).

Reimbursement

Medicare reimburses DSME and DSMS, when provided by a program that meets the national standards (2) and is recognized by the American Diabetes Association (ADA) or other approval bodies. DSME is also covered by most health insurance plans. DSMS has been shown to be instrumental for improving outcomes when it follows the completion of a DSME program. DSME and DSMS are frequently reimbursed when performed in person. However, although DSME and DSMS can also be provided via phone calls and telehealth, these remote versions may not always be reimbursed. NUTRITION THERAPY

For many individuals with diabetes, the most challenging part of the treatment plan is determining what to eat and following a food plan. There is not a one-size-fits-all eating pattern for individuals with diabetes. Nutrition therapy has an integral role in overall diabetes management, and each person with diabetes should be actively engaged in education, self-management, and treatment planning with his or her health care team, including the collaborative development of an individualized eating plan (36,37). All individuals with diabetes should receive individualized medical nutrition therapy (MNT), preferably provided by a registered dietitian who is knowledgeable and skilled in providing diabetes-specific MNT. MNT delivered by a registered dietitian is associated with A1C decreases of 0.3–1% for people with type 1 diabetes (38–40) and 0.5–2% for people with type 2 diabetes (41–44). It is important that each member of the health care team be knowledgeable about nutrition therapy principles for people with all types of diabetes and be supportive of their implementation. Emphasis should be on healthful eating

Goals of Nutrition Therapy for Adults With Diabetes

1. To promote and support healthful eating patterns, emphasizing a variety of nutrient-dense foods in appropriate portion sizes, in order to improve overall health and specifically to: ○ Achieve and maintain body weight goals ○ Attain individualized glycemic, blood pressure, and lipid goals ○ Delay or prevent the complications of diabetes 2. To address individual nutrition needs based on personal and cultural preferences, health literacy and numeracy, access to healthful foods, willingness and ability to make behavioral changes, and barriers to change 3. To maintain the pleasure of eating by providing nonjudgmental messages about food choices 4. To provide an individual with diabetes the practical tools for developing healthy eating patterns rather than focusing on individual macronutrients, micronutrients, or single foods Weight Management

Body weight management is important for overweight and obese people with type 1 and type 2 diabetes. Lifestyle intervention programs should be intensive and have frequent follow-up to achieve significant reductions in excess body weight and improve clinical indicators. There is strong and consistent evidence that modest persistent weight loss can delay the progression from prediabetes to type 2 diabetes (49,50) and is beneficial to the management of type 2 diabetes (see Section 7 “Obesity Management for the Treatment of Type 2 Diabetes”). In overweight and obese patients with type 2 diabetes, modest weight loss, defined as sustained reduction of

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Table 4.1—MNT recommendations Topic Effectiveness of nutrition therapy

Recommendations c

An individualized MNT program, preferably provided by a registered dietitian, is recommended for all people with type 1 or type 2 diabetes. c For people with type 1 diabetes and those with type 2 diabetes who are prescribed a flexible insulin therapy program, education on how to use carbohydrate counting and in some cases fat and protein gram estimation to determine mealtime insulin dosing can improve glycemic control. c For individuals whose daily insulin dosing is fixed, having a consistent pattern of carbohydrate intake with respect to time and amount can result in improved glycemic control and a reduced risk of hypoglycemia. c A simple and effective approach to glycemia and weight management emphasizing portion control and healthy food choices may be more helpful for those with type 2 diabetes who are not taking insulin, who have limited health literacy or numeracy, and who are elderly and prone to hypoglycemia. c Because diabetes nutrition therapy can result in cost savings B and improved outcomes (e.g., A1C reduction) A, MNT should be adequately reimbursed by insurance and other payers. E

Energy balance

c

Eating patterns and macronutrient distribution

c

A

B

B

B, A, E

A

As there is no single ideal dietary distribution of calories among carbohydrates, fats, and proteins for people with diabetes, macronutrient distribution should be individualized while keeping total calorie and metabolic goals in mind. c A variety of eating patterns are acceptable for the management of type 2 diabetes and prediabetes including Mediterranean, DASH, and plant-based diets. c Carbohydrate intake from whole grains, vegetables, fruits, legumes, and dairy products, with an emphasis on foods higher in fiber and lower in glycemic load, should be advised over other sources, especially those containing sugars. c People with diabetes and those at risk should avoid sugar-sweetened beverages in order to control weight and reduce their risk for CVD and fatty liver B and should minimize the consumption of foods with added sugar that have the capacity to displace healthier, more nutrient-dense food choices A

E

c

Dietary fat

c

In individuals with type 2 diabetes, ingested protein appears to increase insulin response without increasing plasma glucose concentrations. Therefore, carbohydrate sources high in protein should not be used to treat or prevent hypoglycemia.

Whereas data on the ideal total dietary fat content for people with diabetes are inconclusive, an eating plan emphasizing elements of a Mediterranean-style diet rich in monounsaturated fats may improve glucose metabolism and lower CVD risk and can be an effective alternative to a diet low in total fat but relatively high in carbohydrates. c Eating foods rich in long-chain v-3 fatty acids, such as fatty fish (EPA and DHA) and nuts and seeds (ALA) is recommended to prevent or treat CVD B; however, evidence does not support a beneficial role for v-3 dietary supplements. A

Micronutrients and herbal supplements

c

Alcohol

c

Nonnutritive sweeteners

A

Modest weight loss achievable by the combination of reduction of calorie intake and lifestyle modification benefits overweight or obese adults with type 2 diabetes and also those with prediabetes. Intervention programs to facilitate this process are recommended.

Protein

Sodium

Evidence rating

B B

B, A

B

B

B, A

There is no clear evidence that dietary supplementation with vitamins, minerals, herbs, or spices can improve outcomes in people with diabetes who do not have underlying deficiencies, and there may be safety concerns regarding the long-term use of antioxidant supplements such as vitamins E and C and carotene.

C

Adults with diabetes who drink alcohol should do so in moderation (no more than one drink per day for adult women and no more than two drinks per day for adult men). c Alcohol consumption may place people with diabetes at increased risk for hypoglycemia, especially if taking insulin or insulin secretagogues. Education and awareness regarding the recognition and management of delayed hypoglycemia are warranted. c As for the general population, people with diabetes should limit sodium consumption to ,2,300 mg/day, although further restriction may be indicated for those with both diabetes and hypertension.

C

c

The use of nonnutritive sweeteners has the potential to reduce overall calorie and carbohydrate intake if substituted for caloric sweeteners and without compensation by intake of additional calories from other food sources. Nonnutritive sweeteners are generally safe to use within the defined acceptable daily intake levels.

B

B

B

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5% of initial body weight, has been shown to improve glycemic control and to reduce the need for glucose-lowering medications (51–53). Sustaining weight loss can be challenging (54). Weight loss can be attained with lifestyle programs that achieve a 500–750 kcal/day energy deficit or provide ;1,200–1,500 kcal/day for women and 1,500–1,800 kcal/day for men, adjusted for the individual’s baseline body weight. For many obese individuals with type 2 diabetes, weight loss .5% is needed to produce beneficial outcomes in glycemic control, lipids, and blood pressure, and sustained weight loss of $7% is optimal (54). The diets used in intensive lifestyle management for weight loss may differ in the types of foods they restrict (e.g., high-fat vs. high-carbohydrate foods), but their emphasis should be on nutrientdense foods, such as whole grains, vegetables, fruits, legumes, low-fat dairy, lean meats, nuts, and seeds, as well as on achieving the desired energy deficit (55–58). The diet choice should be based on the patients’ health status and preferences. Carbohydrates

Studies examining the ideal amount of carbohydrate intake for people with diabetes are inconclusive, although monitoring carbohydrate intake and considering the blood glucose response to dietary carbohydrate are key for improving postprandial glucose control (59,60). The literature concerning glycemic index and glycemic load in individuals with diabetes is complex, though in some studies lowering the glycemic load of consumed carbohydrates has demonstrated A1C reductions of –0.2% to –0.5% (61,62). A systematic review (61) found that wholegrain consumption was not associated with improvements in glycemic control in type 2 diabetes. One study did find a potential benefit of whole-grain intake in reducing mortality and cardiovascular disease (CVD) among individuals with type 2 diabetes (63). As for all Americans, individuals with diabetes should be encouraged to replace refined carbohydrates and added sugars with whole grains, legumes, vegetables, and fruits. The consumption of sugarsweetened beverages and processed “low-fat” or “nonfat” food products with high amounts of refined grains and added sugars should be strongly discouraged (64).

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Individuals with type 1 or type 2 diabetes taking insulin at mealtimes should be offered intensive education on the need to couple insulin administration with carbohydrate intake. For people whose meal schedules or carbohydrate consumption is variable, regular counseling to help them understand the complex relationship between carbohydrate intake and insulin needs is important. In addition, education regarding the carbohydrate-counting approach to meal planning can assist them with effectively modifying insulin dosing from meal to meal and improving glycemic control (39,59,65–67). Individuals who consume meals containing more protein and fat than usual may also need to make mealtime insulin dose adjustments to compensate for delayed postprandial glycemic excursions (68,69). For individuals on a fixed daily insulin schedule, meal planning should emphasize a relatively fixed carbohydrate consumption pattern with respect to both time and amount (37). By contrast, a simpler diabetes meal planning approach emphasizing portion control and healthful food choices may be better suited for some elderly individuals, those with cognitive dysfunction, and those for whom there are concerns over health literacy and numeracy (37–39,41,59,65). The modified plate method (which uses measuring cups to assist with portion measurement) may be an effective alternative to carbohydrate counting for some patients in improving glycemia (70). Protein

There is no evidence that adjusting the daily level of protein ingestion (typically 1–1.5 g/kg body weight/day or 15–20% total calories) will improve health in individuals without diabetic kidney disease, and research is inconclusive regarding the ideal amount of dietary protein to optimize either glycemic control or CVD risk (61). Therefore, protein intake goals should be individualized based on current eating patterns. Some research has found successful management of type 2 diabetes with meal plans including slightly higher levels of protein (20–30%), which may contribute to increased satiety (47). For those with diabetic kidney disease (with albuminuria and/or reduced estimated glomerular filtration rate), dietary protein should be maintained at

the recommended daily allowance of 0.8 g/kg body weight/day. Reducing the amount of dietary protein below the recommended daily allowance is not recommended because it does not alter glycemic measures, cardiovascular risk measures, or the rate at which glomerular filtration rate declines (71,72). In individuals with type 2 diabetes, ingested protein may enhance the insulin response to dietary carbohydrates (73). Therefore, carbohydrate sources high in protein should not be used to treat or prevent hypoglycemia. Fats

The ideal amount of dietary fat for individuals with diabetes is controversial. The Institute of Medicine has defined an acceptable macronutrient distribution for total fat for all adults to be 20–35% of energy (74). The type of fats consumed is more important than total amount of fat when looking at metabolic goals and CVD risk (64,75–78). Multiple randomized controlled trials including patients with type 2 diabetes have reported that a Mediterranean-style eating pattern (75,79–82), rich in monounsaturated fats, can improve both glycemic control and blood lipids. However, supplements do not seem to have the same effects. A systematic review concluded that dietary supplements with v-3 fatty acids did not improve glycemic control in individuals with type 2 diabetes (61). Randomized controlled trials also do not support recommending v-3 supplements for primary or secondary prevention of CVD (83–87). People with diabetes should be advised to follow the guidelines for the general population for the recommended intakes of saturated fat, dietary cholesterol, and trans fat (64). In general, trans fats should be avoided. Sodium

As for the general population, people with diabetes should limit their sodium consumption to ,2,300 mg/day. Lowering sodium intake (i.e., 1,500 mg/day) may benefit blood pressure in certain circumstances (88). However, other studies (89,90) have recommended caution for universal sodium restriction to 1,500 mg in people with diabetes. Sodium intake recommendations should take into account palatability, availability, affordability, and the difficulty of achieving low-sodium recommendations in a nutritionally adequate diet (91).

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Micronutrients and Supplements

There continues to be no clear evidence of benefit from herbal or nonherbal (i.e., vitamin or mineral) supplementation for people with diabetes without underlying deficiencies (37). Metformin is associated with vitamin B12 deficiency, with a recent report from the Diabetes Prevention Program Outcomes Study (DPPOS) suggesting that periodic testing of vitamin B12 levels should be considered in metformin-treated patients, particularly in those with anemia or peripheral neuropathy (92). Routine supplementation with antioxidants, such as vitamins E and C and carotene, is not advised because of lack of evidence of efficacy and concern related to long-term safety. In addition, there is insufficient evidence to support the routine use of herbals and micronutrients, such as cinnamon (93) and vitamin D (94), to improve glycemic control in people with diabetes (37,95). Alcohol

Moderate alcohol consumption does not have major detrimental effects on long-term blood glucose control in people with diabetes. Risks associated with alcohol consumption include hypoglycemia (particularly for those using insulin or insulin secretagogue therapies), weight gain, and hyperglycemia (for those consuming excessive amounts) (37,95). Nonnutritive Sweeteners

For people who are accustomed to sugarsweetened products, nonnutritive sweeteners have the potential to reduce overall calorie and carbohydrate intake and may be preferred to sugar when consumed in moderation. Regulatory agencies set acceptable daily intake levels for each nonnutritive sweetener, defined as the amount that can be safely consumed over a person’s lifetime (37,96). PHYSICAL ACTIVITY Recommendations c

c

Children and adolescents with type 1 or type 2 diabetes or prediabetes should engage in 60 min/day or more of moderate- or vigorousintensity aerobic activity, with vigorous muscle-strengthening and bone-strengthening activities at least 3 days/week. C Most adults with with type 1 C and type 2 B diabetes should engage in 150 min or more of moderate-to-

c

c

c

vigorous intensity physical activity per week, spread over at least 3 days/week, with no more than 2 consecutive days without activity. Shorter durations (minimum 75 min/week) of vigorous-intensity or interval training may be sufficient for younger and more physically fit individuals. Adults with type 1 C and type 2 B diabetes should engage in 2–3 sessions/week of resistance exercise on nonconsecutive days. All adults, and particularly those with type 2 diabetes, should decrease the amount of time spent in daily sedentary behavior. B Prolonged sitting should be interrupted every 30 min for blood glucose benefits, particularly in adults with type 2 diabetes. C Flexibility training and balance training are recommended 2–3 times/week for older adults with diabetes. Yoga and tai chi may be included based on individual preferences to increase flexibility, muscular strength, and balance. C

Physical activity is a general term that includes all movement that increases energy use and is an important part of the diabetes management plan. Exercise is a more specific form of physical activity that is structured and designed to improve physical fitness. Both physical activity and exercise are important. Exercise has been shown to improve blood glucose control, reduce cardiovascular risk factors, contribute to weight loss, and improve well-being. Physical activity is as important for those with type 1 diabetes as it is for the general population, but its specific role in the prevention of diabetes complications and the management of blood glucose is not as clear as it is for those with type 2 diabetes. Structured exercise interventions of at least 8 weeks’ duration have been shown to lower A1C by an average of 0.66% in people with type 2 diabetes, even without a significant change in BMI (97). There are also considerable data for the health benefits (e.g., increased cardiovascular fitness, greater muscle strength, improved insulin sensitivity, etc.) of regular exercise for those with type 1 diabetes (98). Higher levels of exercise intensity are associated with

greater improvements in A1C and in fitness (99). Other benefits include slowing the decline in mobility among overweight patients with diabetes (100). The ADA position statement “Physical Activity/ Exercise and Diabetes: A Position Statement of the American Diabetes Association” reviews the evidence for the benefits of exercise in people with diabetes (101). Exercise and Children

All children, including children with diabetes or prediabetes, should be encouraged to engage in at least 60 min of physical activity each day. Children should engage in at least 60 min of moderate-to-vigorous aerobic activity every day with muscle- and bonestrengthening activities at least 3 days per week (102). In general, youth with type 1 diabetes benefit from being physically active, and an active lifestyle should be recommended to all. Frequency and Type of Physical Activity

The U.S. Department of Health and Human Services’ physical activity guidelines for Americans (103) suggest that adults over age 18 years engage in 150 min/week of moderate-intensity or 75 min/week of vigorous-intensity aerobic physical activity, or an equivalent combination of the two. In addition, the guidelines suggest that adults do muscle-strengthening activities that involve all major muscle groups 2 or more days/week. The guidelines suggest that adults over age 65 years and those with disabilities follow the adult guidelines if possible or, if not possible, be as physically active as they are able. Recent evidence supports that all individuals, including those with diabetes, should be encouraged to reduce the amount of time spent being sedentary (e.g., working at a computer, watching TV), by breaking up bouts of sedentary activity (.30 min) by briefly standing, walking, or performing at other light physical activities (104,105). Avoiding extended sedentary periods may help prevent type 2 diabetes for those at risk and may also aid in glycemic control for those with diabetes. Physical Activity and Glycemic Control

Clinical trials have provided strong evidence for the A1C-lowering value of

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resistance training in older adults with type 2 diabetes (106) and for an additive benefit of combined aerobic and resistance exercise in adults with type 2 diabetes (107). If not contraindicated, patients with type 2 diabetes should be encouraged to do at least two weekly sessions of resistance exercise (exercise with free weights or weight machines), with each session consisting of at least one set (group of consecutive repetitive exercise motions) of five or more different resistance exercises involving the large muscle groups (106). For type 1 diabetes, although exercise in general is associated with improvement in disease status, care needs to be taken in titrating exercise with respect to glycemic management. Each individual with type 1 diabetes has a variable glycemic response to exercise. This variability should be taken into consideration when recommending the type and duration of exercise for a given individual (98). Women with preexisting diabetes, particularly type 2 diabetes, and those at risk for or presenting with gestational diabetes mellitus should be advised to engage in regular moderate physical activity prior to and during their pregnancies as tolerated (101). Pre-exercise Evaluation

As discussed more fully in Section 9 “Cardiovascular Disease and Risk Management,” the best protocol for assessing asymptomatic patients with diabetes for coronary artery disease remains unclear. The ADA consensus report “Screening for Coronary Artery Disease in Patients With Diabetes” (108) concluded that routine testing is not recommended. However, providers should perform a careful history, assess cardiovascular risk factors, and be aware of the atypical presentation of coronary artery disease in patients with diabetes. Certainly, high-risk patients should be encouraged to start with short periods of low-intensity exercise and slowly increase the intensity and duration. Providers should assess patients for conditions that might contraindicate certain types of exercise or predispose to injury, such as uncontrolled hypertension, untreated proliferative retinopathy, autonomic neuropathy, peripheral neuropathy, and a history of foot ulcers or Charcot foot. The patient’s age and previous physical activity level should be considered. The

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provider should customize the exercise regimen to the individual’s needs. Those with complications may require a more thorough evaluation (98). Hypoglycemia

In individuals taking insulin and/or insulin secretagogues, physical activity may cause hypoglycemia if the medication dose or carbohydrate consumption is not altered. Individuals on these therapies may need to ingest some added carbohydrate if pre-exercise glucose levels are ,100 mg/dL (5.6 mmol/L), depending on whether they can lower insulin levels during the workout (such as with an insulin pump or reduced preexercise insulin dosage), the time of day exercise is done, and the intensity and duration of the activity (98,101). Hypoglycemia is less common in patients with diabetes who are not treated with insulin or insulin secretagogues, and no routine preventive measures for hypoglycemia are usually advised in these cases. In some patients, hypoglycemia after exercise may occur and last for several hours due to increased insulin sensitivity. Intense activities may actually raise blood glucose levels instead of lowering them, especially if pre-exercise glucose levels are elevated (109). Exercise in the Presence of Specific Long-term Complications of Diabetes Retinopathy

If proliferative diabetic retinopathy or severe nonproliferative diabetic retinopathy is present, then vigorous-intensity aerobic or resistance exercise may be contraindicated because of the risk of triggering vitreous hemorrhage or retinal detachment (110). Consultation with an ophthalmologist prior to engaging in an intense exercise regimen may be appropriate. Peripheral Neuropathy

Decreased pain sensation and a higher pain threshold in the extremities result in an increased risk of skin breakdown, infection, and Charcot joint destruction with some forms of exercise. Therefore, a thorough assessment should be done to ensure that neuropathy does not alter kinesthetic or proprioceptive sensation during physical activity, particularly in those with more severe neuropathy. Studies have shown that moderate-intensity walking may not lead to an increased risk of foot ulcers or reulceration in those with peripheral

neuropathy who use proper footwear (111). In addition, 150 min/week of moderate exercise was reported to improve outcomes in patients with prediabetic neuropathy (112). All individuals with peripheral neuropathy should wear proper footwear and examine their feet daily to detect lesions early. Anyone with a foot injury or open sore should be restricted to non–weight-bearing activities. Autonomic Neuropathy

Autonomic neuropathy can increase the risk of exercise-induced injury or adverse events through decreased cardiac responsiveness to exercise, postural hypotension, impaired thermoregulation, impaired night vision due to impaired papillary reaction, and greater susceptibility to hypoglycemia (113). Cardiovascular autonomic neuropathy is also an independent risk factor for cardiovascular death and silent myocardial ischemia (114). Therefore, individuals with diabetic autonomic neuropathy should undergo cardiac investigation before beginning physical activity more intense than that to which they are accustomed. Diabetic Kidney Disease

Physical activity can acutely increase urinary albumin excretion. However, there is no evidence that vigorous-intensity exercise increases the rate of progression of diabetic kidney disease, and there appears to be no need for specific exercise restrictions for people with diabetic kidney disease (110). SMOKING CESSATION: TOBACCO AND e-CIGARETTES Recommendations c

c

Advise all patients not to use cigarettes and other tobacco products A or e-cigarettes. E Include smoking cessation counseling and other forms of treatment as a routine component of diabetes care. B

Results from epidemiological, case-control, and cohort studies provide convincing evidence to support the causal link between cigarette smoking and health risks (115). Recent data show tobacco use is higher among adults with chronic conditions (116). Other studies of individuals with diabetes consistently demonstrate that smokers (and people exposed to secondhand smoke) have a heightened risk of CVD, premature death, and microvascular

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complications. Smoking may have a role in the development of type 2 diabetes (117). One study in smokers with newly diagnosed type 2 diabetes found that smoking cessation was associated with amelioration of metabolic parameters and reduced blood pressure and albuminuria at 1 year (118). The routine and thorough assessment of tobacco use is essential to prevent smoking or encourage cessation. Numerous large randomized clinical trials have demonstrated the efficacy and cost-effectiveness of brief counseling in smoking cessation, including the use of telephone quit lines, in reducing tobacco use. For the patient motivated to quit, the addition of pharmacological therapy to counseling is more effective than either treatment alone. Special considerations should include assessment of level of nicotine dependence, which is associated with difficulty in quitting and relapse (119). Although some patients may gain weight in the period shortly after smoking cessation, recent research has demonstrated that this weight gain does not diminish the substantial CVD benefit realized from smoking cessation (120). Nonsmokers should be advised not to use e-cigarettes. There are no rigorous studies that have demonstrated that e-cigarettes are a healthier alternative to smoking or that e-cigarettes can facilitate smoking cessation. More extensive research of their short- and long-term effects is needed to determine their safety and their cardiopulmonary effects in comparison with smoking and standard approaches to smoking cessation (121–123). PSYCHOSOCIAL ISSUES Recommendations c

Psychosocial care should be integrated with a collaborative, patient-

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c

c

c

centered approach and provided to all people with diabetes, with the goals of optimizing health outcomes and health-related quality of life. A Psychosocial screening and followup may include, but are not limited to, attitudes about the illness, expectations for medical management and outcomes, affect or mood, general and diabetes-related quality of life, available resources (financial, social, and emotional), and psychiatric history. E Providers should consider assessment for symptoms of diabetes distress, depression, anxiety, disordered eating, and cognitive capacities using patient-appropriate standardized and validated tools at the initial visit, at periodic intervals, and when there is a change in disease, treatment, or life circumstance. Including caregivers and family members in this assessment is recommended. B Consider screening older adults (aged $65 years) with diabetes for cognitive impairment and depression. B

Please refer to the ADA position statement “Psychosocial Care for People with Diabetes” for a list of assessment tools and additional details (124). Emotional well-being is an important part of diabetes care and self-management. Psychological and social problems can impair the individual’s (125–127) or family’s (128) ability to carry out diabetes care tasks and therefore potentially compromise health status. There are opportunities for the clinician to routinely assess psychosocial status in a timely and efficient manner for referral to appropriate services. A systematic review and meta-analysis showed that psychosocial

interventions modestly but significantly improved A1C (standardized mean difference –0.29%) and mental health outcomes (129). However, there was a limited association between the effects on A1C and mental health, and no intervention characteristics predicted benefit on both outcomes. Screening

Key opportunities for psychosocial screening occur at diabetes diagnosis, during regularly scheduled management visits, during hospitalizations, with new onset of complications, or when problems with glucose control, quality of life, or self-management are identified (1). Patients are likely to exhibit psychological vulnerability at diagnosis, when their medical status changes (e.g., end of the honeymoon period), when the need for intensified treatment is evident, and when complications are discovered. Providers can start with informal verbal inquires, for example, by asking if there have been changes in mood during the past 2 weeks or since their last visit. Providers should consider asking if there are new or different barriers to treatment and self-management, such as feeling overwhelmed or stressed by diabetes or other life stressors. Standardized and validated tools for psychosocial monitoring and assessment can also be used by providers, with positive findings leading to referral to a mental health provider specializing in diabetes for comprehensive evaluation, diagnosis, and treatment. Diabetes Distress Recommendation c

Routinely monitor people with diabetes for diabetes distress, particularly when treatment targets are not met and/or at the onset of diabetes complications. B

Table 4.2—Situations that warrant referral of a person with diabetes to a mental health provider for evaluation and treatment c If self-care remains impaired in a person with diabetes distress after tailored diabetes education c If a person has a positive screen on a validated screening tool for depressive symptoms c In the presence of symptoms or suspicions of disordered eating behavior, an eating disorder, or disrupted patterns of eating c If intentional omission of insulin or oral medication to cause weight loss is identified c If a person has a positive screen for anxiety or fear of hypoglycemia c If a serious mental illness is suspected c In youth and families with behavioral self-care difficulties, repeated hospitalizations for diabetic ketoacidosis, or significant distress c If a person screens positive for cognitive impairment c Declining or impaired ability to perform diabetes self-care behaviors c Before undergoing bariatric or metabolic surgery and after surgery if assessment reveals an ongoing need for adjustment support

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Diabetes distress (DD) is very common and is distinct from other psychological disorders (130–132). DD refers to significant negative psychological reactions related to emotional burdens and worries specific to an individual’s experience in having to manage a severe, complicated, and demanding chronic disease such as diabetes (131–133). The constant behavioral demands (medication dosing, frequency, and titration; monitoring blood glucose, food intake, eating patterns, and physical activity) of diabetes self-management and the potential or actuality of disease progression are directly associated with reports of DD (131). The prevalence of DD is reported to be 18–45% with an incidence of 38–48% over 18 months (133). In the second Diabetes Attitudes, Wishes and Needs (DAWN2) study, significant DD was reported by 45% of the participants, but only 24% reported that their health care teams asked them how diabetes affected their lives (130). High levels of DD significantly impact medication-taking behaviors and are linked to higher A1C, lower self-efficacy, and poorer dietary and exercise behaviors (14,131,133). DSME has been shown to reduce DD (14). It may be helpful to provide counseling regarding expected diabetes-related versus generalized psychological distress at diagnosis and when disease state or treatment changes (134). DD should be routinely monitored (135) using patient-appropriate validated measures. If DD is identified, the person should be referred for specific diabetes education to address areas of diabetes self-care that are most relevant to the patient and impact clinical management. People whose self-care remains impaired after tailored diabetes education should be referred by their care team to a behavioral health provider for evaluation and treatment. Other psychosocial issues known to affect self-management and health outcomes include attitudes about the illness, expectations for medical management and outcomes, available resources (financial, social, and emotional) (136), and psychiatric history. For additional information on psychiatric comorbidities (depression, anxiety, disordered eating, and serious mental illness), please refer to Section 3 “Comprehensive Medical Evaluation and Assessment of Comorbidities.”

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Referral to a Mental Health Specialist

Indications for referral to a mental health specialist familiar with diabetes management may include positive screening for overall stress related to work-life balance, DD, diabetes management difficulties, depression, anxiety, disordered eating, and cognitive functioning difficulties (see Table 4.2 for a complete list). It is preferable to incorporate psychosocial assessment and treatment into routine care rather than waiting for a specific problem or deterioration in metabolic or psychological status to occur (22,130). Providers should identify behavioral and mental health providers, ideally those who are knowledgeable about diabetes treatment and the psychosocial aspects of diabetes, to whom they can refer patients. Ideally, psychosocial care providers should be embedded in diabetes care settings. Although the clinician may not feel qualified to treat psychological problems (137), optimizing the patient–provider relationship as a foundation may increase the likelihood of the patient accepting referral for other services. Collaborative care interventions and a team approach have demonstrated efficacy in diabetes self-management and psychosocial functioning (14). References 1. Powers MA, Bardsley J, Cypress M, et al. Diabetes self-management education and support in type 2 diabetes: a joint position statement of the American Diabetes Association, the American Association of Diabetes Educators, and the Academy of Nutrition and Dietetics. Diabetes Care 2015;38:1372–1382 2. Haas L, Maryniuk M, Beck J, et al.; 2012 Standards Revision Task Force. National standards for diabetes self-management education and support. Diabetes Care 2014;37(Suppl. 1):S144–S153 3. Tang TS, Funnell MM, Brown MB, Kurlander JE. Self-management support in “real-world” settings: an empowerment-based intervention. Patient Educ Couns 2010;79:178–184 4. Marrero DG, Ard J, Delamater AM, et al. Twenty-first century behavioral medicine: a context for empowering clinicians and patients with diabetes: a consensus report. Diabetes Care 2013;36:463–470 5. Committee on Quailty of Health Care in America; Institute of Medicine. Crossing the Quality Chasm. A New Health System for the 21st Century [Internet]. Washington, DC, National Academies Press, 2001. Available from http://www.nap.edu/catalog/10027. Accessed 8 September 2016 6. Norris SL, Lau J, Smith SJ, Schmid CH, Engelgau MM. Self-management education for adults with type 2 diabetes: a meta-analysis of the effect on glycemic control. Diabetes Care 2002;25:1159–1171

7. Frosch DL, Uy V, Ochoa S, Mangione CM. Evaluation of a behavior support intervention for patients with poorly controlled diabetes. Arch Intern Med 2011;171:2011–2017 8. Cooke D, Bond R, Lawton J, et al.; U.K. NIHR DAFNE Study Group. Structured type 1 diabetes education delivered within routine care: impact on glycemic control and diabetes-specific quality of life. Diabetes Care 2013;36:270–272 9. Chrvala CA, Sherr D, Lipman RD. Diabetes self-management education for adults with type 2 diabetes mellitus: a systematic review of the effect on glycemic control. Patient Educ Couns 2016;99:926–943 10. Steinsbekk A, Rygg LØ, Lisulo M, Rise MB, Fretheim A. Group based diabetes self-management education compared to routine treatment for people with type 2 diabetes mellitus. A systematic review with meta-analysis. BMC Health Serv Res 2012;12:213 11. Deakin T, McShane CE, Cade JE, Williams RDRR. Group based training for self-management strategies in people with type 2 diabetes mellitus. Cochrane Database Syst Rev 2005;2: CD003417 12. Cochran J, Conn VS. Meta-analysis of quality of life outcomes following diabetes self-management training. Diabetes Educ 2008;34:815–823 13. Thorpe CT, Fahey LE, Johnson H, Deshpande M, Thorpe JM, Fisher EB. Facilitating healthy coping in patients with diabetes: a systematic review. Diabetes Educ 2013;39:33–52 14. Fisher L, Hessler D, Glasgow RE, et al. REDEEM: a pragmatic trial to reduce diabetes distress. Diabetes Care 2013;36:2551–2558 15. Robbins JM, Thatcher GE, Webb DA, Valdmanis VG. Nutritionist visits, diabetes classes, and hospitalization rates and charges: the Urban Diabetes Study. Diabetes Care 2008;31:655–660 16. Duncan I, Ahmed T, Li QE, et al. Assessing the value of the diabetes educator. Diabetes Educ 2011;37:638–657 17. Piatt GA, Anderson RM, Brooks MM, et al. 3-year follow-up of clinical and behavioral improvements following a multifaceted diabetes care intervention: results of a randomized controlled trial. Diabetes Educ 2010;36:301–309 18. Glazier RH, Bajcar J, Kennie NR, Willson K. A systematic review of interventions to improve diabetes care in socially disadvantaged populations. Diabetes Care 2006;29:1675–1688 19. Hawthorne K, Robles Y, Cannings-John R, Edwards AG. Culturally appropriate health education for type 2 diabetes mellitus in ethnic minority groups. Cochrane Database Syst Rev 2008;3:CD006424 20. Chodosh J, Morton SC, Mojica W, et al. Meta-analysis: chronic disease self-management programs for older adults. Ann Intern Med 2005; 143:427–438 21. Sarkisian CA, Brown AF, Norris KC, Wintz RL, Mangione CM. A systematic review of diabetes self-care interventions for older, African American, or Latino adults. Diabetes Educ 2003;29:467–479 22. Peyrot M, Rubin RR. Behavioral and psychosocial interventions in diabetes: a conceptual review. Diabetes Care 2007;30:2433–2440 23. Naik AD, Palmer N, Petersen NJ, et al. Comparative effectiveness of goal setting in diabetes mellitus group clinics: randomized clinical trial. Arch Intern Med 2011;171:453–459 24. Duke S-AS, Colagiuri S, Colagiuri R. Individual patient education for people with type 2

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diabetes mellitus. Cochrane Database Syst Rev 2009;1:CD005268 25. Pereira K, Phillips B, Johnson C, Vorderstrasse A. Internet delivered diabetes self-management education: a review. Diabetes Technol Ther 2015;17:55–63 26. Sepah SC, Jiang L, Peters AL. Long-term outcomes of a Web-based diabetes prevention program: 2-year results of a single-arm longitudinal study. J Med Internet Res 2015;17:e92 27. Shah M, Kaselitz E, Heisler M. The role of community health workers in diabetes: update on current literature. Curr Diab Rep 2013;13: 163–171 28. Heisler M, Vijan S, Makki F, Piette JD. Diabetes control with reciprocal peer support versus nurse care management: a randomized trial. Ann Intern Med 2010;153:507–515 29. Long JA, Jahnle EC, Richardson DM, Loewenstein G, Volpp KG. Peer mentoring and financial incentives to improve glucose control in African American veterans: a randomized trial. Ann Intern Med 2012;156:416–424 30. Foster G, Taylor SJC, Eldridge SE, Ramsay J, Griffiths CJ. Self-management education programmes by lay leaders for people with chronic conditions. Cochrane Database Syst Rev 2007;4: CD005108 31. Duncan I, Birkmeyer C, Coughlin S, Li QE, Sherr D, Boren S. Assessing the value of diabetes education. Diabetes Educ 2009;35:752–760 32. Johnson TM, Murray MR, Huang Y. Associations between self-management education and comprehensive diabetes clinical care. Diabetes Spectrum 2010;23:41–46 33. Strawbridge LM, Lloyd JT, Meadow A, Riley GF, Howell BL. Use of Medicare’s diabetes selfmanagement training benefit. Health Educ Behav 2015;42:530–538 34. Li R, Shrestha SS, Lipman R, Burrows NR, Kolb LE, Rutledge S; Centers for Disease Control and Prevention (CDC). Diabetes self-management education and training among privately insured persons with newly diagnosed diabetes–United States, 2011-2012. MMWR Morb Mortal Wkly Rep 2014;63:1045–1049 35. Horigan G, Davies M, Findlay-White F, Chaney D, Coates V. Reasons why patients referred to diabetes education programmes choose not to attend: a systematic review. Diabet Med. Epub ahead of print 21 March 2016. DOI: 10.1111/dme.13120 36. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2015;38:140–149 37. Evert AB, Boucher JL, Cypress M, et al. Nutrition therapy recommendations for the management of adults with diabetes. Diabetes Care. 2014;37(Suppl. 1):S120–S143 38. Kulkarni K, Castle G, Gregory R, et al. Nutrition practice guidelines for type 1 diabetes mellitus positively affect dietitian practices and patient outcomes. The Diabetes Care and Education Dietetic Practice Group. J Am Diet Assoc 1998;98:62–70; quiz 71–72 39. Rossi MCE, Nicolucci A, Di Bartolo P, et al. Diabetes Interactive Diary: a new telemedicine system enabling flexible diet and insulin therapy while improving quality of life: an open-label,

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international, multicenter, randomized study. Diabetes Care 2010;33:109–115 40. Scavone G, Manto A, Pitocco D, et al. Effect of carbohydrate counting and medical nutritional therapy on glycaemic control in type 1 diabetic subjects: a pilot study. Diabet Med 2010;27: 477–479 41. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854–865 42. Ziemer DC, Berkowitz KJ, Panayioto RM, et al. A simple meal plan emphasizing healthy food choices is as effective as an exchange-based meal plan for urban African Americans with type 2 diabetes. Diabetes Care 2003;26:1719–1724 43. Wolf AM, Conaway MR, Crowther JQ, et al.; Improving Control with Activity and Nutrition (ICAN) Study. Translating lifestyle intervention to practice in obese patients with type 2 diabetes: Improving Control with Activity and Nutrition (ICAN) study. Diabetes Care 2004;27:1570–1576 44. Coppell KJ, Kataoka M, Williams SM, Chisholm AW, Vorgers SM, Mann JI. Nutritional intervention in patients with type 2 diabetes who are hyperglycaemic despite optimised drug treatment–Lifestyle Over and Above Drugs in Diabetes (LOADD) study: randomised controlled trial. BMJ 2010;341:c3337 45. Esposito K, Maiorino MI, Ciotola M, et al. Effects of a Mediterranean-style diet on the need for antihyperglycemic drug therapy in patients with newly diagnosed type 2 diabetes: a randomized trial. Ann Intern Med 2009;151: 306–314 46. Cespedes EM, Hu FB, Tinker L, et al. Multiple healthful dietary patterns and type 2 diabetes in the Women’s Health Initiative. Am J Epidemiol 2016;183:622–633 47. Ley SH, Hamdy O, Mohan V, Hu FB. Prevention and management of type 2 diabetes: dietary components and nutritional strategies. Lancet 2014;383:1999–2007 48. Rinaldi S, Campbell EE, Fournier J, O’Connor C, Madill J. A comprehensive review of the literature supporting recommendations from the Canadian Diabetes Association for the use of a plant-based diet for management of type 2 diabetes. Can J Diabetes 2016;40:471–477 49. Mudaliar U, Zabetian A, Goodman M, et al. Cardiometabolic risk factor changes observed in diabetes prevention programs in US settings: a systematic review and meta-analysis. PLoS Med 2016;13:e1002095 50. Balk EM, Earley A, Raman G, Avendano EA, Pittas AG, Remington PL. Combined diet and physical activity promotion programs to prevent type 2 diabetes among persons at increased risk: a systematic review for the Community Preventive Services Task Force. Ann Intern Med 2015;164: 164–175 51. UK Prospective Diabetes Study 7. UK Prospective Diabetes Study 7: response of fasting plasma glucose to diet therapy in newly presenting type II diabetic patients, UKPDS Group. Metabolism 1990;39:905–912 52. Goldstein DJ. Beneficial health effects of modest weight loss. Int J Obes Relat Metab Disord 1992;16:397–415 53. Pastors JG, Warshaw H, Daly A, Franz M, Kulkarni K. The evidence for the effectiveness

of medical nutrition therapy in diabetes management. Diabetes Care 2002;25:608–613 54. Franz MJ, Boucher JL, Rutten-Ramos S, VanWormer JJ. Lifestyle weight-loss intervention outcomes in overweight and obese adults with type 2 diabetes: a systematic review and meta-analysis of randomized clinical trials. J Acad Nutr Diet 2015;115:1447–1463 55. Sacks FM, Bray GA, Carey VJ, et al. Comparison of weight-loss diets with different compositions of fat, protein, and carbohydrates. N Engl J Med 2009;360:859–873 56. de Souza RJ, Bray GA, Carey VJ, et al. Effects of 4 weight-loss diets differing in fat, protein, and carbohydrate on fat mass, lean mass, visceral adipose tissue, and hepatic fat: results from the POUNDS LOST trial. Am J Clin Nutr 2012;95:614–625 57. Johnston BC, Kanters S, Bandayrel K, et al. Comparison of weight loss among named diet programs in overweight and obese adults: a meta-analysis. JAMA 2014;312:923–933 58. Fox CS, Golden SH, Anderson C, et al.; American Heart Association Diabetes Committee of the Council on Lifestyle and Cardiometabolic Health; Council on Clinical Cardiology, Council on Cardiovascular and Stroke Nursing, Council on Cardiovascular Surgery and Anesthesia, Council on Quality of Care and Outcomes Research; American Diabetes Association. Update on prevention of cardiovascular disease in adults with type 2 diabetes mellitus in light of recent evidence: a scientific statement from the American Heart Association and the American Diabetes Association. Diabetes Care 2015;38:1777–1803 59. DAFNE Study Group. Training in flexible, intensive insulin management to enable dietary freedom in people with type 1 diabetes: Dose Adjustment for Normal Eating (DAFNE) randomised controlled trial. BMJ 2002;325:746 60. Delahanty LM, Nathan DM, Lachin JM, et al.; Diabetes Control and Complications Trial/ Epidemiology of Diabetes. Association of diet with glycated hemoglobin during intensive treatment of type 1 diabetes in the Diabetes Control and Complications Trial. Am J Clin Nutr 2009;89:518–524 61. Wheeler ML, Dunbar SA, Jaacks LM, et al. Macronutrients, food groups, and eating patterns in the management of diabetes: a systematic review of the literature, 2010. Diabetes Care 2012;35:434–445 62. Thomas D, Elliott EJ. Low glycaemic index, or low glycaemic load, diets for diabetes mellitus. Cochrane Database Syst Rev 2009;1:CD006296 63. He M, van Dam RM, Rimm E, Hu FB, Qi L. Whole-grain, cereal fiber, bran, and germ intake and the risks of all-cause and cardiovascular disease-specific mortality among women with type 2 diabetes mellitus. Circulation 2010;121:2162–2168 64. Office of Disease Prevention and Health Promotion, U.S. Department of Health and Human Services. Dietary Guidelines for Americans: 2015–2020. 8th ed. Available from http:// health.gov/dietaryguidelines/2015/guidelines/. Accessed 17 October 2016 65. Laurenzi A, Bolla AM, Panigoni G, et al. Effects of carbohydrate counting on glucose control and quality of life over 24 weeks in adult patients with type 1 diabetes on continuous subcutaneous insulin infusion: a randomized,

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prospective clinical trial (GIOCAR). Diabetes Care 2011;34:823–827 66. S¨amann A, M¨uhlhauser I, Bender R, Kloos Ch, M¨uller UA. Glycaemic control and severe hypoglycaemia following training in flexible, intensive insulin therapy to enable dietary freedom in people with type 1 diabetes: a prospective implementation study. Diabetologia 2005;48:1965–1970 67. Bell KJ, Barclay AW, Petocz P, Colagiuri S, Brand-Miller JC. Efficacy of carbohydrate counting in type 1 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol 2014;2:133–140 68. Bell KJ, Smart CE, Steil GM, Brand-Miller JC, King B, Wolpert HA. Impact of fat, protein, and glycemic index on postprandial glucose control in type 1 diabetes: implications for intensive diabetes management in the continuous glucose monitoring era. Diabetes Care 2015;38:1008–1015 69. Bell KJ, Toschi E, Steil GM, Wolpert HA. Optimized mealtime insulin dosing for fat and protein in type 1 diabetes: application of a model-based approach to derive insulin doses for open-loop diabetes management. Diabetes Care 2016;39:1631–1634 70. Bowen ME, Cavanaugh KL, Wolff K, et al. The diabetes nutrition education study randomized controlled trial: a comparative effectiveness study of approaches to nutrition in diabetes selfmanagement education. Patient Educ Couns 2016;99:1368–1376 71. Pan Y, Guo LL, Jin HM. Low-protein diet for diabetic nephropathy: a meta-analysis of randomized controlled trials. Am J Clin Nutr 2008; 88:660–666 72. Robertson L, Waugh N, Robertson A. Protein restriction for diabetic renal disease. Cochrane Database Syst Rev 2007;4:CD002181 73. Layman DK, Clifton P, Gannon MC, Krauss RM, Nuttall FQ. Protein in optimal health: heart disease and type 2 diabetes. Am J Clin Nutr 2008;87:1571S–1575S 74. Institute of Medicine. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids [Internet]. Washington, DC, National Academies Press, 2005. Available from http://www.iom .edu/Reports/2002/Dietary-Reference-Intakesfor-Energy-Carbohydrate-Fiber-Fat-Fatty-AcidsCholesterol-Protein-and-Amino-Acids.aspx. Accessed 75. Estruch R, Ros E, Salas-Salvado´ J, et al.; PREDIMED Study Investigators. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013;368:1279–1290 76. Ros E. Dietary cis-monounsaturated fatty acids and metabolic control in type 2 diabetes. Am J Clin Nutr 2003;78(Suppl.):617S–625S 77. Forouhi NG, Imamura F, Sharp SJ, et al. Association of plasma phospholipid n-3 and n-6 polyunsaturated fatty acids with type 2 diabetes: the EPIC-InterAct Case-Cohort Study. PLoS Med 2016;13:e1002094 78. Wang DD, Li Y, Chiuve SE, et al. Association of specific dietary fats with total and causespecific mortality. JAMA Intern Med 2016;176: 1134–1145 79. Brehm BJ, Lattin BL, Summer SS, et al. Oneyear comparison of a high-monounsaturated fat diet with a high-carbohydrate diet in type 2 diabetes. Diabetes Care 2009;32:215–220

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80. Shai I, Schwarzfuchs D, Henkin Y, et al.; Dietary Intervention Randomized Controlled Trial (DIRECT) Group. Weight loss with a lowcarbohydrate, Mediterranean, or low-fat diet. N Engl J Med 2008;359:229–241 81. Brunerova L, Smejkalova V, Potockova J, Andel M. A comparison of the influence of a high-fat diet enriched in monounsaturated fatty acids and conventional diet on weight loss and metabolic parameters in obese non-diabetic and type 2 diabetic patients. Diabet Med 2007;24:533–540 82. Bloomfield HE, Koeller E, Greer N, MacDonald R, Kane R, Wilt TJ. Effects on health outcomes of a Mediterranean diet with no restriction on fat intake: a systematic review and meta-analysis. Ann Intern Med 2016;165:491–500 83. Harris WS, Mozaffarian D, Rimm E, et al. Omega-6 fatty acids and risk for cardiovascular disease: a science advisory from the American Heart Association Nutrition Subcommittee of the Council on Nutrition, Physical Activity, and Metabolism; Council on Cardiovascular Nursing; and Council on Epidemiology and Prevention. Circulation 2009;119:902–907 84. Crochemore ICC, Souza AFP, de Souza ACF, Rosado EL. v-3 polyunsaturated fatty acid supplementation does not influence body composition, insulin resistance, and lipemia in women with type 2 diabetes and obesity. Nutr Clin Pract 2012;27:553–560 85. Holman RR, Paul S, Farmer A, Tucker L, Stratton IM, Neil HA; Atorvastatin in Factorial with Omega-3 EE90 Risk Reduction in Diabetes Study Group. Atorvastatin in Factorial with Omega-3 EE90 Risk Reduction in Diabetes (AFORRD): a randomised controlled trial. Diabetologia 2009;52:50–59 86. Kromhout D, Geleijnse JM, de Goede J, et al. n-3 fatty acids, ventricular arrhythmia-related events, and fatal myocardial infarction in postmyocardial infarction patients with diabetes. Diabetes Care 2011;34:2515–2520 87. Bosch J, Gerstein HC, Dagenais GR, et al.; ORIGIN Trial Investigators. n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med 2012;367:309–318 88. Bray GA, Vollmer WM, Sacks FM, Obarzanek E, Svetkey LP, Appel LJ; DASH Collaborative Research Group. A further subgroup analysis of the effects of the DASH diet and three dietary sodium levels on blood pressure: results of the DASH-Sodium Trial. Am J Cardiol 2004; 94:222–227 89. Thomas MC, Moran J, Forsblom C, et al.; FinnDiane Study Group. The association between dietary sodium intake, ESRD, and allcause mortality in patients with type 1 diabetes. Diabetes Care 2011;34:861–866 90. Ekinci EI, Clarke S, Thomas MC, et al. Dietary salt intake and mortality in patients with type 2 diabetes. Diabetes Care 2011;34:703–709 91. Maillot M, Drewnowski A. A conflict between nutritionally adequate diets and meeting the 2010 dietary guidelines for sodium. Am J Prev Med 2012;42:174–179 92. Aroda VR, Edelstein SL, Goldberg RB, et al.; Diabetes Prevention Program Research Group. Long-term metformin use and vitamin B12 deficiency in the Diabetes Prevention Program Outcomes Study. J Clin Endocrinol Metab 2016;101:1754–1761

93. Allen RW, Schwartzman E, Baker WL, Coleman CI, Phung OJ. Cinnamon use in type 2 diabetes: an updated systematic review and meta-analysis. Ann Fam Med 2013;11:452–459 94. Mitri J, Pittas AG. Vitamin D and diabetes. Endocrinol Metab Clin North Am 2014;43:205–232 95. Mozaffarian D. Dietary and policy priorities for cardiovascular disease, diabetes, and obesity: a comprehensive review. Circulation 2016;133:187–225 96. Gardner C, Wylie-Rosett J, Gidding SS, et al.; American Heart Association Nutrition Committee of the Council on Nutrition, Physical Activity and Metabolism, Council on Arteriosclerosis, Thrombosis and Vascular Biology, Council on Cardiovascular Disease in the Young; American Diabetes Association. Nonnutritive sweeteners: current use and health perspectives: a scientific statement from the American Heart Association and the American Diabetes Association. Diabetes Care 2012;35:1798–1808 97. Boule´ NG, Haddad E, Kenny GP, Wells GA, Sigal RJ. Effects of exercise on glycemic control and body mass in type 2 diabetes mellitus: a meta-analysis of controlled clinical trials. JAMA 2001;286:1218–1227 98. Colberg SR, Riddell MC. Physical activity: regulation of glucose metabolism, clinicial management strategies, and weight control. In American Diabetes Association/JDRF Type 1 Diabetes Sourcebook. Peters A, Laffel L, Eds. Alexandria, VA, American Diabetes Association, 2013 99. Boule´ NG, Kenny GP, Haddad E, Wells GA, Sigal RJ. Meta-analysis of the effect of structured exercise training on cardiorespiratory fitness in type 2 diabetes mellitus. Diabetologia 2003;46:1071–1081 100. Rejeski WJ, Ip EH, Bertoni AG, et al.; Look AHEAD Research Group. Lifestyle change and mobility in obese adults with type 2 diabetes. N Engl J Med 2012;366:1209–1217 101. Colberg SR, Sigal RJ, Yardley JE, et al. Physical activity/exercise and diabetes: a position statement of the American Diabetes Association. Diabetes Care 2016;39:2065–2079 102. Janssen I, Leblanc AG. Systematic review of the health benefits of physical activity and fitness in school-aged children and youth. Int J Behav Nutr Phys Act 2010;7:40 103. Office of Disease Prevention and Health Promotion, U.S. Department of Health and Human Services. 2008 Physical Activity Guidelines for Americans [Internet]. Available from http:// www.health.gov/paguidelines/guidelines/ default.aspx. Accessed 1 October 2014 104. Katzmarzyk PT, Church TS, Craig CL, Bouchard C. Sitting time and mortality from all causes, cardiovascular disease, and cancer. Med Sci Sports Exerc 2009;41:998–1005 105. Dempsey PC, Larsen RN, Sethi P, et al. Benefits for type 2 diabetes of interrupting prolonged sitting with brief bouts of light walking or simple resistance activities. Diabetes Care 2016;39:964–972 106. Colberg SR, Sigal RJ, Fernhall B, et al.; American College of Sports Medicine; American Diabetes Association. Exercise and type 2 diabetes: the American College of Sports Medicine and the American Diabetes Association: joint position statement executive summary. Diabetes Care 2010;33:2692–2696

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107. Church TS, Blair SN, Cocreham S, et al. Effects of aerobic and resistance training on hemoglobin A1c levels in patients with type 2 diabetes: a randomized controlled trial. JAMA 2010;304:2253–2262 108. Bax JJ, Young LH, Frye RL, Bonow RO, Steinberg HO, Barrett EJ; American Diabetes Association. Screening for coronary artery disease in patients with diabetes. Diabetes Care 2007; 30:2729–2736 109. Peters AL, Laffel L; American Diabetes Association; JDRF. American Diabetes Association/ JDRF Type 1 Diabetes Sourcebook. Peters A, Laffel L, Eds. Alexandria, VA, American Diabetes Association, 2013 110. Colberg SR. Exercise and Diabetes: A Clinician’s Guide to Prescribing Physical Activity. 1st ed. Alexandria, VA, American Diabetes Association, 2013 111. Lemaster JW, Reiber GE, Smith DG, Heagerty PJ, Wallace C. Daily weight-bearing activity does not increase the risk of diabetic foot ulcers. Med Sci Sports Exerc 2003;35:1093–1099 112. Smith AG, Russell J, Feldman EL, et al. Lifestyle intervention for pre-diabetic neuropathy. Diabetes Care 2006;29:1294–1299 113. Spallone V, Ziegler D, Freeman R, et al.; Toronto Consensus Panel on Diabetic Neuropathy. Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev 2011;27:639–653 114. Pop-Busui R, Evans GW, Gerstein HC, et al.; Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of cardiac autonomic dysfunction on mortality risk in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Diabetes Care 2010;33:1578–1584 115. Suarez L, Barrett-Connor E. Interaction between cigarette smoking and diabetes mellitus in the prediction of death attributed to cardiovascular disease. Am J Epidemiol 1984;120:670– 675 116. Stanton CA, Keith DR, Gaalema DE, et al. Trends in tobacco use among US adults with chronic health conditions: National Survey on Drug Use and Health 2005-2013. Prev Med 2016;92:160–168 117. Jankowich M, Choudhary G, Taveira TH, Wu W-C. Age-, race-, and gender-specific prevalence of diabetes among smokers. Diabetes Res Clin Pract 2011;93:e101–e105

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118. Voulgari C, Katsilambros N, Tentolouris N. Smoking cessation predicts amelioration of microalbuminuria in newly diagnosed type 2 diabetes mellitus: a 1-year prospective study. Metabolism 2011;60:1456–1464 119. Ranney L, Melvin C, Lux L, McClain E, Lohr KN. Systematic review: smoking cessation intervention strategies for adults and adults in special populations. Ann Intern Med 2006;145: 845–856 120. Clair C, Rigotti NA, Porneala B, et al. Association of smoking cessation and weight change with cardiovascular disease among adults with and without diabetes. JAMA 2013;309:1014–1021 121. Schraufnagel DE, Blasi F, Drummond MB, et al.; Forum of International Respiratory Societies. Electronic cigarettes. A position statement of the Forum of International Respiratory Societies. Am J Respir Crit Care Med 2014;190:611–618 122. Bam TS, Bellew W, Berezhnova I, et al.; Tobacco Control Department International Union Against Tuberculosis and Lung Disease. Position statement on electronic cigarettes or electronic nicotine delivery systems. Int J Tuberc Lung Dis 2014;18:5–7 123. Bhatnagar A, Whitsel LP, Ribisl KM, et al.; American Heart Association Advocacy Coordinating Committee, Council on Cardiovascular and Stroke Nursing, Council on Clinical Cardiology, and Council on Quality of Care and Outcomes Research. Electronic cigarettes: a policy statement from the American Heart Association. Circulation 2014;130:1418–1436 124. Young-Hyman D, de Groot M, Hill-Briggs F, Gonzalez JS, Hood K, Peyrot M. Psychosocial care for people with diabetes: a position statement of the American Diabetes Association. Diabetes Care 2016;39:2126–2140 125. Anderson RJ, Grigsby AB, Freedland KE, et al. Anxiety and poor glycemic control: a meta-analytic review of the literature. Int J Psychiatry Med 2002;32:235–247 126. Delahanty LM, Grant RW, Wittenberg E, et al. Association of diabetes-related emotional distress with diabetes treatment in primary care patients with type 2 diabetes. Diabet Med 2007; 24:48–54 127. Anderson RJ, Freedland KE, Clouse RE, Lustman PJ. The prevalence of comorbid depression in adults with diabetes: a meta-analysis. Diabetes Care 2001;24:1069–1078

128. Kovacs Burns K, Nicolucci A, Holt RIG, et al.; DAWN2 Study Group. Diabetes Attitudes, Wishes and Needs second study (DAWN2Ô): cross-national benchmarking indicators for family members living with people with diabetes. Diabet Med 2013;30:778–788 129. Harkness E, Macdonald W, Valderas J, Coventry P, Gask L, Bower P. Identifying psychosocial interventions that improve both physical and mental health in patients with diabetes: a systematic review and meta-analysis. Diabetes Care 2010;33:926–930 130. Nicolucci A, Kovacs Burns K, Holt RIG, et al.; DAWN2 Study Group. Diabetes Attitudes, Wishes and Needs second study (DAWN2Ô): cross-national benchmarking of diabetesrelated psychosocial outcomes for people with diabetes. Diabet Med 2013;30:767–777 131. Fisher L, Hessler DM, Polonsky WH, Mullan J. When is diabetes distress clinically meaningful?: Establishing cut points for the Diabetes Distress Scale. Diabetes Care 2012;35: 259–264 132. Fisher L, Glasgow RE, Strycker LA. The relationship between diabetes distress and clinical depression with glycemic control among patients with type 2 diabetes. Diabetes Care 2010;33:1034–1036 133. Aikens JE. Prospective associations between emotional distress and poor outcomes in type 2 diabetes. Diabetes Care 2012;35:2472–2478 134. Fisher L, Skaff MM, Mullan JT, et al. Clinical depression versus distress among patients with type 2 diabetes: not just a question of semantics. Diabetes Care 2007;30:542–548 135. Snoek FJ, Bremmer MA, Hermanns N. Constructs of depression and distress in diabetes: time for an appraisal. Lancet Diabetes Endocrinol 2015;3:450–460 136. Gary TL, Safford MM, Gerzoff RB, et al. Perception of neighborhood problems, health behaviors, and diabetes outcomes among adults with diabetes in managed care: the Translating Research Into Action for Diabetes (TRIAD) study. Diabetes Care 2008;31:273–278 137. Beverly EA, Hultgren BA, Brooks KM, Ritholz MD, Abrahamson MJ, Weinger K. Understanding physicians’ challenges when treating type 2 diabetic patients’ social and emotional difficulties: a qualitative study. Diabetes Care 2011;34:1086–1088

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5. Prevention or Delay of Type 2 Diabetes

American Diabetes Association

Diabetes Care 2017;40(Suppl. 1):S44–S47 | DOI: 10.2337/dc17-S008

For guidelines related to screening for increased risk for type 2 diabetes (prediabetes), please refer to Section 2 “Classification and Diagnosis of Diabetes.”

5. PREVENTION OR DELAY OF TYPE 2 DIABETES

Recommendations c c

c

c

At least annual monitoring for the development of diabetes in those with prediabetes is suggested. E Patients with prediabetes should be referred to an intensive behavioral lifestyle intervention program modeled on the Diabetes Prevention Program to achieve and maintain 7% loss of initial body weight and increase moderateintensity physical activity (such as brisk walking) to at least 150 min/week. A Technology-assisted tools including Internet-based social networks, distance learning, DVD-based content, and mobile applications may be useful elements of effective lifestyle modification to prevent diabetes. B Given the cost-effectiveness of diabetes prevention, such intervention programs should be covered by third-party payers. B

Screening for prediabetes and type 2 diabetes through an informal assessment of risk factors (Table 2.3) or with an assessment tool, such as the American Diabetes Association risk test (Fig. 2.1), is recommended to guide providers on whether performing a diagnostic test for prediabetes (Table 2.4) and previously undiagnosed type 2 diabetes (Table 2.2) is appropriate (see Section 2 “Classification and Diagnosis of Diabetes”). Those determined to be at high risk for type 2 diabetes, including people with A1C 5.7–6.4% (39–47 mmol/mol), impaired glucose tolerance, or impaired fasting glucose, are ideal candidates for diabetes prevention efforts. At least annual monitoring for the development of diabetes in those with prediabetes is suggested. LIFESTYLE INTERVENTIONS The Diabetes Prevention Program

The strongest evidence for diabetes prevention comes from the Diabetes Prevention Program (DPP) (1). The DPP demonstrated that an intensive lifestyle intervention could reduce the incidence of type 2 diabetes by 58% over 3 years. Follow-up of three large studies of lifestyle intervention for diabetes prevention has shown sustained reduction in the rate of conversion to type 2 diabetes: 43% reduction at 20 years in the Da Qing study (2), 43% reduction at 7 years in the Finnish Diabetes Prevention Study (DPS) (1), and 34% reduction at 10 years in the U.S. Diabetes Prevention Program Outcomes Study (DPPOS) (3). The two major goals of the DPP intensive, behavioral, lifestyle intervention were to achieve and maintain a minimum of 7% weight loss and 150 min of physical activity per week similar in intensity to brisk walking. The DPP lifestyle intervention was a goal-based intervention: all participants were given the same weight loss and physical activity goals, but individualization was permitted in the specific methods used to achieve the goals (4). The 7% weight loss goal was selected because it was feasible to achieve and maintain and likely to lessen the risk of developing diabetes. Participants were encouraged to achieve the 7% weight loss during the first 6 months of the intervention. The recommended pace of weight loss was 1–2 lb/week. Calorie goals were calculated by estimating the daily calories needed to maintain the participant’s initial weight and subtracting 500–1,000 calories/day (depending on initial body

Suggested citation: American Diabetes Association. Prevention or delay of type 2 diabetes. Sec. 5. In Standards of Medical Care in Diabetesd2017. Diabetes Care 2017;40(Suppl. 1):S44–S47 © 2017 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals .org/content/license.

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weight). The initial focus was on reducing total dietary fat. After several weeks, the concept of calorie balance and the need to restrict calories as well as fat was introduced (4). The goal for physical activity was selected to approximate at least 700 kcal/week expenditure from physical activity. For ease of translation, this goal was described as at least 150 min of moderateintensity physical activity per week similar in intensity to brisk walking. Participants were encouraged to distribute their activity throughout the week with a minimum frequency of three times per week with at least 10 min per session. A maximum of 75 min of strength training could be applied toward the total 150 min/week physical activity goal (4). To implement the weight loss and physical activity goals, the DPP used an individual model of treatment rather than a group-based approach. This choice was based on a desire to intervene before participants had the possibility of developing diabetes or losing interest in the program. The individual approach also allowed for tailoring of interventions to reflect the diversity of the population (4). The DPP intervention was administered as a structured core curriculum followed by a more flexible maintenance program of individual sessions, group classes, motivational campaigns, and restart opportunities. The 16-session core curriculum was completed within the first 24 weeks of the program and included sections on lowering calories, increasing physical activity, self-monitoring, maintaining healthy lifestyle behaviors, and psychological, social, and motivational challenges. For further details on the core curriculum sessions, refer to ref. 4. Nutrition

Reducing caloric intake is of paramount importance for those at high risk for developing type 2 diabetes, though recent evidence suggests that the quality of fats consumed in the diet is more important than the total quantity of dietary fat (5–7). For example, the Mediterranean diet, which is relatively high in monounsaturated fats, may help to prevent type 2 diabetes (8–10). Whereas overall healthy low-calorie eating patterns should be encouraged, there is also some evidence that particular dietary components impact diabetes risk. Data suggest that whole

Prevention or Delay of Type 2 Diabetes

grains may help to prevent type 2 diabetes (11). Higher intakes of nuts (12), berries (13), yogurt (14), coffee, and tea (15) are associated with reduced diabetes risk. Conversely, red meats and sugar-sweetened beverages are associated with an increased risk of type 2 diabetes (6). As is the case for those with diabetes, individualized medical nutrition therapy (see Section 4 “Lifestyle Management” for more detailed information) is effective in lowering A1C in individuals diagnosed with prediabetes (16). Physical Activity

Just as 150 min/week of moderateintensity physical activity, such as brisk walking, showed beneficial effects in those with prediabetes (17), moderateintensity physical activity has been shown to improve insulin sensitivity and reduce abdominal fat in children and young adults (18,19). On the basis of these findings, providers are encouraged to promote a DPP-style program, including its focus on physical activity, to all individuals who have been identified to be at an increased risk of type 2 diabetes. In addition to aerobic activity, an exercise regimen designed to prevent diabetes may include resistance training (1,20). Breaking up prolonged sedentary time may also be encouraged, as it is associated with moderately lower postprandial glucose levels (21,22). The preventative effects of exercise appear to extend to the prevention of gestational diabetes mellitus (GDM) (23).

begun to certify electronic and mobile health-based modalities as effective vehicles for DPP-based interventions that may be considered alongside more traditional face-to-face and coach-driven programs. A recent study showed that an all-mobile approach to administering DPP content can be effective as a prevention tool, at least over the short term, in overweight and obese individuals at high risk for diabetes (32). Cost-effectiveness

A cost-effectiveness model suggested that the lifestyle intervention used in the DPP was cost-effective (33). Actual cost data from the DPP and DPPOS confirmed this (34). Group delivery of DPP content in community settings has the potential to reduce overall program costs while still producing weight loss and diabetes risk reduction (35,36). The CDC helps to coordinate the National Diabetes Prevention Program, a resource designed to bring evidence-based lifestyle change programs for preventing type 2 diabetes to communities (http://www.cdc.gov/diabetes/ prevention/index.htm). On 7 July 2016, the Centers for Medicare and Medicaid Services (CMS) proposed expanded Medicare reimbursement coverage for DPP programs in an effort to expand preventive services using a cost-effective model (http://www.cms.gov/site-search/searchresults.html?q5diabetes%20prevention). PHARMACOLOGIC INTERVENTIONS Recommendations c

Technology Assistance to Deliver Lifestyle Interventions

New information technology platforms may effectively deliver the core components of the DPP (24–26). Initial studies have validated DVD-based content delivery (27). This has been corroborated in a primary care patient population (28). Recent studies support content delivery through virtual small groups (29), Internet-driven social networks (30,31), cellular phones, and other mobile devices. Mobile applications for weight loss and diabetes prevention have been validated for their ability to reduce A1C in the setting of prediabetes (31). The Centers for Disease Control and Prevention (CDC) Diabetes Prevention Recognition Program (DPRP) (http://www.cdc.gov/diabetes/ prevention/recognition/index.htm) has

c

Metformin therapy for prevention of type 2 diabetes should be considered in those with prediabetes, especially for those with BMI $35 kg/m2, those aged ,60 years, women with prior gestational diabetes mellitus, and/or those with rising A1C despite lifestyle intervention. A Long-term use of metformin may be associated with biochemical vitamin B12 deficiency, and periodic measurement of vitamin B12 levels should be considered in metformin-treated patients, especially in those with anemia or peripheral neuropathy. B

Pharmacologic agents including metformin, a-glucosidase inhibitors, orlistat, glucagon-like peptide 1 (GLP-1) receptor

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Prevention or Delay of Type 2 Diabetes

agonists, and thiazolidinediones have each been shown to decrease incident diabetes to various degrees in those with prediabetes. Metformin has the strongest evidence base and demonstrated longterm safety as pharmacologic therapy for diabetes prevention (37). For other drugs, cost, side effects, and durable efficacy require consideration. Metformin was less effective than lifestyle modification in the DPP and DPPOS but may be cost-saving over a 10-year period (34). It was as effective as lifestyle modification in participants with BMI $35 kg/m 2 but not significantly better than placebo in those over 60 years of age (17). In the DPP, for women with history of GDM, metformin and intensive lifestyle modification led to an equivalent 50% reduction in diabetes risk (38), and both interventions remained highly effective during a 10-year follow-up period (39). Metformin should be recommended as an option for high-risk individuals (e.g., those with a history of GDM, those who are very obese, and/or those with relatively more hyperglycemia) and/or those with rising A1C despite lifestyle intervention. Consider monitoring B12 levels in those taking metformin chronically to check for possible deficiency (see Section 8 “Pharmacologic Approaches to Glycemic Treatment” for more details). PREVENTION OF CARDIOVASCULAR DISEASE Recommendation c

Screening for and treatment of modifiable risk factors for cardiovascular disease is suggested for those with prediabetes. B

People with prediabetes often have other cardiovascular risk factors, including hypertension and dyslipidemia, and are at increased risk for cardiovascular disease (40). Although treatment goals for people with prediabetes are the same as for the general population, increased vigilance is warranted to identify and treat these and other cardiovascular risk factors (e.g., smoking). DIABETES SELF-MANAGEMENT EDUCATION AND SUPPORT Recommendation c

Diabetes self-management education and support programs may be

Diabetes Care Volume 40, Supplement 1, January 2017

appropriate venues for people with prediabetes to receive education and support to develop and maintain behaviors that can prevent or delay the development of diabetes. B As for those with established diabetes, the standards for diabetes self-management education and support (see Section 4 “Lifestyle Management”) can also apply to people with prediabetes. Currently, there are significant barriers to the provision of education and support to those with prediabetes. However, the strategies for supporting successful behavior change, and the healthy behaviors recommended for people with prediabetes are comparable to those for diabetes. Although reimbursement remains a barrier, studies show that providers of diabetes selfmanagement education and support are particularly well equipped to assist people with prediabetes in developing and maintaining behaviors that can prevent or delay the development of diabetes (16,41).

References 1. Lindstr¨om J, Ilanne-Parikka P, Peltonen M, et al.; Finnish Diabetes Prevention Study Group. Sustained reduction in the incidence of type 2 diabetes by lifestyle intervention: follow-up of the Finnish Diabetes Prevention Study. Lancet 2006;368:1673–1679 2. Li G, Zhang P, Wang J, et al. The long-term effect of lifestyle interventions to prevent diabetes in the China Da Qing Diabetes Prevention Study: a 20-year follow-up study. Lancet 2008; 371:1783–1789 3. Knowler WC, Fowler SE, Hamman RF, et al.; Diabetes Prevention Program Research Group. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet 2009;374:1677–1686 4. Diabetes Prevention Program (DPP) Research Group. The Diabetes Prevention Program (DPP): description of lifestyle intervention. Diabetes Care 2002;25:2165–2171 5. Jacobs S, Harmon BE, Boushey CJ, et al. A priori-defined diet quality indexes and risk of type 2 diabetes: the Multiethnic Cohort. Diabetologia 2015;58:98–112 6. Ley SH, Hamdy O, Mohan V, Hu FB. Prevention and management of type 2 diabetes: dietary components and nutritional strategies. Lancet 2014;383:1999–2007 7. Chiuve SE, Fung TT, Rimm EB, et al. Alternative dietary indices both strongly predict risk of chronic disease. J Nutr 2012;142:1009–1018 8. Salas-Salvado´ J, Bullo´ M, Babio N, et al.; PREDIMED Study Investigators. Reduction in the incidence of type 2 diabetes with the Mediterranean diet: results of the PREDIMED-Reus nutrition intervention randomized trial. Diabetes Care 2011;34:14–19

9. Salas-Salvado´ J, Guasch-Ferre´ M, Lee CH, Estruch R, Clish CB, Ros E. Protective effects of the Mediterranean diet on type 2 diabetes and metabolic syndrome. J Nutr 2016;jn218487 10. Bloomfield HE, Koeller E, Greer N, MacDonald R, Kane R, Wilt TJ. Effects on health outcomes of a Mediterranean diet with no restriction on fat intake: a systematic review and meta-analysis. Ann Intern Med 2016;165:491– 500 11. Montonen J, Knekt P, J¨arvinen R, Aromaa A, Reunanen A. Whole-grain and fiber intake and the incidence of type 2 diabetes. Am J Clin Nutr 2003;77:622–629 12. Afshin A, Micha R, Khatibzadeh S, Mozaffarian D. Consumption of nuts and legumes and risk of incident ischemic heart disease, stroke, and diabetes: a systematic review and meta-analysis. Am J Clin Nutr 2014;100: 278–288 13. Mursu J, Virtanen JK, Tuomainen T-P, Nurmi T, Voutilainen S. Intake of fruit, berries, and vegetables and risk of type 2 diabetes in Finnish men: the Kuopio Ischaemic Heart Disease Risk Factor Study. Am J Clin Nutr 2014;99:328–333 14. Chen M, Sun Q, Giovannucci E, et al. Dairy consumption and risk of type 2 diabetes: 3 cohorts of US adults and an updated metaanalysis. BMC Med 2014;12:215 15. Mozaffarian D. Dietary and policy priorities for cardiovascular disease, diabetes, and obesity: a comprehensive review. Circulation 2016; 133:187–225 16. Parker AR, Byham-Gray L, Denmark R, Winkle PJ. The effect of medical nutrition therapy by a registered dietitian nutritionist in patients with prediabetes participating in a randomized controlled clinical research trial. J Acad Nutr Diet 2014;114:1739–1748 17. Knowler WC, Barrett-Connor E, Fowler SE, et al.; Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393–403 18. Fedewa MV, Gist NH, Evans EM, Dishman RK. Exercise and insulin resistance in youth: a meta-analysis. Pediatrics 2014;133:e163–e174 19. Davis CL, Pollock NK, Waller JL, et al. Exercise dose and diabetes risk in overweight and obese children: a randomized controlled trial. JAMA 2012;308:1103–1112 20. Sigal RJ, Alberga AS, Goldfield GS, et al. Effects of aerobic training, resistance training, or both on percentage body fat and cardiometabolic risk markers in obese adolescents: the healthy eating aerobic and resistance training in youth randomized clinical trial. JAMA Pediatr 2014;168:1006–1014 21. Thorp AA, Kingwell BA, Sethi P, Hammond L, Owen N, Dunstan DW. Alternating bouts of sitting and standing attenuate postprandial glucose responses. Med Sci Sports Exerc 2014;46: 2053–2061 22. Healy GN, Dunstan DW, Salmon J, et al. Breaks in sedentary time: beneficial associations with metabolic risk. Diabetes Care 2008; 31:661–666 23. Russo LM, Nobles C, Ertel KA, Chasan-Taber L, Whitcomb BW. Physical activity interventions in pregnancy and risk of gestational diabetes mellitus: a systematic review and meta-analysis. Obstet Gynecol 2015;125:576–582

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24. Levine DM, Savarimuthu S, Squires A, Nicholson J, Jay M. Technology-assisted weight loss interventions in primary care: a systematic review. J Gen Intern Med 2015;30:107–117 25. Allen JK, Stephens J, Patel A. Technologyassisted weight management interventions: systematic review of clinical trials. Telemed J E Health 2014;20:1103–1120 26. Oldenburg B, Taylor CB, O’Neil A, Cocker F, Cameron LD. Using new technologies to improve the prevention and management of chronic conditions in populations. Annu Rev Public Health 2015;36:483–505 27. Kramer MK, Kriska AM, Venditti EM, et al. A novel approach to diabetes prevention: evaluation of the Group Lifestyle Balance program delivered via DVD. Diabetes Res Clin Pract 2010; 90:e60–e63 28. Ma J, Yank V, Xiao L, et al. Translating the Diabetes Prevention Program lifestyle intervention for weight loss into primary care: a randomized trial. JAMA Intern Med 2013;173: 113–121 29. Azar KM, Aurora M, Wang EJ, Muzaffar A, Pressman A, Palaniappan LP. Virtual small groups for weight management: an innovative delivery mechanism for evidence-based lifestyle interventions among obese men. Transl Behav Med 2015;5:37–44 30. Sepah SC, Jiang L, Peters AL. Translating the Diabetes Prevention Program into an online

Prevention or Delay of Type 2 Diabetes

social network: validation against CDC standards. Diabetes Educ 2014;40:435–443 31. Sepah SC, Jiang L, Peters AL. Long-term outcomes of a Web-based diabetes prevention program: 2-year results of a single-arm longitudinal study. J Med Internet Res 2015;17:e92 32. Michaelides A, Raby C, Wood M, Farr K, Toro-Ramos T. Weight loss efficacy of a novel mobile Diabetes Prevention Program delivery platform with human coaching. BMJ Open Diabetes Res Care 2016;4:e000264 33. Herman WH, Hoerger TJ, Brandle M, et al.; Diabetes Prevention Program Research Group. The cost-effectiveness of lifestyle modification or metformin in preventing type 2 diabetes in adults with impaired glucose tolerance. Ann Intern Med 2005;142:323–332 34. Diabetes Prevention Program Research Group. The 10-year cost-effectiveness of lifestyle intervention or metformin for diabetes prevention: an intent-to-treat analysis of the DPP/DPPOS. Diabetes Care 2012;35:723–730 35. Ackermann RT, Finch EA, Brizendine E, Zhou H, Marrero DG. Translating the Diabetes Prevention Program into the community: the DEPLOY pilot study. Am J Prev Med 2008;35: 357–363 36. Balk EM, Earley A, Raman G, Avendano EA, Pittas AG, Remington PL. Combined diet and physical activity promotion programs to prevent type 2 diabetes among persons at increased risk: a

systematic review for the Community Preventive Services Task. Ann Intern Med 2015;163:437–451 37. Diabetes Prevention Program Research Group. Long-term safety, tolerability, and weight loss associated with metformin in the Diabetes Prevention Program Outcomes Study. Diabetes Care 2012;35:731–737 38. Ratner RE, Christophi CA, Metzger BE, et al.; Diabetes Prevention Program Research Group. Prevention of diabetes in women with a history of gestational diabetes: effects of metformin and lifestyle interventions. J Clin Endocrinol Metab 2008;93:4774–4779 39. Aroda VR, Christophi CA, Edelstein SL, et al.; Diabetes Prevention Program Research Group. The effect of lifestyle intervention and metformin on preventing or delaying diabetes among women with and without gestational diabetes: the Diabetes Prevention Program Outcomes Study 10-year follow-up. J Clin Endocrinol Metab 2015;100:1646–1653 40. Ford ES, Zhao G, Li C. Pre-diabetes and the risk for cardiovascular disease: a systematic review of the evidence. J Am Coll Cardiol 2010; 55:1310–1317 41. Butcher MK, Vanderwood KK, Hall TO, Gohdes D, Helgerson SD, Harwell TS. Capacity of diabetes education programs to provide both diabetes self-management education and to implement diabetes prevention services. J Public Health Manag Pract 2011;17:242–247

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6. Glycemic Targets

American Diabetes Association

Diabetes Care 2017;40(Suppl. 1):S48–S56 | DOI: 10.2337/dc17-S009

ASSESSMENT OF GLYCEMIC CONTROL

Patient self-monitoring of blood glucose (SMBG) and A1C are available to health care providers and patients to assess the effectiveness and safety of the management plan on glycemic control. Continuous glucose monitoring (CGM) also has an important role in assessing the effectiveness and safety of treatment in subgroups of patients with type 1 diabetes and in selected patients with type 2 diabetes. Recommendations

6. GLYCEMIC TARGETS

c

c

c

c

c

c c c c

Most patients using intensive insulin regimens (multiple-dose insulin or insulin pump therapy) should perform self-monitoring of blood glucose (SMBG) prior to meals and snacks, at bedtime, occasionally postprandially, prior to exercise, when they suspect low blood glucose, after treating low blood glucose until they are normoglycemic, and prior to critical tasks such as driving. B When prescribed as part of a broad educational program, SMBG may help to guide treatment decisions and/or self-management for patients taking less frequent insulin injections B or noninsulin therapies. E When prescribing SMBG, ensure that patients receive ongoing instruction and regular evaluation of SMBG technique, SMBG results, and their ability to use SMBG data to adjust therapy. E When used properly, continuous glucose monitoring (CGM) in conjunction with intensive insulin regimens is a useful tool to lower A1C in selected adults (aged $25 years) with type 1 diabetes. A Although the evidence for A1C lowering is less strong in children, teens, and younger adults, CGM may be helpful in these groups. Success correlates with adherence to ongoing use of the device. B CGM may be a useful tool in those with hypoglycemia unawareness and/or frequent hypoglycemic episodes. C Given the variable adherence to CGM, assess individual readiness for continuing CGM use prior to prescribing. E When prescribing CGM, robust diabetes education, training, and support are required for optimal CGM implementation and ongoing use. E People who have been successfully using CGM should have continued access after they turn 65 years of age. E

Self-monitoring of Blood Glucose

Major clinical trials of insulin-treated patients have included SMBG as part of the multifactorial interventions to demonstrate the benefit of intensive glycemic control on diabetes complications. SMBG is thus an integral component of effective therapy (1). SMBG allows patients to evaluate their individual response to therapy and assess whether glycemic targets are being achieved. Integrating SMBG results into diabetes management can be a useful tool for guiding medical nutrition therapy and physical activity, preventing hypoglycemia, and adjusting medications (particularly prandial insulin doses). Among patients with type 1 diabetes, there is a correlation between greater SMBG frequency and lower A1C (2). The patient’s specific needs and goals should dictate SMBG frequency and timing. Optimization

SMBG accuracy is dependent on the instrument and user, so it is important to evaluate each patient’s monitoring technique, both initially and at regular intervals thereafter. Optimal use of SMBG requires proper review and interpretation of the data, by both the patient and the provider. Among patients who check their blood

Suggested citation: American Diabetes Association. Glycemic targets. Sec. 6. In Standards of Medical Care in Diabetesd2017. Diabetes Care 2017;40(Suppl. 1):S48–S56 © 2017 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals .org/content/license.

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glucose at least once daily, many report taking no action when results are high or low. In a yearlong study of insulin-naive patients with suboptimal initial glycemic control, a group trained in structured SMBG (a paper tool was used at least quarterly to collect and interpret 7-point SMBG profiles taken on 3 consecutive days) reduced their A1C by 0.3 percentage points more than the control group (3). Patients should be taught how to use SMBG data to adjust food intake, exercise, or pharmacological therapy to achieve specific goals. The ongoing need for and frequency of SMBG should be reevaluated at each routine visit to avoid overuse (4–6). SMBG is especially important for insulin-treated patients to monitor for and prevent asymptomatic hypoglycemia and hyperglycemia. For Patients on Intensive Insulin Regimens

Most patients using intensive insulin regimens (multiple-dose insulin or insulin pump therapy) should perform SMBG prior to meals and snacks, at bedtime, occasionally postprandially, prior to exercise, when they suspect low blood glucose, after treating low blood glucose until they are normoglycemic, and prior to critical tasks such as driving. For many patients, this will require testing 6–10 (or more) times daily, although individual needs may vary. A database study of almost 27,000 children and adolescents with type 1 diabetes showed that, after adjustment for multiple confounders, increased daily frequency of SMBG was significantly associated with lower A1C (–0.2% per additional test per day) and with fewer acute complications. For Patients Using Basal Insulin or Oral Agents

The evidence is insufficient regarding when to prescribe SMBG and how often testing is needed for patients who do not use intensive insulin regimens, such as those with type 2 diabetes using oral agents or basal insulin. For patients using basal insulin, lowering of A1C has been demonstrated for those who adjust their dose to attain a fasting glucose as determined by SMBG within a targeted range (7,8). For individuals with type 2 diabetes on less intensive insulin therapy, more frequent SMBG (e.g., fasting, before/after meals) may be helpful, as increased frequency is associated with meeting A1C targets (9). Several randomized trials have called into question the clinical utility and costeffectiveness of routine SMBG in noninsulintreated patients (10–12). Meta-analyses have suggested that SMBG can reduce A1C

Glycemic Targets

by 0.25–0.3% at 6 months (10,13), but the effect was attenuated at 12 months in one analysis (13). A key consideration is that performing SMBG alone does not lower blood glucose levels. To be useful, the information must be integrated into clinical and selfmanagement plans. Continuous Glucose Monitoring

CGM measures interstitial glucose (which correlates well with plasma glucose) and includes sophisticated alarms for hypo- and hyperglycemic excursions. The U.S. Food and Drug Administration (FDA) has not yet approved these devices as a sole device to monitor glucose. CGMs require calibration with SMBG, and SMBG is still required to make treatment decisions. An FDA advisory panel recently recommended approval for use of one CGM device alone (without SMBG) to make treatment decisions, but the final FDA decision is still pending. A 26-week randomized trial of 322 patients with type 1 diabetes showed that adults aged $25 years using intensive insulin therapy and CGM experienced a 0.5% reduction in A1C (from ;7.6% to 7.1% [;60 mmol/mol to 54 mmol/mol]) compared with those using intensive insulin therapy with SMBG (14). CGM use in those aged ,25 years (children, teens, and adults) did not result in significant A1C lowering, and there was no significant difference in hypoglycemia in any group. The greatest predictor of A1C lowering for all age-groups was frequency of sensor use, which was highest in those aged $25 years and lower in younger age-groups. Other small, short-term studies have demonstrated similar A1C reductions using CGM compared with SMBG in adults with A1C levels $7% (53 mmol/mol) (15,16). A registry study of 17,317 participants confirmed that more frequent CGM use is associated with lower A1C (17), whereas another study showed that children with .70% sensor use (i.e., $5 days per week) missed fewer school days (18). Small randomized controlled trials in adults and children with baseline A1C ,7.0–7.5% (53– 58 mmol/mol) have confirmed favorable outcomes including a reduced frequency of hypoglycemia (defined as a blood glucose level ,70 mg/dL [3.9 mmol/L]) and maintaining A1C ,7% (53 mmol/mol) during the study period in groups using CGM, suggesting that CGM may provide further benefit for individuals with type 1 diabetes who already have good glycemic control (19–21).

A meta-analysis suggests that compared with SMBG, CGM is associated with short-term A1C lowering of ;0.26% in insulin-treated patients (22). The long-term effectiveness of CGM needs to be determined. This technology may be particularly useful in insulin-treated patients with hypoglycemia unawareness and/or frequent hypoglycemic episodes, although studies have not shown consistent reductions in severe hypoglycemia (22–24). A CGM device equipped with an automatic low glucose suspend feature has been approved by the FDA. The Automation to Simulate Pancreatic Insulin Response (ASPIRE) trial of 247 patients with type 1 diabetes and documented nocturnal hypoglycemia showed that sensor-augmented insulin pump therapy with a low glucose suspend function significantly reduced nocturnal hypoglycemia over 3 months without increasing A1C levels (25). These devices may offer the opportunity to reduce hypoglycemia for those with a history of nocturnal hypoglycemia. In September 2016, the FDA approved the first hybrid closed-loop system, which may be considered as an option in those already on an insulin pump when it is available on the market. The safety of hybrid closed-loop systems has been supported in the literature (26). Due to variable adherence, optimal CGM use requires an assessment of individual readiness for the technology as well as initial and ongoing education and support (17,27). Additionally, providers need to provide robust diabetes education, training, and support for optimal CGM implementation and ongoing use. As people with type 1 or type 2 diabetes are living longer healthier lives, individuals who have been successfully using CGM should have continued access to these devices after they turn 65 years of age (28). A1C TESTING Recommendations c

c

c

Perform the A1C test at least two times a year in patients who are meeting treatment goals (and who have stable glycemic control). E Perform the A1C test quarterly in patients whose therapy has changed or who are not meeting glycemic goals. E Point-of-care testing for A1C provides the opportunity for more timely treatment changes. E

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A1C reflects average glycemia over approximately 3 months and has strong predictive value for diabetes complications (29,30). Thus, A1C testing should be performed routinely in all patients with diabetesdat initial assessment and as part of continuing care. Measurement approximately every 3 months determines whether patients’ glycemic targets have been reached and maintained. The frequency of A1C testing should depend on the clinical situation, the treatment regimen, and the clinician’s judgment. The use of point-of-care A1C testing may provide an opportunity for more timely treatment changes during encounters between patients and providers. Patients with type 2 diabetes with stable glycemia well within target may do well with A1C testing only twice per year. Unstable or intensively managed patients (e.g., pregnant women with type 1 diabetes) may require testing more frequently than every 3 months (31). A1C Limitations

The A1C test is an indirect measure of average glycemia and, as such, is subject to limitations. Conditions that affect red blood cell turnover (hemolysis, blood loss) and hemoglobin variants must be considered, particularly when the A1C result does not correlate with the patient’s SMBG levels. For patients in whom A1C/estimated average glucose (eAG) and measured blood glucose appear discrepant, clinicians should consider the possibilities of altered red blood cell turnover. Options for monitoring include more frequent and/or different timing of SMBG or CGM use. Other measures of average glycemia such as fructosamine and 1,5anhydroglucitol (1,5-AG) are available, but their translation into average glucose levels and their prognostic significance are not as clear as for A1C (see Section 2 “Classification and Diagnosis of Diabetes”). A1C does not provide a measure of glycemic variability or hypoglycemia. For patients prone to glycemic variability, especially patients with type 1 diabetes or type 2 diabetes with severe insulin deficiency, glycemic control is best evaluated by the combination of results from SMBG and A1C. A1C may also confirm the accuracy of the patient’s meter (or the patient’s reported

Diabetes Care Volume 40, Supplement 1, January 2017

SMBG results) and the adequacy of the SMBG testing schedule. A1C and Mean Glucose

Table 6.1 shows the correlation between A1C levels and mean glucose levels based on two studies: the international A1C-Derived Average Glucose (ADAG) study, which assessed the correlation between A1C and frequent SMBG and CGM in 507 adults (83% non-Hispanic whites) with type 1, type 2, and no diabetes (32), and an empirical study of the average blood glucose levels at premeal, postmeal, and bedtime associated with specified A1C levels using data from the ADAG trial (27). The American Diabetes Association (ADA) and the American Association for Clinical Chemistry have determined that the correlation (r 5 0.92) in the ADAG trial is strong enough to justify reporting both the A1C result and the eAG result when a clinician orders the A1C test (Table 6.1). Clinicians should note that the mean plasma glucose numbers in the table are based on ;2,700 readings per A1C in the ADAG trial. A1C Differences in Ethnic Populations and Children

In the ADAG study, there were no significant differences among racial and ethnic groups in the regression lines between A1C and mean glucose, although the study was underpowered to detect a difference and there was a trend toward a difference between the African/African American and non-Hispanic white cohorts, with higher values observed in Africans/African Americans compared with non-Hispanic whites. Other studies have also demonstrated higher A1C levels in African Amercans than in whites (33). A small study comparing A1C to CGM data in children with type 1 diabetes found a highly statistically significant correlation between A1C and mean blood glucose, although the correlation (r 5 0.7) was significantly lower than in the ADAG trial (34). Whether there are clinically meaningful differences in how A1C relates to average glucose in children or in different ethnicities is an area for further study (35,36). For the time being, the question has not led to different recommendations about testing A1C or to different interpretations of the clinical meaning of given levels of A1C in those populations. Until further evidence is

available, it seems prudent to establish A1C goals in these populations with consideration of both individualized SMBG and A1C results. A1C GOALS

For glycemic goals in children, please refer to Section 12 “Children and Adolescents.” For glycemic goals in pregnant women, please refer to Section 13 “Management of Diabetes in Pregnancy.” Recommendations c

c

c

A reasonable A1C goal for many nonpregnant adults is ,7% (53 mmol/mol). A Providers might reasonably suggest more stringent A1C goals (such as ,6.5% [48 mmol/mol]) for selected individual patients if this can be achieved without significant hypoglycemia or other adverse effects of treatment (i.e., polypharmacy). Appropriate patients might include those with short duration of diabetes, type 2 diabetes treated with lifestyle or metformin only, long life expectancy, or no significant cardiovascular disease. C Less stringent A1C goals (such as ,8% [64 mmol/mol]) may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid conditions, or long-standing diabetes in whom the goal is difficult to achieve despite diabetes self-management education, appropriate glucose monitoring, and effective doses of multiple glucose-lowering agents including insulin. B

A1C and Microvascular Complications

Hyperglycemia defines diabetes, and glycemic control is fundamental to diabetes management. The Diabetes Control and Complications Trial (DCCT) (1), a prospective randomized controlled trial of intensive versus standard glycemic control in patients with type 1 diabetes, showed definitively that better glycemic control is associated with significantly decreased rates of development and progression of microvascular (retinopathy [37] and diabetic kidney disease) and neuropathic complications. Follow-up of the

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Glycemic Targets

Table 6.1—Mean glucose levels for specified A1C levels (27,32) A1C % (mmol/mol)

Mean plasma glucose*

Mean bedtime glucose

mg/dL

mmol/L

mg/dL

mmol/L

mg/dL

mmol/L

5.5–6.49 (37–47)

122 (117–127)

6.8 (6.5–7.0)

118 (115–121)

6.5 (6.4–6.7)

144 (139–148)

8.0 (7.7–8.2)

136 (131–141)

7.5 (7.3–7.8)

6.5–6.99 (47–53)

142 (135–150)

7.9 (7.5–8.3)

139 (134–144)

7.7 (7.4–8.0)

164 (159–169)

9.1 (8.8–9.4)

153 (145–161)

8.5 (8.0–8.9)

7.0–7.49 (53–58)

152 (143–162)

8.4 (7.9–9.0)

152 (147–157)

8.4 (8.2–8.7)

176 (170–183)

9.8 (9.4–10.2)

177 (166–188)

9.8 (9.2–10.4)

7.5–7.99 (58–64)

167 (157–177)

9.3 (8.7–9.8)

155 (148–161)

8.6 (8.2–8.9)

189 (180–197)

10.5 175 (10.0–10.9) (163–188)

9.7 (9.0–10.4)

178 9.9 179 (164–192) (9.1–10.7) (167–191)

9.9 (9.3–10.6)

206 (195–217)

11.4 222 12.3 (10.8–12.0) (197–248) (10.9–13.8)

8 (64)

7.0 (5.5–8.5)

Mean postmeal glucose

mmol/L

7 (53)

mmol/L

126 (100–152)

Mean premeal glucose

mg/dL

6 (42)

mg/dL

Mean fasting glucose

154 (123–185)

183 (147–217)

8.6 (6.8–10.3)

10.2 (8.1–12.1)

8.0–8.5 (64–69) 9 (75)

212 (170–249)

11.8 (9.4–13.9)

10 (86)

240 13.4 (193–282) (10.7–15.7)

11 (97)

269 14.9 (217–314) (12.0–17.5)

12 (108)

298 16.5 (240–347) (13.3–19.3)

Data in parentheses represent 95% CI, unless otherwise noted. A calculator for converting A1C results into eAG, in either mg/dL or mmol/L, is available at http://professional.diabetes.org/eAG. *These estimates are based on ADAG data of ;2,700 glucose measurements over 3 months per A1C measurement in 507 adults with type 1, type 2, and no diabetes. The correlation between A1C and average glucose was 0.92 (32).

DCCT cohorts in the Epidemiology of Diabetes Interventions and Complications (EDIC) study (38) demonstrated persistence of these microvascular benefits despite the fact that the glycemic separation between the treatment groups diminished and disappeared during follow-up. The Kumamoto Study (39) and UK Prospective Diabetes Study (UKPDS) (40,41) confirmed that intensive glycemic control significantly decreased rates of microvascular and neuropathic complications in patients with type 2 diabetes. Long-term follow-up of the UKPDS cohorts showed enduring effects of early glycemic control on most microvascular complications (42). Therefore, achieving A1C targets of ,7% (53 mmol/mol) has been shown to reduce microvascular complications of diabetes. Epidemiological analyses of the DCCT (1) and UKPDS (43) demonstrate a curvilinear relationship between A1C and microvascular complications. Such analyses suggest that, on a population level, the greatest number of complications will be averted by taking patients from very poor control to fair/good control. These analyses also

suggest that further lowering of A1C from 7% to 6% [53 mmol/mol to 42 mmol/mol] is associated with further reduction in the risk of microvascular complications, although the absolute risk reductions become much smaller. Given the substantially increased risk of hypoglycemia in type 1 diabetes trials and with polypharmacy in type 2 diabetes, the risks of lower glycemic targets outweigh the potential benefits on microvascular complications.

and patient preferences, select patients, especially those with little comorbidity and long life expectancy, may benefit from adopting more intensive glycemic targets (e.g., A1C target ,6.5% [48 mmol/mol]) as long as significant hypoglycemia does not become a barrier.

ACCORD, ADVANCE, and VADT

Cardiovascular disease (CVD) is a more common cause of death than microvascular complications in populations with diabetes. There is evidence for a cardiovascular benefit of intensive glycemic control after long-term follow-up of cohorts treated early in the course of type 1 and type 2 diabetes. In the DCCT, there was a trend toward lower risk of CVD events with intensive control. In the 9-year post-DCCT follow-up of the EDIC cohort, participants previously randomized to the intensive arm had a significant 57% reduction in the risk of nonfatal myocardial infarction (MI), stroke, or cardiovascular death compared with those previously randomized to the

Three landmark trials (Action to Control Cardiovascular Risk in Diabetes [ACCORD], Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation [ADVANCE], and Veterans Affairs Diabetes Trial [VADT]) showed that lower A1C levels were associated with reduced onset or progression of microvascular complications (44–46). The concerning mortality findings in the ACCORD trial (47), discussed below, and the relatively intense efforts required to achieve near-euglycemia should also be considered when setting glycemic targets. However, on the basis of physician judgment

A1C and Cardiovascular Disease Outcomes Cardiovascular Disease and Type 1 Diabetes

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standard arm (48). The benefit of intensive glycemic control in this cohort with type 1 diabetes has been shown to persist for several decades (49) and to be associated with a modest reduction in all-cause mortality (50). Cardiovascular Disease and Type 2 Diabetes

In type 2 diabetes, there is evidence that more intensive treatment of glycemia in newly diagnosed patients may reduce long-term CVD rates. During the UKPDS, there was a 16% reduction in CVD events (combined fatal or nonfatal MI and sudden death) in the intensive glycemic control arm that did not reach statistical significance (P 5 0.052), and there was no suggestion of benefit on other CVD outcomes (e.g., stroke). However, after 10 years of observational follow-up, those originally randomized to intensive glycemic control had significant long-term reductions in MI (15% with sulfonylurea or insulin as initial pharmacotherapy, 33% with metformin as initial pharmacotherapy) and in all-cause mortality (13% and 27%, respectively) (42). The ACCORD, ADVANCE, and VADT suggested no significant reduction in CVD outcomes with intensive glycemic control in participants followed for 3.5– 5.6 years who had more advanced type 2 diabetes than UKPDS participants. All three trials were conducted in relatively older participants with longer known duration of diabetes (mean duration 8–11 years) and either CVD or multiple cardiovascular risk factors. The target A1C among intensive control subjects was ,6% (42 mmol/mol) in ACCORD, ,6.5% (48 mmol/mol) in ADVANCE, and a 1.5% reduction in A1C compared with control subjects in VADT, with achieved A1C of 6.4% versus 7.5% (46 mmol/mol vs. 58 mmol/mol) in ACCORD, 6.5% versus 7.3% (48 mmol/ mol vs. 56 mmol/mol) in ADVANCE, and 6.9% versus 8.4% (52 mmol/mol vs. 68 mmol/mol) in VADT. Details of these studies are reviewed extensively in the ADA position statement “Intensive Glycemic Control and the Prevention of Cardiovascular Events: Implications of the ACCORD, ADVANCE, and VA Diabetes Trials: A Position Statement of the American Diabetes Association and a Scientific Statement of the American College of Cardiology Foundation and the American Heart Association” (51). The glycemic control comparison in ACCORD was halted early due to an

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increased mortality rate in the intensive compared with the standard treatment arm (1.41% vs. 1.14% per year; hazard ratio 1.22 [95% CI 1.01–1.46]), with a similar increase in cardiovascular deaths. Analysis of the ACCORD data did not identify a clear explanation for the excess mortality in the intensive treatment arm (47). Longer-term follow-up has shown no evidence of cardiovascular benefit or harm in the ADVANCE trial (52). The end-stage renal disease rate was lower in the intensive treatment group over follow-up. However, 10-year follow-up of the VADT cohort (53) showed a reduction in the risk of cardiovascular events (52.7 [control group] vs. 44.1 [intervention group] events per 1,000 person-years) with no benefit in cardiovascular or overall mortality. Heterogeneity of mortality effects across studies was noted, which may reflect differences in glycemic targets, therapeutic approaches, and population characteristics (54). Mortality findings in ACCORD (47) and subgroup analyses of VADT (55) suggest that the potential risks of intensive glycemic control may outweigh its benefits in higher-risk patients. In all three trials, severe hypoglycemia was significantly more likely in participants who were randomly assigned to the intensive glycemic control arm. Those patients with long duration of diabetes, a known history of hypoglycemia, advanced atherosclerosis, or advanced age/frailty may benefit from less aggressive targets (56,57). Providers should be vigilant in preventing hypoglycemia in patients with advanced disease and should not aggressively attempt to achieve near-normal A1C levels in patients in whom such targets cannot be safely and reasonably achieved. Severe or frequent hypoglycemia is an absolute indication for the modification of treatment regimens, including setting higher glycemic goals.

Many factors, including patient preferences, should be taken into account when developing a patient’s individualized goals (Table 6.2) A1C and Glycemic Targets

Numerous aspects must be considered when setting glycemic targets. The ADA proposes optimal targets, but each target must be individualized to the needs of each patient and his or her disease factors. When possible, such decisions should be made with the patient, reflecting his or her preferences, needs, and values. Figure 6.1 is not designed to be applied rigidly but to be used as a broad construct to guide clinical decision making (58), both in type 1 and type 2 diabetes. Recommended glycemic targets for many nonpregnant adults are shown in Table 6.2. The recommendations include blood glucose levels that appear to correlate with achievement of an A1C of ,7% (53 mmol/mol). The issue of preprandial versus postprandial SMBG targets is complex (59). Elevated postchallenge (2-h oral glucose tolerance test) glucose values have been associated with increased cardiovascular risk independent of fasting plasma glucose in some epidemiological studies, but intervention trials have not shown postprandial glucose to be a cardiovascular risk factor independent of A1C. In subjects with diabetes, surrogate measures of vascular pathology, such as endothelial dysfunction, are negatively affected by postprandial hyperglycemia. It is clear that postprandial hyperglycemia, like preprandial hyperglycemia, contributes to elevated A1C levels, with its relative contribution being greater at A1C levels that are closer to 7% (53 mmol/mol). However, outcome studies have clearly shown A1C to be the primary predictor of complications, and landmark trials

Table 6.2—Summary of glycemic recommendations for many nonpregnant adults with diabetes A1C ,7.0% (53 mmol/mol)* Preprandial capillary plasma glucose Peak postprandial capillary plasma glucose†

80–130 mg/dL* (4.4–7.2 mmol/L) ,180 mg/dL* (10.0 mmol/L)

*More or less stringent glycemic goals may be appropriate for individual patients. Goals should be individualized based on duration of diabetes, age/life expectancy, comorbid conditions, known CVD or advanced microvascular complications, hypoglycemia unawareness, and individual patient considerations. †Postprandial glucose may be targeted if A1C goals are not met despite reaching preprandial glucose goals. Postprandial glucose measurements should be made 1–2 h after the beginning of the meal, generally peak levels in patients with diabetes.

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c

c

c

Figure 6.1—Depicted are patient and disease factors used to determine optimal A1C targets. Characteristics and predicaments toward the left justify more stringent efforts to lower A1C; those toward the right suggest less stringent efforts. Adapted with permission from Inzucchi et al. (58).

of glycemic control such as the DCCT and UKPDS relied overwhelmingly on preprandial SMBG. Additionally, a randomized controlled trial in patients with known CVD found no CVD benefit of insulin regimens targeting postprandial glucose compared with those targeting preprandial glucose (60). Therefore, it is reasonable for postprandial testing to be recommended for individuals who have premeal glucose values within target but have A1C values above target. Measuring postprandial plasma glucose 1–2 h after the start of a meal and using treatments aimed at reducing postprandial plasma glucose values to ,180 mg/dL (10.0 mmol/L) may help to lower A1C. An analysis of data from 470 participants in the ADAG study (237 with type 1 diabetes and 147 with type 2 diabetes) found that actual average glucose levels associated with conventional A1C targets were higher than older DCCT and ADA targets (Table 6.1) (27,29). These findings support that premeal glucose targets may be relaxed without undermining overall glycemic control as measured by A1C. These data prompted the revision in the ADArecommended premeal glucose target to 80–130 mg/dL (4.4–7.2 mmol/L) but did not affect the definition of hypoglycemia.

HYPOGLYCEMIA Recommendations c

c

c

Individuals at risk for hypoglycemia should be asked about symptomatic and asymptomatic hypoglycemia at each encounter. C Glucose (15–20 g) is the preferred treatment for the conscious individual with hypoglycemia (glucose alert value of #70 mg/dL [3.9 mmol/L]), although any form of carbohydrate that contains glucose may be used. Fifteen minutes after treatment, if SMBG shows continued hypoglycemia, the treatment should be repeated. Once SMBG returns to normal, the individual should consume a meal or snack to prevent recurrence of hypoglycemia. E Glucagon should be prescribed for all individuals at increased risk of clinically significant hypoglycemia, defined as blood glucose ,54 mg/dL (3.0 mmol/L), so it is available should it be needed. Caregivers, school personnel, or family members of these individuals should know where it is and when and how to administer it. Glucagon administration is not limited to health care professionals. E

Hypoglycemia unawareness or one or more episodes of severe hypoglycemia should trigger reevaluation of the treatment regimen. E Insulin-treated patients with hypoglycemia unawareness or an episode of clinically significant hypoglycemia should be advised to raise their glycemic targets to strictly avoid hypoglycemia for at least several weeks in order to partially reverse hypoglycemia unawareness and reduce risk of future episodes. A Ongoing assessment of cognitive function is suggested with increased vigilance for hypoglycemia by the clinician, patient, and caregivers if low cognition or declining cognition is found. B

Hypoglycemia is the major limiting factor in the glycemic management of type 1 and type 2 diabetes. Recommendations from the International Hypoglycaemia Study Group regarding the classification of hypoglycemia are outlined in Table 6.3 (61). Of note, this classification scheme considers a blood glucose ,54 mg/dL (3.0 mmol/L) detected by SMBG, CGM (for at least 20 min), or laboratory measurement of plasma glucose as sufficiently low to indicate serious, clinically significant hypoglycemia that should be included in reports of clinical trials of glucose-lowering drugs for the treatment of diabetes (61). However, a glucose alert value of $70 mg/dL (3.9 mmol/L) can be important for therapeutic dose adjustment of glucose-lowering drugs in clinical care and is often related to symptomatic hypoglycemia. Severe hypoglycemia is defined as severe cognitive impairment requiring assistance from another person for recovery (62). Symptoms of hypoglycemia include, but are not limited to, shakiness, irritability, confusion, tachycardia, and hunger. Hypoglycemia may be inconvenient or frightening to patients with diabetes. Severe hypoglycemia may be recognized or unrecognized and can progress to loss of consciousness, seizure, coma, or death. It is reversed by administration of rapid-acting glucose or glucagon. Clinically significant hypoglycemia can cause acute harm to the person with diabetes or others, especially if it causes falls, motor vehicle

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Table 6.3—Classification of hypoglycemia (61) Level

Glycemic criteria

Description

Glucose alert value (level 1)

#70 mg/dL (3.9 mmol/L)

Sufficiently low for treatment with fast-acting carbohydrate and dose adjustment of glucose-lowering therapy

Clinically significant hypoglycemia (level 2)

,54 mg/dL (3.0 mmol/L)

Sufficiently low to indicate serious, clinically important hypoglycemia

Severe hypoglycemia (level 3)

accidents, or other injury. A large cohort study suggested that among older adults with type 2 diabetes, a history of severe hypoglycemia was associated with greater risk of dementia (63). Conversely, in a substudy of the ACCORD trial, cognitive impairment at baseline or decline in cognitive function during the trial was significantly associated with subsequent episodes of severe hypoglycemia (64). Evidence from DCCT/EDIC, which involved adolescents and younger adults with type 1 diabetes, found no association between frequency of severe hypoglycemia and cognitive decline (65), as discussed in Section 12 “Children and Adolescents.” Severe hypoglycemia was associated with mortality in participants in both the standard and the intensive glycemia arms of the ACCORD trial, but the relationships between hypoglycemia, achieved A1C, and treatment intensity were not straightforward. An association of severe hypoglycemia with mortality was also found in the ADVANCE trial (66). An association between self-reported severe hypoglycemia and 5-year mortality has also been reported in clinical practice (67). Young children with type 1 diabetes and the elderly are noted as particularly vulnerable to clinically significant hypoglycemia because of their reduced ability to recognize hypoglycemic symptoms and effectively communicate their needs. Individualized glucose targets, patient education, dietary intervention (e.g., bedtime snack to prevent overnight hypoglycemia), exercise management, medication adjustment, glucose monitoring, and routine clinical surveillance may improve patient outcomes (62). In 2015, the ADA changed its preprandial glycemic target from 70–130 mg/dL (3.9–7.2 mmol/L) to 80–130 mg/dL (4.4–7.2 mmol/L). This change reflects the results of the ADAG study, which demonstrated that higher glycemic targets corresponded to A1C goals (27). An

No specific glucose threshold

Hypoglycemia associated with severe cognitive impairment requiring external assistance for recovery

additional goal of raising the lower range of the glycemic target was to limit overtreatment and provide a safety margin in patients titrating glucose-lowering drugs such as insulin to glycemic targets. Hypoglycemia Treatment

Providers should continue to counsel patients to treat hypoglycemia with fast-acting carbohydrates at the blood glucose alert value of 70 mg/dL (3.9 mmol/L) or less. Hypoglycemia treatment requires ingestion of glucose- or carbohydrate-containing foods. The acute glycemic response correlates better with the glucose content of food than with the carbohydrate content of food. Pure glucose is the preferred treatment, but any form of carbohydrate that contains glucose will raise blood glucose. Added fat may retard and then prolong the acute glycemic response. Ongoing insulin activity or insulin secretagogues may lead to recurrent hypoglycemia unless further food is ingested after recovery. Once the glucose returns to normal, the individual should be counseled to eat a meal or snack to prevent recurrent hypoglycemia. Glucagon

The use of glucagon is indicated for the treatment of hypoglycemia in people unable or unwilling to consume carbohydrates by mouth. Those in close contact with, or having custodial care of, people with hypoglycemia-prone diabetes (family members, roommates, school personnel, child care providers, correctional institution staff, or coworkers) should be instructed on the use of glucagon kits including where the kit is and when and how to administer glucagon. An individual does not need to be a health care professional to safely administer glucagon. Care should be taken to ensure that glucagon kits are not expired. Hypoglycemia Prevention

Hypoglycemia prevention is a critical component of diabetes management.

SMBG and, for some patients, CGM are essential tools to assess therapy and detect incipient hypoglycemia. Patients should understand situations that increase their risk of hypoglycemia, such as fasting for tests or procedures, delayed meals, during or after intense exercise, and during sleep. Hypoglycemia may increase the risk of harm to self or others, such as with driving. Teaching people with diabetes to balance insulin use and carbohydrate intake and exercise are necessary, but these strategies are not always sufficient for prevention. In type 1 diabetes and severely insulindeficient type 2 diabetes, hypoglycemia unawareness (or hypoglycemia-associated autonomic failure) can severely compromise stringent diabetes control and quality of life. This syndrome is characterized by deficient counterregulatory hormone release, especially in older adults, and a diminished autonomic response, which both are risk factors for, and caused by, hypoglycemia. A corollary to this “vicious cycle” is that several weeks of avoidance of hypoglycemia has been demonstrated to improve counterregulation and hypoglycemia awareness in many patients (68). Hence, patients with one or more episodes of clinically significant hypoglycemia may benefit from at least shortterm relaxation of glycemic targets. INTERCURRENT ILLNESS

For further information on management of patients with hyperglycemia in the hospital, please refer to Section 14 “Diabetes Care in the Hospital.” Stressful events (e.g., illness, trauma, surgery, etc.) may worsen glycemic control and precipitate diabetic ketoacidosis or nonketotic hyperosmolar state, lifethreatening conditions that require immediate medical care to prevent complications and death. Any condition leading to deterioration in glycemic control necessitates more frequent monitoring of blood glucose; ketosis-prone patients also require

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urine or blood ketone monitoring. If accompanied by ketosis, vomiting, or alteration in the level of consciousness, marked hyperglycemia requires temporary adjustment of the treatment regimen and immediate interaction with the diabetes care team. The patient treated with noninsulin therapies or medical nutrition therapy alone may temporarily require insulin. Adequate fluid and caloric intake must be ensured. Infection or dehydration is more likely to necessitate hospitalization of the person with diabetes than the person without diabetes. A physician with expertise in diabetes management should treat the hospitalized patient. For further information on the management of diabetic ketoacidosis and the hyperglycemic nonketotic hyperosmolar state, please refer to the ADA consensus report “Hyperglycemic Crises in Adult Patients With Diabetes” (69). References 1. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977–986 2. Miller KM, Beck RW, Bergenstal RM, et al.; T1D Exchange Clinic Network. Evidence of a strong association between frequency of selfmonitoring of blood glucose and hemoglobin A1c levels in T1D Exchange clinic registry participants. Diabetes Care 2013;36:2009–2014 3. Polonsky WH, Fisher L, Schikman CH, et al. Structured self-monitoring of blood glucose significantly reduces A1C levels in poorly controlled, noninsulin-treated type 2 diabetes: results from the Structured Testing Program study. Diabetes Care 2011;34:262–267 4. Gellad WF, Zhao X, Thorpe CT, Mor MK, Good CB, Fine MJ. Dual use of Department of Veterans Affairs and Medicare benefits and use of test strips in veterans with type 2 diabetes mellitus. JAMA Intern Med 2015;175:26–34 5. Grant RW, Huang ES, Wexler DJ, et al. Patients who self-monitor blood glucose and their unused testing results. Am J Manag Care 2015; 21:e119–e129 6. Endocrine Society. Choosing wisely [Internet], 2013. Available from http://www.choosingwisely .org/societies/endocrine-society/. Accessed 18 August 2015 7. Rosenstock J, Davies M, Home PD, Larsen J, Koenen C, Schernthaner G. A randomised, 52-week, treat-to-target trial comparing insulin detemir with insulin glargine when administered as add-on to glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetologia 2008;51:408–416 8. Garber AJ. Treat-to-target trials: uses, interpretation and review of concepts. Diabetes Obes Metab 2014;16:193–205 9. Elgart JF, Gonza´ lez L, Prestes M, Rucci E, Gagliardino JJ. Frequency of self-monitoring blood glucose and attainment of HbA1c target values. Acta Diabetol 2016;53:57–62

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reduces severe hypoglycemia in hypoglycemiaunaware patients with type 1 diabetes. Diabetes Care 2013;36:4160–4162 24. Choudhary P, Rickels MR, Senior PA, et al. Evidence-informed clinical practice recommendations for treatment of type 1 diabetes complicated by problematic hypoglycemia. Diabetes Care 2015;38:1016–1029 25. Bergenstal RM, Klonoff DC, Garg SK, et al.; ASPIRE In-Home Study Group. Threshold-based insulin-pump interruption for reduction of hypoglycemia. N Engl J Med 2013;369:224–232 26. Bergenstal RM, Garg S, Weinzimer SA, et al. Safety of a hybrid closed-loop insulin delivery system in patients with type 1 diabetes. JAMA 2016;316:1407–1408 27. Wei N, Zheng H, Nathan DM. Empirically establishing blood glucose targets to achieve HbA1c goals. Diabetes Care 2014;37:1048–1051 28. Herman WH, Ilag LL, Johnson SL, et al. A clinical trial of continuous subcutaneous insulin infusion versus multiple daily injections in older adults with type 2 diabetes. Diabetes Care 2005; 28:1568–1573 29. Albers JW, Herman WH, Pop-Busui R, et al.; Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications Research Group. Effect of prior intensive insulin treatment during the Diabetes Control and Complications Trial (DCCT) on peripheral neuropathy in type 1 diabetes during the Epidemiology of Diabetes Interventions and Complications (EDIC) Study. Diabetes Care 2010;33:1090–1096 30. Stratton IM, Adler AI, Neil HAW, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321:405–412 31. Jovanoviˇc L, Savas H, Mehta M, Trujillo A, Pettitt DJ. Frequent monitoring of A1C during pregnancy as a treatment tool to guide therapy. Diabetes Care 2011;34:53–54 32. Nathan DM, Kuenen J, Borg R, Zheng H, Schoenfeld D, Heine RJ; A1c-Derived Average Glucose (ADAG) Study Group. Translating the A1C assay into estimated average glucose values. Diabetes Care 2008;31:1473–1478 33. Selvin E. Are there clinical implications of racial differences in HbA1c? A difference, to be a difference, must make a difference. Diabetes Care 2016;39:1462–1467 34. Diabetes Research in Children Network (DirecNet) Study Group. Relationship of A1C to glucose concentrations in children with type 1 diabetes: assessments by high-frequency glucose determinations by sensors. Diabetes Care 2008;31:381–385 35. Buse JB, Kaufman FR, Linder B, Hirst K, El Ghormli L, Willi S; HEALTHY Study Group. Diabetes screening with hemoglobin A1c versus fasting plasma glucose in a multiethnic middle-school cohort. Diabetes Care 2013;36:429–435 36. Kamps JL, Hempe JM, Chalew SA. Racial disparity in A1C independent of mean blood glucose in children with type 1 diabetes. Diabetes Care 2010;33:1025–1027 37. The Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Research Group. Effect of intensive diabetes therapy on the progression of diabetic retinopathy in patients with

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type 1 diabetes: 18 years of follow-up in the DCCT/EDIC. Diabetes 2015;64:631–642. 38. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med 2000;342:381–389 39. Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract 1995;28:103–117 40. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854–865 41. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837–853 42. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HAW. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359:1577–1589 43. Adler AI, Stratton IM, Neil HAW, et al. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ 2000;321:412–419 44. Duckworth W, Abraira C, Moritz T, et al.; VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009;360:129–139 45. ADVANCE Collaborative Group, Patel A, MacMahon S, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560–2572 46. Ismail-Beigi F, Craven T, Banerji MA, et al.; ACCORD trial group. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet 2010;376:419–430 47. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545–2559 48. Nathan DM, Cleary PA, Backlund J-YC, et al.; Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and

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cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005;353:2643–2653 49. Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Research Group, Nathan DM, Zinman B, et al. Modern-day clinical course of type 1 diabetes mellitus after 30 years’ duration: the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications and Pittsburgh Epidemiology of Diabetes Complications Experience (1983-2005). Arch Intern Med 2009;169: 1307–1316 50. Writing Group for the DCCT/EDIC Research Group, Orchard TJ, Nathan DM, et al. Association between 7 years of intensive treatment of type 1 diabetes and long-term mortality. JAMA 2015;313:45–53 51. Skyler JS, Bergenstal R, Bonow RO, et al. Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA Diabetes Trials: a position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association [published correction appears in Diabetes Care 2009;32: 754]. Diabetes Care 2009;32:187–192 52. Zoungas S, Chalmers J, Neal B, et al.; ADVANCE-ON Collaborative Group. Follow-up of blood-pressure lowering and glucose control in type 2 diabetes. N Engl J Med 2014;371:1392– 1406 53. Hayward RA, Reaven PD, Wiitala WL, et al.; VADT Investigators. Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015;372:2197–2206 54. Control Group, Turnbull FM, Abraira C, et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes [published correction appears in Diabetologia 2009;52: 2470]. Diabetologia 2009;52:2288–2298 55. Duckworth WC, Abraira C, Moritz TE, et al.; Investigators of the VADT. The duration of diabetes affects the response to intensive glucose control in type 2 subjects: the VA Diabetes Trial. J Diabetes Complications 2011;25:355–361 56. Lipska KJ, Ross JS, Miao Y, Shah ND, Lee SJ, Steinman MA. Potential overtreatment of diabetes mellitus in older adults with tight glycemic control. JAMA Intern Med 2015;175:356–362 57. Vijan S, Sussman JB, Yudkin JS, Hayward RA. Effect of patients’ risks and preferences on health gains with plasma glucose level lowering in type 2 diabetes mellitus. JAMA Intern Med 2014;174:1227–1234

58. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2015; 38:140–149 59. American Diabetes Association. Postprandial blood glucose. Diabetes Care 2001;24: 775–778 60. Raz I, Wilson PWF, Strojek K, et al. Effects of prandial versus fasting glycemia on cardiovascular outcomes in type 2 diabetes: the HEART2D trial. Diabetes Care 2009;32:381–386 61. International Hypoglycaemia Study Group. Glucose concentrations of less than 3.0 mmol/L (54 mg/dL) should be reported in clinical trials: a joint position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2017; 40:155–157 62. Seaquist ER, Anderson J, Childs B, et al. Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. Diabetes Care 2013;36:1384–1395 63. Whitmer RA, Karter AJ, Yaffe K, Quesenberry CP Jr, Selby JV. Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus. JAMA 2009;301:1565–1572 64. Punthakee Z, Miller ME, Launer LJ, et al.; ACCORD Group of Investigators; ACCORDMIND Investigators. Poor cognitive function and risk of severe hypoglycemia in type 2 diabetes: post hoc epidemiologic analysis of the ACCORD trial. Diabetes Care 2012;35:787–793 65. Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications Study Research Group, Jacobson AM, Musen G, et al. Long-term effect of diabetes and its treatment on cognitive function. N Engl J Med 2007;356:1842–1852 66. Zoungas S, Patel A, Chalmers J, et al.; ADVANCE Collaborative Group. Severe hypoglycemia and risks of vascular events and death. N Engl J Med 2010;363:1410–1418 67. McCoy RG, Van Houten HK, Ziegenfuss JY, Shah ND, Wermers RA, Smith SA. Increased mortality of patients with diabetes reporting severe hypoglycemia. Diabetes Care 2012;35:1897–1901 68. Cryer PE. Diverse causes of hypoglycemiaassociated autonomic failure in diabetes. N Engl J Med 2004;350:2272–2279 69. Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with diabetes. Diabetes Care 2009;32:1335–1343

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7. Obesity Management for the Treatment of Type 2 Diabetes

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Diabetes Care 2017;40(Suppl. 1):S57–S63 | DOI: 10.2337/dc17-S010

7. OBESITY MANAGEMENT FOR THE TREATMENT OF TYPE 2 DIABETES

There is strong and consistent evidence that obesity management can delay the progression from prediabetes to type 2 diabetes (1,2) and may be beneficial in the treatment of type 2 diabetes (3–8). In overweight and obese patients with type 2 diabetes, modest and sustained weight loss has been shown to improve glycemic control and to reduce the need for glucose-lowering medications (3–5). Small studies have demonstrated that in obese patients with type 2 diabetes more extreme dietary energy restriction with very low-calorie diets can reduce A1C to ,6.5% (48 mmol/mol) and fasting glucose to ,126 mg/dL (7.0 mmol/L) in the absence of pharmacological therapy or ongoing procedures (7,9,10). Weight loss–induced improvements in glycemia are most likely to occur early in the natural history of type 2 diabetes when obesityassociated insulin resistance has caused reversible b-cell dysfunction but insulin secretory capacity remains relatively preserved (5,8,10). The goal of this section is to provide evidence-based recommendations for dietary, pharmacological, and surgical interventions for obesity management as treatments for hyperglycemia in type 2 diabetes. ASSESSMENT Recommendation c

At each patient encounter, BMI should be calculated and documented in the medical record. B

At each routine patient encounter, BMI should be calculated from the height and weight. BMI should be classified to determine the presence of overweight or obesity, discussed with the patient, and documented in the patient record. In Asian Americans, the BMI cutoff points to define overweight and obesity are lower than in other populations (Table 7.1) (11,12). Providers should advise overweight and obese patients that higher BMIs increase the risk of cardiovascular disease and allcause mortality. Providers should assess each patient’s readiness to achieve weight loss and jointly determine weight loss goals and intervention strategies. Strategies include diet, physical activity, behavioral therapy, pharmacological therapy, and metabolic surgery (Table 7.1). The latter two strategies may be prescribed for carefully selected patients as adjuncts to diet, physical activity, and behavioral therapy. DIET, PHYSICAL ACTIVITY, AND BEHAVIORAL THERAPY Recommendations c

c

c

c

Diet, physical activity, and behavioral therapy designed to achieve .5% weight loss should be prescribed for overweight and obese patients with type 2 diabetes ready to achieve weight loss. A Such interventions should be high intensity ($16 sessions in 6 months) and focus on diet, physical activity, and behavioral strategies to achieve a 500–750 kcal/day energy deficit. A Diets should be individualized, as those that provide the same caloric restriction but differ in protein, carbohydrate, and fat content are equally effective in achieving weight loss. A For patients who achieve short-term weight loss goals, long-term ($1-year) comprehensive weight maintenance programs should be prescribed. Such programs should provide at least monthly contact and encourage ongoing monitoring of body weight (weekly or more frequently), continued

Suggested citation: American Diabetes Association. Obesity management for the treatment of type 2 diabetes. Sec. 7. In Standards of Medical Care in Diabetesd2017. Diabetes Care 2017; 40(Suppl. 1):S57–S63 © 2017 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals .org/content/license.

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Table 7.1—Treatment for overweight and obesity in type 2 diabetes 2

BMI category (kg/m ) Treatment Diet, physical activity, and behavioral therapy

23.0* or 25.0–26.9

27.0–29.9

27.5* or 30.0–34.9

35.0–39.9

$40











┼ ┼

┼ ┼

┼ ┼



Pharmacotherapy Metabolic surgery

*Cutoff points for Asian American individuals. ┼Treatment may be indicated for selected motivated patients.

c

consumption of a reduced calorie diet, and participation in high levels of physical activity (200– 300 min/week). A To achieve weight loss of .5%, short-term (3-month) interventions that use very low-calorie diets (#800 kcal/day) and total meal replacements may be prescribed for carefully selected patients by trained practitioners in medical care settings with close medical monitoring. To maintain weight loss, such programs must incorporate long-term comprehensive weight maintenance counseling. B

Among overweight or obese patients with type 2 diabetes and inadequate glycemic, blood pressure, and lipid control and/or other obesity-related medical conditions, lifestyle changes that result in modest and sustained weight loss produce clinically meaningful reductions in blood glucose, A1C, and triglycerides (3–5). Greater weight loss produces even greater benefits, including reductions in blood pressure, improvements in LDL and HDL cholesterol, and reductions in the need for medications to control blood glucose, blood pressure, and lipids (13,14). Look AHEAD Trial

Although the Action for Health in Diabetes (Look AHEAD) trial did not show that an intensive lifestyle intervention reduced cardiovascular events in overweight or obese adults with type 2 diabetes (13), it did show the feasibility of achieving and maintaining long-term weight loss in patients with type 2 diabetes. In the Look AHEAD intensive lifestyle intervention group, mean weight loss was 4.7% at 8 years (14). Approximately 50% of intensive lifestyle intervention participants lost $5% and

27% lost $10% of their initial body weight at 8 years (14). Participants randomly assigned to the intensive lifestyle group achieved equivalent risk factor control but required fewer glucose-, blood pressure–, and lipid-lowering medications than those randomly assigned to standard care. Secondary analyses of the Look AHEAD trial and other large cardiovascular outcome studies document other benefits of weight loss in patients with type 2 diabetes, including improvements in mobility, physical and sexual functioning, and health-related quality of life (15). Lifestyle Interventions

Weight loss can be attained with lifestyle programs that achieve a 500–750 kcal/day energy deficit or provide approximately 1,200–1,500 kcal/day for women and 1,500–1,800 kcal/day for men, adjusted for the individual’s baseline body weight. Although benefits may be seen with as little as 5% weight loss, sustained weight loss of $7% is optimal. These diets may differ in the types of foods they restrict (such as high-fat or high-carbohydrate foods) but are effective if they create the necessary energy deficit (16–19). Use of meal replacement plans prescribed by trained practitioners, with close patient monitoring, can be beneficial. Within the intensive lifestyle intervention group of the Look AHEAD trial, for example, use of a partial meal replacement plan was associated with improvements in diet quality (20). The diet choice should be based on the patient’s health status and preferences. Intensive behavioral lifestyle interventions should include $16 sessions in 6 months and focus on diet, physical activity, and behavioral strategies to achieve an ;500–750 kcal/day energy

deficit. Interventions should be provided by trained interventionists in either individual or group sessions (21). Overweight and obese patients with type 2 diabetes who have lost weight during the 6-month intensive behavioral lifestyle intervention should be enrolled in long-term ($1-year) comprehensive weight loss maintenance programs that provide at least monthly contact with a trained interventionist and focus on ongoing monitoring of body weight (weekly or more frequently), continued consumption of a reduced calorie diet, and participation in high levels of physical activity (200–300 min/week). Some commercial and proprietary weight loss programs have shown promising weight loss results (22). When provided by trained practitioners in medical care settings with close medical monitoring, short-term (3-month) interventions that use very low-calorie diets (defined as #800 kcal/ day) and total meal replacements may achieve greater short-term weight loss (10–15%) than intensive behavioral lifestyle interventions that typically achieve 5% weight loss. Weight regain following the cessation of very low-calorie diets is greater than following intensive behavioral lifestyle interventions unless a long-term comprehensive weight loss maintenance program is provided (23,24). PHARMACOTHERAPY Recommendations c

c

c

c

When choosing glucose-lowering medications for overweight or obese patients with type 2 diabetes, consider their effect on weight. E Whenever possible, minimize the medications for comorbid conditions that are associated with weight gain. E Weight loss medications may be effective as adjuncts to diet, physical activity, and behavioral counseling for selected patients with type 2 diabetes and BMI $27 kg/m2. Potential benefits must be weighed against the potential risks of the medications. A If a patient’s response to weight loss medications is ,5% weight loss after 3 months or if there are any safety or tolerability issues at

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any time, the medication should be discontinued and alternative medications or treatment approaches should be considered. A Antihyperglycemic Therapy

When evaluating pharmacological treatments for overweight or obese patients with type 2 diabetes, providers should first consider their choice of glucose-lowering medications. Whenever possible, medications should be chosen to promote weight loss or to be weight neutral. Agents associated with weight loss include metformin, a-glucosidase inhibitors, sodium–glucose cotransporter 2 inhibitors, glucagon-like peptide 1 agonists, and amylin mimetics. Dipeptidyl peptidase 4 inhibitors appear to be weight neutral. Unlike these agents, insulin secretagogues, thiazolidinediones, and insulin have often been associated with weight gain (see Section 8 “Pharmacologic Approaches to Glycemic Treatment”). Concomitant Medications

Providers should carefully review the patient’s concomitant medications and, whenever possible, minimize or provide alternatives for medications that promote weight gain. Medications associated with weight gain include atypical antipsychotics (e.g., clozapine, olanzapine, risperidone, etc.) and antidepressants (e.g., tricyclic antidepressants, selective serotonin reuptake inhibitors, and monoamine oxidase inhibitors), glucocorticoids, oral contraceptives that contain progestins, anticonvulsants including gabapentin, and a number of antihistamines and anticholinergics. Approved Weight Loss Medications

The U.S. Food and Drug Administration (FDA) has approved five weight loss medications (or combination medications) for long-term use (more than a few weeks) by patients with BMI $27 kg/m2 with one or more obesityassociated comorbid conditions (e.g., type 2 diabetes. hypertension, and dyslipidemia) and by patients with BMI $30 kg/m2 who are motivated to lose weight (25–27). Medications approved for long-term weight loss and weight loss maintenance and their advantages and disadvantages are summarized in Table 7.2. The rationale for weight loss medications is to help patients to more consistently adhere to

Obesity Management for the Treatment of Type 2 Diabetes

low-calorie diets and to reinforce lifestyle changes including physical activity. Providers should be knowledgeable about the product label and should balance the potential benefits of successful weight loss against the potential risks of the medication for each patient. These medications are contraindicated in women who are or may become pregnant. Women in their reproductive years must be cautioned to use a reliable method of contraception.

c

Assessing Efficacy and Safety

Efficacy and safety should be assessed at least monthly for the first 3 months of treatment. If a patient’s response is deemed insufficient (weight loss ,5%) or if there are any safety or tolerability issues at any time, the medication should be discontinued and alternative medications or treatment approaches should be considered. In general, pharmacological treatment of obesity has been limited by low adherence, modest efficacy, adverse effects, and weight regain after medication cessation (25). METABOLIC SURGERY Recommendations c

c

c

c

Metabolic surgery should be recommended to treat type 2 diabetes in appropriate surgical candidates with BMI $40 kg/m2 (BMI $37.5 kg/m2 in Asian Americans), regardless of the level of glycemic control or complexity of glucose-lowering regimens, and in adults with BMI 35.0– 39.9 kg/m2 (32.5–37.4 kg/m2 in Asian Americans) when hyperglycemia is inadequately controlled despite lifestyle and optimal medical therapy. A Metabolic surgery should be considered for adults with type 2 diabetes and BMI 30.0–34.9 kg/m2 (27.5–32.4 kg/m2 in Asian Americans) if hyperglycemia is inadequately controlled despite optimal medical control by either oral or injectable medications (including insulin). B Metabolic surgery should be performed in high-volume centers with multidisciplinary teams that understand and are experienced in the management of diabetes and gastrointestinal surgery. C Long-term lifestyle support and routine monitoring of micronutrient

c

and nutritional status must be provided to patients after surgery, according to guidelines for postoperative management of metabolic surgery by national and international professional societies. C People presenting for metabolic surgery should receive a comprehensive mental health assessment. B Surgery should be postponed in patients with histories of alcohol or substance abuse, significant depression, suicidal ideation, or other mental health conditions until these conditions have been fully addressed. E People who undergo metabolic surgery should be evaluated to assess the need for ongoing mental health services to help them adjust to medical and psychosocial changes after surgery. C

Several gastrointestinal (GI) operations promote dramatic and durable improvement of type 2 diabetes. Given the magnitude and rapidity of the effect of GI surgery on hyperglycemia, and experimental evidence that rearrangements of GI anatomy similar to those in some metabolic procedures directly affect glucose homeostasis (28), GI interventions have been suggested as treatments for type 2 diabetes, and in that context are termed “metabolic surgery.” A substantial body of evidence has now accumulated, including data from numerous randomized controlled clinical trials, demonstrating that metabolic surgery achieves superior glycemic control and reduction of cardiovascular risk factors in obese patients with type 2 diabetes compared with various lifestyle/medical interventions (29). Improvements in micro- and macrovascular complications of diabetes, cardiovascular disease, and cancer have been observed only in nonrandomized observational studies (30–37). Cohort studies attempting to match surgical and nonsurgical subjects suggest that the procedure may reduce longer-term mortality (31). On the basis of this mounting evidence, several organizations and government agencies have recommended expanding the indications for metabolic surgery to include patients with inadequately controlled type 2 diabetes and BMI as low as 30 kg/m2 (27.5 kg/m2 for

S59

60 mg or 120 mg t.i.d. (during or up to 1 h after a low-fat meal)

Adult dosing frequency

$1,385

$251 (maximum dose)

$239 (maximum dose using the highest strength)

$263

$43–86 (60 mg); $670 (120 mg)

Average wholesale price (per month)1

5.8–5.9 kg

2.0–4.1 kg (32 mg/360 mg)

6.7 kg (7.5 mg/46 mg); 8.9 kg (15 mg/92 mg)

3.2 kg

2.5 kg (60 mg); 3.4 kg (120 mg)

Average weight loss relative to placebo

51–73%

36–57%

45–70%

38–48%

35–73%

% Patients with $5% loss of baseline weight

1-Year weight change status2–5

Hypoglycemia, nausea, vomiting, diarrhea, constipation, headache

Nausea, constipation, headache, vomiting

Paresthesia, xerostomia, constipation, headache

Hypoglycemia, headache, fatigue

Abdominal pain/discomfort, oily spotting/stool, fecal urgency, flatulence, malabsorption of fatsoluble vitamins (A, D, E, K) and medications (e.g., cyclosporine, thyroid hormone replacement, oranticonvulsants),potentiation of the effects of warfarin

Common7

Serious7

Pancreatitis, thyroid C-cell tumors in rodents, contraindicated in patients with personal/family history of MTC or MEN2, acute renal failure

Depression,precipitationofmania, contraindicated in patients with a seizure disorder

Topiramate is teratogenic and has been associated with cleft lip/palate

Serotonin syndrome or NMS-like reactions, suicidal ideation, heart valvedisorder(,2.4%),bradycardia

Liver failure and oxalate nephropathy

Adverse effects2,6–12

Obesity Management for the Treatment of Type 2 Diabetes

All medications are contraindicated in women who are or may become pregnant. Women in their reproductive years must be cautioned to use a reliable method of contraception. Caps, capsules; ER, extended release; MEN2, multiple endocrine neoplasia type 2; MTC, medullary thyroid carcinoma; NMS, neuroleptic malignant syndrome; s.c., subcutaneous; tabs, tablets. 1 RED BOOK Online. Micromedex 2.0 (electronic version). Truven Health Analytics, Greenwood Village, CO. 2 Physicians’ Desk Reference. PDR Network, LLC (electronic version). Truven Health Analytics, Greenwood Village, CO. 3 Yanovski SZ, Yanovski JA. Long-term drug treatment for obesity: a systematic and clinical review. JAMA 2014;311:74–86. 4 Astrup A, Carraro R, Finer N, et al.; NN8022–1807 Investigators. Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide. Int J Obes (Lond) 2012;36:843–854. 5 Wadden TA, Hollander P, Klein S, et al.; NN8022–1923 Investigators. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study. Int J Obes (Lond) 2013;37:1443–1451. 6 DrugPoints System (electronic version). Truven Health Analytics, Greenwood Village, CO. 7 Selective common (defined as an incidence of .5%) and serious adverse effects are noted. Refer to the medication package inserts for full information about adverse effects, cautions, and contraindications. 8 Data of common adverse effects for Xenical were derived from seven double-blind, placebo-controlled clinical trials in mixed-type study populations (i.e., patients with or without type 2 diabetes), but the percentage of patients with type 2 diabetes was not reported. In clinical trials in obese patients with diabetes, hypoglycemia and abdominal distension were also observed. 9 Data of common adverse effects for Belviq were derived from placebo-controlled clinical trials in patients with type 2 diabetes. 10 Data of common adverse effects for Qsymia were derived from four clinical trials in mixed-type study populations (i.e., patients with or without type 2 diabetes); 13% had type 2 diabetes. 11 Data of common adverse effects for Contrave were derived from five double-blind, placebo-controlled clinical trials in mixed-type study populations (i.e., patients with or without type 2 diabetes); 13% had type 2 diabetes. 12 Data of common adverse effects for Saxenda were derived from clinical trials in mixed-type study populations (i.e., patients with or without type 2 diabetes). Percentage of patients with type 2 diabetes was not reported.

Acylated human glucagon-like peptide 1 receptor agonist Liraglutide (Saxenda) Maintenance dose: 3 mg s.c. q.d. 6 mg/mL prefilled pen

Opioid antagonist/aminoketone antidepressant combination Naltrexone/bupropion (Contrave) Maximum dose: two tablets of 8 mg/90 mg tabs Contrave b.i.d. for a total daily dosage of naltrexone 32 mg/bupropion 360 mg

Sympathomimetic amine anorectic/antiepileptic combination Recommended dose: 3.75 Phentermine/topiramate ER (Qsymia) 3.75 mg/23 mg caps, mg/23 mg q.d. for 14 days, 7.5 mg/46 mg caps, then increase to 7.5 mg/46 mg 11.25 mg/69 mg caps, q.d. Maximum dose: 15 mg/92 mg caps 15 mg/92 mg q.d.

Selective serotonin (5-HT) 5-HT2C receptor agonist Lorcaserin (Belviq) 10 mg tabs 10 mg b.i.d.

Lipase inhibitor Orlistat (Alli) 60 mg caps or orlistat (Xenical) 120 mg caps

Generic drug name (proprietary name[s]) and dosage strength and form

Table 7.2—Medications approved by the FDA for the long-term (more than a few weeks) treatment of obesity

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Asian Americans) (38–41). Please refer to the American Diabetes Association consensus report “Metabolic Surgery in the Treatment Algorithm for Type 2 Diabetes: A Joint Statement by International Diabetes Organizations” for a thorough review (29). Randomized controlled trials with postoperative follow-up ranging from 1 to 5 years have documented sustained diabetes remission in 30–63% of patients (29). Available data suggest an erosion of diabetes remission over time: 35–50% or more of patients who initially achieve remission of diabetes eventually experience recurrence. However, the median disease-free period among such individuals following Roux-en-Y gastric bypass (RYGB) is 8.3 years (42,43). With or without diabetes relapse, the majority of patients who undergo surgery maintain substantial improvement of glycemic control from baseline for at least 5 (44) to 15 (31,32,43,45–47) years. Younger age, shorter duration of diabetes (e.g., ,8 years) (48), nonuse of insulin, and better glycemic control are consistently associated with higher rates of diabetes remission and/or lower risk of recidivism (31,46,48). Greater baseline visceral fat area may also help to predict better postoperative outcomes, especially among Asian American patients with type 2 diabetes, who typically have more visceral fat compared with Caucasians with diabetes of the same BMI (49). Beyond improving glycemia, metabolic surgery has been shown to confer additional health benefits in randomized controlled trials, including greater reductions in cardiovascular disease risk factors (29) and enhancements in quality of life (44,48,50). The safety of metabolic surgery has improved significantly over the past two decades, with continued refinement of minimally invasive approaches (laparoscopic surgery), enhanced training and credentialing, and involvement of multidisciplinary teams. Mortality rates with metabolic operations are typically 0.1–0.5%, similar to cholecystectomy or hysterectomy (51–55). Morbidity has also dramatically declined with laparoscopic approaches. Major complications rates are 2–6%, with minor complications in up to 15% (51–59), comparing favorably with other commonly performed elective operations (55). Empirical data

Obesity Management for the Treatment of Type 2 Diabetes

suggest that proficiency of the operating surgeon is an important factor for determining mortality, complications, reoperations, and readmissions (60). Although metabolic surgery has been shown to improve the metabolic profiles of morbidly obese patients with type 1 diabetes, establishing the role of metabolic surgery in such patients will require larger and longer studies (61). Retrospective analyses and modeling studies suggest that metabolic surgery may be cost-effective or even cost-saving for patients with type 2 diabetes, but the results are largely dependent on assumptions about the long-term effectiveness and safety of the procedures (62,63). Adverse Effects

Metabolic surgery is costly and has associated risks. Longer-term concerns include dumping syndrome (nausea, colic, diarrhea), vitamin and mineral deficiencies, anemia, osteoporosis, and, rarely (64), severe hypoglycemia from insulin hypersecretion. Long-term nutritional and micronutrient deficiencies and related complications occur with variable frequency depending on the type of procedure and require lifelong vitamin/ nutritional supplementation (65,66). Postprandial hypoglycemia is most likely to occur with RYGB (66,67). The exact prevalence of symptomatic hypoglycemia is unknown. In one study, it affected 11% of 450 patients who had undergone RYGB or vertical sleeve gastrectomy (67). Patients who undergo metabolic surgery may be at increased risk for substance use, including drug and alcohol use and cigarette smoking (68). People with diabetes presenting for metabolic surgery also have increased rates of depression and other major psychiatric disorders (69). Candidates for metabolic surgery with histories of alcohol or substance abuse, significant depression, suicidal ideation, or other mental health conditions should therefore first be assessed by a mental health professional with expertise in obesity management prior to consideration for surgery (70). Individuals with preoperative psychopathology should be assessed regularly following metabolic surgery to optimize mental health management and to ensure psychiatric symptoms do not interfere with weight loss and lifestyle changes.

References 1. Tuomilehto J. The emerging global epidemic of type 1 diabetes. Curr Diab Rep 2013;13:795–804 2. Knowler WC, Barrett-Connor E, Fowler SE, et al.; Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393–403 3. UK Prospective Diabetes Study 7. UK Prospective Diabetes Study 7: response of fasting plasma glucose to diet therapy in newly presenting type II diabetic patients, UKPDS Group. Metabolism 1990;39:905–912 4. Goldstein DJ. Beneficial health effects of modest weight loss. Int J Obes Relat Metab Disord 1992;16:397–415 5. Pastors JG, Warshaw H, Daly A, Franz M, Kulkarni K. The evidence for the effectiveness of medical nutrition therapy in diabetes management. Diabetes Care 2002;25:608–613 6. Lim EL, Hollingsworth KG, Aribisala BS, Chen MJ, Mathers JC, Taylor R. Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia 2011;54:2506–2514 7. Jackness C, Karmally W, Febres G, et al. Very low-calorie diet mimics the early beneficial effect of Roux-en-Y gastric bypass on insulin sensitivity and b-cell Function in type 2 diabetic patients. Diabetes 2013;62:3027–3032 8. Rothberg AE, McEwen LN, Kraftson AT, Fowler CE, Herman WH. Very-low-energy diet for type 2 diabetes: an underutilized therapy? J Diabetes Complications 2014;28:506–510 9. Day JW, Ottaway N, Patterson JT, et al. A new glucagon and GLP-1 co-agonist eliminates obesity in rodents. Nat Chem Biol 2009;5:749–757 10. Steven S, Hollingsworth KG, Al-Mrabeh A, et al. Very low-calorie diet and 6 months of weight stability in type 2 diabetes: pathophysiological changes in responders and nonresponders. Diabetes Care 2016;39:808–815 11. WHO Expert Consultation. Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet 2004;363:157–163 12. Araneta MRG, Kanaya A, Fujimoto W, et al. Optimum BMI cut-points to screen Asian Americans for type 2 diabetes: The UCSD Filipino Health Study and the North Kohala Study [Abstract]. Diabetes 2014;63(Suppl. 1):A20 13. Wing RR, Bolin P, Brancati FL, et al.; Look AHEAD Research Group. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med 2013;369:145–154 14. Look AHEAD Research Group. Eight-year weight losses with an intensive lifestyle intervention: the Look AHEAD study. Obesity (Silver Spring) 2014;22:5–13 15. Wilding JPH. The importance of weight management in type 2 diabetes mellitus. Int J Clin Pract 2014;68:682–691 16. Sacks FM, Bray GA, Carey VJ, et al. Comparison of weight-loss diets with different compositions of fat, protein, and carbohydrates. N Engl J Med 2009;360:859–873 17. de Souza RJ, Bray GA, Carey VJ, et al. Effects of 4 weight-loss diets differing in fat, protein, and carbohydrate on fat mass, lean mass, visceral adipose tissue, and hepatic fat: results from the POUNDS LOST trial. Am J Clin Nutr 2012;95:614–625

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18. Johnston BC, Kanters S, Bandayrel K, et al. Comparison of weight loss among named diet programs in overweight and obese adults: a meta-analysis. JAMA 2014;312:923–933 19. Jensen MD, Ryan DH, Apovian CM, et al.; American College of Cardiology/American Heart Association Task Force on Practice Guidelines; Obesity Society. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. J Am Coll Cardiol 2014;63(25 Pt B):2985–3023 20. Raynor HA, Anderson AM, Miller GD, et al.; Look AHEAD Research Group. Partial meal replacement plan and quality of the diet at 1 year: Action for Health in Diabetes (Look AHEAD) Trial. J Acad Nutr Diet 2015;115:731–742 21. U.S. Preventative Services Task Force. Final recommendation statement: abnormal blood glucose and type 2 diabetes mellitus: screening [Internet]. Available from http://www .uspreventiveservicestaskforce.org/page/ document/recommendationstatementfinal/ screening-for-abnormal-blood-glucose-andtype-2-diabetes. Accessed 18 November 2016 22. Gudzune KA, Doshi RS, Mehta AK, et al. Efficacy of commercial weight-loss programs: an updated systematic review. Ann Intern Med 2015;162:501–512 23. Tsai AG, Wadden TA. The evolution of verylow-calorie diets: an update and meta-analysis. Obesity (Silver Spring) 2006;14:1283–1293 24. Johansson K, Neovius M, Hemmingsson E. Effects of anti-obesity drugs, diet, and exercise on weight-loss maintenance after a very-low-calorie diet or low-calorie diet: a systematic review and meta-analysis of randomized controlled trials. Am J Clin Nutr 2014;99:14–23 25. Yanovski SZ, Yanovski JA. Long-term drug treatment for obesity: a systematic and clinical review. JAMA 2014;311:74–86 26. Greenway FL, Fujioka K, Plodkowski RA, et al.; COR-I Study Group. Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2010;376:595–605 27. Pi-Sunyer X, Astrup A, Fujioka K, et al.; SCALE Obesity and Prediabetes NN8022-1839 Study Group. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med 2015;373:11–22 28. Rubino F, Marescaux J. Effect of duodenaljejunal exclusion in a non-obese animal model of type 2 diabetes: a new perspective for an old disease. Ann Surg 2004;239:1–11 29. Rubino F, Nathan DM, Eckel RH, et al.; Delegates of the 2nd Diabetes Surgery Summit. Metabolic surgery in the treatment algorithm for type 2 diabetes: a joint statement by international diabetes organizations. Diabetes Care 2016;39:861–877 30. Sj¨ostr¨om L, Lindroos A-K, Peltonen M, et al.; Swedish Obese Subjects Study Scientific Group. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med 2004;351:2683–2693 31. Sj¨ostr¨om L, Peltonen M, Jacobson P, et al. Association of bariatric surgery with long-term remission of type 2 diabetes and with microvascular

Diabetes Care Volume 40, Supplement 1, January 2017

and macrovascular complications. JAMA 2014;311: 2297–2304 32. Adams TD, Davidson LE, Litwin SE, et al. Health benefits of gastric bypass surgery after 6 years. JAMA 2012;308:1122–1131 33. Sj¨ostr¨om L, Narbro K, Sj¨ostr¨om CD, et al.; Swedish Obese Subjects Study. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med 2007;357:741–752 34. Sj¨ostr¨om L, Gummesson A, Sj¨ostr¨om CD, et al.; Swedish Obese Subjects Study. Effects of bariatric surgery on cancer incidence in obese patients in Sweden (Swedish Obese Subjects Study): a prospective, controlled intervention trial. Lancet Oncol 2009;10:653–662 35. Sj¨ostr¨om L, Peltonen M, Jacobson P, et al. Bariatric surgery and long-term cardiovascular events. JAMA 2012;307:56–65 36. Adams TD, Gress RE, Smith SC, et al. Longterm mortality after gastric bypass surgery. N Engl J Med 2007;357:753–761 37. Arterburn DE, Olsen MK, Smith VA, et al. Association between bariatric surgery and long-term survival. JAMA 2015;313:62–70 38. Rubino F, Kaplan LM, Schauer PR, Cummings DE; Diabetes Surgery Summit Delegates. The Diabetes Surgery Summit consensus conference: recommendations for the evaluation and use of gastrointestinal surgery to treat type 2 diabetes mellitus. Ann Surg 2010;251:399–405 39. Cummings DE, Cohen RV. Beyond BMI: the need for new guidelines governing the use of bariatric and metabolic surgery. Lancet Diabetes Endocrinol 2014;2:175–181 40. Zimmet P, Alberti KGMM, Rubino F, Dixon JB. IDF’s view of bariatric surgery in type 2 diabetes. Lancet 2011;378:108–110 41. Kasama K, Mui W, Lee WJ, et al. IFSO-APC consensus statements 2011. Obes Surg 2012; 22:677–684 42. Sj¨oholm K, Pajunen P, Jacobson P, et al. Incidence and remission of type 2 diabetes in relation to degree of obesity at baseline and 2 year weight change: the Swedish Obese Subjects (SOS) study. Diabetologia 2015;58:1448–1453 43. Arterburn DE, Bogart A, Sherwood NE, et al. A multisite study of long-term remission and relapse of type 2 diabetes mellitus following gastric bypass. Obes Surg 2013;23:93–102 44. Mingrone G, Panunzi S, De Gaetano A, et al. Bariatric-metabolic surgery versus conventional medical treatment in obese patients with type 2 diabetes: 5 year follow-up of an open-label, single-centre, randomised controlled trial. Lancet 2015;386:964–973 45. Cohen RV, Pinheiro JC, Schiavon CA, Salles JE, Wajchenberg BL, Cummings DE. Effects of gastric bypass surgery in patients with type 2 diabetes and only mild obesity. Diabetes Care 2012;35:1420–1428 46. Brethauer SA, Aminian A, Romero-Talam´as H, et al. Can diabetes be surgically cured? Long-term metabolic effects of bariatric surgery in obese patients with type 2 diabetes mellitus. Ann Surg 2013;258:628–636; discussion 636–637 47. Hsu C-C, Almulaifi A, Chen J-C, et al. Effect of bariatric surgery vs medical treatment on type 2 diabetes in patients with body mass index lower than 35: five-year outcomes. JAMA Surg 2015; 150:1117–1124 48. Schauer PR, Bhatt DL, Kirwan JP, et al.; STAMPEDE Investigators. Bariatric surgery versus

intensive medical therapy for diabetes–3-year outcomes. N Engl J Med 2014;370:2002–2013 49. Yu H, Di J, Bao Y, et al. Visceral fat area as a new predictor of short-term diabetes remission after Roux-en-Y gastric bypass surgery in Chinese patients with a body mass index less than 35 kg/m2. Surg Obes Relat Dis 2015;11:6–11 50. Halperin F, Ding S-A, Simonson DC, et al. Roux-en-Y gastric bypass surgery or lifestyle with intensive medical management in patients with type 2 diabetes: feasibility and 1-year results of a randomized clinical trial. JAMA Surg 2014;149:716–726 51. Flum DR, Belle SH, King WC, et al.; Longitudinal Assessment of Bariatric Surgery (LABS) Consortium. Perioperative safety in the Longitudinal Assessment of Bariatric Surgery. N Engl J Med 2009;361:445–454 52. Courcoulas AP, Christian NJ, Belle SH, et al.; Longitudinal Assessment of Bariatric Surgery (LABS) Consortium. Weight change and health outcomes at 3 years after bariatric surgery among individuals with severe obesity. JAMA 2013;310:2416–2425 53. Arterburn DE, Courcoulas AP. Bariatric surgery for obesity and metabolic conditions in adults. BMJ 2014;349:g3961 54. Young MT, Gebhart A, Phelan MJ, Nguyen NT. Use and outcomes of laparoscopic sleeve gastrectomy vs laparoscopic gastric bypass: analysis of the American College of Surgeons NSQIP. J Am Coll Surg 2015;220:880–885 55. Aminian A, Brethauer SA, Kirwan JP, Kashyap SR, Burguera B, Schauer PR. How safe is metabolic/diabetes surgery? Diabetes Obes Metab 2015;17:198–201 56. Birkmeyer NJO, Dimick JB, Share D, et al.; Michigan Bariatric Surgery Collaborative. Hospital complication rates with bariatric surgery in Michigan. JAMA 2010;304:435–442 57. Altieri MS, Yang J, Telem DA, et al. Lap band outcomes from 19,221 patients across centers and over a decade within the state of New York. Surg Endosc 2016;30:1725–1732 58. Hutter MM, Schirmer BD, Jones DB, et al. First report from the American College of Surgeons Bariatric Surgery Center Network: laparoscopic sleeve gastrectomy has morbidity and effectiveness positioned between the band and the bypass. Ann Surg 2011;254:410–420; discussion 420–422 59. Nguyen NT, Slone JA, Nguyen X-MT, Hartman JS, Hoyt DB. A prospective randomized trial of laparoscopic gastric bypass versus laparoscopic adjustable gastric banding for the treatment of morbid obesity: outcomes, quality of life, and costs. Ann Surg 2009;250: 631–641 60. Birkmeyer JD, Finks JF, O’Reilly A, et al.; Michigan Bariatric Surgery Collaborative. Surgical skill and complication rates after bariatric surgery. N Engl J Med 2013;369:1434–1442 61. Kirwan JP, Aminian A, Kashyap SR, Burguera B, Brethauer SA, Schauer PR. Bariatric surgery in obese patients with type 1 diabetes. Diabetes Care 2016;39:941–948 62. Rubin JK, Hinrichs-Krapels S, Hesketh R, Martin A, Herman WH, Rubino F. Identifying barriers to appropriate use of metabolic/ bariatric surgery for type 2 diabetes treatment: Policy Lab results. Diabetes Care 2016; 39:954–963

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63. Fouse T, Schauer P. The socioeconomic impact of morbid obesity and factors affecting access to obesity surgery. Surg Clin North Am 2016;96:669–679 64. Service GJ, Thompson GB, Service FJ, Andrews JC, Collazo-Clavell ML, Lloyd RV. Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery. N Engl J Med 2005;353:249–254 65. Mechanick JI, Kushner RF, Sugerman HJ, et al.; American Association of Clinical Endocrinologists; Obesity Society; American Society for Metabolic & Bariatric Surgery. American Association of Clinical Endocrinologists, The Obesity Society, and American Society for Metabolic & Bariatric Surgery medical guidelines for clinical

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practice for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient. Obesity (Silver Spring) 2009;17 (Suppl. 1):S1–S70 66. Mechanick JI, Youdim A, Jones DB, et al.; American Association of Clinical Endocrinologists; Obesity Society; American Society for Metabolic & Bariatric Surgery. Clinical practice guidelines for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient–2013 update: cosponsored by American Association of Clinical Endocrinologists, The Obesity Society, and American Society for Metabolic & Bariatric Surgery. Obesity (Silver Spring) 2013;21(Suppl. 1): S1–S27

67. Lee CJ, Clark JM, Schweitzer M, et al. Prevalence of and risk factors for hypoglycemic symptoms after gastric bypass and sleeve gastrectomy. Obesity (Silver Spring) 2015;23:1079– 1084 68. Conason A, Teixeira J, Hsu C-H, Puma L, Knafo D, Geliebter A. Substance use following bariatric weight loss surgery. JAMA Surg 2013; 148:145–150 69. Young-Hyman D, Peyrot M. Psychosocial Care for People with Diabetes. 1st ed. Alexandria, VA, American Diabetes Association, 2012 70. Greenberg I, Sogg S, M Perna F. Behavioral and psychological care in weight loss surgery: best practice update. Obesity (Silver Spring) 2009;17:880–884

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8. Pharmacologic Approaches to Glycemic Treatment

American Diabetes Association

Diabetes Care 2017;40(Suppl. 1):S64–S74 | DOI: 10.2337/dc17-S011

PHARMACOLOGIC THERAPY FOR TYPE 1 DIABETES

8. PHARMACOLOGIC APPROACHES TO GLYCEMIC TREATMENT

Recommendations c c c

c

Most people with type 1 diabetes should be treated with multiple daily injections of prandial insulin and basal insulin or continuous subcutaneous insulin infusion. A Most individuals with type 1 diabetes should use rapid-acting insulin analogs to reduce hypoglycemia risk. A Consider educating individuals with type 1 diabetes on matching prandial insulin doses to carbohydrate intake, premeal blood glucose levels, and anticipated physical activity. E Individuals with type 1 diabetes who have been successfully using continuous subcutaneous insulin infusion should have continued access to this therapy after they turn 65 years of age. E

Insulin Therapy

Insulin is the mainstay of therapy for individuals with type 1 diabetes. Generally, the starting insulin dose is based on weight, with doses ranging from 0.4 to 1.0 units/kg/ day of total insulin with higher amounts required during puberty. The American Diabetes Association/JDRF Type 1 Diabetes Sourcebook notes 0.5 units/kg/day as a typical starting dose in patients who are metabolically stable, with higher weight-based dosing required immediately following presentation with ketoacidosis (1), and provides detailed information on intensification of therapy to meet individualized needs. The American Diabetes Association (ADA) position statement “Type 1 Diabetes Management Through the Life Span” additionally provides a thorough overview of type 1 diabetes treatment and associated recommendations (2). Education regarding matching prandial insulin dosing to carbohydrate intake, premeal glucose levels, and anticipated activity should be considered, and selected individuals who have mastered carbohydrate counting should be educated on fat and protein gram estimation (3–5). Although most studies of multiple daily injections (MDI) versus continuous subcutaneous insulin infusion (CSII) have been small and of short duration, a systematic review and meta-analysis concluded that there are minimal differences between the two forms of intensive insulin therapy in A1C (combined mean between-group difference favoring insulin pump therapy 20.30% [95% CI 20.58 to 20.02]) and severe hypoglycemia rates in children and adults (6). A 3-month randomized trial in patients with type 1 diabetes with nocturnal hypoglycemia reported that sensor-augmented insulin pump therapy with the threshold suspend feature reduced nocturnal hypoglycemia without increasing glycated hemoglobin levels (7). Intensive management using CSII and continuous glucose monitoring (CGM) should be encouraged in selected patients when there is active patient/family participation (8–10). The Diabetes Control and Complications Trial (DCCT) clearly showed that intensive therapy with MDI or CSII delivered by multidisciplinary teams of physicians, nurses, dietitians, and behavioral scientists improved glycemia and resulted in better long-term outcomes (11–13). The study was carried out with short-acting and intermediate-acting human insulins. Despite better microvascular, macrovascular, and all-cause mortality outcomes, intensive therapy was associated with a high rate of severe hypoglycemia (61 episodes per 100 patient-years of therapy). Since the DCCT, a number of rapidacting and long-acting insulin analogs have been developed. These analogs are associated with less hypoglycemia in type 1 diabetes, while matching the A1C lowering of human insulins (14,15).

Suggested citation: American Diabetes Association. Pharmacologic approaches to glycemic treatment. Sec. 8. In Standards of Medical Care in Diabetesd2017. Diabetes Care 2017; 40(Suppl. 1):S64–S74 © 2017 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals .org/content/license.

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Rapid-acting inhaled insulin used before meals in type 1 diabetes was shown to be noninferior when compared with aspart insulin for A1C lowering, with less hypoglycemia observed with inhaled insulin therapy (16). However, the mean reduction in A1C was greater with aspart (20.21% vs. 20.40%, satisfying the noninferiority margin of 0.4%), and more patients in the insulin aspart group achieved A1C goals of #7.0% (53 mmol/mol) and #6.5% (48 mmol/mol). Because inhaled insulin cartridges are only available in 4, 8, and 12 unit doses, people with type 1 diabetes may have limited dosing increments to fine-tune prandial insulin doses when using this therapy. Postprandial glucose excursions may be better controlled by adjusting the timing of prandial (bolus) insulin dose administration. The optimal time to administer prandial insulin varies, based on the type of insulin used (regular, rapid-acting analog, inhaled, etc.), the measured blood glucose level, timing of meals, and carbohydrate consumption. Recommendations for prandial insulin dose administration should therefore be individualized. Pramlintide

Pramlintide, an amylin analog, is an agent that delays gastric emptying, blunts pancreatic secretion of glucagon, and enhances satiety. It is U.S. Food and Drug Administration (FDA)–approved for use in adults with type 1 diabetes. It has been shown to induce weight loss and lower insulin doses. Concurrent reduction of prandial insulin dosing is required to reduce the risk of severe hypoglycemia. Pancreas and Islet Transplantation

Pancreas and islet transplantation have been shown to normalize glucose levels but require lifelong immunosuppression to prevent graft rejection and recurrence of autoimmune islet destruction. Given the potential adverse effects of immunosuppressive therapy, pancreas transplantation should be reserved for patients with type 1 diabetes undergoing simultaneous renal transplantation, following renal transplantation, or for those with recurrent ketoacidosis or severe hypoglycemia despite intensive glycemic management (17). Islet transplantation remains investigational. Autoislet transplantation may be considered for patients requiring

Pharmacologic Approaches to Glycemic Treatment

total pancreatectomy for medically refractory chronic pancreatitis.

c

Investigational Agents Metformin

Adding metformin to insulin therapy may reduce insulin requirements and improve metabolic control in overweight/obese patients with poorly controlled type 1 diabetes. In a meta-analysis, metformin in type 1 diabetes was found to reduce insulin requirements (6.6 units/day, P , 0.001) and led to small reductions in weight and total and LDL cholesterol but not to improved glycemic control (absolute A1C reduction 0.11%, P 5 0.42) (18). Metformin is not FDA-approved for use in patients with type 1 diabetes.

c

c

Incretin-Based Therapies

Due to their potential protection of b-cell mass and suppression of glucagon release, glucagon-like peptide 1 (GLP-1) receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors are being studied in patients with type 1 diabetes but are not currently FDAapproved for use in patients with type 1 diabetes. Sodium–Glucose Cotransporter 2 Inhibitors

Sodium–glucose cotransporter 2 (SGLT2) inhibitors provide insulin-independent glucose lowering by blocking glucose reabsorption in the proximal renal tubule by inhibiting SGLT2. These agents provide modest weight loss and blood pressure reduction in type 2 diabetes. There are three FDA-approved agents for patients with type 2 diabetes, but none are FDAapproved for the treatment of patients with type 1 diabetes (2). The FDA issued a warning about the risk of ketoacidosis occurring in the absence of significant hyperglycemia (euglycemic diabetic ketoacidosis) in patients with type 1 and type 2 diabetes treated with SGLT2 inhibitors. Symptoms of ketoacidosis include dyspnea, nausea, vomiting, and abdominal pain. Patients should be instructed to stop taking SGLT2 inhibitors and seek medical attention immediately if they have symptoms or signs of ketoacidosis (19). PHARMACOLOGIC THERAPY FOR TYPE 2 DIABETES Recommendations c

Metformin, if not contraindicated and if tolerated, is the preferred initial pharmacologic agent for the treatment of type 2 diabetes. A

c

c

c

Long-term use of metformin may be associated with biochemical vitamin B12 deficiency, and periodic measurement of vitamin B12 levels should be considered in metformin-treated patients, especially in those with anemia or peripheral neuropathy. B Consider initiating insulin therapy (with or without additional agents) in patients with newly diagnosed type 2 diabetes who are symptomatic and/or have A1C $10% (86 mmol/mol) and/or blood glucose levels $300 mg/dL (16.7 mmol/L). E If noninsulin monotherapy at maximum tolerated dose does not achieve or maintain the A1C target after 3 months, add a second oral agent, a glucagon-like peptide 1 receptor agonist, or basal insulin. A A patient-centered approach should be used to guide the choice of pharmacologic agents. Considerations include efficacy, hypoglycemia risk, impact on weight, potential side effects, cost, and patient preferences. E For patients with type 2 diabetes who are not achieving glycemic goals, insulin therapy should not be delayed. B In patients with long-standing suboptimally controlled type 2 diabetes and established atherosclerotic cardiovascular disease, empagliflozin or liraglutide should be considered as they have been shown to reduce cardiovascular and all-cause mortality when added to standard care. Ongoing studies are investigating the cardiovascular benefits of other agents in these drug classes. B

The use of metformin as first-line therapy was supported by findings from a large meta-analysis, with selection of second-line therapies based on patient-specific considerations (20). An ADA/European Association for the Study of Diabetes position statement (21) recommended a patient-centered approach, including assessment of efficacy, hypoglycemia risk, impact on weight, side effects, costs, and patient preferences. Renal effects may also be considered when selecting glucose-lowering medications for individual patients. Lifestyle modifications that improve health

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Pharmacologic Approaches to Glycemic Treatment

(see Section 4 “Lifestyle Management”) should be emphasized along with any pharmacologic therapy. Initial Therapy

Metformin monotherapy should be started at diagnosis of type 2 diabetes unless there are contraindications. Metformin is effective and safe, is inexpensive, and may reduce risk of cardiovascular events and death (22). Metformin may be safely used in patients with estimated glomerular filtration rate (eGFR) as low as 30 mL/min/1.73 m2 (23), and the U.S. label for metformin was recently revised to reflect its safety in patients with eGFR $30 mL/min/1.73 m2 (24). Patients should be advised to stop the

Diabetes Care Volume 40, Supplement 1, January 2017

medication in cases of nausea, vomiting, or dehydration. Metformin is associated with vitamin B12 deficiency, with a recent report from the Diabetes Prevention Program Outcomes Study (DPPOS) suggesting that periodic testing of vitamin B12 levels should be considered in metformin-treated patients, especially in those with anemia or peripheral neuropathy (25). In patients with metformin contraindications or intolerance, consider an initial drug from another class depicted in Fig. 8.1 under “Dual Therapy” and proceed accordingly. When A1C is $9% (75 mmol/mol), consider initiating dual combination therapy (Fig. 8.1) to more expeditiously achieve the target A1C level. Insulin has the advantage of being

effective where other agents may not be and should be considered as part of any combination regimen when hyperglycemia is severe, especially if symptoms are present or any catabolic features (weight loss, ketosis) are present. Consider initiating combination insulin injectable therapy (Fig. 8.2) when blood glucose is $300 mg/dL (16.7 mmol/L) or A1C is $10% (86 mmol/mol) or if the patient has symptoms of hyperglycemia (i.e., polyuria or polydipsia). As the patient’s glucose toxicity resolves, the regimen may, potentially, be simplified. Combination Therapy

Although there are numerous trials comparing dual therapy with metformin alone,

Figure 8.1—Antihyperglycemic therapy in type 2 diabetes: general recommendations. The order in the chart was determined by historical availability and the route of administration, with injectables to the right; it is not meant to denote any specific preference. Potential sequences of antihyperglycemic therapy for patients with type 2 diabetes are displayed, with the usual transition moving vertically from top to bottom (although horizontal movement within therapy stages is also possible, depending on the circumstances). DPP-4-i, DPP-4 inhibitor; fxs, fractures; GI, gastrointestinal; GLP-1 RA, GLP-1 receptor agonist; GU, genitourinary; HF, heart failure; Hypo, hypoglycemia; SGLT2-i, SGLT2 inhibitor; SU, sulfonylurea; TZD, thiazolidinedione. *See ref. 21 for description of efficacy and cost categorization. §Usually a basal insulin (NPH, glargine, detemir, degludec). Adapted with permission from Inzucchi et al. (21).

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Pharmacologic Approaches to Glycemic Treatment

Figure 8.2—Combination injectable therapy for type 2 diabetes. FBG, fasting blood glucose; GLP-1 RA, GLP-1 receptor agonist; hypo, hypoglycemia. Adapted with permission from Inzucchi et al. (21).

few directly compare drugs as add-on therapy. A comparative effectiveness metaanalysis (23) suggests that each new class of noninsulin agents added to initial therapy generally lowers A1C approximately 0.9–1.1%. If the A1C target is not achieved after approximately 3 months, consider a combination of metformin and one of

the six available treatment options: sulfonylurea, thiazolidinedione, DPP-4 inhibitor, SGLT2 inhibitor, GLP-1 receptor agonist, or basal insulin (Fig. 8.1). If A1C target is still not achieved after ;3 months of dual therapy, proceed to three-drug combination (Fig. 8.1). Again, if A1C target is not achieved after

;3 months of triple therapy, proceed to combination injectable therapy (Fig. 8.2). Drug choice is based on patient preferences (26), as well as various patient, disease, and drug characteristics, with the goal of reducing blood glucose levels while minimizing side effects, especially

S67

Acarbose Miglitol

c

Binds bile acids in intestinal tract, increasing hepatic bile acid production

c

Bile acid sequestrants

Colesevelam

Inhibits DPP-4 activity, increasing postprandial incretin (GLP-1, GIP) concentrations

c

Sitagliptin Saxagliptin c Linagliptin c Alogliptin

Inhibits intestinal a-glucosidase

DPP-4 inhibitors

c

c

Slows intestinal carbohydrate digestion/absorption

↑ Insulin sensitivity

↓ Postprandial glucose excursions c Dosing flexibility

↑ Insulin secretion

c

? ↓ Hepatic glucose production c ? ↑ Incretin levels

↑ Insulin secretion (glucose dependent) c ↓ Glucagon secretion (glucose dependent) c

c

c

Extensive experience ↓ Microvascular risk (UKPDS) c Relatively higher A1C efficacy

Rare hypoglycemia Relatively higher A1C efficacy c Durability c ↓ Triglycerides (pioglitazone) c ? ↓ CVD events (PROactive, pioglitazone) c ↓ Risk of stroke and MI in patients without diabetes and with insulin resistance and history of recent stroke or TIA (IRIS study [42], pioglitazone)

c

c

c

c

Rare hypoglycemia ↓ LDL-C

Rare hypoglycemia Well tolerated

Rare hypoglycemia ↓ Postprandial glucose excursions c ? ↓ CVD events in prediabetes (STOP-NIDDM) c Nonsystemic c

c

c

c

c

c

c

↑ Insulin secretion

Extensive experience Rare hypoglycemia c ↓ CVD events (UKPDS) c Relatively higher A1C efficacy c

c

↓ Hepatic glucose production

Hypoglycemia ↑ Weight

Hypoglycemia ↑ Weight c Frequent dosing schedule ↑ Weight Edema/heart failure c Bone fractures c ↑ LDL-C (rosiglitazone)

Generally modest A1C efficacy Gastrointestinal side effects (flatulence, diarrhea) c Frequent dosing schedule

Modest A1C efficacy Constipation c ↑ Triglycerides c May ↓ absorption of other medications c

c

High

High

Low to moderate

Low

Moderate

Low

Low

Continued on p. S69

Angioedema/urticaria and other immune-mediated dermatological effects c ? Acute pancreatitis c ↑ Heart failure hospitalizations (saxagliptin; ? alogliptin)

c

c

c

c

c

c

c

c

c

Gastrointestinal side effects (diarrhea, abdominal cramping, nausea) c Vitamin B12 deficiency c Contraindications: eGFR ,30 mL/min/1.73 m2, acidosis, hypoxia, dehydration, etc. c Lactic acidosis risk (rare)

c

Cost*

Pharmacologic Approaches to Glycemic Treatment

a-Glucosidase inhibitors

Activates the nuclear transcription factor PPAR-g

Pioglitazone‡ Rosiglitazone§

c

c

TZDs

c

Closes KATP channels on b-cell plasma membranes

Repaglinide Nateglinide

c

c

Meglitinides (glinides)

c

Closes KATP channels on b-cell plasma membranes

2nd generation c Glyburide c Glipizide c Glimepiride

Sulfonylureas

c

Metformin

Activates AMP-kinase (? other)

c

Biguanides

Table 8.1—Properties of available glucose-lowering agents in the U.S. that may guide individualized treatment choices in patients with type 2 diabetes (21) Primary physiological Class Compound(s) Cellular mechanism(s) action(s) Advantages Disadvantages

S68 Diabetes Care Volume 40, Supplement 1, January 2017

c

Activates GLP-1 receptors Exenatide Exenatide extended release c Liraglutide c Albiglutide c Lixisenatide c Dulaglutide

c

c Rapid-acting analogs

Amylin mimetics

Insulins

- Lispro - Aspart - Glulisine - Inhaled insulin c Short-acting - Human Regular c Intermediate-acting - Human NPH

Pramlintide§

c

GLP-1 receptor agonists

Activates insulin receptors

Activates amylin receptors

Inhibits SGLT2 in the proximal nephron

Canagliflozin Dapagliflozin‡ c Empagliflozin

c

c

Activates dopaminergic receptors

SGLT2 inhibitors

Bromocriptine (quick release)§

Cellular mechanism(s)

c

Compound(s)

Dopamine-2 agonists

Class

Table 8.1—Continued

Rare hypoglycemia ? ↓ CVD events (Cycloset Safety Trial)

Rare hypoglycemia ↓ Weight c ↓ Blood pressure c Associated with lower CVD event rate and mortality in patients with CVD (empagliflozin EMPA-REG OUTCOME)

↓ Postprandial glucose excursions ↓ Weight

↓ Glucagon secretion Slows gastric emptying c ↑ Satiety

c

c

↑ Glucose disposal ↓ Hepatic glucose production c Suppresses ketogenesis

c

c

Rare hypoglycemia ↓ Weight c ↓ Postprandial glucose excursions c ↓ Some cardiovascular risk factors c Associated with lower CVD event rate and mortality in patients with CVD (liraglutide LEADER) (30)

Nearly universal response Theoretically unlimited efficacy c ↓ Microvascular risk (UKPDS) c

c

c

c

c

c

c

c

c

c

Advantages

↑ Insulin secretion (glucose dependent) c ↓ Glucagon secretion (glucose dependent) c Slows gastric emptying c ↑ Satiety c

by the kidney, increasing glucosuria

c Blocks glucose reabsorption

Modulates hypothalamic regulation of metabolism c ↑ Insulin sensitivity

c

Primary physiological action(s)

Genitourinary infections Polyuria c Volume depletion/hypotension/dizziness c ↑ LDL-C c ↑ Creatinine (transient) c DKA, urinary tract infections leading to urosepsis, pyelonephritis

Modest A1C efficacy Gastrointestinal side effects (nausea/vomiting) c Hypoglycemia unless insulin dose is simultaneously reduced c Injectable c Frequent dosing schedule c Training requirements

High#

High

High

High

High

Cost*

Continued on p. S70

Hypoglycemia Weight gain c Training requirements c Patient and provider reluctance c Injectable (except inhaled insulin) c Pulmonary toxicity (inhaled insulin) c

c

c

c

Gastrointestinal side effects (nausea/vomiting/diarrhea) c ↑ Heart rate c ? Acute pancreatitis c C-cell hyperplasia/medullary thyroid tumors in animals c Injectable c Training requirements

c

c

c

c

Modest A1C efficacy Dizziness/syncope c Nausea c Fatigue c Rhinitis

c

Disadvantages

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Basal insulin analogs - Glargine - Detemir - Degludec c Premixed insulin products - NPH/Regular 70/30 270/30 aspart mix 275/25 lispro mix 250/50 lispro mix

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CVD, cardiovascular disease; EMPA-REG OUTCOME, BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (29); GIP, glucose-dependent insulinotropic peptide; HDL-C, HDL cholesterol; IRIS, Insulin Resistance Intervention After Stroke Trial; LDL-C, LDL cholesterol; PPAR-g, peroxisome proliferator–activated receptor g; PROactive, Prospective Pioglitazone Clinical Trial in Macrovascular Events (43); STOP-NIDDM, Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (44); TIA, transient ischemic attack; TZD, thiazolidinedione; UKPDS, UK Prospective Diabetes Study (45,46). Cycloset trial of quick-release bromocriptine (47). *Cost is based on lowest-priced member of the class (21). ‡lnitial concerns regarding bladder cancer risk are decreasing after subsequent study. §Not licensed in Europe for type 2 diabetes. #Cost is highly dependent on type/brand (analogs . human insulins) and dosage. Adapted with permission from Inzucchi et al. (21).

Class

c

Compound(s)

Cellular mechanism(s)

Primary physiological action(s)

Advantages

Disadvantages

Cost*

Pharmacologic Approaches to Glycemic Treatment

Table 8.1—Continued

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hypoglycemia. Table 8.1 lists drugs commonly used in the U.S. Cost-effectiveness models have suggested that some of the newer agents may be of relatively lower clinical utility based on high cost and moderate glycemic effect (27). Table 8.2 provides cost information for currently approved noninsulin therapies. Of note, prices listed are average wholesale prices (AWP) and do not account for discounts, rebates, or other price adjustments often involved in prescription sales that affect the actual cost incurred by the patient. While there are alternative means to estimate medication prices, AWP was utilized to provide a comparison of list prices with the primary goal of highlighting the importance of cost considerations when prescribing antihyperglycemic treatments. The ongoing Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) will compare four drug classes (sulfonylurea, DPP-4 inhibitor, GLP-1 receptor agonist, and basal insulin) when added to metformin therapy over 4 years on glycemic control and other medical, psychosocial, and health economic outcomes (28). Rapid-acting secretagogues (meglitinides) may be used instead of sulfonylureas in patients with sulfa allergies, irregular meal schedules, or those who develop late postprandial hypoglycemia when taking a sulfonylurea. Other drugs not shown in Fig. 8.1 (e.g., inhaled insulin, a-glucosidase inhibitors, colesevelam, bromocriptine, and pramlintide) may be tried in specific situations but are not often used due to modest efficacy in type 2 diabetes, the frequency of administration, the potential for drug interactions, and/or side effects. Cardiovascular Outcome Trials

Several recently published cardiovascular outcome trials (CVOTs) have provided data on patients with type 2 diabetes with cardiovascular disease or at high risk for cardiovascular disease. The BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) was a randomized, double-blind trial that assessed the effect of empagliflozin, a SGLT2 inhibitor, versus placebo and standard care, on cardiovascular outcomes in patients with type 2 diabetes and existing cardiovascular disease. Study participants had a mean age of 63 years, 57% had diabetes for more than 10 years, and 99%

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Pharmacologic Approaches to Glycemic Treatment

Table 8.2—Median monthly cost of maximum approved daily dose of noninsulin glucose-lowering agents in the U.S. (48) Class

Compound(s)

Dosage strength/product (if applicable)

Median AWP (min, max)†

Maximum approved daily dose*

Biguanides

c

Metformin

500 mg (IR) 850 mg (IR) 1,000 mg (IR) 500 mg (ER) 750 mg (ER) 1,000 mg (ER)

$84 ($5, $94) $108 ($5, $108) $86 ($4, $87) $90 ($82, $6,672) $72 ($65, $92) $1,028 ($1,010, $7,213)

2,000 mg 2,550 mg 2,000 mg 2,000 mg 1,500 mg 2,000 mg

Sulfonylureas (2nd Gen)

c

Glyburide

5 mg 6 mg (micronized)

$94 ($64, $103) $50 ($48, $71)

20 mg 12 mg (micronized)

c

Glipizide

10 mg (IR) 10 mg (XL)

$74 ($67, $97) $97

40 mg (IR) 20 mg (XL)

c

Glimepiride

4 mg

$74 ($71, $198)

8 mg

Repaglinide c Nateglinide c Pioglitazone c Rosiglitazone

2 mg 120 mg 45 mg 4 mg

$799 ($163, $878) $156 $349 ($348, $349) $355

16 mg 360 mg 45 mg 8 mg

c

Acarbose Miglitol

100 mg 100 mg

$104 ($104, 105) $241

300 mg 300 mg

Sitagliptin Saxagliptin c Linagliptin c Alogliptin

100 mg 5 mg 5 mg 25 mg

$436 $436 $428 $436

100 mg 5 mg 5 mg 25 mg

625 mg tabs 1.875 g suspension

$679 $1,357

3.75 g 3.75 g

Meglitinides (glinides) TZDs a-Glucosidase inhibitors

c

c

DPP-4 inhibitors

c c

Bile acid sequestrant

c

Colesevelam Bromocriptine

Dopamine-2 agonists

c

0.8 mg

$719

4.8 mg

SGLT2 inhibitors

c

300 mg 10 mg 25 mg

$470 $470 $470

300 mg 10 mg 25 mg

GLP-1 receptor agonists

c

10 mg pen 2 mg powder for suspension or pen

$729 $692

20 mg 2 mg**

18 mg/3 mL pen 50 mg pen 1.5/0.5 mL pen

$831 $527 $690

1.8 mg 50 mg** 1.5 mg**

120 mg pen

$2,124

120 mg/injection††

Canagliflozin c Dapagliflozin c Empagliflozin Exenatide Exenatide (extended-release) c Liraglutide c Albiglutide c Dulaglutide c

Amylin mimetics

c

Pramlintide

ER and XL, extended release; IR, immediate release; TZD, thiazolidinedione. †Calculated for 30 day supply (AWP unit price 3 number of doses required to provide maximum approved daily dose 3 30 days); median AWP listed alone when only one product and/or price. *Utilized to calculate median AWP (min, max); generic prices used, if available commercially. **Administered once weekly. ††AWP calculated based on 120 mg three times daily.

had established cardiovascular disease. EMPA-REG OUTCOME showed that over a median follow-up of 3.1 years, treatment reduced the composite outcome of MI, stroke, and cardiovascular death by 14% (absolute rate 10.5% vs. 12.1% in the placebo group) and cardiovascular death by 38% (absolute rate 3.7% vs. 5.9%) (29). The FDA recently added a new indication for empagliflozin, to reduce the risk of cardiovascular death in adults with type 2 diabetes and cardiovascular disease. Whether other SGLT2 inhibitors will have the same effect in high-risk patients and whether empagliflozin or other SGLT2 inhibitors will have a similar effect in lower-risk patients with diabetes remains unknown. The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results: A Long Term Evaluation

(LEADER) trial was a randomized doubleblind trial that assessed the effect of liraglutide, a GLP-1 receptor agonist, versus placebo and standard care, on cardiovascular outcomes in patients with type 2 diabetes at high risk for cardiovascular disease or with cardiovascular disease. Study participants had a mean age of 64 years and a mean duration of diabetes of nearly 13 years. Over 80% of study participants had established cardiovascular disease inclusive of a prior myocardial infarction (MI), prior stroke or transient ischemic attack, prior revascularization procedure, or $50% stenosis of coronary, carotid, or lower-extremity arteries. LEADER showed that the composite primary outcome (MI, stroke, or cardiovascular death) occurred in fewer participants in the treatment group (13.0%) when compared with

the placebo group (14.9%) after a median follow-up of 3.8 years (30). Whether other GLP-1 receptor agonists will have the same effect in high-risk patients or if this drug class will have similar effects in lower-risk patients with diabetes remains unknown. CVOT data for the DPP-4 inhibitors sitagliptin (31), saxagliptin (32), and alogliptin (33) have also been reported, with no significant difference in rates of major cardiovascular events noted between treatment and placebo groups in any of these trials. Insulin Therapy

Many patients with type 2 diabetes eventually require and benefit from insulin therapy. The progressive nature of type 2 diabetes should be regularly and objectively explained to patients. Providers

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should avoid using insulin as a threat or describing it as a sign of personal failure or punishment. Equipping patients with an algorithm for self-titration of insulin doses based on selfmonitoring of blood glucose (SMBG) improves glycemic control in patients with type 2 diabetes initiating insulin (34). Comprehensive education regarding SMBG, diet, and the avoidance of and appropriate treatment of hypoglycemia are critically important in any patient using insulin. Basal Insulin

Basal insulin alone is the most convenient initial insulin regimen, beginning at 10 units per day or 0.1–0.2 units/kg/day, depending on the degree of hyperglycemia. Basal insulin is usually prescribed in conjunction with metformin and sometimes one additional noninsulin agent. While there is evidence for reduced risk of hypoglycemia with newer, longer-acting basal insulin analogs, people with type 2 diabetes

Diabetes Care Volume 40, Supplement 1, January 2017

recommended starting dose of mealtime insulin is 4 units, 0.1 U/kg, or 10% of the basal dose. If A1C is ,8% (64 mmol/mol) when starting mealtime bolus insulin, consideration should be given to decreasing the basal insulin dose.

without a history of hypoglycemia may use NPH insulin safely and at much lower cost (27,35). Table 8.3 provides average wholesale price information (cost per 1,000 units) for currently available insulin products in the U.S. There have been substantial increases in the price of insulin over the past decade and the cost-effectiveness of different antihyperglycemic agents is an important consideration when selecting therapies (36). A follow-on U-100 (100 units/mL) glargine product (basaglar) is now available in the U.S. This product was approved through an abbreviated FDA approval pathway based, in part, on the FDA’s finding of safety and effectiveness for the reference U-100 glargine product.

Premixed insulin products contain both a basal and prandial component, allowing coverage of both basal and prandial needs with a single injection. NPH/Regular 70/30 insulin, for example, is composed of 70% NPH insulin and 30% regular insulin. The use of premixed insulin products has its advantages and disadvantages, as discussed below in COMBINATION INJECTABLE THERAPY.

Bolus Insulin

Concentrated Insulin Products

Many individuals with type 2 diabetes may require mealtime bolus insulin dosing in addition to basal insulin. Rapid-acting analogs are preferred due to their prompt onset of action after dosing. The

Several concentrated insulin preparations are currently available. U-500 regular insulin, by definition, is five times as concentrated as U-100 regular insulin and has a delayed onset and longer duration of

Premixed Insulin

Table 8.3—Median cost of insulins in the U.S. calculated as average wholesale price per 1,000 units of specified dosage form/product (48) Insulins

Compounds

Dosage form/product

Median AWP package price (min, max)*

Rapid-acting analogs c

Lispro

c

Aspart

c

Glulisine

c

Inhaled insulin

U-100 vial U-100 3 mL cartridges U-100 prefilled pen; U-200 prefilled pen U-100 vial U-100 3 mL cartridges U-100 prefilled pen U-100 vial U-100 prefilled pen Inhalation cartridges

c

Human Regular

U-100 vial

$165

c

Human NPH

U-100 vial U-100 prefilled pen

$165 $350

c

U-500 Human Regular insulin

U-500 vial U-500 prefilled pen

$165 $213

Glargine Detemir c Degludec

U-100 vial; U-100 prefilled pen; U-300 prefilled pen U-100 vial; U-100 prefilled pen U-100 prefilled pen; U-200 prefilled pen

$298 $323 $355

c

NPH/Regular 70/30

c

Lispro 50/50

c

Lispro 75/25

c

Aspart 70/30

U-100 vial U-100 prefilled pen U-100 vial U-100 prefilled pen U-100 vial U-100 prefilled pen U-100 vial U-100 prefilled pen

$165 $350 $317 $394 $317 $394 $318 $395

$306 $306 ($306, $379) $394 $306 $380 $395 $283 $365 $557 ($453, $754)

Short-acting Intermediate-acting

Concentrated Human Regular insulin

Basal analogs c c

Premixed products

AWP listed alone when only one product and/or price.

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action than U-100 regular, posessing both prandial and basal properties. U-300 glargine and U-200 degludec are three and two times as concentrated as their U-100 formulations, have longer durations of action, and allow higher doses of basal insulin administration per volume used. The FDA has also approved a concentrated formulation of rapid-acting insulin lispro, U-200 (200 units/mL). These concentrated preparations may be more comfortable for the patient and may improve adherence for patients with insulin resistance who require large doses of insulin. While U-500 regular insulin is available in both prefilled pens and vials (a dedicated syringe was FDA approved in July 2016), other concentrated insulins are available only in prefilled pens to minimize the risk of dosing errors. Inhaled Insulin

Inhaled insulin is available for prandial use with a more limited dosing range. It is contraindicated in patients with chronic lung disease such as asthma and chronic obstructive pulmonary disease and is not recommended in patients who smoke or who recently stopped smoking. It requires spirometry (FEV1) testing to identify potential lung disease in all patients prior to and after starting therapy. Combination Injectable Therapy

If basal insulin has been titrated to an acceptable fasting blood glucose level (or if the dose is .0.5 units/kg/day) and A1C remains above target, consider advancing to combination injectable therapy (Fig. 8.2). When initiating combination injectable therapy, metformin therapy should be maintained while other oral agents may be discontinued on an individual basis to avoid unnecessarily complex or costly regimens (i.e., adding a fourth antihyperglycemic agent). In general, GLP-1 receptor agonists should not be discontinued with the initiation of basal insulin. Sulfonylureas, DPP-4 inhibitors, and GLP-1 receptor agonists are typically stopped once more complex insulin regimens beyond basal are used. In patients with suboptimal blood glucose control, especially those requiring large insulin doses, adjunctive use of a thiazolidinedione or SGLT2 inhibitor may help to improve control and reduce the amount of insulin needed, though potential side effects should be considered. Once an insulin regimen is initiated, dose titration is

Pharmacologic Approaches to Glycemic Treatment

important with adjustments made in both mealtime and basal insulins based on the blood glucose levels and an understanding of the pharmacodynamic profile of each formulation (pattern control). Studies have demonstrated the noninferiority of basal insulin plus a single injection of rapid-acting insulin at the largest meal relative to basal insulin plus a GLP-1 receptor agonist relative to two daily injections of premixed insulins (Fig. 8.2). Basal insulin plus GLP-1 receptor agonists are associated with less hypoglycemia and with weight loss instead of weight gain but may be less tolerable and have a greater cost (37,38). In November 2016, the FDA approved two different once-daily combination products containing basal insulin plus a GLP-1 receptor agonist: insulin glargine plus lixisenatide and insulin degludec plus liraglutide. Other options for treatment intensification include adding a single injection of rapid-acting insulin analog (lispro, aspart, or glulisine) before the largest meal or stopping the basal insulin and initiating a premixed (or biphasic) insulin (NPH/Regular 70/30, 70/30 aspart mix, 75/25 or 50/50 lispro mix) twice daily, usually before breakfast and before dinner. Each approach has its advantages and disadvantages. For example, providers may wish to consider regimen flexibility when devising a plan for the initiation and adjustment of insulin therapy in people with type 2 diabetes, with rapid-acting insulin offering greater flexibility in terms of meal planning than premixed insulin. If one regimen is not effective (i.e., basal insulin 1 GLP-1 receptor agonist), consider switching to another regimen to achieve A1C targets (i.e., basal insulin 1 single injection of rapid-acting insulin or premixed insulin twice daily) (39,40). Regular human insulin and human NPH/Regular premixed formulations (70/30) are less costly alternatives to rapid-acting insulin analogs and premixed insulin analogs, respectively, but their pharmacodynamic profiles may make them less optimal. Figure 8.2 outlines these options, as well as recommendations for further intensification, if needed, to achieve glycemic goals. If a patient is still above the A1C target on premixed insulin twice daily, consider switching to premixed analog insulin three times daily (70/30 aspart mix, 75/25 or 50/50 lispro mix). In general, three times daily premixed analog insulins have been found to be noninferior to basal-bolus regimens with

similar rates of hypoglycemia (41). If a patient is still above the A1C target on basal insulin 1 single injection of rapidacting insulin before the largest meal, advance to a basal-bolus regimen with $2 injections of rapid-acting insulin before meals. Consider switching patients from one regimen to another (i.e., premixed analog insulin three times daily to basalbolus regimen or vice-versa) if A1C targets are not being met and/or depending on other patient considerations (39,40). References 1. American Diabetes Association, JDRF. American Diabetes Association/JDRF Type 1 Diabetes Sourcebook. Peters AL, Laffel L, Eds. Alexandria, VA, American Diabetes Association, 2013 2. Chiang JL, Kirkman MS, Laffel LMB, Peters AL. Type 1 diabetes through the life span: a position statement of the American Diabetes Association. Diabetes Care 2014;37:2034–2054 3. Wolpert HA, Atakov-Castillo A, Smith SA, Steil GM. Dietary fat acutely increases glucose concentrations and insulin requirements in patients with type 1 diabetes: implications for carbohydrate-based bolus dose calculation and intensive diabetes management. Diabetes Care 2013;36:810–816 4. Bell KJ, Toschi E, Steil GM, Wolpert HA. Optimized mealtime insulin dosing for fat and protein in type 1 diabetes: application of a model-based approach to derive insulin doses for open-loop diabetes management. Diabetes Care 2016;39:1631–1634 5. Bell KJ, Smart CE, Steil GM, Brand-Miller JC, King B, Wolpert HA. Impact of fat, protein, and glycemic index on postprandial glucose control in type 1 diabetes: implications for intensive diabetes management in the continuous glucose monitoring era. Diabetes Care 2015;38:1008–1015 6. Yeh H-C, Brown TT, Maruthur N, et al. Comparative effectiveness and safety of methods of insulin delivery and glucose monitoring for diabetes mellitus: a systematic review and meta-analysis. Ann Intern Med 2012;157:336–347 7. Bergenstal RM, Klonoff DC, Garg SK, et al.; ASPIRE In-Home Study Group. Threshold-based insulin-pump interruption for reduction of hypoglycemia. N Engl J Med 2013;369:224–232 8. Wood JR, Miller KM, Maahs DM, et al.; T1D Exchange Clinic Network. Most youth with type 1 diabetes in the T1D Exchange Clinic Registry do not meet American Diabetes Association or International Society for Pediatric and Adolescent Diabetes clinical guidelines. Diabetes Care 2013;36:2035–2037 9. Kmietowicz Z Insulin pumps improve control and reduce complications in children with type 1 diabetes. BMJ 2013;347:f5154 10. Phillip M, Battelino T, Atlas E, et al. Nocturnal glucose control with an artificial pancreas at a diabetes camp. N Engl J Med 2013;368:824–833 11. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977–986

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12. Nathan DM, Cleary PA, Backlund J-YC, et al.; Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005;353:2643–2653 13. Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Study Research Group. Mortality in type 1 diabetes in the DCCT/EDIC versus the general population. Diabetes Care 2016;39:1378–1383 14. DeWitt DE, Hirsch IB. Outpatient insulin therapy in type 1 and type 2 diabetes mellitus: scientific review. JAMA 2003;289:2254–2264 15. Rosenstock J, Dailey G, Massi-Benedetti M, Fritsche A, Lin Z, Salzman A. Reduced hypoglycemia risk with insulin glargine: a meta-analysis comparing insulin glargine with human NPH insulin in type 2 diabetes. Diabetes Care 2005;28:950–955 16. Bode BW, McGill JB, Lorber DL, Gross JL, Chang PC, Bregman DB; Affinity 1 Study Group. Inhaled technosphere insulin compared with injected prandial insulin in type 1 diabetes: a randomized 24-week trial. Diabetes Care 2015;38:2266–2273 17. American Diabetes Association. Pancreas and islet transplantation in type 1 diabetes. Diabetes Care 2006;29:935 18. Vella S, Buetow L, Royle P, Livingstone S, Colhoun HM, Petrie JR. The use of metformin in type 1 diabetes: a systematic review of efficacy. Diabetologia 2010;53:809–820 19. –U.S. Food and Drug Administration. SGLT2 Inhibitors: Drug Safety Communication - Labels to Include Warnings About Too Much Acid in the Blood and Serious Urinary Tract Infections [Internet]. Available from http://www.fda .gov/safety/medwatch/safetyinformation/ safetyalertsforhumanmedicalproducts/ucm475553 .htm. Accessed 3 October 2016 20. Palmer SC, Mavridis D, Nicolucci A, et al. Comparison of clinical outcomes and adverse events associated with glucose-lowering drugs in patients with type 2 diabetes: a meta-analysis. JAMA 2016;316:313–324 21. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2015;38:140–149 22. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HAW. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359: 1577–1589 23. Bennett WL, Maruthur NM, Singh S, et al. Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations. Ann Intern Med 2011;154:602–613 24. U.S. Food and Drug Administration. Metformincontaining Drugs: Drug Safety Communication Revised Warnings for Certain Patients With Reduced Kidney Function [Internet]. Available from http://www.fda.gov/Safety/MedWatch/

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SafetyInformation/SafetyAlertsforHumanMedical Products/ucm494829.htm?source5govdelivery& utm_medium5email&utm_source5govdelivery. Accessed 3 October 2016 25. Aroda VR, Edelstein SL, Goldberg RB, et al.; Diabetes Prevention Program Research Group. Long-term metformin use and vitamin B12 deficiency in the Diabetes Prevention Program Outcomes Study. J Clin Endocrinol Metab 2016;101: 1754–1761 26. Vijan S, Sussman JB, Yudkin JS, Hayward RA. Effect of patients’ risks and preferences on health gains with plasma glucose level lowering in type 2 diabetes mellitus. JAMA Intern Med 2014;174:1227–1234 27. Institute for Clinical and Economic Review. Controversies in the Management of Patients with Type 2 Diabetes [Internet]. Available from http://icer-review.org/wp-content/uploads/2015/ 03/CEPAC-T2D-Final-Report-December-22.pdf. Accessed 17 November 2016 28. Nathan DM, Buse JB, Kahn SE, et al.; GRADE Study Research Group. Rationale and design of the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE). Diabetes Care 2013;36:2254–2261 29. Zinman B, Wanner C, Lachin JM, et al.; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117– 2128 30. Marso SP, Daniels GH, Brown-Frandsen K, et al.; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311–322 31. Green JB, Bethel MA, Armstrong PW, et al.; TECOS Study Group. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015;373:232–242 32. Scirica BM, Bhatt DL, Braunwald E, et al.; SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369:1317–1326 33. White WB, Cannon CP, Heller SR, et al.; EXAMINE Investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013;369:1327–1335 34. Blonde L, Merilainen M, Karwe V, Raskin P; TITRATE Study Group. Patient-directed titration for achieving glycaemic goals using a once-daily basal insulin analogue: an assessment of two different fasting plasma glucose targets - the TITRATE study. Diabetes Obes Metab 2009;11: 623–631 35. Tricco AC, Ashoor HM, Soobiah C, et al. Safety, effectiveness, and cost of long-acting versus intermediate-acting insulin for type 1 diabetes: protocol for a systematic review and network meta-analysis. Syst Rev 2013;2:73 36. Hua X, Carvalho N, Tew M, Huang ES, Herman WH, Clarke P. Expenditures and prices of antihyperglycemic medications in the United States: 2002-2013. JAMA 2016;315: 1400–1402

37. Diamant M, Nauck MA, Shaginian R, et al.; 4B Study Group. Glucagon-like peptide 1 receptor agonist or bolus insulin with optimized basal insulin in type 2 diabetes. Diabetes Care 2014;37: 2763–2773 38. Eng C, Kramer CK, Zinman B, Retnakaran R. Glucagon-like peptide-1 receptor agonist and basal insulin combination treatment for the management of type 2 diabetes: a systematic review and meta-analysis. Lancet 2014;384: 2228–2234 39. Dieuzeide G, Chuang L-M, Almaghamsi A, Zilov A, Chen J-W, Lavalle-Gonza´ lez FJ. Safety and effectiveness of biphasic insulin aspart 30 in people with type 2 diabetes switching from basal-bolus insulin regimens in the A1chieve study. Prim Care Diabetes 2014;8:111–117 40. Mathieu C, Storms F, Tits J, Veneman TF, Colin IM. Switching from premixed insulin to basal-bolus insulin glargine plus rapid-acting insulin: the ATLANTIC study. Acta Clin Belg 2013; 68:28–33 41. Giugliano D, Chiodini P, Maiorino MI, Bellastella G, Esposito K. Intensification of insulin therapy with basal-bolus or premixed insulin regimens in type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Endocrine 2016;51:417–428 42. Kernan WN, Viscoli CM, Furie KL, et al.; IRIS Trial Investigators. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med 2016;374:1321–1331 43. Dormandy JA, Charbonnel B, Eckland DJA, et al.; PROactive Investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005;366:1279–1289 44. Chiasson J-L, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M; STOP-NIDDM Trial Research Group. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet 2002;359:2072–2077 45. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837–853 46. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854–865 47. Gaziano JM, Cincotta AH, O’Connor CM, et al. Randomized clinical trial of quick-release bromocriptine among patients with type 2 diabetes on overall safety and cardiovascular outcomes. Diabetes Care 2010;33:1503– 1508 48. Truven Health Analytics. Red Book: A Comprehensive, Consistent Drug Pricing Resource [Internet], 2016. Available from http://micromedix .com/products/product-suites/clinical-knowledge/ redbook. Accessed 29 July 2016

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9. Cardiovascular Disease and Risk Management

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Diabetes Care 2017;40(Suppl. 1):S75–S87 | DOI: 10.2337/dc17-S012

9. CARDIOVASCULAR DISEASE AND RISK MANAGEMENT

For prevention and management of diabetes complications in children and adolescents, please refer to Section 12 “Children and Adolescents.” Atherosclerotic cardiovascular disease (ASCVD)ddefined as acute coronary syndromes (ACSs), a history of myocardial infarction (MI), stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack, or peripheral arterial disease presumed to be of atherosclerotic origindis the leading cause of morbidity and mortality for individuals with diabetes and is the largest contributor to the direct and indirect costs of diabetes. The common conditions coexisting with type 2 diabetes (e.g., hypertension and dyslipidemia) are clear risk factors for ASCVD, and diabetes itself confers independent risk. Numerous studies have shown the efficacy of controlling individual cardiovascular risk factors in preventing or slowing ASCVD in people with diabetes. Large benefits are seen when multiple risk factors are addressed simultaneously. There is evidence that measures of 10-year coronary heart disease (CHD) risk among U.S. adults with diabetes have improved significantly over the past decade (1) and that ASCVD morbidity and mortality have decreased (2–4). In all patients with diabetes, cardiovascular risk factors should be systematically assessed at least annually. These risk factors include hypertension, dyslipidemia, smoking, a family history of premature coronary disease, and the presence of albuminuria. Abnormal risk factors should be treated as described in these guidelines. HYPERTENSION/BLOOD PRESSURE CONTROL Recommendations

Screening and Diagnosis c

Blood pressure should be measured at every routine visit. Patients found to have elevated blood pressure should have blood pressure confirmed on a separate day. B

Goals c

c

c

Most patients with diabetes and hypertension should be treated to a systolic blood pressure goal of ,140 mmHg and a diastolic blood pressure goal of ,90 mmHg. A Lower systolic and diastolic blood pressure targets, such as 130/80 mmHg, may be appropriate for individuals at high risk of cardiovascular disease, if they can be achieved without undue treatment burden. C In pregnant patients with diabetes and chronic hypertension, blood pressure targets of 120–160/80–105 mmHg are suggested in the interest of optimizing long-term maternal health and minimizing impaired fetal growth. E

Treatment c

c

Patients with confirmed office-based blood pressure .140/90 mmHg should, in addition to lifestyle therapy, have prompt initiation and timely titration of pharmacologic therapy to achieve blood pressure goals. A Patients with confirmed office-based blood pressure .160/100 mmHg should, in addition to lifestyle therapy, have prompt initiation and timely titration of two drugs or a single pill combination of drugs demonstrated to reduce cardiovascular events in patients with diabetes. A

Suggested citation: American Diabetes Association. Cardiovascular disease and risk management. Sec. 9. In Standards of Medical Care in Diabetesd2017. Diabetes Care 2017;40(Suppl. 1): S75–S87 © 2017 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals .org/content/license.

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c

c

c

c

Treatment for hypertension should include drug classes demonstrated to reduce cardiovascular events in patients with diabetes (ACE inhibitors, angiotensin receptor blockers, thiazide-like diuretics, or dihydropyridine calcium channel blockers). Multipledrug therapy is generally required to achieve blood pressure targets (but not a combination of ACE inhibitors and angiotensin receptor blockers). A An ACE inhibitor or angiotensin receptor blocker, at the maximum tolerated dose indicated for blood pressure treatment, is the recommended first-line treatment for hypertension in patients with diabetes and urinary albumin–to– creatinine ratio $300 mg/g creatinine (A) or 30–299 mg/g creatinine (B). If one class is not tolerated, the other should be substituted. B For patients treated with an ACE inhibitor, angiotensin receptor blocker, or diuretic, serum creatinine/ estimated glomerular filtration rate and serum potassium levels should be monitored. B For patients with blood pressure .120/80 mmHg, lifestyle intervention consists of weight loss if overweight or obese; a Dietary Approaches to Stop Hypertension– style dietary pattern including reducing sodium and increasing potassium intake; moderation of alcohol intake; and increased physical activity. B

Hypertension, defined as a sustained blood pressure $140/90 mmHg, is a common comorbidity of type 1 and type 2 diabetes. The prevalence of hypertension depends on type of diabetes, age, sex, BMI, and race/ethnicity. Hypertension is a major risk factor for both ASCVD and microvascular complications. In type 1 diabetes, hypertension is often the result of underlying diabetic kidney disease, while in type 2 diabetes, it usually coexists with other cardiometabolic risk factors. Please refer to the American Diabetes Association (ADA) position statement “Diabetes and Hypertension” for a detailed review (5).

Diabetes Care Volume 40, Supplement 1, January 2017

population: measurement in the seated position, with feet on the floor and arm supported at heart level, after 5 min of rest. Cuff size should be appropriate for the upper-arm circumference. Elevated values should be confirmed on a separate day. Postural changes in blood pressure and pulse may be evidence of autonomic neuropathy and therefore require adjustment of blood pressure targets. Home blood pressure self-monitoring and 24-h ambulatory blood pressure monitoring may provide evidence of white-coat hypertension, masked hypertension, or other discrepancies between office and “true” blood pressure. Studies in individuals without diabetes found that home measurements may better correlate with ASCVD risk than office measurements (6,7). However, most of the evidence of benefits of hypertension treatment in people with diabetes is based on office measurements. Treatment Goals

Epidemiological analyses show that blood pressure .115/75 mmHg is associated with increased cardiovascular event rates and mortality in individuals with diabetes (8). Randomized clinical trials have demonstrated the benefit (reduction of CHD events, stroke, and diabetic kidney disease) of lowering blood pressure to ,140 mmHg systolic and ,90 mmHg diastolic in individuals with diabetes (9,10). There is limited prespecified clinical trial evidence for the benefits of lower systolic blood pressure (SBP) or diastolic blood pressure (DBP) targets (11). A meta-analysis of randomized trials of adults with type 2 diabetes comparing intensive blood pressure targets (upper limit of 130 mmHg systolic and 80 mmHg diastolic) with standard targets (upper limit of 140–160 mmHg systolic and 85–100 mmHg diastolic) found no significant reduction in mortality or nonfatal MI. There was a statistically significant 35% relative risk (RR) reduction in stroke with intensive targets, but the absolute risk reduction was only 1%, and intensive targets were associated with an increased risk for adverse events such as hypotension and syncope (12).

Screening and Diagnosis

Randomized Controlled Trials of Intensive Versus Standard Blood Pressure Control

Blood pressure should be measured by a trained individual and should follow the guidelines established for the general

Given the epidemiological relationship between lower blood pressure and better long-term clinical outcomes, two

landmark trials, Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation–Blood Pressure (ADVANCEBP), examined the benefit of tighter blood pressure control in patients with type 2 diabetes. Additional studies, such as the Systolic Blood Pressure Intervention Trial (SPRINT) and the Hypertension Optimal Treatment (HOT) trial, also examined the potential benefits of intensive versus standard control, though the relevance of their results to people with diabetes is less clear. ACCORD. The ACCORD trial examined whether an SBP of ,120 mmHg in patients with type 2 diabetes at high risk for ASCVD provided greater cardiovascular protection than an SBP of 130–140 mmHg (13). The study did not find a benefit in the primary end point (nonfatal MI, nonfatal stroke, and cardiovascular death) comparing intensive blood pressure treatment (intensive BP; goal ,120 mmHg, average blood pressure achieved 119/64 mmHg on 3.4 medications) with standard treatment (standard BP; average blood pressure achieved 143/70 mmHg on 2.1 medications). However, a follow-up analysis found a strong interaction between glycemic control and blood pressure control. Compared with the standard glycemia/standard BP control group in the blood pressure trial, the intensive BP/intensive glycemia, intensive BP/standard glycemia, and standard BP/intensive glycemia groups all showed benefit for reducing the risk of major cardiovascular disease (14). Stroke was significantly reduced in the intensive BP treatment groups, but the intensive BP/ intensive glycemia group showed no evidence of incremental benefit compared with either single intensive intervention (14). Thus, more intensive blood pressure control may be reasonable in certain motivated, ACCORD-like patients (40–79 years of age with prior evidence of cardiovascular disease or multiple cardiovascular risk factors) who have been educated about the added treatment burden, side effects, and costs of more intensive blood pressure control and for patients who prefer to lower their risk of stroke beyond what can be achieved through standard care. ADVANCE. In ADVANCE, the active blood

pressure intervention arm (a single-pill, fixed-dose combination of perindopril

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and indapamide) showed a significant reduction in the risk of the primary composite end point (major macrovascular or microvascular event) and significant reductions in the risk of death from any cause and of death from cardiovascular causes (15). The baseline blood pressure among the study subjects was 145/81 mmHg. Compared with the placebo group, the patients treated with a single-pill, fixed-dose combination of perindopril and indapamide experienced an average reduction of 5.6 mmHg in SBP and 2.2 mmHg in DBP. The final blood pressure in the treated group was 136/73 mmHg, not quite the intensive or tight control achieved in ACCORD. The recently published 6-year follow-up of the ADVANCE trial, the ADVANCE–PostTrial Observational Study (ADVANCE-ON), reported that the reductions in the risk of death from any cause and of death from cardiovascular causes in the intervention group were attenuated but remained significant (16). The Hypertension Optimal Treatment (HOT) trial included patients with and without diabetes and compared DBP targets of #90, #85, and #80 mmHg. Post hoc analyses found cardiovascular benefit with more intensive targets in the subpopulation with diabetes (17). The HOT trial results, taken together with the higher quality data from ACCORD and ADVANCE, support the current recommendation to achieve blood pressure levels ,140/90 mmHg, with lower targets in selected patients. HOT.

The Systolic Blood Pressure Intervention Trial (SPRINT) was a multicenter, randomized controlled trial that compared two strategies for treating SBP with either the standard target of ,140 mmHg or an intensive target of ,120 mmHg; primary outcomes were MI, ACS, stroke, heart failure, and death due to cardiovascular disease. Patients assigned to the intensive SBP target of ,120 mmHg, compared with a target SBP of 140 mmHg, had reduced RR of cardiovascular events by almost a third and of death by almost a quarter, though risks of electrolyte abnormalities and acute kidney injury were increased (18). Of note, patients with diabetes were excluded from participating in this trial, so the results have no direct implications for blood pressure management in patients with diabetes. SPRINT.

Cardiovascular Disease and Risk Management

Systolic Blood Pressure

The evidence that SBP .140 mmHg is harmful is irrefutable, suggesting that clinicians promptly initiate and titrate therapy to achieve and maintain SBP ,140 mmHg in most patients. For some patients, lower SBP targets closer to 130 mmHg are appropriate. A recent systematic review and meta-analysis evaluating SBP lowering in adults with type 2 diabetes showed that each 10 mmHg reduction of SBP was associated with significantly lower risk of mortality, cardiovascular events, CHD, stroke, albuminuria, and retinopathy. However, when trials were stratified by mean baseline SBP $140 mmHg or ,140 mmHg, blood pressure–lowering treatment was associated with lower risks of stroke and albuminuria, regardless of initial SBP (9). Therefore, individuals in whom cardiovascular disease risk, particularly stroke, is a concern may, as part of shared decision making, have lower systolic targets than 140 mmHg. This is especially true if lower blood pressure can be achieved with few drugs and without side effects of therapy. For older adults, treating to an SBP of ,130 mmHg has not been shown to improve cardiovascular outcomes (19). Diastolic Blood Pressure

Similarly, strong evidence from randomized clinical trials supports DBP targets of ,90 mmHg. These targets are in harmony with the Eighth Joint National Committee (JNC 8) recommendation of a DBP threshold of ,90 mmHg for individuals over 18 years of age with diabetes (11). A DBP of ,80 mmHg may still be appropriate for patients with long life expectancy, chronic kidney disease, elevated urinary albumin excretion, evidence of cardiovascular disease, or additional risk factors such as dyslipidemia, smoking, or obesity (17). In older adults, treating to a DBP of ,70 mmHg has been associated with a greater risk of mortality (20). Treatment Strategies Lifestyle Intervention

Although there are no well-controlled studies of diet and exercise in the treatment of elevated blood pressure or hypertension in individuals with diabetes, the Dietary Approaches to Stop Hypertension (DASH) study evaluated the impact of healthy dietary patterns in individuals

without diabetes and has shown antihypertensive effects similar to those of pharmacologic monotherapy. Lifestyle therapy consists of reducing excess body weight through caloric restriction, restricting sodium intake (,2,300 mg/day), increasing consumption of fruits and vegetables (8–10 servings per day) and low-fat dairy products (2–3 servings per day), avoiding excessive alcohol consumption (no more than 2 servings per day in men and no more than 1 serving per day in women) (21), and increasing activity levels (11). These lifestyle (nonpharmacologic) strategies may also positively affect glycemia and lipid control and should be encouraged in those with even mildly elevated blood pressure, although the impact of lifestyle therapy on cardiovascular events has not been established. Nonpharmacologic therapy is reasonable in individuals with diabetes and mildly elevated blood pressure (SBP .120 mmHg or DBP .80 mmHg). If the blood pressure is confirmed to be $140 mmHg systolic and/or $90 mmHg diastolic, pharmacologic therapy should be initiated along with nonpharmacologic therapy (11). A lifestyle therapy plan should be developed in collaboration with the patient and discussed as part of diabetes management. Pharmacologic Interventions

Lowering of blood pressure with regimens based on a variety of antihypertensive agents, including ACE inhibitors, angiotensin receptor blockers (ARBs), diuretics, and calcium channel blockers has been shown to be effective in reducing cardiovascular events (9,22). In people with diabetes and albuminuria, ACE inhibitors or ARBs may have unique advantages for initial or early treatment of hypertension. In a trial of individuals at high risk for ASCVD, including a large subset with diabetes, an ACE inhibitor reduced ASCVD outcomes and the development of albuminuria when compared with placebo, even after adjustment for differences in blood pressure, an effect that has been termed a “blood pressure independent effect” (23). In patients with congestive heart failure, including subgroups with diabetes, ARBs have been shown to reduce major ASCVD outcomes (24–26). Among patients with type 2 diabetes, urine albumin–to–creatinine ratio (UACR)

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$300 mg/g creatinine, and elevated serum creatinine concentration, an ARB significantly reduced progression of kidney disease compared with placebo (27). A meta-analysis confirmed that treatment of patients with diabetic kidney disease with an ACE inhibitor or ARB reduces the risk of progressing to end-stage renal disease, though strong evidence of benefit was limited to participants with baseline UACR $300 mg/g creatinine (28). Smaller trials also suggest reduction in composite cardiovascular events and reduced progression of advanced nephropathy (29–31). However, the superiority of ACE inhibitors or ARBs over other antihypertensive agents for prevention of cardiovascular outcomes has not been consistently shown for all patients with diabetes (22,28,32,33). In particular, a recent meta-analysis suggests that thiazidetype diuretics or dihydropyridine calcium channel blockers have cardiovascular benefit similar to that of ACE inhibitors or ARBs (22). Therefore, among patients without albuminuria for whom cardiovascular disease prevention is the primary goal of blood pressure control, a thiazide-like diuretic or dihydropyridine calcium channel blocker may be considered instead of or in addition to an ACE inhibitor or ARB. There are no adequate head-to-head comparisons of ACE inhibitors and ARBs, but there is clinical trial support for each of the following statements: In patients with type 1 diabetes with hypertension and any degree of albuminuria, ACE inhibitors have been shown to reduce loss of glomerular filtration rate and delay the progression of nephropathy. In patients with type 2 diabetes, hypertension, and UACR 30–299 mg/g creatinine, ACE inhibitors and ARBs have been shown to delay the progression to UACR $300 mg/g creatinine. The use of both ACE inhibitors and ARBs in combination is not recommended given the lack of added ASCVD benefit and increased rate of adverse eventsdnamely, hyperkalemia, syncope, and acute kidney injury (34,35). Combination Drug Therapy

The blood pressure arm of the ADVANCE trial demonstrated that routine administration of a fixed-dose combination of the ACE inhibitor perindopril and the thiazide-like diuretic indapamide

Diabetes Care Volume 40, Supplement 1, January 2017

significantly reduced combined microvascular and macrovascular outcomes, as well as death from cardiovascular causes and total mortality. The improved outcomes could also have been due to lower achieved blood pressure in the perindopril–indapamide arm (15). Another trial showed a decrease in morbidity and mortality in those receiving ACE inhibitor benazepril and calcium channel blocker amlodipine versus benazepril and thiazide-like diuretic hydrochlorothiazide (36,37). If needed to achieve blood pressure targets, amlodipine and indapamide or hydrochlorothiazide or thiazide-like diuretic chlorthalidone can be added. If estimated glomerular filtration rate is ,30 mL/min/1.73 m2, a loop diuretic should be prescribed. Titration of and/or addition of further blood pressure medications should be made in a timely fashion to overcome clinical inertia in achieving blood pressure targets. Bedtime Dosing

Growing evidence suggests that there is an association between absence of nocturnal blood pressure dipping and the incidence of ASCVD. A randomized controlled trial of 448 participants with type 2 diabetes and hypertension demonstrated reduced cardiovascular events and mortality with median follow-up of 5.4 years if at least one antihypertensive medication was given at bedtime (38). Consider administering one or more antihypertensive medications at bedtime (39). Other Considerations

An important caveat is that most patients with diabetes and hypertension require multiple-drug therapy to reach blood pressure treatment goals (21). Identifying and addressing barriers to medication adherence (such as cost and side effects) should routinely be done. If blood pressure remains uncontrolled despite confirmed adherence to optimal doses of at least three antihypertensive agents of different classes, one of which should be a diuretic, clinicians should consider an evaluation for secondary causes of hypertension. Pregnancy and Antihypertensive Medications

Since there is a lack of randomized controlled trials of antihypertensive therapy in pregnant women with diabetes,

recommendations for the management of hypertension in pregnant women with diabetes should be similar to those for all pregnant women. The American College of Obstetricians and Gynecologists (ACOG) has recommended that women with mild gestational hypertension (SBP ,160 mmHg or DBP ,110 mmHg) do not need to be treated with antihypertensive medications as there is no benefit identified that clearly outweighs potential risks of therapy (40). A 2014 Cochrane systematic review of antihypertensive therapy for mild to moderate chronic hypertension that included 49 trials and over 4,700 women did not find any conclusive evidence for or against blood pressure treatment to reduce the risk of preeclampsia for the mother or effects on perinatal outcomes such as preterm birth, small-for-gestational-age infants, or fetal death (41). For pregnant women who require antihypertensive therapy, SBP levels of 120–160 mmHg and DBP levels of 80–105 mmHg are suggested to optimize maternal health without risking fetal harm. Lower targets (SBP 110–119 mmHg and DBP 65– 79 mmHg) may contribute to improved long-term maternal health; however, they may be associated with impaired fetal growth. Pregnant women with hypertension and evidence of end-organ damage from cardiovascular and/or renal disease may be considered for lower blood pressure targets to avoid progression of these conditions during pregnancy. During pregnancy, treatment with ACE inhibitors, ARBs, and spironolactone are contraindicated as they may cause fetal damage. Antihypertensive drugs known to be effective and safe in pregnancy include methyldopa, labetalol, hydralazine, carvedilol, clonidine, and long-acting nifedipine (40). Diuretics are not recommended for blood pressure control in pregnancy but may be used during late-stage pregnancy if needed for volume control (40,42). ACOG also recommends that postpartum patients with gestational hypertension, preeclampsia, and superimposed preeclampsia have their blood pressures observed for 72 h in hospital and for 7–10 days postpartum. Long-term follow-up is recommended for these women as they have increased lifetime cardiovascular risk (43).

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LIPID MANAGEMENT

Cardiovascular Disease and Risk Management

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Recommendations c

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In adults not taking statins, it is reasonable to obtain a lipid profile at the time of diabetes diagnosis, at an initial medical evaluation, and every 5 years thereafter, or more frequently if indicated. E Obtain a lipid profile at initiation of statin therapy and periodically thereafter as it may help to monitor the response to therapy and inform adherence. E Lifestyle modification focusing on weight loss (if indicated); the reduction of saturated fat, trans fat, and cholesterol intake; increase of dietary v-3 fatty acids, viscous fiber, and plant stanols/sterols intake; and increased physical activity should be recommended to improve the lipid profile in patients with diabetes. A Intensify lifestyle therapy and optimize glycemic control for patients with elevated triglyceride levels ($150 mg/dL [1.7 mmol/L]) and/or low HDL cholesterol (,40 mg/dL [1.0 mmol/L] for men, ,50 mg/dL [1.3 mmol/L] for women). C For patients with fasting triglyceride levels $500 mg/dL (5.7 mmol/L), evaluate for secondary causes of hypertriglyceridemia and consider medical therapy to reduce the risk of pancreatitis. C For patients of all ages with diabetes and atherosclerotic cardiovascular disease, high-intensity statin therapy should be added to lifestyle therapy. A For patients with diabetes aged ,40 years with additional atherosclerotic cardiovascular disease risk factors, consider using moderateintensity or high-intensity statin and lifestyle therapy. C For patients with diabetes aged 40–75 years without additional atherosclerotic cardiovascular disease risk factors, consider using moderate-intensity statin and lifestyle therapy. A For patients with diabetes aged 40–75 years with additional atherosclerotic cardiovascular disease risk factors, consider using high-intensity statin and lifestyle therapy. B

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For patients with diabetes aged .75 years without additional atherosclerotic cardiovascular disease risk factors, consider using moderate-intensity statin therapy and lifestyle therapy. B For patients with diabetes aged .75 years with additional atherosclerotic cardiovascular disease risk factors, consider using moderateintensity or high-intensity statin therapy and lifestyle therapy. B In clinical practice, providers may need to adjust intensity of statin therapy based on individual patient response to medication (e.g., side effects, tolerability, LDL cholesterol levels). E The addition of ezetimibe to moderate-intensity statin therapy has been shown to provide additional cardiovascular benefit compared with moderate-intensity statin therapy alone for patients with recent acute coronary syndrome and LDL cholesterol $50 mg/dL (1.3 mmol/L) and should be considered for these patients A and also in patients with diabetes and history of ASCVD who cannot tolerate high-intensity statin therapy. E Combination therapy (statin/fibrate) has not been shown to improve atherosclerotic cardiovascular disease outcomes and is generally not recommended. A However, therapy with statin and fenofibrate may be considered for men with both triglyceride level $204 mg/dL (2.3 mmol/L) and HDL cholesterol level #34 mg/dL (0.9 mmol/L). B Combination therapy (statin/niacin) has not been shown to provide additional cardiovascular benefit above statin therapy alone and may increase the risk of stroke and is not generally recommended. A Statin therapy is contraindicated in pregnancy. B

Lifestyle Intervention

Lifestyle intervention, including weight loss, increased physical activity, and medical nutrition therapy, allows some patients to reduce ASCVD risk factors. Nutrition intervention should be tailored according to each patient’s age, diabetes type, pharmacologic treatment, lipid levels, and medical conditions.

Recommendations should focus on reducing saturated fat, cholesterol, and trans fat intake and increasing plant stanols/sterols, v-3 fatty acids, and viscous fiber (such as in oats, legumes, and citrus). Glycemic control may also beneficially modify plasma lipid levels, particularly in patients with very high triglycerides and poor glycemic control. Statin Treatment Initiating Statin Therapy Based on Risk

Patients with type 2 diabetes have an increased prevalence of lipid abnormalities, contributing to their high risk of ASCVD. Multiple clinical trials have demonstrated the beneficial effects of pharmacologic (statin) therapy on ASCVD outcomes in subjects with and without CHD (44,45). Subgroup analyses of patients with diabetes in larger trials (46–50) and trials in patients with diabetes (51,52) showed significant primary and secondary prevention of ASCVD events and CHD death in patients with diabetes. Meta-analyses, including data from over 18,000 patients with diabetes from 14 randomized trials of statin therapy (mean follow-up 4.3 years), demonstrate a 9% proportional reduction in all-cause mortality and 13% reduction in vascular mortality for each mmol/L (39 mg/dL) reduction in LDL cholesterol (53). As in those without diabetes, absolute reductions in ASCVD outcomes (CHD death and nonfatal MI) are greatest in people with high baseline ASCVD risk (known ASCVD and/or very high LDL cholesterol levels), but the overall benefits of statin therapy in people with diabetes at moderate or even low risk for ASCVD are convincing (54,55). Statins are the drugs of choice for LDL cholesterol lowering and cardioprotection. Most trials of statins and ASCVD outcomes tested specific doses of statins against placebo or other statins rather than aiming for specific LDL cholesterol goals (56), suggesting that the initiation and intensification of statin therapy be based on risk profile (Table 9.1 and Table 9.2). The Risk Calculator. The American College

of Cardiology/American Heart Association ASCVD risk calculator may be a useful tool to estimate 10-year ASCVD risk (http://my.americanheart.org). As diabetes itself confers increased risk for ASCVD, the risk calculator has limited

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Table 9.1—Recommendations for statin and combination treatment in people with diabetes Recommended Age Risk factors statin intensity* ,40 years

40–75 years

.75 years

None ASCVD risk factor(s)** ASCVD None ASCVD risk factors ASCVD ACS and LDL cholesterol $50 mg/dL (1.3 mmol/L) or in patients with a history of ASCVD who cannot tolerate high-dose statins

None Moderate or high High Moderate High High Moderate plus ezetimibe

None ASCVD risk factors ASCVD ACS and LDL cholesterol $50 mg/dL (1.3 mmol/L) or in patients with a history of ASCVD who cannot tolerate high-dose statins

Moderate Moderate or high High Moderate plus ezetimibe

*In addition to lifestyle therapy. **ASCVD risk factors include LDL cholesterol $100 mg/dL (2.6 mmol/L), high blood pressure, smoking, chronic kidney disease, albuminuria, and family history of premature ASCVD.

use for assessing cardiovascular risk in individuals with diabetes. Age 40–75 Years

In low-risk patients with diabetes aged 40–75 years, moderate-intensity statin treatment should be considered in addition to lifestyle therapy. Clinical trials in high-risk patients with increased cardiovascular risk (e.g., LDL cholesterol $100 mg/dL [2.6 mmol/L], high blood pressure, smoking, albuminuria, and family history of premature ASCVD) and with ASCVD (57–59) have demonstrated that more aggressive therapy with high doses of statins led to a significant reduction in cardiovascular events. Highintensity statins are recommended in all such patients. Age >75 Years

For adults with diabetes .75 years of age, there are limited data regarding the benefits and risks of statin therapy. Statin therapy should be individualized

based on risk profile. High-intensity statins, if well tolerated, are still appropriate and recommended for older adults with ASCVD. High-intensity statin therapy may also be appropriate in adults with diabetes .75 years of age with additional ASCVD risk factors. However, the risk–benefit profile should be routinely evaluated in this population, with downward titration (e.g., high to moderate intensity) performed as needed. See Section 11 “Older Adults” for more details on clinical considerations for this population. Age <40 Years and/or Type 1 Diabetes

Very little clinical trial evidence exists for patients with type 2 diabetes under the age of 40 years or for patients with type 1 diabetes of any age. In the Heart Protection Study (lower age limit 40 years), the subgroup of ;600 patients with type 1 diabetes had a proportionately similar, although not statistically

Table 9.2—High-intensity and moderate-intensity statin therapy* High-intensity statin therapy (lowers LDL cholesterol by $50%)

Moderate-intensity statin therapy (lowers LDL cholesterol by 30% to ,50%)

Atorvastatin 40–80 mg Rosuvastatin 20–40 mg

Atorvastatin 10–20 mg Rosuvastatin 5–10 mg Simvastatin 20–40 mg Pravastatin 40–80 mg Lovastatin 40 mg Fluvastatin XL 80 mg Pitavastatin 2–4 mg

*Once-daily dosing. XL, extended release.

significant, reduction in risk as patients with type 2 diabetes (47). Even though the data are not definitive, similar statin treatment approaches should be considered for patients with type 1 or type 2 diabetes, particularly in the presence of other cardiovascular risk factors. Please refer to “Type 1 Diabetes Mellitus and Cardiovascular Disease: A Scientific Statement From the American Heart Association and American Diabetes Association” (60) for additional discussion. High-intensity statin therapy is recommended for all patients with diabetes and ASCVD. Treatment with a moderate dose of statin should be considered if the patient does not have ASCVD but has additional ASCVD risk factors. Ongoing Therapy and Monitoring With Lipid Panel

In adults with diabetes, it is reasonable to obtain a lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides) at the time of diagnosis, at the initial medical evaluation, and at least every 5 years thereafter. A lipid panel should also be obtained immediately before initiating statin therapy. Once a patient is taking a statin, testing for LDL cholesterol may be considered on an individual basis (e.g., to monitor for adherence and efficacy). In cases where patients are adherent but the LDL cholesterol level is not responding, clinical judgment is recommended to determine the need for and timing of lipid panels. In individual patients, the highly variable LDL cholesterol–lowering response seen with statins is poorly understood (61). When maximally tolerated doses of statins fail to substantially lower LDL cholesterol (,30% reduction from the patient’s baseline), there is no strong evidence that combination therapy should be used. Clinicians should attempt to find a dose or alternative statin that is tolerable, if side effects occur. There is evidence for benefit from even extremely low, less than daily, statin doses (62). Increased frequency of LDL cholesterol monitoring should be considered for patients with new-onset ACS. Increased frequency of LDL cholesterol monitoring may also be considered in adults with heterozygous familial hypercholesterolemia who require additional lowering of LDL cholesterol.

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Combination Therapy for LDL Cholesterol Lowering Statins and Ezetimibe

The IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) was a randomized controlled trial comparing the addition of ezetimibe to simvastatin therapy versus simvastatin alone. Individuals were $50 years of age, had experienced an ACS within the preceding 10 days, and had an LDL cholesterol level $50 mg/dL (1.3 mmol/L). In those with diabetes (27%), the combination of moderateintensity simvastatin (40 mg) and ezetimibe (10 mg) showed a significant reduction of major adverse cardiovascular events with an absolute risk reduction of 5% (40% vs. 45%) and RR reduction of 14% (RR 0.86 [95% CI 0.78–0.94]) over moderate-intensity simvastatin (40 mg) alone (63). Therefore, for people meeting IMPROVE-IT eligibility criteria, ezetimibe should be added to moderate-intensity statin therapy. Though not explicitly studied, these results may also suggest that the addition of ezetimibe should be considered for any patient with diabetes and history of ASCVD who cannot tolerate high-intensity statin therapy. Statins and PCSK9 Inhibitors

Placebo-controlled trials evaluating the addition of the PCSK9 inhibitors evolocumab and alirocumab to maximally tolerated doses of statin therapy in participants who were at high risk for ASCVD demonstrated an average reduction in LDL cholesterol ranging from 36% to 59%. These agents may therefore be considered as adjunctive therapy for patients with diabetes at high risk for ASCVD events who require additional lowering of LDL cholesterol or who require but are intolerant to high-intensity statin therapy (64,65). It is important to note that the effects of this novel class of agents on ASCVD outcomes are unknown as phase 4 studies are currently under way. Treatment of Other Lipoprotein Fractions or Targets

Hypertriglyceridemia should be addressed with dietary and lifestyle changes including abstinence from alcohol (66). Severe hypertriglyceridemia (.1,000 mg/dL) may warrant pharmacologic therapy (fibric acid derivatives and/or fish oil) to reduce the risk of acute pancreatitis.

Cardiovascular Disease and Risk Management

Low levels of HDL cholesterol, often associated with elevated triglyceride levels, are the most prevalent pattern of dyslipidemia in individuals with type 2 diabetes. However, the evidence for the use of drugs that target these lipid fractions is substantially less robust than that for statin therapy (67). In a large trial in patients with diabetes, fenofibrate failed to reduce overall cardiovascular outcomes (68). Combination Therapy Statin and Fibrate

Combination therapy (statin and fibrate) is associated with an increased risk for abnormal transaminase levels, myositis, and rhabdomyolysis. The risk of rhabdomyolysis is more common with higher doses of statins and renal insufficiency and appears to be higher when statins are combined with gemfibrozil (compared with fenofibrate) (69). In the ACCORD study, in patients with type 2 diabetes who were at high risk for ASCVD, the combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal MI, or nonfatal stroke as compared with simvastatin alone. Prespecified subgroup analyses suggested heterogeneity in treatment effects with possible benefit for men with both a triglyceride level $204 mg/dL (2.3 mmol/L) and an HDL cholesterol level #34 mg/dL (0.9 mmol/L) (70). Statin and Niacin

The Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) trial randomized over 3,000 patients (about one-third with diabetes) with established ASCVD, low LDL cholesterol levels (,180 mg/dL [4.7 mmol/L]), low HDL cholesterol levels (men ,40 mg/dL [1.0 mmol/L] and women ,50 mg/dL [1.3 mmol/L]), and triglyceride levels of 150–400 mg/dL (1.7–4.5 mmol/L) to statin therapy plus extended-release niacin or placebo. The trial was halted early due to lack of efficacy on the primary ASCVD outcome (first event of the composite of death from CHD, nonfatal MI, ischemic stroke, hospitalization for an ACS, or symptom-driven coronary or cerebral revascularization) and a possible increase in ischemic stroke in those on combination therapy (71). Therefore, combination therapy with a statin and

niacin is not recommended given the lack of efficacy on major ASCVD outcomes, possible increase in risk of ischemic stroke, and side effects. Diabetes With Statin Use

Several studies have reported an increased risk of incident diabetes with statin use (72,73), which may be limited to those with diabetes risk factors. An analysis of one of the initial studies suggested that although statins were linked to diabetes risk, the cardiovascular event rate reduction with statins far outweighed the risk of incident diabetes even for patients at highest risk for diabetes (74). The absolute risk increase was small (over 5 years of follow-up, 1.2% of participants on placebo developed diabetes and 1.5% on rosuvastatin developed diabetes) (74). A meta-analysis of 13 randomized statin trials with 91,140 participants showed an odds ratio of 1.09 for a new diagnosis of diabetes, so that (on average) treatment of 255 patients with statins for 4 years resulted in one additional case of diabetes while simultaneously preventing 5.4 vascular events among those 255 patients (73). Statins and Cognitive Function

A recent systematic review of the U.S. Food and Drug Administration’s postmarketing surveillance databases, randomized controlled trials, and cohort, case-control, and cross-sectional studies evaluating cognition in patients receiving statins found that published data do not reveal an adverse effect of statins on cognition. Therefore, a concern that statins might cause cognitive dysfunction or dementia should not deter their use in individuals with diabetes at high risk for ASCVD (75). ANTIPLATELET AGENTS Recommendations c

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Use aspirin therapy (75–162 mg/day) as a secondary prevention strategy in those with diabetes and a history of atherosclerotic cardiovascular disease. A For patients with atherosclerotic cardiovascular disease and documented aspirin allergy, clopidogrel (75 mg/day) should be used. B Dual antiplatelet therapy is reasonable for up to a year after an acute coronary syndrome and may have benefits beyond this period. B

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Consider aspirin therapy (75–162 mg/day) as a primary prevention strategy in those with type 1 or type 2 diabetes who are at increased cardiovascular risk. This includes most men and women with diabetes aged $50 years who have at least one additional major risk factor (family history of premature atherosclerotic cardiovascular disease, hypertension, dyslipidemia, smoking, or albuminuria) and are not at increased risk of bleeding. C Aspirin should not be recommended for atherosclerotic cardiovascular disease prevention for adults with diabetes at low atherosclerotic cardiovascular disease risk, such as in men or women with diabetes aged ,50 years with no other major atherosclerotic cardiovascular disease risk factors, as the potential adverse effects from bleeding likely offset the potential benefits. C When considering aspirin therapy in patients with diabetes ,50 years of age with multiple other atherosclerotic cardiovascular disease risk factors, clinical judgment is required. E

Risk Reduction

Aspirin has been shown to be effective in reducing cardiovascular morbidity and mortality in high-risk patients with previous MI or stroke (secondary prevention). Its net benefit in primary prevention among patients with no previous cardiovascular events is more controversial both for patients with diabetes and for patients without diabetes (76,77). Previous randomized controlled trials of aspirin specifically in patients with diabetes failed to consistently show a significant reduction in overall ASCVD end points, raising questions about the efficacy of aspirin for primary prevention in people with diabetes, although some sex differences were suggested (78–80). The Antithrombotic Trialists’ (ATT) collaborators published an individual patient-level meta-analysis of the six large trials of aspirin for primary prevention in the general population. These trials collectively enrolled over 95,000 participants, including almost 4,000 with diabetes. Overall, they found that aspirin reduced the risk of serious

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vascular events by 12% (RR 0.88 [95% CI 0.82–0.94]). The largest reduction was for nonfatal MI, with little effect on CHD death (RR 0.95 [95% CI 0.78– 1.15]) or total stroke. There was some evidence of a difference in aspirin effect by sex: aspirin significantly reduced ASCVD events in men but not in women. Conversely, aspirin had no effect on stroke in men but significantly reduced stroke in women. However, there was no heterogeneity of effect by sex in the risk of serious vascular events (P 5 0.9). Sex differences in aspirin’s effects have not been observed in studies of secondary prevention (76). In the six trials examined by the ATT collaborators, the effects of aspirin on major vascular events were similar for patients with or without diabetes: RR 0.88 (95% CI 0.67– 1.15) and RR 0.87 (95% CI 0.79–0.96), respectively. The confidence interval was wider for those with diabetes because of smaller numbers. Aspirin appears to have a modest effect on ischemic vascular events, with the absolute decrease in events depending on the underlying ASCVD risk. The main adverse effects appear to be an increased risk of gastrointestinal bleeding. The excess risk may be as high as 1–5 per 1,000 per year in real-world settings. In adults with ASCVD risk .1% per year, the number of ASCVD events prevented will be similar to or greater than the number of episodes of bleeding induced, although these complications do not have equal effects on long-term health (81). Treatment Considerations

In 2010, a position statement of the ADA, the American Heart Association, and the American College of Cardiology Foundation recommended that low-dose (75–162 mg/day) aspirin for primary prevention is reasonable for adults with diabetes and no previous history of vascular disease who are at increased ASCVD risk and who are not at increased risk for bleeding (82). This previous statement included sex-specific recommendations for use of aspirin therapy as primary prevention persons with diabetes. However, since that time, multiple recent well-conducted studies and meta-analyses have reported a risk of heart disease and stroke that is equivalent if not higher in women compared with men with diabetes, including among nonelderly adults. Thus, current

recommendations for using aspirin as primary prevention include both men and women aged $50 years with diabetes and at least one additional major risk factor (family history of premature ASCVD, hypertension, dyslipidemia, smoking, or chronic kidney disease/ albuminuria) who are not at increased risk of bleeding (83–86). While risk calculators such as those from the American College of Cardiology/American Heart Association (http://my.americanheart.org) may be a useful tool to estimate 10-year ASCVD risk, diabetes itself confers increased risk for ASCVD. As a result, such risk calculators have limited utility in helping to assess the potential benefits of aspirin therapy in individuals with diabetes. Noninvasive imaging techniques such as coronary computed tomography angiography may potentially help further tailor aspirin therapy, particularly in those at low risk (87), but are not generally recommended. Sex differences in the antiplatelet effect of aspirin have been suggested in the general population (88); however, further studies are needed to investigate the presence of such differences in individuals with diabetes. Aspirin Use in People <50 Years of Age

Aspirin is not recommended for those at low risk of ASCVD (such as men and women aged ,50 years with diabetes with no other major ASCVD risk factors) as the low benefit is likely to be outweighed by the risks of bleeding. Clinical judgment should be used for those at intermediate risk (younger patients with one or more risk factors or older patients with no risk factors) until further research is available. Patients’ willingness to undergo long-term aspirin therapy should also be considered (89). Aspirin use in patients aged ,21 years is generally contraindicated due to the associated risk of Reye syndrome. Aspirin Dosing

Average daily dosages used in most clinical trials involving patients with diabetes ranged from 50 mg to 650 mg but were mostly in the range of 100– 325 mg/day. There is little evidence to support any specific dose, but using the lowest possible dose may help to reduce side effects (90). In the U.S., the most common low-dose tablet is 81 mg. Although platelets from patients with diabetes have altered function, it is

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unclear what, if any, effect that finding has on the required dose of aspirin for cardioprotective effects in the patient with diabetes. Many alternate pathways for platelet activation exist that are independent of thromboxane A2 and thus not sensitive to the effects of aspirin (91). “Aspirin resistance” has been described in patients with diabetes when measured by a variety of ex vivo and in vitro methods (platelet aggregometry, measurement of thromboxane B2) (88), but other studies suggest no impairment in aspirin response among patients with diabetes (92). A recent trial suggested that more frequent dosing regimens of aspirin may reduce platelet reactivity in individuals with diabetes (93); however, these observations alone are insufficient to empirically recommend that higher doses of aspirin be used in this group at this time. It appears that 75– 162 mg/day is optimal. Indications for P2Y12 Use

A P2Y12 receptor antagonist in combination with aspirin should be used for at least 1 year in patients following an ACS and may have benefits beyond this period. Evidence supports use of either ticagrelor or clopidogrel if no percutaneous coronary intervention was performed and clopidogrel, ticagrelor, or prasugrel if a percutaneous coronary intervention was performed (94). In patients with diabetes and prior MI (1–3 years before), adding ticagrelor to aspirin significantly reduces the risk of recurrent ischemic events including cardiovascular and coronary heart disease death (95). More studies are needed to investigate the longer-term benefits of these therapies after ACS among patients with diabetes. CORONARY HEART DISEASE Recommendations

Screening c

c

In asymptomatic patients, routine screening for coronary artery disease is not recommended as it does not improve outcomes as long as atherosclerotic cardiovascular disease risk factors are treated. A Consider investigations for coronary artery disease in the presence of any of the following: atypical cardiac symptoms (e.g., unexplained dyspnea, chest discomfort); signs

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or symptoms of associated vascular disease including carotid bruits, transient ischemic attack, stroke, claudication, or peripheral arterial disease; or electrocardiogram abnormalities (e.g., Q waves). E Treatment c

c

c

c

In patients with known atherosclerotic cardiovascular disease, use aspirin and statin therapy (if not contraindicated) A and consider ACE inhibitor therapy C to reduce the risk of cardiovascular events. In patients with prior myocardial infarction, b-blockers should be continued for at least 2 years after the event. B In patients with symptomatic heart failure, thiazolidinedione treatment should not be used. A In patients with type 2 diabetes with stable congestive heart failure, metformin may be used if estimated glomerular filtration remains .30 mL/min but should be avoided in unstable or hospitalized patients with congestive heart failure. B

Cardiac Testing

Candidates for advanced or invasive cardiac testing include those with 1) typical or atypical cardiac symptoms and 2) an abnormal resting electrocardiogram (ECG). Exercise ECG testing without or with echocardiography may be used as the initial test. In adults with diabetes $40 years of age, measurement of coronary artery calcium is also reasonable for cardiovascular risk assessment. Pharmacologic stress echocardiography or nuclear imaging should be considered in individuals with diabetes in whom resting ECG abnormalities preclude exercise stress testing (e.g., left bundle branch block or ST-T abnormalities). In addition, individuals who require stress testing and are unable to exercise should undergo pharmacologic stress echocardiography or nuclear imaging. Screening Asymptomatic Patients

The screening of asymptomatic patients with high ASCVD risk is not recommended (96), in part because these high-risk patients should already be receiving intensive medical therapydan approach that provides similar benefit as invasive revascularization (97,98). There is also some evidence that silent

MI may reverse over time, adding to the controversy concerning aggressive screening strategies (99). In prospective trials, coronary artery calcium has been established as an independent predictor of future ASCVD events in patients with diabetes and is superior to both the UK Prospective Diabetes Study (UKPDS) risk engine and the Framingham Risk Score in predicting risk in this population (100–102). However, a randomized observational trial demonstrated no clinical benefit to routine screening of asymptomatic patients with type 2 diabetes and normal ECGs (103). Despite abnormal myocardial perfusion imaging in more than one in five patients, cardiac outcomes were essentially equal (and very low) in screened versus unscreened patients. Accordingly, indiscriminate screening is not considered cost-effective. Studies have found that a risk factor– based approach to the initial diagnostic evaluation and subsequent follow-up for coronary artery disease fails to identify which patients with type 2 diabetes will have silent ischemia on screening tests (104,105). Any benefit of newer noninvasive coronary artery disease screening methods, such as computed tomography and computed tomography angiography, to identify patient subgroups for different treatment strategies remains unproven. Although asymptomatic patients with diabetes with higher coronary disease burden have more future cardiac events (100,106,107), the role of these tests beyond risk stratification is not clear. Their routine use leads to radiation exposure and may result in unnecessary invasive testing such as coronary angiography and revascularization procedures. The ultimate balance of benefit, cost, and risks of such an approach in asymptomatic patients remains controversial, particularly in the modern setting of aggressive ASCVD risk factor control. Lifestyle and Pharmacologic Interventions

Intensive lifestyle intervention focusing on weight loss through decreased caloric intake and increased physical activity as performed in the Action for Health in Diabetes (Look AHEAD) trial may be considered for improving glucose control, fitness, and some ASCVD risk factors (108). Patients at increased ASCVD risk should receive aspirin and a statin and ACE inhibitor or ARB therapy if the

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patient has hypertension, unless there are contraindications to a particular drug class. While clear benefit exists for ACE inhibitor and ARB therapy in patients with nephropathy or hypertension, the benefits in patients with ASCVD in the absence of these conditions are less clear, especially when LDL cholesterol is concomitantly controlled (109,110). In patients with prior MI, b-blockers should be continued for at least 2 years after the event (111). Diabetes and Heart Failure

As many as 50% of patients with type 2 diabetes may develop heart failure (112). Data on the effects of glucose-lowering agents on heart failure outcomes have demonstrated that thiazolidinediones have a strong and consistent relationship with heart failure (113–115). Therefore, thiazolidinedione use should be avoided in patients with symptomatic heart failure. Recent studies have also examined the relationship between dipeptidyl peptidase 4 (DPP-4) inhibitors and heart failure and have had mixed results. The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) study showed that patients treated with saxagliptin (a DPP-4 inhibitor) were more likely to be hospitalized for heart failure than were those given placebo (3.5% vs. 2.8%, respectively) (116). Two other recent multicenter, randomized, double-blind, noninferiority trials, Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) and Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), did not show associations between DPP-4 inhibitor use and heart failure. EXAMINE reported that the hospital admission rate for heart failure was 3.1% for patients randomly assigned to alogliptin compared with 2.9% for those randomly assigned to placebo (hazard ratio 1.07 [95% CI 0.79–1.46]) (117). Alogliptin had no effect on the composite end point of cardiovascular death and hospital admission for heart failure in the post hoc analysis (hazard ratio 1.00 [95% CI 0.82–1.21]) (117). TECOS showed a nonsignificant difference in the rate of heart failure hospitalization for the sitagliptin group (3.1%; 1.07 per 100 person-years) compared

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with the placebo group (3.1%; 1.09 per 100 person-years) (118). Antihyperglycemic Therapies and Cardiovascular Outcomes

Recently published cardiovascular outcome trials have provided additional data on cardiovascular outcomes in patients with type 2 diabetes with cardiovascular disease or at high risk for cardiovascular disease. The BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) was a randomized, double-blind trial that assessed the effect of empagliflozin, a sodium–glucose cotransporter 2 (SGLT2) inhibitor, versus placebo and standard care on cardiovascular outcomes in patients with type 2 diabetes and existing cardiovascular disease. Study participants had a mean age of 63 years, 57% had diabetes for more than 10 years, and 99% had established cardiovascular disease. EMPA-REG OUTCOME showed that over a median follow-up of 3.1 years, treatment reduced the composite outcome of MI, stroke, and cardiovascular death by 14% (absolute rate 10.5% vs. 12.1% in the placebo group) and cardiovascular death by 38% (absolute rate 3.7% vs. 5.9%) (119). The FDA recently added a new indication for empagliflozin, to reduce the risk of cardiovascular death in adults with type 2 diabetes and cardiovascular disease. Whether other SGLT2 inhibitors will have the same effect in high-risk patients and whether empagliflozin or other SGLT2 inhibitors will have a similar effect in lower-risk patients with diabetes remains unknown. The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome ResultsdA Long Term Evaluation (LEADER) trial was a randomized, doubleblind trial that assessed the effect of liraglutide, a glucagon-like peptide 1 receptor agonist, versus placebo and standard care on cardiovascular outcomes in patients with type 2 diabetes at high risk for cardiovascular disease or with cardiovascular disease. Study participants had a mean age of 64 years and a mean duration of diabetes of nearly 13 years. Over 80% of study participants had established cardiovascular disease inclusive of a prior MI, prior stroke or transient ischemic attack, prior revascularization procedure, or $50% stenosis of coronary, carotid, or lower-extremity arteries. LEADER showed that the composite

primary outcome (MI, stroke, or cardiovascular death) occurred in fewer participants in the treatment group (13.0%) when compared with the placebo group (14.9%) after a median follow-up of 3.8 years (120). Whether other glucagon-like peptide 1 receptor agonists will have the same effect in high-risk patients or if this drug class will have similar effects in lower-risk patients with diabetes remains unknown. References 1. Ali MK, Bullard KM, Saaddine JB, Cowie CC, Imperatore G, Gregg EW. Achievement of goals in U.S. diabetes care, 1999-2010. N Engl J Med 2013;368:1613–1624 2. Buse JB, Ginsberg HN, Bakris GL, et al.; American Heart Association; American Diabetes Association. Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association. Diabetes Care 2007;30:162–172 3. Gaede P, Lund-Andersen H, Parving H-H, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008;358:580–591 4. Centers for Disease Control and Prevention (CDC), National Center for Health Statistics, Division of Health Care Statistics. Crude and age-adjusted hospital discharge rates for major cardiovascular disease as first-listed diagnosis per 1,000 diabetic population, United States, 1988–2006 [Internet]. Available from http:// www.cdc.gov/diabetes/statistics/cvdhosp/cvd/ fig3.htm. Accessed 27 August 2015 5. de Boer I, Bangalore S, Benetos A, et al. Diabetes and hypertension: a position statement of the American Diabetes Association. Diabetes Care. In press 6. Bobrie G, Gene` s N, Vaur L, et al. Is “isolated home” hypertension as opposed to “isolated office” hypertension a sign of greater cardiovascular risk? Arch Intern Med 2001;161:2205–2211 7. Sega R, Facchetti R, Bombelli M, et al. Prognostic value of ambulatory and home blood pressures compared with office blood pressure in the general population: follow-up results from the Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA) study. Circulation 2005;111:1777–1783 8. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R; Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360:1903–1913 9. Emdin CA, Rahimi K, Neal B, Callender T, Perkovic V, Patel A. Blood pressure lowering in type 2 diabetes: a systematic review and metaanalysis. JAMA 2015;313:603–615 10. Arguedas JA, Leiva V, Wright JM. Blood pressure targets for hypertension in people with diabetes mellitus. Cochrane Database Syst Rev 2013;10:CD008277 11. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014;311:507–520

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12. McBrien K, Rabi DM, Campbell N, et al. Intensive and standard blood pressure targets in patients with type 2 diabetes mellitus: systematic review and meta-analysis. Arch Intern Med 2012;172:1296–1303 13. ACCORD Study Group, Cushman WC, Evans GW, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010;362:1575–1585 14. Margolis KL, O’Connor PJ, Morgan TM, et al. Outcomes of combined cardiovascular risk factor management strategies in type 2 diabetes: the ACCORD randomized trial. Diabetes Care 2014;37:1721–1728 15. Patel A, ADVANCE Collaborative Group, MacMahon S, et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007;370:829–840 16. Zoungas S, Chalmers J, Neal B, et al.; ADVANCE-ON Collaborative Group. Follow-up of blood-pressure lowering and glucose control in type 2 diabetes. N Engl J Med 2014;371:1392– 1406 17. Hansson L, Zanchetti A, Carruthers SG, et al.; HOT Study Group. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 1998;351:1755–1762 18. Wright JT Jr, Williamson JD, Whelton PK, et al.; SPRINT Research Group. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015;373:2103–2116 19. Kirkman MS, Briscoe VJ, Clark N, et al. Diabetes in older adults. Diabetes Care 2012;35: 2650–2664 20. Anderson RJ, Bahn GD, Moritz TE, Kaufman D, Abraira C, Duckworth W; VADT Study Group. Blood pressure and cardiovascular disease risk in the Veterans Affairs Diabetes Trial. Diabetes Care 2011;34:34–38 21. Sacks FM, Svetkey LP, Vollmer WM, et al.; DASH-Sodium Collaborative Research Group. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. N Engl J Med 2001;344: 3–10 22. Bangalore S, Fakheri R, Toklu B, Messerli FH. Diabetes mellitus as a compelling indication for use of renin angiotensin system blockers: systematic review and meta-analysis of randomized trials [published correction appears in BMJ 2016;352:i1525]. BMJ 2016;352:i438 23. Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 2000; 355:253–259 24. Granger CB, McMurray JJV, Yusuf S, et al.; CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-convertingenzyme inhibitors: the CHARM-Alternative trial. Lancet 2003;362:772–776 25. McMurray JJV, Ostergren J, Swedberg K, et al.; CHARM Investigators and Committees. Effects of candesartan in patients with chronic

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heart failure and reduced left-ventricular systolic function taking angiotensin-convertingenzyme inhibitors: the CHARM-Added trial. Lancet 2003;362:767–771 26. Pfeffer MA, Swedberg K, Granger CB, et al.; CHARM Investigators and Committees. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet 2003;362: 759–766 27. Brenner BM, Cooper ME, de Zeeuw D, et al. RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861–869 28. Palmer SC, Mavridis D, Navarese E, et al. Comparative efficacy and safety of blood pressurelowering agents in adults with diabetes and kidney disease: a network meta-analysis. Lancet 2015;385:2047–2056 29. Tatti P, Pahor M, Byington RP, et al. Outcome results of the Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial (FACET) in patients with hypertension and NIDDM. Diabetes Care 1998;21:597–603 30. Estacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL, Gifford N, Schrier RW. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. N Engl J Med 1998; 338:645–652 31. Schrier RW, Estacio RO, Mehler PS, Hiatt WR. Appropriate blood pressure control in hypertensive and normotensive type 2 diabetes mellitus: a summary of the ABCD trial. Nat Clin Pract Nephrol 2007;3:428–438 32. Whelton PK, Barzilay J, Cushman WC, et al.; ALLHAT Collaborative Research Group. Clinical outcomes in antihypertensive treatment of type 2 diabetes, impaired fasting glucose concentration, and normoglycemia: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med 2005;165:1401–1409 33. Remonti LR, Dias S, Leitão CB, et al. Classes of antihypertensive agents and mortality in hypertensive patients with type 2 diabetesNetwork meta-analysis of randomized trials. J Diabetes Complications 2016;30:1192–1200 34. ONTARGET Investigators, Yusuf S, Teo KK, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008; 358:1547–1559 35. Fried LF, Emanuele N, Zhang JH, et al.; VA NEPHRON-D Investigators. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med 2013;369:1892–1903 36. Jamerson K, Weber MA, Bakris GL, et al.; ACCOMPLISH Trial Investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med 2008;359:2417–2428 37. Weber MA, Bakris GL, Jamerson K, et al.; ACCOMPLISH Investigators. Cardiovascular events during differing hypertension therapies in patients with diabetes. J Am Coll Cardiol 2010;56:77–85 ´ A, Fern´andez 38. Hermida RC, Ayala DE, Mojon JR. Influence of time of day of blood pressurelowering treatment on cardiovascular risk in hypertensive patients with type 2 diabetes. Diabetes Care 2011;34:1270–1276

39. Zhao P, Xu P, Wan C, Wang Z. Evening versus morning dosing regimen drug therapy for hypertension. Cochrane Database Syst Rev 2011;10:CD004184 40. American College of Obstetricians and Gynecologists; Task Force on Hypertension in Pregnancy. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy. Obstet Gynecol 2013;122:1122– 1131 41. Abalos E, Duley L, Steyn DW. Antihypertensive drug therapy for mild to moderate hypertension during pregnancy. Cochrane Database Syst Rev2014;2:CD002252 42. Al-Balas M, Bozzo P, Einarson A. Use of diuretics during pregnancy. Can Fam Physician 2009;55:44–45 43. Irgens HU, Reisaeter L, Irgens LM, Lie RT. Long term mortality of mothers and fathers after pre-eclampsia: population based cohort study. BMJ 2001;323:1213–1217 44. Cholesterol Treatment Trialists’ (CTT) Collaborators, Mihaylova B, Emberson J, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012;380:581–590 45. Baigent C, Keech A, Kearney PM, et al.; Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267–1278 46. Py o˘ r¨al¨a K, Pedersen TR, Kjekshus J, Faergeman O, Olsson AG, Thorgeirsson G. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S). Diabetes Care 1997;20:614–620 47. Collins R, Armitage J, Parish S, Sleigh P, Peto R; Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterollowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003;361:2005–2016 48. Goldberg RB, Mellies MJ, Sacks FM, et al.; The Care Investigators. Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the Cholesterol And Recurrent Events (CARE) trial. Circulation 1998;98:2513– 2519 49. Shepherd J, Barter P, Carmena R, et al. Effect of lowering LDL cholesterol substantially below currently recommended levels in patients with coronary heart disease and diabetes: the Treating to New Targets (TNT) study. Diabetes Care 2006;29:1220–1226 50. Sever PS, Poulter NR, Dahl¨of B, et al. Reduction in cardiovascular events with atorvastatin in 2,532 patients with type 2 diabetes: Anglo-Scandinavian Cardiac Outcomes Trial– Lipid-Lowering Arm (ASCOT-LLA). Diabetes Care 2005;28:1151–1157 51. Knopp RH, d’Emden M, Smilde JG, Pocock SJ. Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary Heart Disease

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Endpoints in Non-Insulin-Dependent Diabetes Mellitus (ASPEN). Diabetes Care 2006;29: 1478–1485 52. Colhoun HM, Betteridge DJ, Durrington PN, et al.; CARDS investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebocontrolled trial. Lancet 2004;364:685–696 53. Cholesterol Treatment Trialists’ (CTT) Collaborators, Kearney PM, Blackwell L, Collins R, et al. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet 2008; 371:117–125 54. Taylor F, Huffman MD, Macedo AF, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 2013 (1):CD004816 55. Carter AA, Gomes T, Camacho X, Juurlink DN, Shah BR, Mamdani MM. Risk of incident diabetes among patients treated with statins: population based study [published correction appears in BMJ 2013;347:f4356]. BMJ 2013; 346:f2610 56. Hayward RA, Hofer TP, Vijan S. Narrative review: lack of evidence for recommended low-density lipoprotein treatment targets: a solvable problem. Ann Intern Med 2006;145: 520–530 57. Cannon CP, Braunwald E, McCabe CH, et al.; Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495–1504 58. de Lemos JA, Blazing MA, Wiviott SD, et al.; Investigators. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA 2004;292:1307–1316 59. Nissen SE, Tuzcu EM, Schoenhagen P, et al.; REVERSAL Investigators. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004;291: 1071–1080 60. de Ferranti SD, de Boer IH, Fonseca V, et al. Type 1 diabetes mellitus and cardiovascular disease: a scientific statement from the American Heart Association and American Diabetes Association. Circulation 2014;130:1110–1130 61. Chasman DI, Posada D, Subrahmanyan L, Cook NR, Stanton VP Jr, Ridker PM. Pharmacogenetic study of statin therapy and cholesterol reduction. JAMA 2004;291:2821–2827 62. Meek C, Wierzbicki AS, Jewkes C, et al. Daily and intermittent rosuvastatin 5 mg therapy in statin intolerant patients: an observational study. Curr Med Res Opin 2012;28:371–378 63. Cannon CP, Blazing MA, Giugliano RP, et al.; IMPROVE-IT Investigators. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387–2397 64. Moriarty PM, Jacobson TA, Bruckert E, et al. Efficacy and safety of alirocumab, a monoclonal antibody to PCSK9, in statin-intolerant patients: design and rationale of ODYSSEY ALTERNATIVE, a randomized phase 3 trial. J Clin Lipidol 2014;8: 554–561 65. Zhang X-L, Zhu Q-Q, Zhu L, et al. Safety and efficacy of anti-PCSK9 antibodies: a meta-analysis

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of 25 randomized, controlled trials. BMC Med 2015;13:123 66. Berglund L, Brunzell JD, Goldberg AC, et al.; Endocrine Society. Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2012;97:2969–2989 67. Singh IM, Shishehbor MH, Ansell BJ. Highdensity lipoprotein as a therapeutic target: a systematic review. JAMA 2007;298:786–798 68. Keech A, Simes RJ, Barter P, et al.; FIELD study investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005;366:1849–1861 69. Jones PH, Davidson MH. Reporting rate of rhabdomyolysis with fenofibrate 1 statin versus gemfibrozil 1 any statin. Am J Cardiol 2005; 95:120–122 70. ACCORD Study Group, Ginsberg HN, Elam MB, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010; 362:1563–1574 71. AIM-HIGH Investigators, Boden WE, Probstfield JL, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011;365:2255–2267 72. Rajpathak SN, Kumbhani DJ, Crandall J, Barzilai N, Alderman M, Ridker PM. Statin therapy and risk of developing type 2 diabetes: a metaanalysis. Diabetes Care 2009;32:1924–1929 73. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010;375:735–742 74. Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet 2012; 380:565–571 75. Richardson K, Schoen M, French B, et al. Statins and cognitive function: a systematic review. Ann Intern Med 2013;159:688–697 76. Antithrombotic Trialists’ (ATT) Collaboration, Baigent C, Blackwell L, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009;373: 1849–1860 77. Perk J, De Backer G, Gohlke H, et al.; European Association for Cardiovascular Prevention & Rehabilitation (EACPR); ESC Committee for Practice Guidelines (CPG). European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur Heart J 2012;33:1635–1701 78. Belch J, MacCuish A, Campbell I, et al. The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. BMJ 2008;337:a1840 79. Zhang C, Sun A, Zhang P, et al. Aspirin for primary prevention of cardiovascular events in patients with diabetes: a meta-analysis. Diabetes Res Clin Pract 2010;87:211–218

80. De Berardis G, Sacco M, Strippoli GFM, et al. Aspirin for primary prevention of cardiovascular events in people with diabetes: meta-analysis of randomised controlled trials. BMJ 2009;339: b4531 81. Pignone M, Earnshaw S, Tice JA, Pletcher MJ. Aspirin, statins, or both drugs for the primary prevention of coronary heart disease events in men: a cost-utility analysis. Ann Intern Med 2006;144:326–336 82. Pignone M, Alberts MJ, Colwell JA, et al.; American Diabetes Association; American Heart Association; American College of Cardiology Foundation. Aspirin for primary prevention of cardiovascular events in people with diabetes: a position statement of the American Diabetes Association, a scientific statement of the American Heart Association, and an expert consensus document of the American College of Cardiology Foundation. Diabetes Care 2010;33:1395– 1402 83. Huxley RR, Peters SAE, Mishra GD, Woodward M. Risk of all-cause mortality and vascular events in women versus men with type 1 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol 2015;3:198–206 84. Peters SAE, Huxley RR, Woodward M. Diabetes as risk factor for incident coronary heart disease in women compared with men: a systematic review and meta-analysis of 64 cohorts including 858,507 individuals and 28,203 coronary events. Diabetologia 2014;57:1542–1551 85. Kalyani RR, Lazo M, Ouyang P, et al. Sex differences in diabetes and risk of incident coronary artery disease in healthy young and middle-aged adults. Diabetes Care 2014;37: 830–838 86. Peters SAE, Huxley RR, Woodward M. Diabetes as a risk factor for stroke in women compared with men: a systematic review and meta-analysis of 64 cohorts, including 775,385 individuals and 12,539 strokes. Lancet 2014; 383:1973–1980 87. Dimitriu-Leen AC, Scholte AJHA, van Rosendael AR, et al. Value of coronary computed tomography angiography in tailoring aspirin therapy for primary prevention of atherosclerotic events in patients at high risk with diabetes mellitus. Am J Cardiol 2016; 117:887–893 88. Larsen SB, Grove EL, Neergaard-Petersen S, W¨urtz M, Hvas A-M, Kristensen SD. Determinants of reduced antiplatelet effect of aspirin in patients with stable coronary artery disease. PLoS One 2015;10:e0126767 89. Mora S, Ames JM, Manson JE. Low-dose aspirin in the primary prevention of cardiovascular disease: shared decision making in clinical practice. JAMA 2016;316:709–710 90. Campbell CL, Smyth S, Montalescot G, Steinhubl SR. Aspirin dose for the prevention of cardiovascular disease: a systematic review. JAMA 2007;297:2018–2024 91. Dav`ı G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med 2007;357: 2482–2494 92. Zaccardi F, Rizzi A, Petrucci G, et al. In vivo platelet activation and aspirin responsiveness in type 1 diabetes. Diabetes 2016;65:503–509 93. Bethel MA, Harrison P, Sourij H, et al. Randomized controlled trial comparing impact on platelet reactivity of twice-daily with once-daily

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aspirin in people with type 2 diabetes. Diabet Med 2016;33:224–230 94. Vandvik PO, Lincoff AM, Gore JM, et al.; American College of Chest Physicians. Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines [published correction appears in Chest 2012;141:1129]. Chest 2012;141 (Suppl.):e637S–e668S 95. Bhatt DL, Bonaca MP, Bansilal S, et al. Reduction in ischemic events with ticagrelor in diabetic patients with prior myocardial infarction in PEGASUS-TIMI 54. J Am Coll Cardiol 2016;67: 2732–2740 96. Bax JJ, Young LH, Frye RL, Bonow RO, Steinberg HO, Barrett EJ; ADA. Screening for coronary artery disease in patients with diabetes. Diabetes Care 2007;30:2729–2736 97. Boden WE, O’Rourke RA, Teo KK, et al.; COURAGE Trial Research Group. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007;356:1503–1516 98. BARI 2D Study Group, Frye RL, August P, et al. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med 2009;360:2503–2015 99. Wackers FJT, Chyun DA, Young LH, et al.; Detection of Ischemia in Asymptomatic Diabetics (DIAD) Investigators. Resolution of asymptomatic myocardial ischemia in patients with type 2 diabetes in the Detection of Ischemia in Asymptomatic Diabetics (DIAD) study. Diabetes Care 2007;30:2892–2898 100. Elkeles RS, Godsland IF, Feher MD, et al.; PREDICT Study Group. Coronary calcium measurement improves prediction of cardiovascular events in asymptomatic patients with type 2 diabetes: the PREDICT study. Eur Heart J 2008;29: 2244–2251 101. Raggi P, Shaw LJ, Berman DS, Callister TQ. Prognostic value of coronary artery calcium screening in subjects with and without diabetes. J Am Coll Cardiol 2004;43:1663–1669 102. Anand DV, Lim E, Hopkins D, et al. Risk stratification in uncomplicated type 2 diabetes: prospective evaluation of the combined use of coronary artery calcium imaging and selective

Cardiovascular Disease and Risk Management

myocardial perfusion scintigraphy. Eur Heart J 2006;27:713–721 103. Young LH, Wackers FJT, Chyun DA, et al.; DIAD Investigators. Cardiac outcomes after screening for asymptomatic coronary artery disease in patients with type 2 diabetes: the DIAD study: a randomized controlled trial. JAMA 2009;301:1547–1555 104. Wackers FJT, Young LH, Inzucchi SE, et al.; Detection of Ischemia in Asymptomatic Diabetics Investigators. Detection of silent myocardial ischemia in asymptomatic diabetic subjects: the DIAD study. Diabetes Care 2004; 27:1954–1961 105. Scognamiglio R, Negut C, Ramondo A, Tiengo A, Avogaro A. Detection of coronary artery disease in asymptomatic patients with type 2 diabetes mellitus. J Am Coll Cardiol 2006;47:65–71 106. Hadamitzky M, Hein F, Meyer T, et al. Prognostic value of coronary computed tomographic angiography in diabetic patients without known coronary artery disease. Diabetes Care 2010;33:1358–1363 107. Choi E-K, Chun EJ, Choi S-I, et al. Assessment of subclinical coronary atherosclerosis in asymptomatic patients with type 2 diabetes mellitus with single photon emission computed tomography and coronary computed tomography angiography. Am J Cardiol 2009;104: 890–896 108. Look AHEAD Research Group, Wing RR, Bolin P, et al. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med 2013;369:145–154 109. Braunwald E, Domanski MJ, Fowler SE, et al.; PEACE Trial Investigators. Angiotensinconverting-enzyme inhibition in stable coronary artery disease. N Engl J Med 2004;351:2058– 2068 110. Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) Investigators, Yusuf S, Teo K, et al. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensinconverting enzyme inhibitors: a randomised controlled trial. Lancet 2008;372:1174–1183

111. Kezerashvili A, Marzo K, De Leon J. Beta blocker use after acute myocardial infarction in the patient with normal systolic function: when is it “ok” to discontinue? Curr Cardiol Rev 2012; 8:77–84 112. Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: the Framingham study. Am J Cardiol 1974;34:29–34 113. Dormandy JA, Charbonnel B, Eckland DJA, et al.; PROactive Investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005;366:1279–1289 114. Singh S, Loke YK, Furberg CD. Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. JAMA 2007;298:1189–1195 115. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA 2007;298:1180–1188 116. Scirica BM, Bhatt DL, Braunwald E, et al.; SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369:1317–1326 117. Zannad F, Cannon CP, Cushman WC, et al.; EXAMINE Investigators. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet 2015;385:2067–2076 118. Green JB, Bethel MA, Armstrong PW, et al.; TECOS Study Group. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015;373:232–242 119. Zinman B, Wanner C, Lachin JM, et al.; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117– 2128 120. Marso SP, Daniels GH, Brown-Frandsen K, et al.; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311–322

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10. Microvascular Complications and Foot Care

American Diabetes Association

Diabetes Care 2017;40(Suppl. 1):S88–S98 | DOI: 10.2337/dc17-S013

DIABETIC KIDNEY DISEASE Recommendations

Screening c

At least once a year, assess urinary albumin (e.g., spot urinary albumin–to– creatinine ratio) and estimated glomerular filtration rate in patients with type 1 diabetes with duration of $5 years, in all patients with type 2 diabetes, and in all patients with comorbid hypertension. B

Treatment

10. MICROVASCULAR COMPLICATIONS AND FOOT CARE

c c c

c

c

c

c

c c c

Optimize glucose control to reduce the risk or slow the progression of diabetic kidney disease. A Optimize blood pressure control to reduce the risk or slow the progression of diabetic kidney disease. A For people with nondialysis-dependent diabetic kidney disease, dietary protein intake should be approximately 0.8 g/kg body weight per day (the recommended daily allowance). For patients on dialysis, higher levels of dietary protein intake should be considered. B In nonpregnant patients with diabetes and hypertension, either an ACE inhibitor or an angiotensin receptor blocker is recommended for those with modestly elevated urinary albumin–to–creatinine ratio (30–299 mg/g creatinine) B and is strongly recommended for those with urinary albumin– to–creatinine ratio $300 mg/g creatinine and/or estimated glomerular filtration rate ,60 mL/min/1.73 m2. A Periodically monitor serum creatinine and potassium levels for the development of increased creatinine or changes in potassium when ACE inhibitors, angiotensin receptor blockers, or diuretics are used. E Continued monitoring of urinary albumin–to–creatinine ratio in patients with albuminuria treated with an ACE inhibitor or an angiotensin receptor blocker is reasonable to assess the response to treatment and progression of diabetic kidney disease. E An ACE inhibitor or an angiotensin receptor blocker is not recommended for the primary prevention of diabetic kidney disease in patients with diabetes who have normal blood pressure, normal urinary albumin–to–creatinine ratio (,30 mg/g creatinine), and normal estimated glomerular filtration rate. B When estimated glomerular filtration rate is ,60 mL/min/1.73 m2, evaluate and manage potential complications of chronic kidney disease. E Patients should be referred for evaluation for renal replacement treatment if they have an estimated glomerular filtration rate ,30 mL/min/1.73 m2. A Promptly refer to a physician experienced in the care of kidney disease for uncertainty about the etiology of kidney disease, difficult management issues, and rapidly progressing kidney disease. B

Assessment of Albuminuria and Estimated Glomerular Filtration Rate

Chronic kidney disease (CKD) is diagnosed by the presence of elevated urinary albumin excretion (albuminuria), low estimated glomerular filtration rate (eGFR), or other manifestations of kidney damage (1,2). Diabetic kidney disease, or CKD attributed to diabetes, occurs in 20–40% of patients with diabetes and is the leading

Suggested citation: American Diabetes Association. Microvascular complications and foot care. Sec. 10. In Standards of Medical Care in Diabetesd2017. Diabetes Care 2017;40(Suppl. 1): S88–S98 © 2017 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals .org/content/license.

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cause of end-stage renal disease (ESRD) (1). Diabetic kidney disease typically develops after a diabetes duration of 10 years, or at least 5 years in type 1 diabetes, but may be present at diagnosis of type 2 diabetes. Screening for albuminuria can be most easily performed by urinary albumin–to– creatinine ratio (UACR) in a random spot urine collection (1,2). Timed or 24-h collections are more burdensome and add little to prediction or accuracy. Measurement of a spot urine sample for albumin alone (whether by immunoassay or by using a sensitive dipstick test specific for albuminuria) without simultaneously measuring urine creatinine (Cr) is less expensive but susceptible to false-negative and falsepositive determinations as a result of variation in urine concentration due to hydration. Normal UACR is generally defined as ,30 mg/g Cr, and increased urinary albumin excretion is defined as $30 mg/g Cr. However, UACR is a continuous measurement, and differences within the normal and abnormal ranges are associated with renal and cardiovascular outcomes. Furthermore, because of biological variability in urinary albumin excretion, two of three specimens of UACR collected within a 3- to 6-month period should be abnormal before considering a patient to have albuminuria. Exercise within 24 h, infection, fever, congestive heart failure, marked hyperglycemia, menstruation, and marked hypertension may elevate UACR independently of kidney damage. eGFR should be calculated from serum Cr using a validated formula. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation is generally preferred (2). eGFR is routinely reported by laboratories with serum Cr, and eGFR calculators are available from http://www .nkdep.nih.gov. An eGFR ,60 mL/min/ 1.73 m2 is generally considered abnormal, though optimal thresholds for clinical diagnosis are debated (3). Urinary albumin excretion and eGFR each vary within people over time, and abnormal results should be confirmed to stage CKD (1,2). Since 2003, stage 1–2 CKD has been defined by evidence of kidney damage (usually albuminuria) with eGFR $60 mL/min/1.73 m2, while stages 3–5 CKD have been defined by progressively lower ranges of eGFR (4) (Table 10.1). More recently, Kidney Disease: Improving Global Outcomes (KDIGO) recommended a more comprehensive

Microvascular Complications and Foot Care

Table 10.1—Stages of CKD Stage

eGFR (mL/min/1.73 m2)

Description

$90

1

Kidney damage* with normal or increased eGFR

2

Kidney damage* with mildly decreased eGFR

60–89 30–59

3

Moderately decreased eGFR

4

Severely decreased eGFR

5

Kidney failure

15–29 ,15 or dialysis

*Kidney damage is defined as UACR persistently $30 mg/g Cr or other abnormalities on pathological, urine, blood, or imaging tests. Adapted from Levey et al. (4).

CKD staging that incorporates albuminuria and is more closely associated with risks of cardiovascular disease (CVD) and CKD progression (2). It has not been determined whether application of the more complex system aids clinical care or improves health outcomes. Diagnosis of Diabetic Kidney Disease

Diabetic kidney disease is usually a clinical diagnosis made based on the presence of albuminuria and/or reduced eGFR in the absence of signs or symptoms of other primary causes of kidney damage. The typical presentation of diabetic kidney disease is considered to include a long-standing duration of diabetes, retinopathy, albuminuria without hematuria, and gradually progressive kidney disease. However, signs of CKD may be present at diagnosis or without retinopathy in type 2 diabetes, and reduced eGFR without albuminuria has been frequently reported in type 1 and type 2 diabetes and is becoming more common over time as the prevalence of diabetes increases in the U.S. (5–8). An active urinary sediment (containing red or white blood cells or cellular casts), rapidly increasing albuminuria or nephrotic syndrome, rapidly decreasing eGFR, or the absence of retinopathy (in type 1 diabetes) may suggest alternative or additional causes of kidney disease. For patients with these features, referral to a nephrologist for further diagnosis, including the possibility of kidney biopsy, should be considered. It is rare for patients with type 1 diabetes to develop kidney disease without retinopathy. In type 2 diabetes, retinopathy is only moderately sensitive and specific for CKD caused by diabetes, as confirmed by kidney biopsy (9). Surveillance

Albuminuria and eGFR should be monitored regularly to enable timely diagnosis

of diabetic kidney disease, monitor progression of diabetic kidney disease, assess risk of CKD complications, dose drugs appropriately, and determine whether nephrology referral is needed (Table 10.2). Albuminuria and eGFR may change due to progression of diabetic kidney disease, development of superimposed kidney disease, or the effects of medication, including many antihypertensive medications (e.g., ACE inhibitors, angiotensin receptor blockers [ARBs], and diuretics) and some glucose-lowering medications (e.g., sodium–glucose cotransporter 2 [SGLT2] inhibitors). For patients with eGFR ,60 mL/min/1.73 m2, appropriate medication dosing should be verified, exposure to nephrotoxins (e.g., nonsteroidal antiinflammatory drugs and iodinated contrast) should be minimized, and potential CKD complications should be evaluated. The need for annual quantitative assessment of albumin excretion after diagnosis of albuminuria, institution of ACE inhibitors or ARB therapy, and achieving blood pressure control is a subject of debate. Continued surveillance can assess both response to therapy and disease progression and may aid in assessing adherence to ACE inhibitor or ARB therapy. In addition, in clinical trials of ACE inhibitors or ARB therapy in type 2 diabetes, reducing albuminuria from levels $300 mg/g Cr has been associated with improved renal and cardiovascular outcomes, leading some to suggest that medications should be titrated to minimize UACR. However, this approach has not been formally evaluated in prospective trials, and in type 1 diabetes, remission of albuminuria may occur spontaneously and is not associated with improved clinical outcomes (10). The prevalence of CKD complications correlates with eGFR. When eGFR is ,60 mL/min/1.73 m2, screening for complications of CKD is indicated (Table 10.2). Early vaccination

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Diabetes Care Volume 40, Supplement 1, January 2017

Table 10.2—Management of CKD in diabetes eGFR (mL/min/1.73 m2)

Recommended management

All patients

Yearly measurement of UACR, serum Cr, potassium

45–60

Referral to a nephrologist if possibility for nondiabetic kidney disease exists (duration of type 1 diabetes ,10 years, persistent albuminuria, abnormal findings on renal ultrasound, resistant hypertension, rapid fall in eGFR, or active urinary sediment on urine microscopic examination) Consider the need for dose adjustment of medications Monitor eGFR every 6 months Monitor electrolytes, bicarbonate, hemoglobin, calcium, phosphorus, and parathyroid hormone at least yearly Assure vitamin D sufficiency Vaccinate against Hep B virus Consider bone density testing Referral for dietary counseling

30–44

Monitor eGFR every 3 months Monitor electrolytes, bicarbonate, calcium, phosphorus, parathyroid hormone, hemoglobin, albumin, and weight every 3–6 months Consider the need for dose adjustment of medications

,30

Referral to a nephrologist

against hepatitis B virus is indicated in patients likely to progress to ESRD. Interventions Nutrition

For people with nondialysis-dependent diabetic kidney disease, dietary protein intake should be approximately 0.8 g/kg body weight per day (the recommended daily allowance) (1). Compared with higher levels of dietary protein intake, this level slowed GFR decline with evidence of a greater effect over time. Higher levels of dietary protein intake (.20% of daily calories from protein or .1.3 g/kg/day) have been associated with increased albuminuria, more rapid kidney function loss, and CVD mortality and therefore should be avoided. Reducing the amount of dietary protein below the recommended daily allowance of 0.8 g/kg/day is not recommended because it does not alter glycemic measures, cardiovascular risk measures, or the course of GFR decline. Glycemia

Intensive glycemic control with the goal of achieving near-normoglycemia has been shown in large prospective randomized studies to delay the onset and progression of albuminuria and reduced eGFR in patients with type 1 diabetes (11,12) and type 2 diabetes (1,13–17). Insulin alone was used to lower blood glucose in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study of type 1 diabetes,

while a variety of agents were used in clinical trials of type 2 diabetes, supporting the conclusion that glycemic control itself helps prevent diabetic kidney disease and its progression. The effects of glucoselowering therapies on diabetic kidney disease have helped define hemoglobin A1C targets (Table 6.2). Some glucose-lowering medications also have effects on the kidney that are direct, i.e., not mediated through glycemia. For example, SGLT2 inhibitors reduce renal tubular glucose reabsorption, intraglomerular pressure, and albuminuria and slow GFR loss through mechanisms that appear independent of glycemia (18–20). Glucagon-like peptide 1 receptor agonists and dipeptidyl peptidase 4 inhibitors also have direct effects on the kidney and have been reported to improve renal outcomes compared with placebo (21,22). Renal effects may be considered among other factors when selecting glucose-lowering medications for individual patients (see Section 8 “Pharmacologic Approaches to Glycemic Treatment”). The presence of diabetic kidney disease affects the risks and benefits of intensive glycemic control and a number of specific glucose-lowering medications. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial of type 2 diabetes, adverse effects of intensive glycemic control (hypoglycemia and mortality) were increased among patients with kidney disease at baseline (23,24). Moreover, there is a lag time

of at least 2 years in type 2 diabetes to over 10 years in type 1 diabetes for the effects of intensive glucose control to manifest as improved eGFR outcomes (17,25,26). Therefore, in some patients with prevalent diabetic kidney disease and substantial comorbidity, target A1C levels should be .7% (53 mmol/mol) (1,27). The glucose-lowering effects of SGLT2 inhibitors are blunted with reduced eGFR, but the renal and cardiovascular benefits of empagliflozin, compared with placebo, were not reduced among trial participants with baseline eGFR 30–59 mL/min/1.73 m2, compared with participants with baseline eGFR $60 mL/min/1.73 m2 (19,28). With reduced eGFR, drug dosing may require modification (1). The U.S. Food and Drug Administration (FDA) revised guidance for the use metformin in diabetic kidney disease in 2016 (29), recommending use of eGFR instead of serum Cr to guide treatment and expanding the pool of patients with kidney disease for whom metformin treatment should be considered. Revised FDA guidance states that metformin is contraindicated in patients with an eGFR ,30 mL/min/ 1.73 m2, eGFR should be monitored while taking metformin, the benefits and risks of continuing treatment should be reassessed when eGFR falls ,45 mL/min/1.73 m2, metformin should not be initiated for patients with an eGFR ,45 mL/min/1.73 m2, and metformin should be temporarily discontinued at the time of or before iodinated contrast imaging procedures in patients with eGFR 30–60 mL/min/ 1.73 m2. Other glucose-lowering medications also require dose adjustment or discontinuation at low eGFR (1). Cardiovascular Disease and Blood Pressure

Patients with diabetic kidney disease are at high risk of CVD. To reduce cardiovascular risk, statin therapy and blood pressure treatment should be considered in patients with diabetic kidney disease. Blood pressure control reduces risk of cardiovascular events (30). Hypertension is a strong risk factor for the development and progression of diabetic kidney disease. Antihypertensive therapy reduces the risk of albuminuria (30–32), and among patients with type 1 or 2 diabetes with established diabetic kidney disease (eGFR ,60 mL/min/1.73 m2 and UACR $300 mg/g Cr), ACE inhibitor or ARB therapy reduce the risk of progression to ESRD (33–35).

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Blood pressure levels ,140/90 mmHg in diabetes are recommended to reduce CVD mortality and slow CKD progression. In individuals with albuminuria, who are at increased risk of CVD and CKD progression, lower blood pressure targets (e.g., ,130/80 mmHg) may be considered (36). Of note, there is an adverse safety signal in clinical trials of diabetic kidney disease when diastolic blood pressure is treated to ,70 mmHg and especially ,60 mmHg in older populations. As a result, clinical judgment should be used when attempting to achieve systolic blood pressure targets ,130 mmHg to avoid diastolic blood pressure levels ,60–70 mmHg. ACE inhibitors or ARBs are the preferred first-line agent for blood pressure treatment among patients with diabetes, hypertension, eGFR ,60 mL/min/1.73 m2, and UACR $300 mg/g Cr because of their proven benefits for prevention of CKD progression and major CVD events (37). In general, ACE inhibitors and ARBs are considered to have similar benefits (38) and risks. In the setting of lower levels of albuminuria (30–299 mg/g Cr), ACE inhibitor or ARB therapy has been demonstrated to reduce progression to more advanced albuminuria ($300 mg/g Cr) and cardiovascular events but not progression to ESRD (37,39). While ACE inhibitors or ARB are often prescribed for albuminuria without hypertension, clinical trials have not been performed in this setting to determine whether this improves renal outcomes. Absent kidney disease, ACE inhibitors or ARBs are useful to control blood pressure but may not be superior to alternative classes of antihypertensive therapy (40). In a trial of people with type 2 diabetes and normal urine albumin excretion, an ARB reduced or suppressed the development of albuminuria but increased the rate of cardiovascular events (41). In a trial of people with type 1 diabetes exhibiting neither albuminuria nor hypertension, ACE inhibitors or ARBs did not prevent the development of diabetic glomerulopathy assessed by kidney biopsy (42). Therefore, ACE inhibitors or ARBs are not recommended for patients without hypertension to prevent the development of diabetic kidney disease. Two clinical trials studied the combinations of ACE inhibitors and ARBs and found no benefits on CVD or diabetic kidney disease, and the drug combination had higher adverse event rates (hyperkalemia and/or

Microvascular Complications and Foot Care

acute kidney injury) (43). Therefore, the combined use of ACE inhibitors and ARBs should be avoided. Mineralocorticoid receptor antagonists (spironolactone, eplerenone, and finerenone) in combination with ACE inhibitors or ARBs remain an area of great interest. Mineralocorticoid receptor antagonists are effective for management of resistant hypertension, have been shown to reduce albuminuria in short-term studies of diabetic kidney disease, and may have additional cardiovascular benefits (44–46). There has been, however, an increase in hyperkalemic episodes in those on dual therapy, and larger, longer trials with clinical outcomes are needed before recommending such therapy. Diuretics, calcium channel blockers, and b-blockers can be used as add-on therapy to achieve blood pressure goals in patients treated with maximum doses of ACE inhibitors or ARBs (47) or as alternate therapy in the rare individual unable to tolerate ACE inhibitors and ARBs.

slow the progression of diabetic retinopathy. A Screening c

c

c

Referral to a Nephrologist

Consider referral to a physician experienced in the care of kidney disease when there is uncertainty about the etiology of kidney disease, difficult management issues (anemia, secondary hyperparathyroidism, metabolic bone disease, resistant hypertension, or electrolyte disturbances), or advanced kidney disease (eGFR ,30 mL/min/1.73 m2) requiring discussion of renal replacement therapy for ESRD. The threshold for referral may vary depending on the frequency with which a provider encounters patients with diabetes and kidney disease. Consultation with a nephrologist when stage 4 CKD develops (eGFR #30 mL/min/1.73 m2) has been found to reduce cost, improve quality of care, and delay dialysis (48). However, other specialists and providers should also educate their patients about the progressive nature of diabetic kidney disease, the kidney preservation benefits of proactive treatment of blood pressure and blood glucose, and the potential need for renal replacement therapy.

c

c

c

Treatment c

DIABETIC RETINOPATHY Recommendations c

c

Optimize glycemic control to reduce the risk or slow the progression of diabetic retinopathy. A Optimize blood pressure and serum lipid control to reduce the risk or

Adults with type 1 diabetes should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist within 5 years after the onset of diabetes. B Patients with type 2 diabetes should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist at the time of the diabetes diagnosis. B If there is no evidence of retinopathy for one or more annual eye exams and glycemia is well controlled, then exams every 2 years may be considered. If any level of diabetic retinopathy is present, subsequent dilated retinal examinations should be repeated at least annually by an ophthalmologist or optometrist. If retinopathy is progressing or sight-threatening, then examinations will be required more frequently. B While retinal photography may serve as a screening tool for retinopathy, it is not a substitute for a comprehensive eye exam. E Women with preexisting type 1 or type 2 diabetes who are planning pregnancy or who are pregnant should be counseled on the risk of development and/or progression of diabetic retinopathy. B Eye examinations should occur before pregnancy or in the first trimester in patients with preexisting type 1 or type 2 diabetes, and then patients should be monitored every trimester and for 1 year postpartum as indicated by the degree of retinopathy. B

c

Promptly refer patients with any level of macular edema, severe nonproliferative diabetic retinopathy (a precursor of proliferative diabetic retinopathy), or any proliferative diabetic retinopathy to an ophthalmologist who is knowledgeable and experienced in the management of diabetic retinopathy. A Laser photocoagulation therapy is indicated to reduce the risk of vision

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c

c

loss in patients with high-risk proliferative diabetic retinopathy and, in some cases, severe nonproliferative diabetic retinopathy. A Intravitreal injections of anti–vascular endothelial growth factor are indicated for central-involved diabetic macular edema, which occurs beneath the foveal center and may threaten reading vision. A The presence of retinopathy is not a contraindication to aspirin therapy for cardioprotection, as aspirin does not increase the risk of retinal hemorrhage. A

Diabetic retinopathy is a highly specific vascular complication of both type 1 and type 2 diabetes, with prevalence strongly related to both the duration of diabetes and the level of glycemic control. Diabetic retinopathy is the most frequent cause of new cases of blindness among adults aged 20–74 years in developed countries. Glaucoma, cataracts, and other disorders of the eye occur earlier and more frequently in people with diabetes. In addition to diabetes duration, factors that increase the risk of, or are associated with, retinopathy include chronic hyperglycemia (49), nephropathy (50), hypertension (51), and dyslipidemia (52). Intensive diabetes management with the goal of achieving near-normoglycemia has been shown in large prospective randomized studies to prevent and/or delay the onset and progression of diabetic retinopathy and potentially improve patient-reported visual function (14,53–55). Lowering blood pressure has been shown to decrease retinopathy progression, although tight targets (systolic blood pressure ,120 mmHg) do not impart additional benefit (54). ACE inhibitors and ARBs are both effective treatments in diabetic retinopathy (56). In patients with dyslipidemia, retinopathy progression may be slowed by the addition of fenofibrate, particularly with very mild nonproliferative diabetic retinopathy (NPDR) at baseline (52). Several case series and a controlled prospective study suggest that pregnancy in patients with type 1 diabetes may aggravate retinopathy and threaten vision, especially when glycemic control is poor at the time of conception (57,58). Laser photocoagulation surgery can minimize the risk of vision loss (58).

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Screening

Type 2 Diabetes

The preventive effects of therapy and the fact that patients with proliferative diabetic retinopathy (PDR) or macular edema may be asymptomatic provide strong support for screening to detect diabetic retinopathy. An ophthalmologist or optometrist who is knowledgeable and experienced in diagnosing diabetic retinopathy should perform the examinations. If diabetic retinopathy is present, prompt referral to an ophthalmologist is recommended. Subsequent examinations for patients with type 1 or type 2 diabetes are generally repeated annually for patients with minimal to no retinopathy. Exams every 2 years may be cost-effective after one or more normal eye exams, and in a population with well-controlled type 2 diabetes, there was essentially no risk of development of significant retinopathy with a 3-year interval after a normal examination (59). More frequent examinations by the ophthalmologist will be required if retinopathy is progressing. Retinal photography with remote reading by experts has great potential to provide screening services in areas where qualified eye care professionals are not readily available (60,61). Highquality fundus photographs can detect most clinically significant diabetic retinopathy. Interpretation of the images should be performed by a trained eye care provider. Retinal photography may also enhance efficiency and reduce costs when the expertise of ophthalmologists can be used for more complex examinations and for therapy (62). In-person exams are still necessary when the retinal photos are of unacceptable quality and for follow-up if abnormalities are detected. Retinal photos are not a substitute for comprehensive eye exams, which should be performed at least initially and at intervals thereafter as recommended by an eye care professional. Results of eye examinations should be documented and transmitted to the referring health care professional.

Patients with type 2 diabetes who may have had years of undiagnosed diabetes and have a significant risk of prevalent diabetic retinopathy at the time of diagnosis should have an initial dilated and comprehensive eye examination at the time of diagnosis.

Type 1 Diabetes

Because retinopathy is estimated to take at least 5 years to develop after the onset of hyperglycemia, patients with type 1 diabetes should have an initial dilated and comprehensive eye examination within 5 years after the diagnosis of diabetes (63).

Pregnancy

Pregnancy is associated with a rapid progression of diabetic retinopathy (64,65). Women with preexisting type 1 or type 2 diabetes who are planning pregnancy or who have become pregnant should be counseled on the risk of development and/or progression of diabetic retinopathy. In addition, rapid implementation of intensive glycemic management in the setting of retinopathy is associated with early worsening of retinopathy (58). Women who develop gestational diabetes mellitus do not require eye examinations during pregnancy and do not appear to be at increased risk of developing diabetic retinopathy during pregnancy (66). Treatment

Two of the main motivations for screening for diabetic retinopathy are to prevent loss of vision and to intervene with treatment when vision loss can be prevented or reversed. Photocoagulation Surgery

Two large trials, the Diabetic Retinopathy Study (DRS) in patients with PDR and the Early Treatment Diabetic Retinopathy Study (ETDRS) in patients with macular edema, provide the strongest support for the therapeutic benefits of photocoagulation surgery. The DRS (67) showed that panretinal photocoagulation surgery reduced the risk of severe vision loss from PDR from 15.9% in untreated eyes to 6.4% in treated eyes with the greatest benefit ratio in those with more advanced baseline disease (disc neovascularization or vitreous hemorrhage). The ETDRS also verified the benefits of panretinal photocoagulation for high-risk PDR and in older-onset patients with severe NPDR or less-than-high-risk PDR. Panretinal laser photocoagulation is still commonly used to manage complications of diabetic retinopathy that involve retinal neovascularization and its complications. Anti–Vascular Endothelial Growth Factor Treatment

While the ETDRS (68) established the benefit of focal laser photocoagulation

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surgery in eyes with clinically significant macular edema (defined as retinal edema located at or within 500 mm of the center of the macula), current data from well-designed clinical trials demonstrate that intravitreal anti–vascular endothelial growth factor (anti-VEGF) agents provide a more effective treatment regimen for central-involved diabetic macular edema than monotherapy or even combination therapy with laser (69–71). In both trials, laser photocoagulation surgery was beneficial in reducing the risk of further visual loss in affected patients but generally not beneficial in reversing already diminished acuity. Now, anti-VEGF improves vision and has replaced the need for laser photocoagulation in the vast majority of patients with diabetic macular edema in most cases (72). Most patients require near-monthly administration of intravitreal therapy with anti-VEGF agents during the first 12 months of treatment with fewer injections needed in subsequent years to maintain remission from centralinvolved diabetic macular edema. Intravitreous anti-VEGF therapy is also a potentially viable alternative treatment for PDR (73). Other emerging therapies for retinopathy that may use sustained intravitreal delivery of pharmacologic agents are currently under investigation. NEUROPATHY Recommendations

Screening c

c

All patients should be assessed for diabetic peripheral neuropathy starting at diagnosis of type 2 diabetes and 5 years after the diagnosis of type 1 diabetes and at least annually thereafter. B Assessment for distal symmetric polyneuropathy should include a careful history and assessment of either temperature or pinprick sensation (small-fiber function) and vibration sensation using a 128-Hz tuning fork (for large-fiber function). All patients should have annual 10-g monofilament testing to identify feet at risk for ulceration and amputation. B

Microvascular Complications and Foot Care

c

Symptoms and signs of autonomic neuropathy should be assessed in patients with microvascular and neuropathic complications. E

Treatment c

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Optimize glucose control to prevent or delay the development of neuropathy in patients with type 1 diabetes A and to slow the progression of neuropathy in patients with type 2 diabetes. B Assess and treat patients to reduce pain related to diabetic peripheral neuropathy B and symptoms of autonomic neuropathy and to improve quality of life. E Either pregabalin or duloxetine are recommended as initial pharmacologic treatments for neuropathic pain in diabetes. A

Diagnosis Diabetic Peripheral Neuropathy

Patients with type 1 diabetes for 5 or more years and all patients with type 2 diabetes should be assessed annually for DPN using the medical history and simple clinical tests. Symptoms vary according to the class of sensory fibers involved. The most common early symptoms are induced by the involvement of small fibers and include pain and dysesthesias (unpleasant sensations of burning and tingling). The involvement of large fibers may cause numbness and loss of protective sensation (LOPS). LOPS indicates the presence of distal sensorimotor polyneuropathy and is a risk factor for diabetic foot ulceration. The following clinical tests may be used to assess smalland large-fiber function and protective sensation:

The diabetic neuropathies are a heterogeneous group of disorders with diverse clinical manifestations. The early recognition and appropriate management of neuropathy in the patient with diabetes is important.

1. Small-fiber function: pinprick and temperature sensation 2. Large-fiber function: vibration perception, 10-g monofilament, and ankle reflexes 3. Protective sensation: 10-g monofilament

1. Diabetic neuropathy is a diagnosis of exclusion. Nondiabetic neuropathies may be present in patients with diabetes and may be treatable. 2. Numerous treatment options exist for symptomatic diabetic neuropathy. 3. Up to 50% of diabetic peripheral neuropathy (DPN) may be asymptomatic. If not recognized and if preventive foot care is not implemented, patients are at risk for injuries to their insensate feet. 4. Recognition and treatment of autonomic neuropathy may improve symptoms, reduce sequelae, and improve quality of life.

These tests not only screen for the presence of dysfunction but also predict future risk of complications. Electrophysiological testing or referral to a neurologist is rarely needed, except in situations where the clinical features are atypical or the diagnosis is unclear. In all patients with diabetes and DPN, causes of neuropathy other than diabetes should be considered, including toxins (alcohol), neurotoxic medications (chemotherapy), vitamin B12 deficiency, hypothyroidism, renal disease, malignancies (multiple myeloma, bronchogenic carcinoma), infections (HIV), chronic inflammatory demyelinating neuropathy, inherited neuropathies, and vasculitis (77).

Specific treatment for the underlying nerve damage, other than improved glycemic control, is currently not available. Glycemic control can effectively prevent DPN and cardiac autonomic neuropathy (CAN) in type 1 diabetes (74,75) and may modestly slow their progression in type 2 diabetes (16) but does not reverse neuronal loss. Therapeutic strategies (pharmacologic and nonpharmacologic) for the relief of painful DPN and symptoms of autonomic neuropathy can potentially reduce pain (76) and improve quality of life.

Diabetic Autonomic Neuropathy

The symptoms and signs of autonomic neuropathy should be elicited carefully during the history and physical examination. Major clinical manifestations of diabetic autonomic neuropathy include hypoglycemia unawareness, resting tachycardia, orthostatic hypotension, gastroparesis, constipation, diarrhea, fecal incontinence, erectile dysfunction, neurogenic bladder, and sudomotor dysfunction with either increased or decreased sweating.

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Cardiac Autonomic Neuropathy

Treatment

CAN is associated with mortality independently of other cardiovascular risk factors (78,79). In its early stages, CAN may be completely asymptomatic and detected only by decreased heart rate variability with deep breathing. Advanced disease may be associated with resting tachycardia (.100 bpm) and orthostatic hypotension (a fall in systolic or diastolic blood pressure by .20 mmHg or .10 mmHg, respectively, upon standing without an appropriate increase in heart rate). CAN treatment is generally focused on alleviating symptoms.

Glycemic Control

Gastrointestinal Neuropathies

Gastrointestinal neuropathies may involve any portion of the gastrointestinal tract with manifestations including esophageal dysmotility, gastroparesis, constipation, diarrhea, and fecal incontinence. Gastroparesis should be suspected in individuals with erratic glycemic control or with upper gastrointestinal symptoms without another identified cause. Exclusion of organic causes of gastric outlet obstruction or peptic ulcer disease (with esophagogastroduodenoscopy or a barium study of the stomach) is needed before considering a diagnosis of or specialized testing for gastroparesis. The diagnostic gold standard for gastroparesis is the measurement of gastric emptying with scintigraphy of digestible solids at 15-min intervals for 4 h after food intake. The use of 13C octanoic acid breath test is emerging as a viable alternative. Genitourinary Disturbances

Diabetic autonomic neuropathy may also cause genitourinary disturbances, including sexual dysfunction and bladder dysfunction. In men, diabetic autonomic neuropathy may cause erectile dysfunction and/or retrograde ejaculation (76). Female sexual dysfunction occurs more frequently in those with diabetes and presents as decreased sexual desire, increased pain during intercourse, decreased sexual arousal, and inadequate lubrication (80). Lower urinary tract symptoms manifest as urinary incontinence and bladder dysfunction (nocturia, frequent urination, urination urgency, and weak urinary stream). Evaluation of bladder function should be performed for individuals with diabetes who have recurrent urinary tract infections, pyelonephritis, incontinence, or a palpable bladder.

Near-normal glycemic control, implemented early in the course of diabetes, has been shown to effectively delay or prevent the development of DPN and CAN in patients with type 1 diabetes (81–84). Although the evidence for the benefit of near-normal glycemic control is not as strong for type 2 diabetes, some studies have demonstrated a modest slowing of progression without reversal of neuronal loss (16,85). Specific glucoselowering strategies may have different effects. In a post hoc analysis, participants, particularly men, in the Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes (BARI 2D) trial treated with insulin sensitizers had a lower incidence of distal symmetric polyneuropathy over 4 years than those treated with insulin/sulfonylurea (86). Neuropathic Pain

Neuropathic pain can be severe and can impact quality of life, limit mobility, and contribute to depression and social dysfunction (87). No compelling evidence exists in support of glycemic control or lifestyle management as therapies for neuropathic pain in diabetes or prediabetes, which leaves only pharmaceutical interventions. Pregabalin and duloxetine have received regulatory approval by the FDA, Health Canada, and the European Medicines Agency for the treatment of neuropathic pain in diabetes. The opioid tapentadol has regulatory approval in the U.S. and Canada, but the evidence of its use is weaker (88). Comparative effectiveness studies and trials that include quality-of-life outcomes are rare, so treatment decisions must consider each patient’s presentation and comorbidities and often follow a trial-and-error approach. Given the range of partially effective treatment options, a tailored and stepwise pharmacologic strategy with careful attention to relative symptom improvement, medication adherence, and medication side effects is recommended to achieve pain reduction and improve quality of life (89–91). Pregabalin, a calcium channel a2-d subunit ligand, is the most extensively studied drug for DPN. The majority of studies testing pregabalin have reported favorable effects on the proportion of participants with at least 30–

50% improvement in pain (88,90,92–95). However, not all trials with pregabalin have been positive (88,90,96,97), especially when treating patients with advanced refractory DPN (94). Adverse effects may be more severe in older patients (98) and may be attenuated by lower starting doses and more gradual titration. Duloxetine is a selective norepinephrine and serotonin reuptake inhibitor. Doses of 60 and 120 mg/day showed efficacy in the treatment of pain associated with DPN in multicenter randomized trials, although some of these had high drop-out rates (88,90,95,97). Duloxetine also appeared to improve neuropathyrelated quality of life (99). In longer-term studies, a small increase in A1C was reported in people with diabetes treated with duloxetine compared with placebo (100). Adverse events may be more severe in older people, but may be attenuated with lower doses and slower titrations of duloxetine. Tapentadol is a centrally acting opioid analgesic that exerts its analgesic effects through both m-opioid receptor agonism and noradrenaline reuptake inhibition. Extended-release tapentadol was approved by the FDA for the treatment of neuropathic pain associated with diabetes based on data from two multicenter clinical trials in which participants titrated to an optimal dose of tapentadol were randomly assigned to continue that dose or switch to placebo (101,102). However, both used a design enriched for patients who responded to tapentadol and therefore their results are not generalizable. A recent systematic review and meta-analysis by the Special Interest Group on Neuropathic Pain of the International Association for the Study of Pain found the evidence supporting the effectiveness of tapentadol in reducing neuropathic pain to be inconclusive (88). Therefore, given the high risk for addiction and safety concerns compared with the relatively modest pain reduction, the use of tapentadol ER is not generally recommended as a firstor second-line therapy. Tricyclic antidepressants, gabapentin, venlafaxine, carbamazepine, tramadol, and topical capsaicin, although not approved for the treatment of painful DPN, may be effective and considered for the treatment of painful DPN (76,88,90).

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Microvascular Complications and Foot Care

Orthostatic Hypotension

Treating orthostatic hypotension is challenging. The therapeutic goal is to minimize postural symptoms rather than to restore normotension. Most patients require both nonpharmacologic measures (e.g., ensuring adequate salt intake, avoiding medications that aggravate hypotension, or using compressive garments over the legs and abdomen) and pharmacologic measures. Physical activity and exercise should be encouraged to avoid deconditioning, which is known to exacerbate orthostatic intolerance, and volume repletion with fluids and salt is critical. Midodrine and droxidopa are approved by the FDA for the treatment of orthostatic hypotension.

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Gastroparesis

Treatment for diabetic gastroparesis may be very challenging. Dietary changes may be useful, such as eating multiple small meals and decreasing dietary fat and fiber intake. Withdrawing drugs with adverse effects on gastrointestinal motility including opioids, anticholinergics, tricyclic antidepressants, glucagon-like peptide 1 receptor agonists, pramlintide, and possibly dipeptidyl peptidase 4 inhibitors, may also improve intestinal motility (103,104). In cases of severe gastroparesis, pharmacologic interventions are needed. Only metoclopramide, a prokinetic agent, is approved by the FDA for the treatment of gastroparesis. However, the level of evidence regarding the benefits of metoclopramide for the management of gastroparesis is weak, and given the risk for serious adverse effects (extrapyramidal signs such as acute dystonic reactions, drug-induced parkinsonism, akathisia, and tardive dyskinesia), its use in the treatment of gastroparesis beyond 5 days is no longer recommended by the FDA or the European Medicines Agency. It should be reserved for severe cases that are unresponsive to other therapies (104).

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Erectile Dysfunction

Treatments for erectile dysfunction may include phosphodiesterase type 5 inhibitors, intracorporeal or intraurethral prostaglandins, vacuum devices, or penile prostheses. As with DPN treatments, these interventions do not change the underlying pathology and natural history of the disease process but may improve the patient’s quality of life. FOOT CARE Recommendations c

Perform a comprehensive foot evaluation at least annually to identify

c

risk factors for ulcers and amputations. B All patients with diabetes should have their feet inspected at every visit. C Obtain a prior history of ulceration, amputation, Charcot foot, angioplasty or vascular surgery, cigarette smoking, retinopathy, and renal disease and assess current symptoms of neuropathy (pain, burning, numbness) and vascular disease (leg fatigue, claudication). B The examination should include inspection of the skin, assessment of foot deformities, neurological assessment (10-g monofilament testing with at least one other assessment: pinprick, temperature, vibration, or ankle reflexes), and vascular assessment including pulses in the legs and feet. B Patients who are 50 years or older and any patients with symptoms of claudication or decreased and/or absent pedal pulses should be referred for further vascular assessment as appropriate. C A multidisciplinary approach is recommended for individuals with foot ulcers and high-risk feet (e.g., dialysis patients and those with Charcot foot, prior ulcers, or amputation). B Refer patients who smoke or who have histories of prior lowerextremity complications, loss of protective sensation, structural abnormalities, or peripheral arterial disease to foot care specialists for ongoing preventive care and lifelong surveillance. C Provide general preventive foot self-care education to all patients with diabetes. B The use specialized therapeutic footwear is recommended for high-risk patients with diabetes including those with severe neuropathy, foot deformities, or history of amputation. B

Foot ulcers and amputation, which are consequences of diabetic neuropathy and/or peripheral arterial disease (PAD), are common and represent major causes of morbidity and mortality in people with diabetes. Early recognition

and treatment of patients with diabetes and feet at risk for ulcers and amputations can delay or prevent adverse outcomes. The risk of ulcers or amputations is increased in people who have the following risk factors: ○ ○ ○ ○ ○ ○ ○ ○ ○ ○

Poor glycemic control Peripheral neuropathy with LOPS Cigarette smoking Foot deformities Preulcerative callus or corn PAD History of foot ulcer Amputation Visual impairment Diabetic nephropathy (especially patients on dialysis)

Clinicians are encouraged to review American Diabetes Association screening recommendations for further details and practical descriptions of how to perform components of the comprehensive foot examination (105). Evaluation for Loss of Protective Sensation

All adults with diabetes should undergo a comprehensive foot evaluation at least annually. Detailed foot assessments may occur more frequently in patients with histories of ulcers or amputations, foot deformities, insensate feet, and PAD (106). Foot inspections should occur at every visit in all patients with diabetes. To assess risk, clinicians should ask about history of foot ulcers or amputation, neuropathic and peripheral vascular symptoms, impaired vision, renal disease, tobacco use, and foot care practices. A general inspection of skin integrity and musculoskeletal deformities should be performed. Vascular assessment should include inspection and palpation of pedal pulses. The neurological exam performed as part of the foot examination is designed to identify LOPS rather than early neuropathy. The 10-g monofilament is the most useful test to diagnose LOPS. Ideally, the 10-g monofilament test should be performed with at least one other assessment (pinprick, temperature or vibration sensation using a 128-Hz tuning fork, or ankle reflexes). Absent monofilament sensation suggests LOPS, while at least two normal tests (and no abnormal test) rules out LOPS.

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Evaluation for Peripheral Arterial Disease

Initial screening for PAD should include a history of decreased walking speed, leg fatigue, claudication, and an assessment of the pedal pulses. Ankle-brachial index testing should be performed in patients with symptoms or signs of PAD. Patient Education

All patients with diabetes and particularly those with high-risk foot conditions (history of ulcer or amputation, deformity, LOPS, or PAD) and their families should be provided general education about risk factors and appropriate management (107). Patients at risk should understand the implications of foot deformities, LOPS, and PAD; the proper care of the foot, including nail and skin care; and the importance of foot monitoring on a daily basis. Patients with LOPS should be educated on ways to substitute other sensory modalities (palpation or visual inspection using an unbreakable mirror) for surveillance of early foot problems. The selection of appropriate footwear and footwear behaviors at home should also be discussed. Patients’ understanding of these issues and their physical ability to conduct proper foot surveillance and care should be assessed. Patients with visual difficulties, physical constraints preventing movement, or cognitive problems that impair their ability to assess the condition of the foot and to institute appropriate responses will need other people, such as family members, to assist with their care. Treatment

People with neuropathy or evidence of increased plantar pressures (e.g., erythema, warmth, or calluses) may be adequately managed with well-fitted walking shoes or athletic shoes that cushion the feet and redistribute pressure. People with bony deformities (e.g., hammertoes, prominent metatarsal heads, bunions) may need extrawide or deep shoes. People with bony deformities, including Charcot foot, who cannot be accommodated with commercial therapeutic footwear, will require custom-molded shoes. Special consideration and a thorough workup should be performed when patients with neuropathy present with the acute onset of a red, hot, swollen foot or ankle, and Charcot neuroarthropathy should be excluded. Early diagnosis and treatment of Charcot

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neuroarthropathy is the best way to prevent deformities that increase the risk of ulceration and amputation. The routine prescription of therapeutic footwear is not generally recommended. However, patients should be provided adequate information to aid in selection of appropriate footwear. General footwear recommendations include a broad and square toe box, laces with three or four eyes per side, padded tongue, quality lightweight materials, and sufficient size to accommodate a cushioned insole. Use of custom therapeutic footwear can help reduce the risk of future foot ulcers in high-risk patients (106,108). Most diabetic foot infections are polymicrobial, with aerobic gram-positive cocci. Staphylococci and Streptococci are the most common causative organisms. Wounds without evidence of softtissue or bone infection do not require antibiotic therapy. Empiric antibiotic therapy can be narrowly targeted at gram-positive cocci in many patients with acute infections, but those at risk for infection with antibiotic-resistant organisms or with chronic, previously treated, or severe infections require broader-spectrum regimens and should be referred to specialized care centers (109). Foot ulcers and wound care may require care by a podiatrist, orthopedic or vascular surgeon, or rehabilitation specialist experienced in the management of individuals with diabetes (109). References 1. Tuttle KR, Bakris GL, Bilous RW, et al. Diabetic kidney disease: a report from an ADA Consensus Conference. Diabetes Care 2014;37:2864–2883 2. National Kidney Foundation. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl 2013;3:1–150 3. Delanaye P, Glassock RJ, Pottel H, Rule AD. An age-calibrated definition of chronic kidney disease: rationale and benefits. Clin Biochem Rev 2016;37:17–26 4. Levey AS, Coresh J, Balk E, et al. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med 2003;139:137–147 5. de Boer IH, Rue TC, Hall YN, Heagerty PJ, Weiss NS, Himmelfarb J. Temporal trends in the prevalence of diabetic kidney disease in the United States. JAMA 2011;305:2532–2539 6. Afkarian M, Zelnick LR, Hall YN, et al. Clinical manifestations of kidney disease among US adults with diabetes, 1988-2014. JAMA 2016; 316:602–610 7. Kramer HJ, Nguyen QD, Curhan G, Hsu C-Y. Renal insufficiency in the absence of albuminuria and retinopathy among adults with type 2 diabetes mellitus. JAMA 2003;289:3273–3277

8. Molitch ME, Steffes M, Sun W, et al. Development and progression of renal insufficiency with and without albuminuria in adults with type 1 diabetes in the Diabetes Control and Complications Trial and the Epidemiology of Diabetes Interventions and Complications study. Diabetes Care 2010;33:1536–1543 9. He F, Xia X, Wu XF, Yu XQ, Huang FX. Diabetic retinopathy in predicting diabetic nephropathy in patients with type 2 diabetes and renal disease: a meta-analysis. Diabetologia 2013;56: 457–466 10. de Boer IH, Gao X, Cleary PA, Bebu I, Lachin JM, Molitch ME, et al. Albuminuria changes and cardiovascular and renal outcomes in type 1 diabetes: the DCCT/EDIC study. Clin J Am Soc Nephrol 2016;11:1969–1977 11. DCCT/EDIC Research Group. Effect of intensive diabetes treatment on albuminuria in type 1 diabetes: long-term follow-up of the Diabetes Control and Complications Trial and Epidemiology of Diabetes Interventions and Complications study. Lancet Diabetes Endocrinol 2014;2:793–800 12. DCCT/EDIC Research Group, de Boer IH, Sun W, et al. Intensive diabetes therapy and glomerular filtration rate in type 1 diabetes. N Engl J Med 2011;365:2366–2376 13. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854–865 14. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837–853 15. ADVANCE Collaborative Group, Patel A, MacMahon S, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560– 2572 16. Ismail-Beigi F, Craven T, Banerji MA, et al. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet 2010;376:419–430 17. Zoungas S, Chalmers J, Neal B, et al. Follow-up of blood-pressure lowering and glucose control in type 2 diabetes. N Engl J Med 2014;371:1392– 1406 18. Cherney DZI, Perkins BA, Soleymanlou N, et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation 2014;129: 587–597 19. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016;375:323–334 20. Heerspink HJL, Desai M, Jardine M, Balis D, Meininger G, Perkovic V. Canagliflozin slows progression of renal function decline independently of glycemic effects. J Am Soc Nephrol. 18 August 2016 [Epub ahead of print]. DOI: 10.1681/ASN. 2016030278 21. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311–322 22. Cooper ME, Perkovic V, McGill JB, et al. Kidney disease end points in a pooled analysis of

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individual patient-level data from a large clinical trials program of the dipeptidyl peptidase 4 inhibitor linagliptin in type 2 diabetes. Am J Kidney Dis 2015;66:441–449 23. Miller ME, Bonds DE, Gerstein HC, et al. The effects of baseline characteristics, glycaemia treatment approach, and glycated haemoglobin concentration on the risk of severe hypoglycaemia: post hoc epidemiological analysis of the ACCORD study. BMJ 2010 340:b5444 24. Papademetriou V, Lovato L, Doumas M, et al. Chronic kidney disease and intensive glycemic control increase cardiovascular risk in patients with type 2 diabetes. Kidney Int 2015;87:649–659 25. Perkovic V, Heerspink HL, Chalmers J, et al. Intensive glucose control improves kidney outcomes in patients with type 2 diabetes. Kidney Int 2013;83:517–523 26. Wong MG, Perkovic V, Chalmers J, et al. Longterm benefits of intensive glucose control for preventing end-stage kidney disease: ADVANCE-ON. Diabetes Care 2016;39:694–700 27. National Kidney Foundation. KDOQI clinical practice guideline for diabetes and CKD: 2012 update. Am J Kidney Dis 2012;60:850–886 28. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373: 2117–2128 29. U.S. Department of Health and Human Services. U.S. Food and Drug Administration: FDA drug safety communication: FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function [Internet]. Available from http:// www.fda.gov/Drugs/DrugSafety/ucm493244 .htm. Accessed 15 October 2016 30. Emdin CA, Rahimi K, Neal B, Callender T, Perkovic V, Patel A. Blood pressure lowering in type 2 diabetes: a systematic review and metaanalysis. JAMA 2015;313:603–615 31. ACCORD Study Group, Cushman WC, Evans GW, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010;362:1575–1585 32. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998;317:703–713 33. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861–869 34. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med 1993;329:1456–1462 35. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001; 345:851–860 36. National Kidney Foundation. KDIGO clinical practice guideline for the management of blood pressure in chronic kidney disease. Kidney Int Suppl 2012;2:337 37. Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 2000; 355:253–259

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38. Barnett AH, Bain SC, Bouter P, et al. Angiotensinreceptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy. N Engl J Med 2004;351:1952–1961 39. Parving HH, Lehnert H, Br¨ochner-Mortensen J, et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001;345:870–878 40. Bangalore S, Fakheri R, Toklu B, Messerli FH. Diabetes mellitus as a compelling indication for use of renin angiotensin system blockers: systematic review and meta-analysis of randomized trials. BMJ 2016;352:i438 41. Haller H, Ito S, Izzo JL, et al. Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med 2011;364:907–917 42. Mauer M, Zinman B, Gardiner R, et al. Renal and retinal effects of enalapril and losartan in type 1 diabetes. N Engl J Med 2009;361:40–51 43. ONTARGET Investigators, Yusuf S, Teo KK, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008; 358:1547–1559 44. Bakris GL, Agarwal R, Chan JC, et al. Effect of finerenone on albuminuria in patients with diabetic nephropathy: a randomized clinical trial. JAMA 2015;314:884–894 45. Williams B, MacDonald TM, Morant S, et al. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet 2015;386:2059–2068 46. Filippatos G, Anker SD, B¨ohm M, et al. A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease. Eur Heart J 2016;37:2105–2114 47. Berl T, Hunsicker LG, Lewis JB, et al. Cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial of patients with type 2 diabetes and overt nephropathy. Ann Intern Med 2003;138:542–549 48. Smart NA, Dieberg G, Ladhani M, Titus T. Early referral to specialist nephrology services for preventing the progression to end-stage kidney disease. Cochrane Database Syst Rev 2014; 6:CD007333 49. Klein R. Hyperglycemie and microvascular and macrovascular disease in diabetes. Diabetes Care 1995;18:258–268 50. Estacio RO, McFarling E, Biggerstaff S, Jeffers BW, Johnson D, Schrier RW. Overt albuminuria predicts diabetic retinopathy in Hispanics with NIDDM. Am J Kidney Dis 1998;31: 947–953 51. Leske MC, Wu S-Y, Hennis A, et al. Hyperglycemia, blood pressure, and the 9-year incidence of diabetic retinopathy: the Barbados Eye Studies. Ophthalmology 2005;112:799–805 52. Chew EY, Davis MD, Danis RP, et al. The effects of medical management on the progression of diabetic retinopathy in persons with type 2 diabetes: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye Study. Ophthalmology 2014;121:2443–2451 53. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-erm complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329: 977–986

54. ACCORD Study Group, ACCORD Eye Study Group, Chew EY, et al. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med 2010;363:233–244 55. Writing Team for the DCCT/EDIC Research Group, Gubitosi-Klug RA, Sun W, et al. Effects of prior intensive insulin therapy and risk factors on patient-reported visual function outcomes in the Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort. JAMA Ophthalmol 2016;134:137–145 56. Shih C-J, Chen H-T, Kuo S-C, et al. Comparative effectiveness of angiotensin-convertingenzyme inhibitors and angiotensin II receptor blockers in patients with type 2 diabetes and retinopathy. CMAJ 2016;188:E148–E157 57. Solomon SD, Chew E, Duh EJ, et al. Diabetic retinopathy: a position statement by the American Diabetes Association. Diabetes Care. In press 58. The Diabetes Control and Complications Trial Research Group. Effect of pregnancy on microvascular complications in the Diabetes Control and Complications Trial. Diabetes Care 2000;23:1084–1091 59. Agardh E, Tababat-Khani P. Adopting 3-year screening intervals for sight-threatening retinal vascular lesions in type 2 diabetic subjects without retinopathy. Diabetes Care 2011;34:1318– 1319 60. Bragge P, Gruen RL, Chau M, Forbes A, Taylor HR. Screening for presence or absence of diabetic retinopathy: a meta-analysis. Arch Ophthalmol 2011;129:435–444 61. Walton OB, Garoon RB, Weng CY, et al. Evaluation of automated teleretinal screening program for diabetic retinopathy. JAMA Ophthalmol 2016; 134:204–209 62. Ahmed J, Ward TP, Bursell S-E, Aiello LM, Cavallerano JD, Vigersky RA. The sensitivity and specificity of nonmydriatic digital stereoscopic retinal imaging in detecting diabetic retinopathy. Diabetes Care 2006;29:2205–2209 63. Hooper P, Boucher MC, Cruess A, et al. Canadian Ophthalmological Society evidence-based clinical practice guidelines for the management of diabetic retinopathy. Can J Ophthalmol 2012; 47(Suppl. 2):S1–S54 64. Axer-Siegel R, Hod M, Fink-Cohen S, et al. Diabetic retinopathy during pregnancy. Ophthalmology 1996;103:1815–1819 65. Best RM, Chakravarthy U. Diabetic retinopathy in pregnancy. Br J Ophthalmol 1997;81:249–251 66. Gunderson EP, Lewis CE, Tsai A-L, et al. A 20-year prospective study of childbearing and incidence of diabetes in young women, controlling for glycemia before conception: the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Diabetes 2007;56:2990–2996 67. The Diabetic Retinopathy Study Research Group. Preliminary report on effects of photocoagulation therapy. Am J Ophthalmol 1976;81: 383–396 68. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema: Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol 1985;103:1796–1806 69. Diabetic Retinopathy Clinical Research Network, Elman MJ, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for

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diabetic macular edema. Ophthalmology 2010; 117:1064–1077.e35 70. Mitchell P, Bandello F, Schmidt-Erfurth U, et al. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology 2011;118:615–625 71. Elman MJ, Bressler NM, Qin H, et al. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2011;118:609–614 72. Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology 2012;119:789–801 73. Writing Committee for the Diabetic Retinopathy Clinical Research Network, Gross JG, Glassman AR, et al. Panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy: a randomized clinical trial. JAMA 2015;314:2137–2146 74. Ang L, Jaiswal M, Martin C, Pop-Busui R. Glucose control and diabetic neuropathy: lessons from recent large clinical trials. Curr Diab Rep 2014;14:528 75. Martin CL, Albers JW, Pop-Busui R; DCCT/ EDIC Research Group. Neuropathy and related findings in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study. Diabetes Care 2014;37:31–38 76. Pop-Busui R, Boulton AJM, Feldman EL, et al. Diabetic neuropathy: a position statement by the American Diabetes Association. Diabetes Care 2017;40:136–154 77. Freeman R. Not all neuropathy in diabetes is of diabetic etiology: differential diagnosis of diabetic neuropathy. Curr Diab Rep 2009;9:423–431 78. Pop-Busui R, Evans GW, Gerstein HC, et al. Effects of cardiac autonomic dysfunction on mortality risk in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Diabetes Care 2010;33:1578–1584 79. Pop-Busui R, Cleary PA, Braffett BH, et al. Association between cardiovascular autonomic neuropathy and left ventricular dysfunction: DCCT/EDIC study (Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications). J Am Coll Cardiol 2013;61:447–454 80. Smith AG, Lessard M, Reyna S, Doudova M, Singleton JR. The diagnostic utility of Sudoscan for distal symmetric peripheral neuropathy. J Diabetes Complications 2014;28:511–516 81. Diabetes Control and Complications Trial (DCCT) Research Group. Effect of intensive diabetes treatment on nerve conduction in the Diabetes Control and Complications Trial. Ann Neurol 1995;38:869–880 82. CDC Study Group. The effect of intensive diabetes therapy on measures of autonomic nervous system function in the Diabetes Control and Complications Trial (DCCT). Diabetologia 1998;41:416–423 83. Albers JW, Herman WH, Pop-Busui R, et al. Effect of prior intensive insulin treatment during the Diabetes Control and Complications Trial (DCCT) on peripheral neuropathy in type 1

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diabetes during the Epidemiology of Diabetes Interventions and Complications (EDIC) Study. Diabetes Care 2010;33:1090–1096 84. Pop-Busui R, Low PA, Waberski BH, et al. Effects of prior intensive insulin therapy on cardiac autonomic nervous system function in type 1 diabetes mellitus: The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC). Circulation 2009;119:2886–2893 85. Callaghan BC, Little AA, Feldman EL, Hughes RAC. Enhanced glucose control for preventing and treating diabetic neuropathy. Cochrane Database Syst Rev 2012;6:CD007543 86. Pop-Busui R, Lu J, Brooks MM, et al. Impact of glycemic control strategies on the progression of diabetic peripheral neuropathy in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) cohort. Diabetes Care 2013;36:3208–3215 87. Sadosky A, Schaefer C, Mann R, et al. Burden of illness associated with painful diabetic peripheral neuropathy among adults seeking treatment in the US: results from a retrospective chart review and cross-sectional survey. Diabetes Metab Syndr Obes 2013;6:79–92 88. Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol 2015;14:162–173 89. Bril V, England J, Franklin GM, et al. Evidencebased guideline: treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology 2011;76:1758–1765 90. Griebeler ML, Morey-Vargas OL, Brito JP, et al. Pharmacologic interventions for painful diabetic neuropathy: an umbrella systematic review and comparative effectiveness network meta-analysis. Ann Intern Med 2014;161:639– 649 91. Ziegler D, Fonseca V. From guideline to patient: a review of recent recommendations for pharmacotherapy of painful diabetic neuropathy. J Diabetes Complications 2015;29:146–156 92. Freeman R, Durso-Decruz E, Emir B. Efficacy, safety, and tolerability of pregabalin treatment for painful diabetic peripheral neuropathy: findings from seven randomized, controlled trials across a range of doses. Diabetes Care 2008; 31:1448–1454 93. Moore RA, Straube S, Wiffen PJ, Derry S, McQuay HJ. Pregabalin for acute and chronic pain in adults. Cochrane Database Syst Rev 2009;3:CD007076 94. Raskin P, Huffman C, Toth C, et al. Pregabalin in patients with inadequately treated painful diabetic peripheral neuropathy: a randomized withdrawal trial. Clin J Pain 2014;30:379–390 95. Tesfaye S, Wilhelm S, Lledo A, et al. Duloxetine and pregabalin: high-dose monotherapy or their combination? The “COMBO-DN study”–a multinational, randomized, double-blind, parallel-group study in patients with diabetic peripheral neuropathic pain. Pain 2013;154:2616–2625 96. Ziegler D, Duan WR, An G, Thomas JW, Nothaft W. A randomized double-blind, placebo-,

and active-controlled study of T-type calcium channel blocker ABT-639 in patients with diabetic peripheral neuropathic pain. Pain 2015;156: 2013–2020 97. Quilici S, Chancellor J, L¨othgren M, et al. Meta-analysis of duloxetine vs. pregabalin and gabapentin in the treatment of diabetic peripheral neuropathic pain. BMC Neurol 2009;9:6 98. Dworkin RH, Jensen MP, Gammaitoni AR, Olaleye DO, Galer BS. Symptom profiles differ in patients with neuropathic versus non-neuropathic pain. J Pain 2007;8:118–126 99. Wernicke JF, Pritchett YL, D’Souza DN, et al. A randomized controlled trial of duloxetine in diabetic peripheral neuropathic pain. Neurology 2006;67:1411–1420 100. Hardy T, Sachson R, Shen S, Armbruster M, Boulton AJM. Does treatment with duloxetine for neuropathic pain impact glycemic control? Diabetes Care 2007;30:21–26 101. Schwartz S, Etropolski M, Shapiro DY, et al. Safety and efficacy of tapentadol ER in patients with painful diabetic peripheral neuropathy: results of a randomized-withdrawal, placebocontrolled trial. Curr Med Res Opin 2011;27: 151–162 102. Vinik AI, Shapiro DY, Rauschkolb C, et al. A randomized withdrawal, placebo-controlled study evaluating the efficacy and tolerability of tapentadol extended release in patients with chronic painful diabetic peripheral neuropathy. Diabetes Care 2014;37:2302–2309 103. Camilleri M, Parkman HP, Shafi MA, Abell TL, Gerson L; American College of Gastroenterology. Clinical guideline: management of gastroparesis. Am J Gastroenterol 2013;108:18–37; quiz 38 104. McCall AL. Hypoglycemia in diabetes. In Therapy for Diabetes Mellitus and Related Disorders. 6th ed. Umpierrez GE, Ed. Alexandria, VA, American Diabetes Association, 2014, p. 704 105. Boulton AJM, Armstrong DG, Albert SF, et al. Comprehensive foot examination and risk assessment: a report of the Task Force of the Foot Care Interest Group of the American Diabetes Association, with endorsement by the American Association of Clinical Endocrinologists. Diabetes Care 2008;31:1679–1685 106. Hingorani A, LaMuraglia GM, Henke P, et al. The management of diabetic foot: a clinical practice guideline by the Society for Vascular Surgery in collaboration with the American Podiatric Medical Association and the Society for Vascular Medicine. J Vasc Surg 2016;63(Suppl.):3S–21S 107. Bonner T, Foster M, Spears-Lanoix E. Type 2 diabetes-related foot care knowledge and foot self-care practice interventions in the United States: a systematic review of the literature. Diabet Foot Ankle 2016;7:29758 108. Rizzo L, Tedeschi A, Fallani E, et al. Custommade orthesis and shoes in a structured follow-up program reduces the incidence of neuropathic ulcers in high-risk diabetic foot patients. Int J Low Extrem Wounds 2012;11:59–64 109. Lipsky BA, Berendt AR, Cornia PB, et al. 2012 Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clin Infect Dis 2012;54:e132–e173

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11. Older Adults

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Diabetes Care 2017;40(Suppl. 1):S99–S104 | DOI: 10.2337/dc17-S014

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Diabetes is an important health condition for the aging population; approximately one-quarter of people over the age of 65 years have diabetes (1), and this proportion is expected to increase rapidly in the coming decades. Older individuals with diabetes have higher rates of premature death, functional disability, and coexisting illnesses, such as hypertension, coronary heart disease, and stroke, than those without diabetes. Older adults with diabetes also are at greater risk than other older adults for several common geriatric syndromes, such as polypharmacy, cognitive impairment, urinary incontinence, injurious falls, and persistent pain.

11. OLDER ADULTS

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Consider the assessment of medical, mental, functional, and social geriatric domains in older adults to provide a framework to determine targets and therapeutic approaches for diabetes management. C Screening for geriatric syndromes may be appropriate in older adults experiencing limitations in their basic and instrumental activities of daily living, as they may affect diabetes self-management and be related to health-related quality of life. C Annual screening for early detection of mild cognitive impairment or dementia is indicated for adults 65 years of age or older. B Older adults ($65 years of age) with diabetes should be considered a highpriority population for depression screening and treatment. B Hypoglycemia should be avoided in older adults with diabetes. It should be assessed and managed by adjusting glycemic targets and pharmacologic interventions. B Older adults who are cognitively and functionally intact and have significant life expectancy may receive diabetes care with goals similar to those developed for younger adults. C Glycemic goals for some older adults might reasonably be relaxed using individual criteria, but hyperglycemia leading to symptoms or risk of acute hyperglycemic complications should be avoided in all patients. C Screening for diabetes complications should be individualized in older adults. Particular attention should be paid to complications that would lead to functional impairment. C Treatment of hypertension to individualized target levels is indicated in most older adults. C Treatment of other cardiovascular risk factors should be individualized in older adults considering the time frame of benefit. Lipid-lowering therapy and aspirin therapy may benefit those with life expectancies at least equal to the time frame of primary prevention or secondary intervention trials. E When palliative care is needed in older adults with diabetes, strict blood pressure control may not be necessary, and withdrawal of therapy may be appropriate. Similarly, the intensity of lipid management can be relaxed, and withdrawal of lipid-lowering therapy may be appropriate. E Consider diabetes education for the staff of long-term care facilities to improve the management of older adults with diabetes. E Patients with diabetes residing in long-term care facilities need careful assessment to establish glycemic goals and to make appropriate choices of glucoselowering agents based on their clinical and functional status. E Overall comfort, prevention of distressing symptoms, and preservation of quality of life and dignity are primary goals for diabetes management at the end of life. E Suggested citation: American Diabetes Association. Older adults. Sec. 11. In Standards of Medical Care in Diabetesd2017. Diabetes Care 2017;40(Suppl. 1):S99–S104 © 2017 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals .org/content/license.

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Screening for diabetes complications in older adults should be individualized and periodically revisited, as the results of screening tests may impact therapeutic approaches and targets. Older adults are at increased risk for depression and should therefore be screened and treated accordingly (2). Diabetes management may require assessment of medical, mental, functional, and social domains. This may provide a framework to determine targets and therapeutic approaches. Particular attention should be paid to complications that can develop over short periods of time and/or that would significantly impair functional status, such as visual and lower-extremity complications. Please refer to the American Diabetes Association (ADA) consensus report “Diabetes in Older Adults” for details (3).

NEUROCOGNITIVE FUNCTION

Older adults with diabetes are at higher risk of cognitive decline and institutionalization (4,5). The presentation of cognitive impairment ranges from subtle executive dysfunction to memory loss and overt dementia. People with diabetes have higher incidences of all-cause dementia, Alzheimer disease, and vascular dementia than people with normal glucose tolerance (6). The effects of hyperglycemia and hyperinsulinemia on the brain are areas of intense research. Clinical trials of specific interventionsd including cholinesterase inhibitors and glutamatergic antagonistsdhave not shown positive therapeutic benefit in maintaining or significantly improving cognitive function or in preventing cognitive decline (7). Recent pilot studies in patients with mild cognitive impairment evaluating the potential benefits of intranasal insulin therapy and metformin therapy provide insights for future clinical trials and mechanistic studies (8–10). The presence of cognitive impairment can make it challenging for clinicians to help their patients to reach individualized glycemic, blood pressure, and lipid targets. Cognitive dysfunction makes it difficult for patients to perform complex self-care tasks, such as glucose monitoring and adjusting insulin doses. It also hinders their ability to appropriately maintain the timing and content of diet. When clinicians are managing these types of patients, it is critical to

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simplify drug regimens and to involve caregivers in all aspects of care. Poor glycemic control is associated with a decline in cognitive function (11), and longer duration of diabetes worsens cognitive function. There are ongoing studies evaluating whether preventing or delaying diabetes onset may help to maintain cognitive function in older adults. However, studies examining the effects of intensive glycemic and blood pressure control to achieve specific targets have not demonstrated a reduction in brain function decline (12). Older adults with diabetes should be carefully screened and monitored for cognitive impairment (3). Several organizations have released simple assessment tools, such as the Mini-Mental State Examination (13) and the Montreal Cognitive Assessment (14), which may help to identify patients requiring neuropsychological evaluation, particularly those in whom dementia is suspected (i.e., experiencing memory loss and decline in their basic and instrumental activities of daily living). Annual screening for cognitive impairment is indicated for adults 65 years of age or older for early detection of mild cognitive impairment or dementia (15). People who screen positive for cognitive impairment should receive diagnostic assessment as appropriate, including referral to a behavioral health provider for formal cognitive/neuropsychological evaluation (16). HYPOGLYCEMIA

It is important to prevent hypoglycemia to reduce the risk of cognitive decline (17) and other major adverse outcomes. It is also important to carefully assess and reassess patients’ risk for worsening of glycemic control and functional decline. Older adults are at higher risk of hypoglycemia for many reasons, including insulin deficiency necessitating insulin therapy and progressive renal insufficiency. In addition, older adults tend to have higher rates of unidentified cognitive deficits, causing difficulty in complex self-care activities (e.g., glucose monitoring, adjusting insulin doses, etc.). These cognitive deficits have been associated with increased risk of hypoglycemia, and, conversely, severe hypoglycemia has been linked to increased risk of dementia. Therefore, it is important to routinely screen

older adults for cognitive dysfunction and discuss findings with the patients and their caregivers. Hypoglycemic events should be diligently monitored and avoided, whereas glycemic targets and pharmacologic interventions may need to be adjusted to accommodate for the changing needs of the older adult (3). TREATMENT GOALS Rationale

The care of older adults with diabetes is complicated by their clinical, mental, and functional heterogeneity. Some older individuals may have developed diabetes years earlier and have significant complications, others are newly diagnosed and may have had years of undiagnosed diabetes with resultant complications, and still other older adults may have truly recent-onset disease with few or no complications (18). Some older adults with diabetes have other underlying chronic conditions, substantial diabetes-related comorbidity, limited cognitive or physical functioning, or frailty (19,20). Other older individuals with diabetes have little comorbidity and are active. Life expectancies are highly variable but are often longer than clinicians realize. Providers caring for older adults with diabetes must take this heterogeneity into consideration when setting and prioritizing treatment goals (21) (Table 11.1). In addition, older adults with diabetes should be assessed for disease treatment and self-management knowledge, health literacy, and mathematical literacy (numeracy) at the onset of treatment. Healthy Patients With Good Functional Status

There are few long-term studies in older adults demonstrating the benefits of intensive glycemic, blood pressure, and lipid control. Patients who can be expected to live long enough to reap the benefits of long-term intensive diabetes management, who have good cognitive and physical function, and who choose to do so via shared decision making may be treated using therapeutic interventions and goals similar to those for younger adults with diabetes. As with all patients with diabetes, diabetes selfmanagement education and ongoing diabetes self-management support are vital components of diabetes care

Patients With Complications and Reduced Functionality

For patients with advanced diabetes complications, life-limiting comorbid illnesses, or substantial cognitive or functional impairments, it is reasonable to set less intensive glycemic goals. These patients are less likely to benefit from reducing the risk of microvascular complications and more likely to suffer serious adverse effects from hypoglycemia. However, patients with poorly controlled diabetes may be subject to acute complications of diabetes, including dehydration, poor wound healing, and hyperglycemic hyperosmolar coma. Glycemic goals at a minimum should avoid these consequences. Vulnerable Patients at the End of Life

For patients receiving palliative care and end-of-life care, the focus should be to avoid symptoms and complications from glycemic management. Thus, when organ failure develops, several agents will have to be titrated or discontinued. For the dying patient, most agents for type 2 diabetes may be removed. There is, however, no consensus for the management of type 1 diabetes in this scenario (23,24).

Beyond Glycemic Control

Although hyperglycemia control may be important in older individuals with diabetes, greater reductions in morbidity and mortality are likely to result from control of other cardiovascular risk factors rather than from tight glycemic control alone. There is strong evidence from clinical trials of the value of treating hypertension in older adults (25,26). There is less evidence for lipid-lowering therapy and aspirin therapy, although the benefits of these interventions for primary prevention and secondary intervention are likely to apply to older adults whose life expectancies equal or exceed the time frames of the clinical trials.

,7.5% (58 mmol/mol)

90–150 mg/dL (5.0–8.3 mmol/L)

90–130 mg/dL (5.0–7.2 mmol/L)

Fasting or preprandial glucose

110–200 mg/dL (6.1–11.1 mmol/L)

100–180 mg/dL (5.6–10.0 mmol/L)

90–150 mg/dL (5.0–8.3 mmol/L)

Bedtime glucose

Reasonable A1C goal‡

Longer remaining life expectancy

,8.0% (64 mmol/mol)

100–180 mg/dL (5.6–10.0 mmol/L)

Rationale

Healthy (few coexisting chronic illnesses, intact cognitive and functional status) Intermediate remaining life expectancy, high treatment burden, hypoglycemia vulnerability, fall risk

,8.5%† (69 mmol/mol)

Patient characteristics/health status

Complex/intermediate (multiple coexisting chronic illnesses* or 21 instrumental ADL impairments or mild-tomoderate cognitive impairment) Limited remaining life expectancy makes benefit uncertain

,150/90 mmHg

,140/90 mmHg

,140/90 mmHg

Blood pressure

Consider likelihood of benefit with statin (secondary prevention more so than primary)

Statin unless contraindicated or not tolerated

Statin unless contraindicated or not tolerated

Lipids

This represents a consensus framework for considering treatment goals for glycemia, blood pressure, and dyslipidemia in older adults with diabetes. The patient characteristic categories are general concepts. Not every patient will clearly fall into a particular category. Consideration of patient and caregiver preferences is an important aspect of treatment individualization. Additionally, a patient’s health status and preferences may change over time. ADL, activities of daily living. ‡A lower A1C goal may be set for an individual if achievable without recurrent or severe hypoglycemia or undue treatment burden. *Coexisting chronic illnesses are conditions serious enough to require medications or lifestyle management and may include arthritis, cancer, congestive heart failure, depression, emphysema, falls, hypertension, incontinence, stage 3 or worse chronic kidney disease, myocardial infarction, and stroke. By “multiple,” we mean at least three, but many patients may have five or more (40). **The presence of a single end-stage chronic illness, such as stage 3–4 congestive heart failure or oxygen-dependent lung disease, chronic kidney disease requiring dialysis, or uncontrolled metastatic cancer, may cause significant symptoms or impairment of functional status and significantly reduce life expectancy. †A1C of 8.5% (69 mmol/mol) equates to an estimated average glucose of ;200 mg/dL (11.1 mmol/L). Looser A1C targets above 8.5% (69 mmol/mol) are not recommended as they may expose patients to more frequent higher glucose values and the acute risks from glycosuria, dehydration, hyperglycemic hyperosmolar syndrome, and poor wound healing.

Very complex/poor health (LTC or end-stage chronic illnesses** or moderate-to-severe cognitive impairment or 21 ADL dependencies)

Table 11.1—Framework for considering treatment goals for glycemia, blood pressure, and dyslipidemia in older adults with diabetes

for older adults and their caregivers. Self-management knowledge and skills should be reassessed when regimen changes are made or an individual’s functional abilities diminish. In addition, declining or impaired ability to perform diabetes self-care behaviors may be an indication for referral of older adults with diabetes for cognitive and physical functional assessment using age-normalized evaluation tools (16,22).

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PHARMACOLOGIC THERAPY

Insulin Therapy

Special care is required in prescribing and monitoring pharmacologic therapies in older adults (27). Cost may be an important consideration, especially as older adults tend to be on many medications.

The use of insulin therapy requires that patients or their caregivers have good visual and motor skills and cognitive ability. Insulin therapy relies on the ability of the older patient to administer insulin on their own or with the assistance of a caregiver. Insulin doses should be titrated to meet individualized glycemic targets and to avoid hypoglycemia. Once-daily basal insulin injection therapy is associated with minimal side effects and may be a reasonable option in many older patients. Multiple daily injections of insulin may be too complex for the older patient with advanced diabetes complications, life-limiting comorbid illnesses, or limited functional status.

Metformin

Metformin is the first-line agent for older adults with type 2 diabetes. Recent studies have indicated that it may be used safely in patients with estimated glomerular filtration rate $30 mL/min/1.73 m2 (28). However, it is contraindicated in patients with advanced renal insufficiency or significant heart failure. Metformin may be temporarily discontinued before procedures, during hospitalizations, and when acute illness may compromise renal or liver function. Thiazolidinediones

Thiazolidinediones, if used at all, should be used very cautiously in those with, or at risk for, congestive heart failure and those at risk for falls or fractures. Insulin Secretagogues

Sulfonylureas and other insulin secretagogues are associated with hypoglycemia and should be used with caution. If used, shorter-duration sulfonylureas such as glipizide are preferred. Glyburide is a longer-duration sulfonylurea and contraindicated in older adults (29). Incretin-Based Therapies

Oral dipeptidyl peptidase 4 inhibitors have few side effects and minimal hypoglycemia, but their costs may be a barrier to some older patients. A systematic review concluded that incretin-based agents do not increase major adverse cardiovascular events (30). Glucagon-like peptide 1 receptor agonists are injectable agents, which require visual, motor, and cognitive skills. They may be associated with nausea, vomiting, and diarrhea. Also, weight loss with GLP-1 receptor agonists may not be desirable in some older patients, particularly those with cachexia. Sodium–Glucose Cotransporter 2 Inhibitors

Sodium–glucose cotransporter 2 inhibitors offer an oral route, which may be convenient for older adults with diabetes; however, long-term experience is limited despite the initial efficacy and safety data reported with these agents.

Other Factors to Consider

The needs of older adults with diabetes and their caregivers should be evaluated to construct a tailored care plan. Social difficulties may impair their quality of life and increase the risk of functional dependency (31). The patient’s living situation must be considered, as it may affect diabetes management and support. Social and instrumental support networks (e.g., adult children, caretakers) that provide instrumental or emotional support for older adults with diabetes should be included in diabetes management discussions and shared decision making. Older adults in assisted living facilities may not have support to administer their own medications, whereas those living in a nursing home (community living centers) may rely completely on the care plan and nursing support. Those receiving palliative care (with or without hospice) may require an approach that emphasizes comfort and symptom management, while deemphasizing strict metabolic and blood pressure control. TREATMENT IN SKILLED NURSING FACILITIES AND NURSING HOMES

Management of diabetes in the longterm care (LTC) setting (i.e., nursing homes and skilled nursing facilities) is unique. Individualization of health care is important in all patients; however, practical guidance is needed for medical providers as well as the LTC staff and caregivers (32). The American Medical Directors Association guidelines offer a 12-step program for staff (33). This

training includes diabetes detection and institutional quality assessment. The guidelines also recommend that LTC facilities develop their own policies and procedures for prevention and management of hypoglycemia. Resources

Staff of LTC facilities should receive appropriate diabetes education to improve the management of older adults with diabetes. Treatments for each patient should be individualized. Special management considerations include the need to avoid both hypoglycemia and the metabolic complications of diabetes and the need to provide adequate diabetes training to LTC staff (3,34). For more information, see the ADA position statement “Management of Diabetes in Long-term Care and Skilled Nursing Facilities: A Position Statement of the American Diabetes Association” (32). Nutritional Considerations

An older adult residing in an LTC facility may have irregular and unpredictable meal consumption, undernutrition, anorexia, and impaired swallowing. Furthermore, therapeutic diets may inadvertently lead to decreased food intake and contribute to unintentional weight loss and undernutrition. Diets tailored to a patient’s culture, preferences, and personal goals might increase quality of life, satisfaction with meals, and nutrition status (35). Hypoglycemia

Older adults with diabetes in LTC are especially vulnerable to hypoglycemia. They have a disproportionately high number of clinical complications and comorbidities that can increase hypoglycemia risk: impaired cognitive and renal function, slowed hormonal regulation and counterregulation, suboptimal hydration, variable appetite and nutritional intake, polypharmacy, and slowed intestinal absorption (36). Another consideration for the LTC setting is that unlike the hospital setting, medical providers are not required to evaluate the patients daily. According to federal guidelines, assessments should be done at least every 30 days for the first 90 days after admission and then at least once every 60 days. Although in practice the patients may actually be seen more frequently, the

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concern is that patients may have uncontrolled glucose levels or wide excursions without the practitioner being notified. Providers may make adjustments to treatment regimens by telephone, fax, or order directly at the LTC facilities provided they are given timely notification from a standardized alert system. The following alert strategy could be considered: 1. Call provider immediately: in case of low blood glucose levels (,70 mg/dL [3.9 mmol/L]). Low finger-stick blood glucose values should be confirmed by laboratory glucose measurement. 2. Call as soon as possible: a) glucose values between 70 and 100 mg/dL (between 3.9 and 5.6 mmol/L) (regimen may need to be adjusted), b) glucose values greater than 250 mg/dL (13.9 mmol/L) within a 24-h period, c) glucose values greater than 300 mg/dL (16.7 mmol/L) within 2 consecutive days, d) when any reading is too high, or e) the patient is sick, with vomiting or other malady that can reflect hyperglycemic crisis and may lead to poor oral intake, thus requiring regimen adjustment.

END-OF-LIFE CARE

The management of the older adult at the end of life receiving palliative medicine or hospice care is a unique situation. Overall, palliative medicine promotes comfort, symptom control and prevention (pain, hypoglycemia, hyperglycemia, and dehydration) and preservation of dignity and quality-oflife in patients with limited life expectancy (34,37). A patient has the right to refuse testing and treatment, whereas providers may consider withdrawing treatment and limiting diagnostic testing, including a reduction in the frequency of finger-stick testing (38). Glucose targets should aim to prevent hypoglycemia and hyperglycemia. Treatment interventions need to be mindful of quality of life. Careful monitoring of oral intake is warranted. The decision process may need to involve the patient, family, and caregivers, leading to a care plan that is both convenient and effective for the goals of care (39). The pharmacologic therapy may include oral agents as first line, followed by a simplified insulin regimen. If needed,

Older Adults

basal insulin can be implemented, accompanied by oral agents and without rapid-acting insulin. Agents that can cause gastrointestinal symptoms such as nausea or excess weight loss may not be good choices in this setting. As symptoms progress, some agents may be slowly tapered and discontinued. Strata have been proposed for diabetes management in those with advanced disease (24). 1. A stable patient: continue with the patient’s previous regimen, with a focus on the prevention of hypoglycemia and the management of hyperglycemia using blood glucose testing, keeping levels below the renal threshold of glucose. There is very little role for A1C monitoring and lowering. 2. A patient with organ failure: preventing hypoglycemia is of greater significance. Dehydration must be prevented and treated. In people with type 1 diabetes, insulin administration may be reduced as the oral intake of food decreases but should not be stopped. For those with type 2 diabetes, agents that may cause hypoglycemia should be titrated. The main goal is to avoid hypoglycemia, allowing for glucose values in the upper level of the desired target range. 3. A dying patient: for patients with type 2 diabetes, the discontinuation of all medications may be a reasonable approach, as patients are unlikely to have any oral intake. In patients with type 1 diabetes, there is no consensus, but a small amount of basal insulin may maintain glucose levels and prevent acute hyperglycemic complications. References 1. Centers for Disease Control and Prevention. National diabetes statistics report: estimates of diabetes and its burden in the United States, 2014 [Internet]. Available from http://www.cdc .gov/diabetes/data/statistics/2014statisticsreport .html. Accessed 21 November 2016 2. Kimbro LB, Mangione CM, Steers WN, et al. Depression and all-cause mortality in persons with diabetes mellitus: are older adults at higher risk? Results from the Translating Research Into Action for Diabetes Study. J Am Geriatr Soc 2014;62:1017–1022 3. Kirkman MS, Briscoe VJ, Clark N, et al. Diabetes in older adults. Diabetes Care 2012;35: 2650–2664

4. Cukierman T, Gerstein HC, Williamson JD. Cognitive decline and dementia in diabetes– systematic overview of prospective observational studies. Diabetologia 2005;48:2460–2469 5. Roberts RO, Knopman DS, Przybelski SA, et al. Association of type 2 diabetes with brain atrophy and cognitive impairment. Neurology 2014;82:1132–1141 6. Xu WL, von Strauss E, Qiu CX, Winblad B, Fratiglioni L. Uncontrolled diabetes increases the risk of Alzheimer’s disease: a populationbased cohort study. Diabetologia 2009;52: 1031–1039 7. Ghezzi L, Scarpini E, Galimberti D. Diseasemodifying drugs in Alzheimer’s disease. Drug Des Devel Ther 2013;7:1471–1478 8. Craft S, Baker LD, Montine TJ, et al. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol 2012;69:29–38 9. Freiherr J, Hallschmid M, Frey WH 2nd, et al. Intranasal insulin as a treatment for Alzheimer’s disease: a review of basic research and clinical evidence. CNS Drugs 2013;27:505–514 10. Alagiakrishnan K, Sankaralingam S, Ghosh M, Mereu L, Senior P. Antidiabetic drugs and their potential role in treating mild cognitive impairment and Alzheimer’s disease. Discov Med 2013;16:277–286 11. Yaffe K, Falvey C, Hamilton N, et al. Diabetes, glucose control, and 9-year cognitive decline among older adults without dementia. Arch Neurol 2012;69:1170–1175 12. Launer LJ, Miller ME, Williamson JD, et al.; ACCORD MIND Investigators. Effects of intensive glucose lowering on brain structure and function in people with type 2 diabetes (ACCORD MIND): a randomised open-label substudy. Lancet Neurol 2011;10:969–977 13. Cummings JL, Frank JC, Cherry D, et al. Guidelines for managing Alzheimer’s disease: part I. Assessment. Am Fam Physician 2002;65: 2263–2272 14. Nasreddine ZS, Phillips NA, Be´ dirian V, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 2005;53:695–699 15. Institute of Medicine. Cognitive aging: progress in understanding and opportunities for action [Internet]. Available from http:// nationalacademies.org/hmd/Reports/2015/ Cognitive-Aging.aspx. Accessed 3 October 2016 16. American Psychological Association. Guidelines for the evaluation of dementia and agerelated cognitive change [Internet]. Available from http://www.apa.org/practice/guidelines/ dementia.aspx. Accessed 3 October 2016 17. Feinkohl I, Aung PP, Keller M, et al.; Edinburgh Type 2 Diabetes Study (ET2DS) Investigators. Severe hypoglycemia and cognitive decline in older people with type 2 diabetes: the Edinburgh type 2 diabetes study. Diabetes Care 2014;37:507–515 18. Selvin E, Coresh J, Brancati FL. The burden and treatment of diabetes in elderly individuals in the U.S. Diabetes Care 2006;29:2415–2419 19. Bandeen-Roche K, Seplaki CL, Huang J, et al. Frailty in older adults: a nationally representative profile in the United States. J Gerontol A Biol Sci Med Sci 2015;70:1427–1434 20. Kalyani RR, Tian J, Xue Q-L, et al. Hyperglycemia and incidence of frailty and lower

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extremity mobility limitations in older women. J Am Geriatr Soc 2012;60:1701–1707 21. Blaum C, Cigolle CT, Boyd C, et al. Clinical complexity in middle-aged and older adults with diabetes: the Health and Retirement Study. Med Care 2010;48:327–334 22. Young-Hyman D, de Groot M, Hill-Briggs F, Gonzalez JS, Hood K, Peyrot M. Psychosocial care for people with diabetes: a position statement of the American Diabetes Association. Diabetes Care 2016;39:2126–2140 23. Sinclair A, Dunning T, Colagiuri S. IDF Global Guideline for Managing Older People With Type 2 Diabetes. Brussels, Belgium, International Diabetes Federation, 2013 24. Angelo M, Ruchalski C, Sproge BJ. An approach to diabetes mellitus in hospice and palliative medicine. J Palliat Med 2011;14:83–87 25. Beckett NS, Peters R, Fletcher AE, et al.; HYVET Study Group. Treatment of hypertension in patients 80 years of age or older. N Engl J Med 2008;358:1887–1898 26. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014;311:507–520 27. Valencia WM, Florez H. Pharmacological treatment of diabetes in older people. Diabetes Obes Metab 2014;16:1192–1203 28. Inzucchi SE, Lipska KJ, Mayo H, Bailey CJ, McGuire DK. Metformin in patients with

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type 2 diabetes and kidney disease: a systematic review. JAMA 2014;312:2668–2675 29. Campanelli CM; American Geriatrics Society 2012 Beers Criteria Update Expert Panel. American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc 2012;60: 616–631 30. Rotz ME, Ganetsky VS, Sen S, Thomas TF. Implications of incretin-based therapies on cardiovascular disease. Int J Clin Pract 2015;69: 531–549 31. Laiteerapong N, Karter AJ, Liu JY, et al. Correlates of quality of life in older adults with diabetes: the Diabetes & Aging Study. Diabetes Care 2011;34:1749–1753 32. Munshi MN, Florez H, Huang ES, et al. Management of diabetes in long-term care and skilled nursing facilities: a position statement of the American Diabetes Association. Diabetes Care 2016;39:308–318 33. American Medical Directors Association. Diabetes management in the long-term care setting [Internet]. Available from http://www .amda.com/tools/guidelines.cfm#diabetes. Accessed 5 October 2015 34. Sinclair A, Morley JE, Rodriguez-Ma~ nas L, et al. Diabetes mellitus in older people: position statement on behalf of the International Association of Gerontology and Geriatrics (IAGG), the European Diabetes Working Party for Older People (EDWPOP), and the International Task

Force of Experts in Diabetes. J Am Med Dir Assoc 2012;13:497–502 35. Dorner B, Friedrich EK, Posthauer ME. Practice paper of the American Dietetic Association: individualized nutrition approaches for older adults in health care communities. J Am Diet Assoc 2010;110:1554–1563 36. Migdal A, Yarandi SS, Smiley D, Umpierrez GE. Update on diabetes in the elderly and in nursing home residents. J Am Med Dir Assoc 2011;12:627–632.e2 37. Quinn K, Hudson P, Dunning T. Diabetes management in patients receiving palliative care. J Pain Symptom Manage 2006;32:275–286 38. Ford-Dunn S, Smith A, Quin J. Management of diabetes during the last days of life: attitudes of consultant diabetologists and consultant palliative care physicians in the UK. Palliat Med 2006;20:197–203 39. Mallery LH, Ransom T, Steeves B, Cook B, Dunbar P, Moorhouse P. Evidence-informed guidelines for treating frail older adults with type 2 diabetes: from the Diabetes Care Program of Nova Scotia (DCPNS) and the Palliative and Therapeutic Harmonization (PATH) program. J Am Med Dir Assoc 2013;14:801– 808 40. Laiteerapong N, Iveniuk J, John PM, Laumann EO, Huang ES. Classification of older adults who have diabetes by comorbid conditions, United States, 2005-2006. Prev Chronic Dis 2012;9:E100

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12. Children and Adolescents

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Diabetes Care 2017;40(Suppl. 1):S105–S113 | DOI: 10.2337/dc17-S015

TYPE 1 DIABETES

12. CHILDREN AND ADOLESCENTS

Three-quarters of all cases of type 1 diabetes are diagnosed in individuals ,18 years of age (although recent data using genetic risk scoring would suggest that over 40% of patients with autoimmune diabetes are diagnosed over the age of 30 years) (1). The provider must consider the unique aspects of care and management of children and adolescents with type 1 diabetes, such as changes in insulin sensitivity related to physical growth and sexual maturation, ability to provide self-care, supervision in the child care and school environment, and neurological vulnerability to hypoglycemia and hyperglycemia in young children, as well as possible adverse neurocognitive effects of diabetic ketoacidosis (DKA) (2,3). Attention to family dynamics, developmental stages, and physiological differences related to sexual maturity are all essential in developing and implementing an optimal diabetes treatment plan (4). Due to the paucity of clinical research in children, the recommendations for children and adolescents are less likely to be based on clinical trial evidence. However, expert opinion and a review of available and relevant experimental data are summarized in the American Diabetes Association (ADA) position statement “Care of Children and Adolescents With Type 1 Diabetes” (5) and have been updated in the ADA position statement “Type 1 Diabetes Through the Life Span” (6). A multidisciplinary team of specialists trained in pediatric diabetes management and sensitive to the challenges of children and adolescents with type 1 diabetes and their families should provide care for this population. It is essential that diabetes self-management education (DSME) and support (DSMS), medical nutrition therapy, and psychosocial support be provided at diagnosis and regularly thereafter in a developmentally appropriate format that builds on prior knowledge by individuals experienced with the educational, nutritional, behavioral, and emotional needs of the growing child and family. The appropriate balance between adult supervision and independent self-care should be defined at the first interaction and reevaluated at subsequent visits. The balance between adult supervision and independent self-care will evolve as the adolescent gradually becomes an emerging young adult. Diabetes Self-management Education and Support Recommendation c

Youth with type 1 diabetes and parents/caregivers (for patients aged ,18 years) should receive culturally sensitive and developmentally appropriate individualized diabetes self-management education and support according to national standards at diagnosis and routinely thereafter. B

No matter how sound the medical regimen, it can only be effective if the family and/or affected individuals are able to implement it. Family involvement is a vital component of optimal diabetes management throughout childhood and adolescence. Health care providers (the diabetes care team) who care for children and adolescents must be capable of evaluating the educational, behavioral, emotional, and psychosocial factors that impact implementation of a treatment plan and must work with the individual and family to overcome barriers or redefine goals as appropriate. DSME and DSMS require periodic reassessment, especially as the youth grows, develops, and acquires the need for greater independent self-care skills. In addition, it is necessary to assess the educational needs and skills of day care providers, school nurses, or other school personnel who participate in the care of the young child with diabetes (7).

Suggested citation: American Diabetes Association. Children and adolescents. Sec. 12. In Standards of Medical Care in Diabetesd2017. Diabetes Care 2017;40(Suppl. 1):S105–S113 © 2017 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals .org/content/license.

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School and Child Care

As a large portion of a child’s day is spent in school, close communication with and the cooperation of school or day care personnel are essential for optimal diabetes management, safety, and maximal academic opportunities. Refer to the ADA position statements “Diabetes Care in the School Setting” (8) and “Care of Young Children With Diabetes in the Child Care Setting” (9) for additional details. Psychosocial Issues Recommendations c

c

c

c

c

c

c

At diagnosis and during routine follow-up care, assess psychosocial issues and family stresses that could impact adherence to diabetes management and provide appropriate referrals to trained mental health professionals, preferably experienced in childhood diabetes. E Mental health professionals should be considered integral members of the pediatric diabetes multidisciplinary team. E Encourage developmentally appropriate family involvement in diabetes management tasks for children and adolescents, recognizing that premature transfer of diabetes care to the child can result in nonadherence and deterioration in glycemic control. B Providers should assess children’s and adolescents’ diabetes distress, social adjustment (peer relationships), and school performance to determine whether further intervention is needed. B In youth and families with behavioral self-care difficulties, repeated hospitalizations for diabetic ketoacidosis, or significant distress, consider referral to a mental health provider for evaluation and treatment. E Adolescents should have time by themselves with their care provider(s) starting at age 12 years. E Starting at puberty, preconception counseling should be incorporated into routine diabetes care for all girls of childbearing potential. A

Rapid and dynamic cognitive, developmental, and emotional changes occur during childhood, adolescence, and emerging

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adulthood. Diabetes management during childhood and adolescence places substantial burdens on the youth and family, necessitating ongoing assessment of psychosocial status and diabetes distress during routine diabetes visits (10–12). Early detection of depression, anxiety, eating disorders, and learning disabilities can facilitate effective treatment options and help minimize adverse effects on diabetes management and disease outcomes (13). Furthermore, the complexities of diabetes management require ongoing parental involvement in care throughout childhood with developmentally appropriate family teamwork between the growing child/teen and parent in order to maintain adherence and to prevent deterioration in glycemic control (14,15). As diabetes-specific family conflict is related to poorer adherence and glycemic control, it is appropriate to inquire about such conflict during visits and to either help to negotiate a plan for resolution or refer to an appropriate mental health specialist (16). Monitoring of social adjustment (peer relationships) and school performance can facilitate both wellbeing and academic achievement. Suboptimal glycemic control is a risk factor for below average school performance and increased absenteeism (17). Shared decision-making with youth regarding the adoption of regimen components and self-management behaviors can improve diabetes self-efficacy, adherence, and metabolic outcomes (18). Although cognitive abilities vary, the ethical position often adopted is the “mature minor rule,” whereby children after age 12 or 13 years who appear to be “mature” have the right to consent or withhold consent to general medical treatment, except in cases in which refusal would significantly endanger health (19). Beginning at the onset of puberty or at diagnosis of diabetes, all adolescent girls and women with childbearing potential should receive education about the risks of malformations associated with unplanned pregnancies and poor metabolic control and the use of effective contraception to prevent unplanned pregnancy. Preconception counseling using developmentally appropriate educational tools enables adolescent girls to make wellinformed decisions (20). Preconception counseling resources tailored for adolescents are available at no cost through the ADA (21).

Screening

Screening for psychosocial distress and mental health problems is an important component of ongoing care. It is important to consider the impact of diabetes on quality of life as well as the development of mental health problems related to diabetes distress, fear of hypoglycemia (and hyperglycemia), symptoms of anxiety, disordered eating behaviors as well as eating disorders, and symptoms of depression (22). Consider assessing youth for diabetes distress, generally starting at 7 or 8 years of age (13). Consider screening for depression and disordered eating behaviors using available screening tools (10,23). With respect to disordered eating, it is important to recognize the unique and dangerous disordered eating behavior of insulin omission for weight control in type 1 diabetes (24). The presence of a mental health professional on pediatric multidisciplinary teams highlights the importance of attending to the psychosocial issues of diabetes. These psychosocial factors are significantly related to nonadherence, suboptimal glycemic control, reduced quality of life, and higher rates of acute and chronic diabetes complications. Glycemic Control Recommendation c

An A1C goal of ,7.5% (58 mmol/mol) is recommended across all pediatric age-groups. E

Current standards for diabetes management reflect the need to lower glucose as safely as possible. This should be done with stepwise goals. When establishing individualized glycemic targets, special consideration should be given to the risk of hypoglycemia in young children (aged ,6 years) who are often unable to recognize, articulate, and/or manage hypoglycemia. Type 1 diabetes can be associated with adverse effects on cognition during childhood and adolescence. Factors that contribute to adverse effects on brain development and function include young age or DKA at onset of type 1 diabetes, severe hypoglycemia ,6 years of age, and chronic hyperglycemia (25,26). However, meticulous use of new therapeutic modalities, such as rapid- and long-acting insulin analogs, technological advances (e.g., continuous glucose monitors, low glucose suspend insulin pumps), and

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intensive self-management education now make it more feasible to achieve excellent glycemic control while reducing the incidence of severe hypoglycemia (27,28). The Diabetes Control and Complications Trial (DCCT), which did not enroll children ,13 years of age, demonstrated that near normalization of blood glucose levels was more difficult to achieve in adolescents than in adults. Nevertheless, the increased use of basal-bolus regimens, insulin pumps, frequent blood glucose monitoring, goal setting, and improved patient education in youth from infancy through adolescence have been associated with more children reaching the blood glucose targets recommended by the ADA (29–32), particularly in those families in which both the parents and the child with diabetes participate jointly to perform the required diabetes-related tasks. Furthermore, studies documenting neurocognitive imaging differences related to hyperglycemia in children provide another motivation for lowering glycemic targets (2). In selecting glycemic goals, the longterm health benefits of achieving a lower A1C should be balanced against the risks of hypoglycemia and the developmental burdens of intensive regimens in children and youth. In addition, achieving lower A1C levels is more likely to be related to setting lower A1C targets (33,34). A1C goals are presented in Table 12.1.

Because of the increased frequency of other autoimmune diseases in type 1 diabetes, screening for thyroid dysfunction and celiac disease should be considered. Periodic screening in asymptomatic individuals has been recommended, but the optimal frequency and benefit of screening are unclear. Although much less common than thyroid dysfunction and celiac disease, other autoimmune conditions, such as Addison disease (primary adrenal insufficiency), autoimmune hepatitis, autoimmune gastritis, dermatomyositis, and myasthenia gravis, occur more commonly in the population with type 1 diabetes than in the general pediatric population and should be assessed and monitored as clinically indicated. Thyroid Disease

Celiac Disease

Recommendations c

c

(36); their presence is predictive of thyroid dysfunctiondmost commonly hypothyroidism, although hyperthyroidism occurs in ;0.5% of patients with type 1 diabetes (37,38). Thyroid function tests may be misleading (euthyroid sick syndrome) if performed at time of diagnosis owing to the effect of previous hyperglycemia, ketosis or ketoacidosis, weight loss, etc. Therefore, thyroid function tests should be performed soon after a period of metabolic stability and good glycemic control. Subclinical hypothyroidism may be associated with increased risk of symptomatic hypoglycemia (39) and reduced linear growth rate. Hyperthyroidism alters glucose metabolism and usually causes deterioration of glycemic control.

Consider testing individuals with type 1 diabetes for antithyroid peroxidase and antithyroglobulin antibodies soon after the diagnosis. E Measure thyroid-stimulating hormone concentrations soon after the diagnosis of type 1 diabetes and after glucose control has been established. If normal, consider rechecking every 1–2 years or sooner if the patient develops symptoms suggestive of thyroid dysfunction, thyromegaly, an abnormal growth rate, or an unexplained glycemic variation. E

Recommendations c

c

Autoimmune Conditions Recommendation c

Assess for the presence of autoimmune conditions associated with type 1 diabetes soon after the diagnosis and if symptoms develop. E

Autoimmune thyroid disease is the most common autoimmune disorder associated with diabetes, occurring in 17–30% of patients with type 1 diabetes (35). At the time of diagnosis, about 25% of children with type 1 diabetes have thyroid autoantibodies

c

Consider screening individuals with type 1 diabetes for celiac disease by measuring either tissue transglutaminase or deamidated gliadin antibodies, with documentation of normal total serum IgA levels, soon after the diagnosis of diabetes. E Consider screening individuals who have a first-degree relative with celiac disease, growth failure, weight loss, failure to gain weight, diarrhea, flatulence, abdominal pain, or signs of malabsorption or in individuals with frequent unexplained hypoglycemia or deterioration in glycemic control. E Individuals with biopsy-confirmed celiac disease should be placed on a gluten-free diet and have a consultation with a dietitian experienced in managing both diabetes and celiac disease. B

Table 12.1—Blood glucose and A1C goals for children and adolescents with type 1 diabetes Blood glucose goal range Before meals 90–130 mg/dL (5.0–7.2 mmol/L)

Bedtime/overnight

A1C

90–150 mg/dL (5.0–8.3 mmol/L)

,7.5% (58 mmol/mol)

Rationale A lower goal (,7.0% [53 mmol/mol]) is reasonable if it can be achieved without excessive hypoglycemia

Key concepts in setting glycemic goals: c Goals

should be individualized, and lower goals may be reasonable based on a benefit-risk assessment. glucose goals should be modified in children with frequent hypoglycemia or hypoglycemia unawareness. c Postprandial blood glucose values should be measured when there is a discrepancy between preprandial blood glucose values and A1C levels and to assess preprandial insulin doses in those on basal-bolus or pump regimens. c Blood

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Celiac disease is an immune-mediated disorder that occurs with increased frequency in patients with type 1 diabetes (1.6–16.4% of individuals compared with 0.3–1% in the general population) (40–42). Screening. Screening for celiac disease includes measuring serum levels of IgA and anti–tissue transglutaminase antibodies, or, with IgA deficiency, screening can include measuring IgG tissue transglutaminase antibodies or IgG deamidated gliadin peptide antibodies. Because most cases of celiac disease are diagnosed within the first 5 years after the diagnosis of type 1 diabetes, screening should be considered at the time of diagnosis and repeated 2 and 5 years thereafter. Although celiac disease can be diagnosed more than 10 years after diabetes diagnosis, there are insufficient data after 5 years to determine the optimal screening frequency. Measurement of anti–tissue transglutaminase antibody should be considered at other times in patients with symptoms suggestive of celiac disease (42). A small-bowel biopsy in antibody-positive children is recommended to confirm the diagnosis (43). European guidelines on screening for celiac disease in children (not specific to children with type 1 diabetes) suggest that biopsy may not be necessary in symptomatic children with high antibody titers (i.e., greater than 10 times the upper limit of normal) provided that further testing is performed (verification of endomysial antibody positivity on a separate blood sample). It is also advisable to check for HLA types in patients who are diagnosed without a small intestinal biopsy. Asymptomatic at-risk children should have an intestinal biopsy (44). In symptomatic children with type 1 diabetes and confirmed celiac disease, gluten-free diets reduce symptoms and rates of hypoglycemia (45). The challenging dietary restrictions associated with having both type 1 diabetes and celiac disease place a significant burden on individuals. Therefore, a biopsy to confirm the diagnosis of celiac disease is recommended, especially in asymptomatic children, before endorsing significant dietary changes.

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Management of Cardiovascular Risk Factors Hypertension Recommendations

Normal blood pressure levels for age, sex, and height and appropriate methods for measurement are available online at www.nhlbi.nih.gov/health/prof/heart/ hbp/hbp_ped.pdf.

Screening c

Blood pressure should be measured at each routine visit. Children found to have high-normal blood pressure (systolic blood pressure or diastolic blood pressure $90th percentile for age, sex, and height) or hypertension (systolic blood pressure or diastolic blood pressure $95th percentile for age, sex, and height) should have elevated blood pressure confirmed on 3 separate days. B

Dyslipidemia Recommendations

Testing c

c

Treatment c

c

c

c

Initial treatment of high-normal blood pressure (systolic blood pressure or diastolic blood pressure consistently $90th percentile for age, sex, and height) includes dietary modification and increased exercise, if appropriate, aimed at weight control. If target blood pressure is not reached within 3–6 months of initiating lifestyle intervention, pharmacologic treatment should be considered. E In addition to lifestyle modification, pharmacologic treatment of hypertension (systolic blood pressure or diastolic blood pressure consistently $95th percentile for age, sex, and height) should be considered as soon as hypertension is confirmed. E ACE inhibitors or angiotensin receptor blockers should be considered for the initial pharmacologic treatment of hypertension, following reproductive counseling and implementation of effective birth control due to the potential teratogenic effects of both drug classes. E The goal of treatment is blood pressure consistently ,90th percentile for age, sex, and height. E

Blood pressure measurements should be performed using the appropriate size cuff with the child seated and relaxed. Hypertension should be confirmed on at least 3 separate days. Evaluation should proceed as clinically indicated. Treatment is generally initiated with an ACE inhibitor, but an angiotensin receptor blocker can be used if the ACE inhibitor is not tolerated (e.g., due to cough) (46).

Obtain a fasting lipid profile in children $10 years of age soon after the diagnosis (after glucose control has been established). E If lipids are abnormal, annual monitoring is reasonable. If LDL cholesterol values are within the accepted risk level (,100 mg/dL [2.6 mmol/L]), a lipid profile repeated every 3–5 years is reasonable. E

Treatment c

c

c

Initial therapy should consist of optimizing glucose control and medical nutrition therapy using a Step 2 American Heart Association diet to decrease the amount of saturated fat in the diet. B After the age of 10 years, addition of a statin is suggested in patients who, despite medical nutrition therapy and lifestyle changes, continue to have LDL cholesterol .160 mg/dL (4.1 mmol/L) or LDL cholesterol .130 mg/dL (3.4 mmol/L) and one or more cardiovascular disease risk factors, following reproductive counseling and implementation of effective birth control due to the potential teratogenic effects of statins. E The goal of therapy is an LDL cholesterol value ,100 mg/dL (2.6 mmol/L). E

Population-based studies estimate that 14–45% of children with type 1 diabetes have two or more cardiovascular disease (CVD) risk factors (47–49), and the prevalence of CVD risk factors increases with age (49), with girls having a higher risk burden than boys (48). Pathophysiology. The atherosclerotic process begins in childhood, and although CVD events are not expected to occur during childhood, observations using a variety of methodologies show that youth with type 1 diabetes may have subclinical CVD within the first decade of diagnosis (50–52). Studies of carotid intima-media thickness have yielded inconsistent results (46).

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Treatment. Pediatric lipid guidelines provide some guidance relevant to children with type 1 diabetes (53–55); however, there are few studies on modifying lipid levels in children with type 1 diabetes. A 6-month trial of dietary counseling produced a significant improvement in lipid levels (56); likewise, a lifestyle intervention trial with 6 months of exercise in adolescents demonstrated improvement in lipid levels (57). Although intervention data are sparse, the American Heart Association (AHA) categorizes children with type 1 diabetes in the highest tier for cardiovascular risk and recommends both lifestyle and pharmacologic treatment for those with elevated LDL cholesterol levels (55,58). Initial therapy should be with a Step 2 AHA diet, which restricts saturated fat to 7% of total calories and restricts dietary cholesterol to 200 mg/day. Data from randomized clinical trials in children as young as 7 months of age indicate that this diet is safe and does not interfere with normal growth and development (59). For children with a significant family history of CVD, the National Heart, Lung, and Blood Institute recommends obtaining a fasting lipid panel beginning at 2 years of age (53). Abnormal results from a random lipid panel should be confirmed with a fasting lipid panel. Data from the SEARCH for Diabetes in Youth (SEARCH) study show that improved glucose control over a 2-year period is associated with a more favorable lipid profile; however, improved glycemic control alone will not normalize lipids in youth with type 1 diabetes and dyslipidemia (60). Neither long-term safety nor cardiovascular outcome efficacy of statin therapy has been established for children; however, studies have shown short-term safety equivalent to that seen in adults and efficacy in lowering LDL cholesterol levels in familial hypercholesterolemia or severe hyperlipidemia, improving endothelial function and causing regression of carotid intimal thickening (61,62). Statins are not approved for patients aged ,10 years, and statin treatment should generally not be used in children with type 1 diabetes before this age. Statins are category X in pregnancy; therefore, prevention of unplanned pregnancies is of paramount importance for postpubertal girls (see Section 13 “Management of Diabetes in Pregnancy” for more information).

Children and Adolescents

Smoking Recommendation c

Elicit a smoking history at initial and follow-up diabetes visits. Discourage smoking in youth who do not smoke and encourage smoking cessation in those who do smoke. B

The adverse health effects of smoking are well recognized with respect to future cancer and CVD risk. Despite this, smoking rates are significantly higher among youth with diabetes than among youth without diabetes (63,64). In youth with diabetes, it is important to avoid additional CVD risk factors. Smoking increases the risk of onset of albuminuria; therefore, smoking avoidance is important to prevent both microvascular and macrovascular complications (53,65). Discouraging cigarette smoking, including e-cigarettes, is an important part of routine diabetes care. In younger children, it is important to assess exposure to cigarette smoke in the home due to the adverse effects of secondhand smoke and to discourage youth from ever smoking if exposed to smokers in childhood. Microvascular Complications Nephropathy

Data from 7,549 participants ,20 years of age in the T1D Exchange clinic registry emphasize the importance of good glycemic and blood pressure control, particularly as diabetes duration increases, in order to reduce the risk of nephropathy. The data also underscore the importance of routine screening to ensure early diagnosis and timely treatment of albuminuria (66). An estimation of glomerular filtration rate (GFR), calculated using GFR estimating equations from the serum creatinine, height, age, and sex (67), should be determined at baseline and repeated as indicated based on clinical status, age, diabetes duration, and therapies. Estimated GFR is calculated from a serum creatinine measurement using an estimating equation. There are ongoing clinical trials assessing the efficacy of early treatment of persistent albuminuria with ACE inhibitors (68). Retinopathy Recommendations c

c

Recommendations

Screening c

c

Annual screening for albuminuria with a random spot urine sample for albumin-to-creatinine ratio should be considered once the child has had type 1 diabetes for 5 years. B Estimate glomerular filtration rate at initial evaluation and then based on age, diabetes duration, and treatment. E

Treatment c

When persistently elevated urinary albumin-to-creatinine ratio (.30 mg/g) is documented with at least two of three urine samples, treatment with an ACE inhibitor should be considered and the dose titrated to maintain blood pressure within the age-appropriate normal range. The urine samples should be obtained over a 6-month interval following efforts to improve glycemic control and normalize blood pressure. C

An initial dilated and comprehensive eye examination is recommended at age $10 years or after puberty has started, whichever is earlier, once the youth has had type 1 diabetes for 3–5 years. B After the initial examination, annual routine follow-up is generally recommended. Less frequent examinations, every 2 years, may be acceptable on the advice of an eye care professional. E

Retinopathy (like albuminuria) most commonly occurs after the onset of puberty and after 5–10 years of diabetes duration (69). Referrals should be made to eye care professionals with expertise in diabetic retinopathy and experience in counseling the pediatric patient and family on the importance of early prevention and intervention. Neuropathy Recommendation c

Consider an annual comprehensive foot exam for the child at the start of puberty or at age $10 years, whichever is earlier, once the youth has had type 1 diabetes for 5 years. E

Diabetic neuropathy rarely occurs in prepubertal children or after only 1–2 years of diabetes (69). A comprehensive foot

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exam, including inspection, palpation of dorsalis pedis and posterior tibial pulses, assessment of the patellar and Achilles reflexes, and determination of proprioception, vibration, and monofilament sensation, should be performed annually along with an assessment of symptoms of neuropathic pain. Foot inspection can be performed at each visit to educate youth regarding the importance of foot care (see Section 10 “Microvascular Complications and Foot Care”).

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diabetes in children can be difficult. Overweight and obesity are common in children with type 1 diabetes (75), and diabetes-associated autoantibodies and ketosis may be present in pediatric patients with features of type 2 diabetes (including obesity and acanthosis nigricans) (76). At onset, DKA occurs in ;6% of youth aged 10–19 years with type 2 diabetes (77). Accurate diagnosis is critical as treatment regimens, educational approaches, dietary advice, and outcomes differ markedly between patients with the two diagnoses.

TYPE 2 DIABETES

For information on testing for type 2 diabetes and prediabetes in children and adolescents, please refer to Section 2 “Classification and Diagnosis of Diabetes.” Type 2 diabetes in youth has increased over the past 20 years and recent estimates suggest an incidence of ;5,000 new cases per year in the U.S. (70). The Centers for Disease Control and Prevention published projections for type 2 diabetes prevalence using the SEARCH database: assuming a 2.3% annual increase, the prevalence in those under 20 years of age will quadruple in 40 years (71,72). Evidence suggests that type 2 diabetes in youth is different not only from type 1 diabetes but also from type 2 diabetes in adults and has unique features, such as a more rapidly progressive decline in b-cell function and accelerated development of diabetes complications (73,74). Type 2 diabetes disproportionately impacts youth of ethnic and racial minorities and can occur in complex psychosocial and cultural environments, which may make it difficult to sustain healthy lifestyle changes and self-management behaviors. Additional risk factors associated with type 2 diabetes in youth include adiposity, family history of diabetes, female sex, and low socioeconomic status (74). As with type 1 diabetes, youth with type 2 diabetes spend much of the day in school. Therefore, close communication with and the cooperation of school personnel are essential for optimal diabetes management, safety, and maximal academic opportunities. Diagnostic Challenges

Given the current obesity epidemic, distinguishing between type 1 and type 2

Treatment

The general treatment goals for youth with type 2 diabetes are the same as those for youth with type 1 diabetes. A multidisciplinary diabetes team, including a physician, diabetes nurse educator, registered dietitian, and psychologist or social worker, is essential. In addition to blood glucose control, initial treatment must include management of comorbidities such as obesity, dyslipidemia, hypertension, and microvascular complications. Current treatment options for youthonset type 2 diabetes are limited to two approved drugsdinsulin and metformin (73). Presentation with ketosis or ketoacidosis requires a period of insulin therapy until fasting and postprandial glycemia have been restored to normal or near-normal levels. Metformin therapy may be used as an adjunct after resolution of ketosis/ketoacidosis. Initial treatment should also be with insulin when the distinction between type 1 diabetes and type 2 diabetes is unclear and in patients who have random blood glucose concentrations $250 mg/dL (13.9 mmol/L) and/or A1C .9% (75 mmol/mol) (78). Patients and their families must prioritize lifestyle modifications such as eating a balanced diet, achieving and maintaining a healthy weight, and exercising regularly. A family-centered approach to nutrition and lifestyle modification is essential in children with type 2 diabetes, and nutrition recommendations should be culturally appropriate and sensitive to family resources (see Section 4 “Lifestyle Management”). Given the complex social and environmental context surrounding youth with type 2 diabetes, individual-level lifestyle interventions may not be sufficient to target the complex interplay of family

dynamics, mental health, community readiness, and the broader environmental system (73). When insulin treatment is not required, initiation of metformin is recommended. The Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study found that metformin alone provided durable glycemic control (A1C #8% [64 mmol/mol] for 6 months) in approximately half of the subjects (79). To date, the TODAY study is the only trial combining lifestyle and metformin therapy in youth with type 2 diabetes; the combination did not perform better than metformin alone in achieving durable glycemic control (79). Small retrospective analyses and a recent prospective multicenter nonrandomized study suggest that bariatric or metabolic surgery may have similar benefits in obese adolescents with type 2 diabetes compared with those observed in adults. Teenagers experience similar degrees of weight loss, diabetes remission, and improvement of cardiometabolic risk factors for at least 3 years after surgery (80). No randomized trials, however, have yet compared the effectiveness and safety of surgery to those of conventional treatment options in adolescents (81). Comorbidities

Comorbidities may already be present at the time of diagnosis of type 2 diabetes in youth (74,82). Therefore, blood pressure measurement, a fasting lipid panel, assessment of random urine albumin-tocreatinine ratio, and a dilated eye examination should be performed at diagnosis. Thereafter, screening guidelines and treatment recommendations for hypertension, dyslipidemia, urine albumin excretion, and retinopathy are similar to those for youth with type 1 diabetes. Additional problems that may need to be addressed include polycystic ovary disease and other comorbidities associated with pediatric obesity, such as sleep apnea, hepatic steatosis, orthopedic complications, and psychosocial concerns. The ADA consensus report “Youth-Onset Type 2 Diabetes Consensus Report: Current Status, Challenges, and Priorities” (73) and an American Academy of Pediatrics clinical practice guideline (83) provide guidance on the prevention, screening, and treatment of type 2 diabetes and its comorbidities in children and adolescents.

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TRANSITION FROM PEDIATRIC TO ADULT CARE Recommendations c

c

Health care providers and families should begin to prepare youth with diabetes in early to midadolescence and, at the latest, at least 1 year before the transition to adult health care. E Both pediatricians and adult health care providers should assist in providing support and links to resources for the teen and emerging adult. B

Care and close supervision of diabetes management are increasingly shifted from parents and other adults to the youth with type 1 or type 2 diabetes throughout childhood and adolescence. The shift from pediatric to adult health care providers, however, often occurs abruptly as the older teen enters the next developmental stage referred to as emerging adulthood (84), which is a critical period for young people who have diabetes. During this period of major life transitions, youth begin to move out of their parents’ homes and must become fully responsible for their diabetes care. Their new responsibilities include self-management of their diabetes, making medical appointments, and financing health care, once they are no longer covered by their parents’ health insurance plans (ongoing coverage until age 26 years is now available under provisions of the Affordable Care Act). In addition to lapses in health care, this is also a period associated with deterioration in glycemic control; increased occurrence of acute complications; psychosocial, emotional, and behavioral challenges; and the emergence of chronic complications (85–88). Although scientific evidence is limited, it is clear that comprehensive and coordinated planning that begins in early adolescence, or at least 1 year before the date of transition, is necessary to facilitate a seamless transition from pediatric to adult health care (85,86). A comprehensive discussion regarding the challenges faced during this period, including specific recommendations, is found in the ADA position statement “Diabetes Care for Emerging Adults: Recommendations for Transition From Pediatric to Adult Diabetes Care Systems” (86).

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The National Diabetes Education Program (NDEP) has materials available to facilitate the transition process (http:// ndep.nih.gov/transitions), and the Endocrine Society in collaboration with the ADA and other organizations has developed transition tools for clinicians and youth and families (http://www .endo-society.org/clinicalpractice/ transition_of_care.cfm).

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29. Rosenbauer J, Dost A, Karges B, et al.; DPV Initiative and the German BMBF Competence Network Diabetes Mellitus. Improved metabolic control in children and adolescents with type 1 diabetes: a trend analysis using prospective multicenter data from Germany and Austria. Diabetes Care 2012;35:80–86 30. Cameron FJ, de Beaufort C, Aanstoot HJ, et al.; Hvidoere International Study Group. Lessons from the Hvidoere International Study Group on childhood diabetes: be dogmatic about outcome and flexible in approach. Pediatr Diabetes 2013;14:473–480 31. Nimri R, Weintrob N, Benzaquen H, Ofan R, Fayman G, Phillip M. Insulin pump therapy in youth with type 1 diabetes: a retrospective paired study. Pediatrics 2006;117:2126–2131 32. Doyle EA, Weinzimer SA, Steffen AT, Ahern JAH, Vincent M, Tamborlane WVA. A randomized, prospective trial comparing the efficacy of continuous subcutaneous insulin infusion with multiple daily injections using insulin glargine. Diabetes Care 2004;27:1554–1558 33. Swift PGF, Skinner TC, de Beaufort CE, et al.; Hvidoere Study Group on Childhood Diabetes. Target setting in intensive insulin management is associated with metabolic control: the Hvidoere Childhood Diabetes Study Group Centre Differences Study 2005. Pediatr Diabetes 2010;11:271–278 34. Maahs DM, Hermann JM, DuBose SN, et al.; DPV Initiative; T1D Exchange Clinic Network. Contrasting the clinical care and outcomes of 2,622 children with type 1 diabetes less than 6 years of age in the United States T1D Exchange and German/Austrian DPV registries. Diabetologia 2014;57:1578–1585 35. Rold´an MB, Alonso M, Barrio R. Thyroid autoimmunity in children and adolescents with type 1 diabetes mellitus. Diabetes Nutr Metab 1999;12:27–31 36. Triolo TM, Armstrong TK, McFann K, et al. Additional autoimmune disease found in 33% of patients at type 1 diabetes onset. Diabetes Care 2011;34:1211–1213 37. Kordonouri O, Deiss D, Danne T, Dorow A, Bassir C, Gr¨uters-Kieslich A. Predictivity of thyroid autoantibodies for the development of thyroid disorders in children and adolescents with type 1 diabetes. Diabet Med 2002;19: 518–521 38. Dost A, Rohrer TR, Fr o¨ hlich-Reiterer E, et al.; DPV Initiative and the German Competence Network Diabetes Mellitus. Hyperthyroidism in 276 children and adolescents with type 1 diabetes from Germany and Austria. Horm Res Paediatr 2015;84:190–198 39. Mohn A, Di Michele S, Di Luzio R, Tumini S, Chiarelli F. The effect of subclinical hypothyroidism on metabolic control in children and adolescents with type 1 diabetes mellitus. Diabet Med 2002;19:70–73 40. Holmes GKT. Screening for coeliac disease in type 1 diabetes. Arch Dis Child 2002;87:495–498 41. Rewers M, Liu E, Simmons J, Redondo MJ, Hoffenberg EJ. Celiac disease associated with type 1 diabetes mellitus. Endocrinol Metab Clin North Am 2004;33:197–214, xi 42. Pham-Short A, Donaghue KC, Ambler G, Phelan H, Twigg S, Craig ME. Screening for celiac disease in type 1 diabetes: a systematic review. Pediatrics 2015;136:e170–e176

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43. Rubio-Tapia A, Hill ID, Kelly CP, Calderwood AH, Murray JA; American College of Gastroenterology. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol 2013;108:656–676; quiz 677 44. Husby S, Koletzko S, Korponay-Szabo´ IR, et al.; ESPGHAN Working Group on Coeliac Disease Diagnosis; ESPGHAN Gastroenterology Committee; European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr 2012;54:136–160 45. Abid N, McGlone O, Cardwell C, McCallion W, Carson D. Clinical and metabolic effects of gluten free diet in children with type 1 diabetes and coeliac disease. Pediatr Diabetes 2011;12: 322–325 46. de Ferranti SD, de Boer IH, Fonseca V, et al. Type 1 diabetes mellitus and cardiovascular disease: a scientific statement from the American Heart Association and American Diabetes Association. Circulation 2014;130:1110–1130 47. Rodriguez BL, Fujimoto WY, Mayer-Davis EJ, et al. Prevalence of cardiovascular disease risk factors in U.S. children and adolescents with diabetes: the SEARCH for Diabetes in Youth study. Diabetes Care 2006;29:1891–1896 48. Margeirsdottir HD, Larsen JR, Brunborg C, Overby NC, Dahl-Jørgensen K; Norwegian Study Group for Childhood Diabetes. High prevalence of cardiovascular risk factors in children and adolescents with type 1 diabetes: a populationbased study. Diabetologia 2008;51:554–561 49. Schwab KO, Doerfer J, Hecker W, et al.; DPV Initiative of the German Working Group for Pediatric Diabetology. Spectrum and prevalence of atherogenic risk factors in 27,358 children, adolescents, and young adults with type 1 diabetes: cross-sectional data from the German diabetes documentation and quality management system (DPV). Diabetes Care 2006;29:218–225 50. Singh TP, Groehn H, Kazmers A. Vascular function and carotid intimal-medial thickness in children with insulin-dependent diabetes mellitus. J Am Coll Cardiol 2003;41:661–665 51. Haller MJ, Stein J, Shuster J, et al. Peripheral artery tonometry demonstrates altered endothelial function in children with type 1 diabetes. Pediatr Diabetes 2007;8:193–198 52. Urbina EM, Wadwa RP, Davis C, Snively BM, Dolan LM, Daniels SR, et al. Prevalence of increased arterial stiffness in children with type 1 diabetes mellitus differs by measurement site and sex: the SEARCH for Diabetes in Youth Study. J Pediatr 2010;156:731–737.e1 53. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents; National Heart, Lung, and Blood Institute. Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report. Pediatrics 2011;128(Suppl. 5): S213–S256 54. Daniels SR, Greer FR; Committee on Nutrition. Lipid screening and cardiovascular health in childhood. Pediatrics 2008;122:198–208 55. Kavey R-EW, Allada V, Daniels SR, et al.; American Heart Association Expert Panel on Population and Prevention Science; American Heart Association Council on Cardiovascular Disease in

the Young; American Heart Association Council on Epidemiology and Prevention; American Heart Association Council on Nutrition, Physical Activity and Metabolism; American Heart Association Council on High Blood Pressure Research; American Heart Association Council on Cardiovascular Nursing; American Heart Association Council on the Kidney in Heart Disease; Interdisciplinary Working Group on Quality of Care and Outcomes Research. Cardiovascular risk reduction in high-risk pediatric patients: a scientific statement from the American Heart Association Expert Panel on Population and Prevention Science; the Councils on Cardiovascular Disease in the Young, Epidemiology and Prevention, Nutrition, Physical Activity and Metabolism, High Blood Pressure Research, Cardiovascular Nursing, and the Kidney in Heart Disease; and the Interdisciplinary Working Group on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics. Circulation 2006;114:2710–2738 56. Cadario F, Prodam F, Pasqualicchio S, et al. Lipid profile and nutritional intake in children and adolescents with type 1 diabetes improve after a structured dietician training to a Mediterranean-style diet. J Endocrinol Invest 2012;35:160–168 57. Salem MA, Aboelasrar MA, Elbarbary NS, Elhilaly RA, Refaat YM. Is exercise a therapeutic tool for improvement of cardiovascular risk factors in adolescents with type 1 diabetes mellitus? A randomised controlled trial. Diabetol Metab Syndr 2010;2:47 58. McCrindle BW, Urbina EM, Dennison BA, et al.; American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee; American Heart Association Council of Cardiovascular Disease in the Young; American Heart Association Council on Cardiovascular Nursing. Drug therapy of high-risk lipid abnormalities in children and adolescents: a scientific statement from the American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee, Council of Cardiovascular Disease in the Young, with the Council on Cardiovascular Nursing. Circulation 2007;115: 1948–1967 59. Salo P, Viikari J, H¨am¨al¨ainen M, et al. Serum cholesterol ester fatty acids in 7- and 13-monthold children in a prospective randomized trial of a low-saturated fat, low-cholesterol diet: the STRIP baby project. Special Turku coronary Risk factor Intervention Project for children. Acta Paediatr 1999;88:505–512 60. Maahs DM, Dabelea D, D’Agostino RB Jr, et al.; SEARCH for Diabetes in Youth Study. Glucose control predicts 2-year change in lipid profile in youth with type 1 diabetes. J Pediatr 2013; 162:101–107.e1 61. McCrindle BW, Ose L, Marais AD. Efficacy and safety of atorvastatin in children and adolescents with familial hypercholesterolemia or severe hyperlipidemia: a multicenter, randomized, placebo-controlled trial. J Pediatr 2003; 143:74–80 62. Wiegman A, Hutten BA, de Groot E, et al. Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized controlled trial. JAMA 2004;292:331–337 63. Karter AJ, Stevens MR, Gregg EW, et al. Educational disparities in rates of smoking among

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diabetic adults: the translating research into action for diabetes study. Am J Public Health 2008; 98:365–370 64. Reynolds K, Liese AD, Anderson AM, et al. Prevalence of tobacco use and association between cardiometabolic risk factors and cigarette smoking in youth with type 1 or type 2 diabetes mellitus. J Pediatr 2011;158:594–601.e1 65. Scott LJ, Warram JH, Hanna LS, Laffel LM, Ryan L, Krolewski AS. A nonlinear effect of hyperglycemia and current cigarette smoking are major determinants of the onset of microalbuminuria in type 1 diabetes. Diabetes 2001;50:2842–2849 66. Daniels M, DuBose SN, Maahs DM, et al.; T1D Exchange Clinic Network. Factors associated with microalbuminuria in 7,549 children and adolescents with type 1 diabetes in the T1D Exchange clinic registry. Diabetes Care 2013;36:2639–2645 67. Schwartz GJ, Work DF. Measurement and estimation of GFR in children and adolescents. Clin J Am Soc Nephrol 2009;4:1832–1843 68. Marcovecchio ML, Woodside J, Jones T, et al.; AdDIT Investigators. Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT): urinary screening and baseline biochemical and cardiovascular assessments. Diabetes Care 2014;37:805–813 69. Cho YH, Craig ME, Hing S, et al. Microvascular complications assessment in adolescents with 2- to 5-yr duration of type 1 diabetes from 1990 to 2006. Pediatr Diabetes 2011;12:682–689 70. Lawrence JM, Imperatore G, Pettitt DJ, et al.; SEARCH for Diabetes in Youth Study Group. Trends in incidence of type 1 diabetes among non-Hispanic white youth in the U.S., 2002– 2009. Diabetes 2014;63:3938–3945 71. Imperatore G, Boyle JP, Thompson TJ, et al.; SEARCH for Diabetes in Youth Study Group. Projections of type 1 and type 2 diabetes burden in the U.S. population aged ,20 years through 2050: dynamic modeling of incidence, mortality, and population growth. Diabetes Care 2012; 35:2515–2520 72. Pettitt DJ, Talton J, Dabelea D, et al.; SEARCH for Diabetes in Youth Study Group.

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Prevalence of diabetes in U.S. youth in 2009: the SEARCH for Diabetes in Youth Study. Diabetes Care 2014;37:402–408 73. Nadeau KJ, Anderson BJ, Berg EG, et al. Youth-onset type 2 diabetes consensus report: current status, challenges, and priorities. Diabetes Care 2016;39:1635–1642 74. Copeland KC, Zeitler P, Geffner M, et al.; TODAY Study Group. Characteristics of adolescents and youth with recent-onset type 2 diabetes: the TODAY cohort at baseline. J Clin Endocrinol Metab 2011;96:159–167 75. DuBose SN, Hermann JM, Tamborlane WV, et al.; Type 1 Diabetes Exchange Clinic Network and Diabetes Prospective Follow-up Registry. Obesity in Youth with Type 1 Diabetes in Germany, Austria, and the United States. J Pediatr 2015;167:627–632.e1–e4 76. Klingensmith GJ, Pyle L, Arslanian S, et al.; TODAY Study Group. The presence of GAD and IA-2 antibodies in youth with a type 2 diabetes phenotype: results from the TODAY study. Diabetes Care 2010;33:1970–1975 77. Dabelea D, Rewers A, Stafford JM, et al. Trends in the prevalence of ketoacidosis at diabetes diagnosis: the SEARCH for Diabetes in Youth Study. Pediatrics 2014 ;133:e938– e945 78. Copeland KC, Silverstein J, Moore KR, et al. Management of newly diagnosed type 2 diabetes mellitus (T2DM) in children and adolescents. Pediatrics 2013;131:364–382 79. Zeitler P, Hirst K, Pyle L, et al.; TODAY Study Group. A clinical trial to maintain glycemic control in youth with type 2 diabetes. N Engl J Med 2012;366:2247–2256 80. Inge TH, Courcoulas AP, Jenkins TM, et al.; Teen-LABS Consortium. Weight loss and health status 3 years after bariatric surgery in adolescents. N Engl J Med 2016;374:113–123 81. Rubino F, Nathan DM, Eckel RH, et al.; Delegates of the 2nd Diabetes Surgery Summit. Metabolic surgery in the treatment algorithm for type 2 diabetes: a joint statement by international diabetes organizations. Diabetes Care 2016;39:861–877

82. Eppens MC, Craig ME, Cusumano J, et al. Prevalence of diabetes complications in adolescents with type 2 compared with type 1 diabetes. Diabetes Care 2006;29:1300–1306 83. Springer SC, Silverstein J, Copeland K, et al.; American Academy of Pediatrics. Management of type 2 diabetes mellitus in children and adolescents. Pediatrics 2013;131:e648–e664 84. Arnett JJ. Emerging adulthood. A theory of development from the late teens through the twenties. Am Psychol 2000;55:469–480 85. Weissberg-Benchell J, Wolpert H, Anderson BJ. Transitioning from pediatric to adult care: a new approach to the post-adolescent young person with type 1 diabetes. Diabetes Care 2007;30:2441–2446 86. Peters A, Laffel L; The American Diabetes Association Transitions Working Group. Diabetes care for emerging adults: recommendations for transition from pediatric to adult diabetes care systems: a position statement of the American Diabetes Association, with representation by the American College of Osteopathic Family Physicians, the American Academy of Pediatrics, the American Association of Clinical Endocrinologists, the American Osteopathic Association, the Centers for Disease Control and Prevention, Children with Diabetes, The Endocrine Society, the International Society for Pediatric and Adolescent Diabetes, Juvenile Diabetes Research Foundation International, the National Diabetes Education Program, and the Pediatric Endocrine Society (formerly Lawson Wilkins Pediatric Endocrine Society) [published correction appears in Diabetes Care 2012;35:191]. Diabetes Care 2011;34:2477–2485 87. Bryden KS, Peveler RC, Stein A, Neil A, Mayou RA, Dunger DB. Clinical and psychological course of diabetes from adolescence to young adulthood: a longitudinal cohort study. Diabetes Care 2001;24:1536–1540 88. Laing SP, Jones ME, Swerdlow AJ, Burden AC, Gatling W. Psychosocial and socioeconomic risk factors for premature death in young people with type 1 diabetes. Diabetes Care 2005;28: 1618–1623

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13. Management of Diabetes in Pregnancy

American Diabetes Association

Diabetes Care 2017;40(Suppl. 1):S114–S119 | DOI: 10.2337/dc17-S016

For guidelines related to the diagnosis of gestational diabetes mellitus, please refer to Section 2 “Classification and Diagnosis of Diabetes.”

13. MANAGEMENT OF DIABETES IN PREGNANCY

Recommendations

Preexisting Diabetes c c

c

c

Starting at puberty, preconception counseling should be incorporated into routine diabetes care for all girls of childbearing potential. A Family planning should be discussed and effective contraception should be prescribed and used until a woman is prepared and ready to become pregnant. A Preconception counseling should address the importance of glycemic control as close to normal as is safely possible, ideally A1C ,6.5% (48 mmol/mol), to reduce the risk of congenital anomalies. B Women with preexisting type 1 or type 2 diabetes who are planning pregnancy or who have become pregnant should be counseled on the risk of development and/or progression of diabetic retinopathy. Dilated eye examinations should occur before pregnancy or in the first trimester, and then patients should be monitored every trimester and for 1 year postpartum as indicated by degree of retinopathy and as recommended by the eye care provider. B

Gestational Diabetes Mellitus c

c

c

Lifestyle change is an essential component of management of gestational diabetes mellitus and may suffice for the treatment for many women. Medications should be added if needed to achieve glycemic targets. A Insulin is the preferred medication for treating hyperglycemia in gestational diabetes mellitus, as it does not cross the placenta to a measurable extent. Metformin and glyburide may be used, but both cross the placenta to the fetus, with metformin likely crossing to a greater extent than glyburide. All oral agents lack long-term safety data. A Metformin, when used to treat polycystic ovary syndrome and induce ovulation, need not be continued once pregnancy has been confirmed. A

General Principles for Management of Diabetes in Pregnancy c

c

c

c

Potentially teratogenic medications (ACE inhibitors, statins, etc.) should be avoided in sexually active women of childbearing age who are not using reliable contraception. B Fasting and postprandial self-monitoring of blood glucose are recommended in both gestational diabetes mellitus and preexisting diabetes in pregnancy to achieve glycemic control. Some women with preexisting diabetes should also test blood glucose preprandially. B Due to increased red blood cell turnover, A1C is lower in normal pregnancy than in normal nonpregnant women. The A1C target in pregnancy is 6–6.5% (42–48 mmol/mol); ,6% (42 mmol/mol) may be optimal if this can be achieved without significant hypoglycemia, but the target may be relaxed to ,7% (53 mmol/mol) if necessary to prevent hypoglycemia. B In pregnant patients with diabetes and chronic hypertension, blood pressure targets of 120–160/80–105 mmHg are suggested in the interest of optimizing long-term maternal health and minimizing impaired fetal growth. E

Suggested citation: American Diabetes Association. Management of diabetes in pregnancy. Sec. 13. In Standards of Medical Care in Diabetesd2017. Diabetes Care 2017; 40(Suppl. 1):S114–S119 © 2017 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals .org/content/license.

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DIABETES IN PREGNANCY

The prevalence of diabetes in pregnancy has been increasing in the U.S. The majority is gestational diabetes mellitus (GDM) with the remainder primarily preexisting type 1 diabetes and type 2 diabetes. The rise in GDM and type 2 diabetes in parallel with obesity both in the U.S. and worldwide is of particular concern. Both type 1 diabetes and type 2 diabetes confer significantly greater maternal and fetal risk than GDM, with some differences according to type of diabetes as outlined below. In general, specific risks of uncontrolled diabetes in pregnancy include spontaneous abortion, fetal anomalies, preeclampsia, fetal demise, macrosomia, neonatal hypoglycemia, and neonatal hyperbilirubinemia, among others. In addition, diabetes in pregnancy may increase the risk of obesity and type 2 diabetes in offspring later in life (1,2). PRECONCEPTION COUNSELING

All women of childbearing age with diabetes should be counseled about the importance of tight glycemic control prior to conception. Observational studies show an increased risk of diabetic embryopathy, especially anencephaly, microcephaly, congenital heart disease, and caudal regression directly proportional to elevations in A1C during the first 10 weeks of pregnancy. Although observational studies are confounded by the association between elevated periconceptional A1C and other poor selfcare behaviors, the quantity and consistency of data are convincing and support the recommendation to optimize glycemic control prior to conception, with A1C ,6.5% (48 mmol/mol) associated with the lowest risk of congenital anomalies (3,4). There are opportunities to educate all women and adolescents of reproductive age with diabetes about the risks of unplanned pregnancies and the opportunities for improved maternal and fetal outcomes with pregnancy planning (5). Effective preconception counseling could avert substantial health and associated cost burden in offspring (6). Family planning should be discussed, and effective contraception should be prescribed and used, until a woman is prepared and ready to become pregnant. To minimize the occurrence of complications, beginning at the onset of puberty or at diagnosis, all women with

Management of Diabetes in Pregnancy

diabetes of childbearing potential should receive education about 1) the risks of malformations associated with unplanned pregnancies and poor metabolic control and 2) the use of effective contraception at all times when preventing a pregnancy. Preconception counseling using developmentally appropriate educational tools enables adolescent girls to make well-informed decisions (5). Preconception counseling resources tailored for adolescents are available at no cost through the American Diabetes Association (ADA) (7). Preconception Testing

Preconception counseling visits should include rubella, syphilis, hepatitis B virus, and HIV testing, as well as Pap smear, cervical cultures, blood typing, prescription of prenatal vitamins (with at least 400 mg of folic acid), and smoking cessation counseling if indicated. Diabetes-specific testing should include A1C, thyroid-stimulating hormone, creatinine, and urinary albumin– to–creatinine ratio; review of the medication list for potentially teratogenic drugs, i.e., ACE inhibitors (8), angiotensin receptor blockers (8), and statins (9,10); and referral for a comprehensive eye exam. Women with preexisting diabetic retinopathy will need close monitoring during pregnancy to ensure that retinopathy does not progress. GLYCEMIC TARGETS IN PREGNANCY

Pregnancy in women with normal glucose metabolism is characterized by fasting levels of blood glucose that are lower than in the nonpregnant state due to insulin-independent glucose uptake by the fetus and placenta and by postprandial hyperglycemia and carbohydrate intolerance as a result of diabetogenic placental hormones.

normal glucose levels. However, in women with GDM and preexisting diabetes, hyperglycemia occurs if treatment is not adjusted appropriately. Glucose Monitoring

Reflecting this physiology, fasting and postprandial monitoring of blood glucose is recommended to achieve metabolic control in pregnant women with diabetes. Preprandial testing is also recommended for women with preexisting diabetes using insulin pumps or basalbolus therapy, so that premeal rapidacting insulin dosage can be adjusted. Postprandial monitoring is associated with better glycemic control and lower risk of preeclampsia (11–13). There are no adequately powered randomized trials comparing different fasting and postmeal glycemic targets in diabetes in pregnancy. Similar to the targets recommended by the American College of Obstetricians and Gynecologists (14), the ADA-recommended targets for women with type 1 or type 2 diabetes (the same as for GDM; described below) are as follows: ○





Fasting #95 mg/dL (5.3 mmol/L) and either One-hour postprandial #140 mg/dL (7.8 mmol/L) or Two-hour postprandial #120 mg/dL (6.7 mmol/L)

These values represent optimal control if they can be achieved safely. In practice, it may be challenging for women with type 1 diabetes to achieve these targets without hypoglycemia, particularly women with a history of recurrent hypoglycemia or hypoglycemia unawareness. If women cannot achieve these targets without significant hypoglycemia, the ADA suggests less stringent targets based on clinical experience and individualization of care.

Insulin Physiology

Early pregnancy is a time of insulin sensitivity, lower glucose levels, and lower insulin requirements in women with type 1 diabetes. The situation rapidly reverses as insulin resistance increases exponentially during the second and early third trimesters and levels off toward the end of the third trimester. In women with normal pancreatic function, insulin production is sufficient to meet the challenge of this physiological insulin resistance and to maintain

A1C in Pregnancy

Observational studies show the lowest rates of adverse fetal outcomes in association with A1C ,6–6.5% (42–48 mmol/mol) early in gestation (4,15–17). Clinical trials have not evaluated the risks and benefits of achieving these targets, and treatment goals should account for the risk of maternal hypoglycemia in setting an individualized target of ,6% (42 mmol/mol) to ,7% (53 mmol/mol). Due to physiological increases in red

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blood cell turnover, A1C levels fall during normal pregnancy (18,19). Additionally, as A1C represents an integrated measure of glucose, it may not fully capture postprandial hyperglycemia, which drives macrosomia. Thus, although A1C may be useful, it should be used as a secondary measure of glycemic control, after self-monitoring of blood glucose. In the second and third trimesters, A1C ,6% (42 mmol/mol) has the lowest risk of large-for-gestational-age infants, whereas other adverse outcomes increase with A1C $6.5% (48 mmol/mol). Taking all of this into account, a target of 6–6.5% (42–48 mmol/mol) is recommended but ,6% (42 mmol/mol) may be optimal as pregnancy progresses. These levels should be achieved without hypoglycemia, which, in addition to the usual adverse sequelae, may increase the risk of low birth weight. Given the alteration in red blood cell kinetics during pregnancy and physiological changes in glycemic parameters, A1C levels may need to be monitored more frequently than usual (e.g., monthly). MANAGEMENT OF GESTATIONAL DIABETES MELLITUS

GDM is characterized by increased risk of macrosomia and birth complications and an increased risk of maternal type 2 diabetes after pregnancy. The association of macrosomia and birth complications with oral glucose tolerance test (OGTT) results is continuous, with no clear inflection points (20). In other words, risks increase with progressive hyperglycemia. Therefore, all women should be tested as outlined in Section 2 “Classification and Diagnosis of Diabetes.” Although there is some heterogeneity, many randomized controlled trials suggest that the risk of GDM may be reduced by diet, exercise, and lifestyle counseling (21,22). Lifestyle Management

After diagnosis, treatment starts with medical nutrition therapy, physical activity, and weight management depending on pregestational weight, as outlined in the section below on preexisting type 2 diabetes, and glucose monitoring aiming for the targets recommended by the Fifth International Workshop-Conference on Gestational Diabetes Mellitus (23): ○

Fasting #95 mg/dL (5.3 mmol/L) and either

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One-hour postprandial #140 mg/dL (7.8 mmol/L) or Two-hour postprandial #120 mg/dL (6.7 mmol/L)

Depending on the population, studies suggest that 70–85% of women diagnosed with GDM under Carpenter-Coustan or National Diabetes Data Group (NDDG) criteria can control GDM with lifestyle modification alone; it is anticipated that this proportion will be even higher if the lower International Association of the Diabetes and Pregnancy Study Groups (IADPSG) (24) diagnostic thresholds are used. Pharmacologic Therapy

Women with greater initial degrees of hyperglycemia may require early initiation of pharmacologic therapy. Treatment has been demonstrated to improve perinatal outcomes in two large randomized studies as summarized in a U.S. Preventive Services Task Force review (25). Insulin is the first-line agent recommended for treatment of GDM in the U.S. While individual randomized controlled trials support the efficacy and short-term safety of metformin (26,27) and glyburide (28) for the treatment of GDM, both agents cross the placenta. Long-term safety data are not available for any oral agent (29). Sulfonylureas

Concentrations of glyburide in umbilical cord plasma are approximately 70% of maternal levels (30). Glyburide may be associated with a higher rate of neonatal hypoglycemia and macrosomia than insulin or metformin (31). Metformin

Metformin may be associated with a lower risk of neonatal hypoglycemia and less maternal weight gain than insulin (31–33); however, metformin may slightly increase the risk of prematurity. Furthermore, nearly half of patients with GDM who were initially treated with metformin in a randomized trial needed insulin in order to achieve acceptable glucose control (26). Umbilical cord blood levels of metformin are higher than simultaneous maternal levels (34,35). None of these studies or meta-analyses evaluated long-term outcomes in the offspring. Patients treated with oral agents should be informed that they cross the placenta, and although no adverse effects on the fetus have been demonstrated, long-term studies are lacking.

Randomized, double-blind, controlled trials comparing metformin with other therapies for ovulation induction in women with polycystic ovary syndrome have not demonstrated benefit in preventing spontaneous abortion or GDM (36), and there is no evidence-based need to continue metformin in such patients once pregnancy has been confirmed (37–39). Insulin

Insulin may be required to treat hyperglycemia, and its use should follow the guidelines below. MANAGEMENT OF PREEXISTING TYPE 1 DIABETES AND TYPE 2 DIABETES IN PREGNANCY Insulin Use

Insulin is the preferred agent for management of both type 1 diabetes and type 2 diabetes in pregnancy. The physiology of pregnancy necessitates frequent titration of insulin to match changing requirements and underscores the importance of daily and frequent self-monitoring of blood glucose. In the first trimester, there is often a decrease in total daily insulin requirements, and women, particularly those with type 1 diabetes, may experience increased hypoglycemia. In the second trimester, rapidly increasing insulin resistance requires weekly or biweekly increases in insulin dose to achieve glycemic targets. In general, a smaller proportion of the total daily dose should be given as basal insulin (,50%) and a greater proportion (.50%) as prandial insulin. In the late third trimester, there is often a leveling off or small decrease in insulin requirements. Due to the complexity of insulin management in pregnancy, referral to a specialized center offering team-based care (with team members including high-risk obstetrician, endocrinologist or other provider experienced in managing pregnancy in women with preexisting diabetes, dietitian, nurse, and social worker, as needed) is recommended if this resource is available. None of the currently available insulin preparations have been demonstrated to cross the placenta. Type 1 Diabetes

Women with type 1 diabetes have an increased risk of hypoglycemia in the first trimester and, like all women, have altered counterregulatory response in

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pregnancy that may decrease hypoglycemia awareness. Education for patients and family members about the prevention, recognition, and treatment of hypoglycemia is important before, during, and after pregnancy to help to prevent and manage the risks of hypoglycemia. Insulin resistance drops rapidly with delivery of the placenta. Women become very insulin sensitive immediately following delivery and may initially require much less insulin than in the prepartum period. Pregnancy is a ketogenic state, and women with type 1 diabetes, and to a lesser extent those with type 2 diabetes, are at risk for diabetic ketoacidosis at lower blood glucose levels than in the nonpregnant state. Women with preexisting diabetes, especially type 1 diabetes, need ketone strips at home and education on diabetic ketoacidosis prevention and detection. In addition, rapid implementation of tight glycemic control in the setting of retinopathy is associated with worsening of retinopathy (40). Type 2 Diabetes

Type 2 diabetes is often associated with obesity. Recommended weight gain during pregnancy for overweight women is 15–25 lb and for obese women is 10–20 lb (41). Glycemic control is often easier to achieve in women with type 2 diabetes than in those with type 1 diabetes but can require much higher doses of insulin, sometimes necessitating concentrated insulin formulations. As in type 1 diabetes, insulin requirements drop dramatically after delivery. The risk for associated hypertension and other comorbidities may be as high or higher with type 2 diabetes as with type 1 diabetes, even if diabetes is better controlled and of shorter apparent duration, with pregnancy loss appearing to be more prevalent in the third trimester in women with type 2 diabetes compared with the first trimester in women with type 1 diabetes (42,43). POSTPARTUM CARE

Postpartum care should include psychosocial assessment and support for self-care. Lactation

In light of the immediate nutritional and immunological benefits of breastfeeding for the baby, all women including

Management of Diabetes in Pregnancy

those with diabetes should be supported in attempts to breastfeed. Breastfeeding may also confer longer-term metabolic benefits to both mother (44) and offspring (45). Gestational Diabetes Mellitus Initial Testing

Because GDM may represent preexisting undiagnosed type 2 or even type 1 diabetes, women with GDM should be tested for persistent diabetes or prediabetes at 4–12 weeks’ postpartum with a 75-g OGTT using nonpregnancy criteria as outlined in Section 2 “Classification and Diagnosis of Diabetes.” Postpartum Follow-up

The OGTT is recommended over A1C at the time of the 4- to 12-week postpartum visit because A1C may be persistently impacted (lowered) by the increased red blood cell turnover related to pregnancy or blood loss at delivery and because the OGTT is more sensitive at detecting glucose intolerance, including both prediabetes and diabetes. Reproductive-aged women with prediabetes may develop type 2 diabetes by the time of their next pregnancy and will need preconception evaluation. Because GDM is associated with increased maternal risk for diabetes, women should also be tested every 1–3 years thereafter if the 4- to 12-week 75-g OGTT is normal, with frequency of testing depending on other risk factors including family history, prepregnancy BMI, and need for insulin or oral glucoselowering medication during pregnancy. Ongoing evaluation may be performed with any recommended glycemic test (e.g., hemoglobin A1C, fasting plasma glucose, or 75-g OGTT using nonpregnant thresholds). Gestational Diabetes Mellitus and Type 2 Diabetes

Women with a history of GDM have a greatly increased risk of conversion to type 2 diabetes over time and not solely within the 4- to 12-week postpartum time frame (46). In the prospective Nurses’ Health Study II, subsequent diabetes risk after a history of GDM was significantly lower in women who followed healthy eating patterns (47). Adjusting for BMI moderately, but not completely, attenuated this association. Interpregnancy or postpartum weight gain is associated with increased

risk of adverse pregnancy outcomes in subsequent pregnancies (48) and earlier progression to type 2 diabetes. Both metformin and intensive lifestyle intervention prevent or delay progression to diabetes in women with prediabetes and a history of GDM. Of women with a history of GDM and prediabetes, only 5–6 women need to be treated with either intervention to prevent one case of diabetes over 3 years (49). In these women, lifestyle intervention and metformin reduced progression to diabetes by 35% and 40%, respectively, over 10 years compared with placebo (50). If the pregnancy has motivated the adoption of a healthier diet, building on these gains to support weight loss is recommended in the postpartum period. Preexisting Type 1 and Type 2 Diabetes

Insulin sensitivity increases with delivery of the placenta and then returns to prepregnancy levels over the following 1–2 weeks. In women taking insulin, particular attention should be directed to hypoglycemia prevention in the setting of breastfeeding and erratic sleep and eating schedules. Contraception

A major barrier to effective preconception care is the fact that the majority of pregnancies are unplanned. Planning pregnancy is critical in women with preexisting diabetes due to the need for preconception glycemic control and preventive health services. Therefore, all women with diabetes of childbearing potential should have family planning options reviewed at regular intervals. This applies to women in the immediate postpartum period. Women with diabetes have the same contraception options and recommendations as those without diabetes. The risk of an unplanned pregnancy outweighs the risk of any given contraception option. PREGNANCY AND DRUG CONSIDERATIONS

In normal pregnancy, blood pressure is lower than in the nonpregnant state. In a pregnancy complicated by diabetes and chronic hypertension, target goals for systolic blood pressure 120– 160 mmHg and diastolic blood pressure 80–105 mmHg are reasonable (51). Lower blood pressure levels may

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be associated with impaired fetal growth. In a 2015 study targeting diastolic blood pressure of 100 mmHg versus 85 mmHg in pregnant women, only 6% of whom had GDM at enrollment, there was no difference in pregnancy loss, neonatal care, or other neonatal outcomes, although women in the less intensive treatment group had a higher rate of uncontrolled hypertension (52). During pregnancy, treatment with ACE inhibitors and angiotensin receptor blockers is contraindicated because they may cause fetal renal dysplasia, oligohydramnios, and intrauterine growth restriction (8). Antihypertensive drugs known to be effective and safe in pregnancy include methyldopa, labetalol, diltiazem, clonidine, and prazosin. Chronic diuretic use during pregnancy is not recommended as it has been associated with restricted maternal plasma volume, which may reduce uteroplacental perfusion (53). On the basis of available evidence, statins should also be avoided in pregnancy (54). References 1. Holmes VA, Young IS, Patterson CC, et al.; Diabetes and Pre-eclampsia Intervention Trial Study Group. Optimal glycemic control, preeclampsia, and gestational hypertension in women with type 1 diabetes in the diabetes and pre-eclampsia intervention trial. Diabetes Care 2011;34:1683–1688 2. Dabelea D, Hanson RL, Lindsay RS, et al. Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: a study of discordant sibships. Diabetes 2000;49:2208–2211 3. Guerin A, Nisenbaum R, Ray JG. Use of maternal GHb concentration to estimate the risk of congenital anomalies in the offspring of women with prepregnancy diabetes. Diabetes Care 2007;30:1920–1925 4. Jensen DM, Korsholm L, Ovesen P, et al. Periconceptional A1C and risk of serious adverse pregnancy outcome in 933 women with type 1 diabetes. Diabetes Care 2009;32:1046–1048 5. Charron-Prochownik D, Sereika SM, Becker D, et al. Long-term effects of the boosterenhanced READY-Girls preconception counseling program on intentions and behaviors for family planning in teens with diabetes. Diabetes Care 2013;36:3870–3874 6. Peterson C, Grosse SD, Li R, et al. Preventable health and cost burden of adverse birth outcomes associated with pregestational diabetes in the United States. Am J Obstet Gynecol 2015; 212:74.e1–74.e9 7. Charron-Prochownik D, Downs J. Diabetes and Reproductive Health for Girls. Alexandria, VA, American Diabetes Association, 2016 8. Bullo M, Tschumi S, Bucher BS, Bianchetti MG, Simonetti GD. Pregnancy outcome following exposure to angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists: a

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systematic review. Hypertension 2012;60:444– 450 9. Taguchi N, Rubin ET, Hosokawa A, et al. Prenatal exposure to HMG-CoA reductase inhibitors: effects on fetal and neonatal outcomes. Reprod Toxicol 2008;26:175–177 10. Bateman BT, Hernandez-Diaz S, Fischer MA, et al. Statins and congenital malformations: cohort study. BMJ 2015;350:h1035 11. Manderson JG, Patterson CC, Hadden DR, Traub AI, Ennis C, McCance DR. Preprandial versus postprandial blood glucose monitoring in type 1 diabetic pregnancy: a randomized controlled clinical trial. Am J Obstet Gynecol 2003; 189:507–512 12. de Veciana M, Major CA, Morgan MA, et al. Postprandial versus preprandial blood glucose monitoring in women with gestational diabetes mellitus requiring insulin therapy. N Engl J Med 1995;333:1237–1241 13. Jovanovic-Peterson L, Peterson CM, Reed GF, et al. Maternal postprandial glucose levels and infant birth weight: the Diabetes in Early Pregnancy Study. The National Institute of Child Health and Human DevelopmentdDiabetes in Early Pregnancy Study. Am J Obstet Gynecol 1991;164:103–111 14. Committee on Practice BulletinsdObstetrics. Practice Bulletin No. 137: gestational diabetes mellitus. Obstet Gynecol 2013;122:406–416 15. Nielsen GL, Møller M, Sørensen HT. HbA1c in early diabetic pregnancy and pregnancy outcomes: a Danish population-based cohort study of 573 pregnancies in women with type 1 diabetes. Diabetes Care 2006;29:2612–2616 16. Suhonen L, Hiilesmaa V, Teramo K. Glycaemic control during early pregnancy and fetal malformations in women with type 1 diabetes mellitus. Diabetologia 2000;43:79–82 17. Maresh MJA, Holmes VA, Patterson CC, et al.; Diabetes and Pre-eclampsia Intervention Trial Study Group. Glycemic targets in the second and third trimester of pregnancy for women with type 1 diabetes. Diabetes Care 2015;38:34–42 18. Nielsen LR, Ekbom P, Damm P, et al. HbA1c levels are significantly lower in early and late pregnancy. Diabetes Care 2004;27:1200–1201 19. Mosca A, Paleari R, Dalfr`a MG, et al. Reference intervals for hemoglobin A1c in pregnant women: data from an Italian multicenter study. Clin Chem 2006;52:1138–1143 20. Metzger BE, Lowe LP, Dyer AR, et al.; HAPO Study Cooperative Research Group. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 2008;358:1991–2002 21. Bain E, Crane M, Tieu J, Han S, Crowther CA, Middleton P. Diet and exercise interventions for preventing gestational diabetes mellitus. Cochrane Database Syst Rev 2015;4:CD010443 22. Koivusalo SB, R¨on¨o K, Klemetti MM, et al. Gestational diabetes mellitus can be prevented by lifestyle intervention: the Finnish Gestational Diabetes Prevention Study (RADIEL): a randomized controlled trial. Diabetes Care 2016;39: 24–30 23. Metzger BE, Buchanan TA, Coustan DR, et al. Summary and recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care 2007;30(Suppl. 2):S251–S260

24. Mayo K, Melamed N, Vandenberghe H, Berger H. The impact of adoption of the International Association of Diabetes in Pregnancy Study Group criteria for the screening and diagnosis of gestational diabetes. Am J Obstet Gynecol 2015;212:224.e1–224.e9 25. Hartling L, Dryden DM, Guthrie A, Muise M, Vandermeer B, Donovan L. Benefits and harms of treating gestational diabetes mellitus: a systematic review and meta-analysis for the U.S. Preventive Services Task Force and the National Institutes of Health Office of Medical Applications of Research. Ann Intern Med 2013;159: 123–129 26. Rowan JA, Hague WM, Gao W, Battin MR, Moore MP; MiG Trial Investigators. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med 2008;358:2003–2015 27. Gui J, Liu Q, Feng L. Metformin vs insulin in the management of gestational diabetes: a meta-analysis. PLoS One 2013;8:e64585 28. Langer O, Conway DL, Berkus MD, Xenakis EM, Gonzales O. A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med 2000;343:1134–1138 29. Coustan DR. Pharmacological management of gestational diabetes: an overview. Diabetes Care 2007;30(Suppl. 2):S206–S208 30. Hebert MF, Ma X, Naraharisetti SB, et al.; Obstetric-Fetal Pharmacology Research Unit Network. Are we optimizing gestational diabetes treatment with glyburide? The pharmacologic basis for better clinical practice. Clin Pharmacol Ther 2009;85:607–614 31. Balsells M, Garc´ıa-Patterson A, Sol`a I, Roqu´e M, Gich I, Corcoy R. Glibenclamide, metformin, and insulin for the treatment of gestational diabetes: a systematic review and meta-analysis. BMJ 2015;350:h102 32. Jiang Y-F, Chen X-Y, Ding T, Wang X-F, Zhu Z-N, Su S-W. Comparative efficacy and safety of OADs in management of GDM: network metaanalysis of randomized controlled trials. J Clin Endocrinol Metab 2015;100:2071–2080 33. Camelo Castillo W, Boggess K, St¨urmer T, Brookhart MA, Benjamin DK Jr, Jonsson Funk M. Association of adverse pregnancy outcomes with glyburide vs insulin in women with gestational diabetes. JAMA Pediatr 2015;169: 452–458 34. Vanky E, Zahlsen K, Spigset O, Carlsen SM. Placental passage of metformin in women with polycystic ovary syndrome. Fertil Steril 2005;83: 1575–1578 35. Charles B, Norris R, Xiao X, Hague W. Population pharmacokinetics of metformin in late pregnancy. Ther Drug Monit 2006;28:67–72 36. Vanky E, Stridsklev S, Heimstad R, et al. Metformin versus placebo from first trimester to delivery in polycystic ovary syndrome: a randomized, controlled multicenter study. J Clin Endocrinol Metab 2010;95:E448–E455 37. Legro RS, Barnhart HX, Schlaff WD, et al.; Cooperative Multicenter Reproductive Medicine Network. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 2007;356:551–566 38. Palomba S, Orio F Jr, Falbo A, et al. Prospective parallel randomized, double-blind, double-dummy controlled clinical trial comparing clomiphene citrate and metformin as the first-line treatment for ovulation induction in

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nonobese anovulatory women with polycystic ovary syndrome. J Clin Endocrinol Metab 2005;90:4068–4074 39. Palomba S, Orio F Jr, Nardo LG, et al. Metformin administration versus laparoscopic ovarian diathermy in clomiphene citrate-resistant women with polycystic ovary syndrome: a prospective parallel randomized double-blind placebocontrolled trial. J Clin Endocrinol Metab 2004; 89:4801–4809 40. Chew EY, Mills JL, Metzger BE, et al. Metabolic control and progression of retinopathy. The Diabetes in Early Pregnancy Study. National Institute of Child Health and Human Development Diabetes in Early Pregnancy Study. Diabetes Care 1995;18:631–637 41. National Research Council; Institute of Medicine; Food and Nutrition Board; Board on Children, Youth, and Families; Committee to Reexamine IOM Pregnancy Weight Guidelines. Weight Gain During Pregnancy: Reexamining the Guidelines. Washington, DC, The National Academies Press, 2009. Available from http:// www.nap.edu/catalog/12584. Accessed 5 October 2016 42. Clausen TD, Mathiesen E, Ekbom P, Hellmuth E, Mandrup-Poulsen T, Damm P. Poor pregnancy outcome in women with type 2 diabetes. Diabetes Care 2005;28:323–328

Management of Diabetes in Pregnancy

43. Cundy T, Gamble G, Neale L, et al. Differing causes of pregnancy loss in type 1 and type 2 diabetes. Diabetes Care 2007;30:2603–2607 44. Stuebe AM, Rich-Edwards JW, Willett WC, Manson JE, Michels KB. Duration of lactation and incidence of type 2 diabetes. JAMA 2005; 294:2601–2610 ´ RM. Does 45. Pereira PF, Alfenas R de C, Araujo breastfeeding influence the risk of developing diabetes mellitus in children? A review of current evidence. J Pediatr (Rio J) 2014;90:7–15 46. Kim C, Newton KM, Knopp RH. Gestational diabetes and the incidence of type 2 diabetes: a systematic review. Diabetes Care 2002;25: 1862–1868 47. Tobias DK, Hu FB, Chavarro J, Rosner B, Mozaffarian D, Zhang C. Healthful dietary patterns and type 2 diabetes mellitus risk among women with a history of gestational diabetes mellitus. Arch Intern Med 2012;172:1566–1572 48. Villamor E, Cnattingius S. Interpregnancy weight change and risk of adverse pregnancy outcomes: a population-based study. Lancet 2006;368:1164–1170 49. Ratner RE, Christophi CA, Metzger BE, et al.; Diabetes Prevention Program Research Group. Prevention of diabetes in women with a history of gestational diabetes: effects of metformin

and lifestyle interventions. J Clin Endocrinol Metab 2008;93:4774–4779 50. Aroda VR, Christophi CA, Edelstein SL, et al.; Diabetes Prevention Program Research Group. The effect of lifestyle intervention and metformin on preventing or delaying diabetes among women with and without gestational diabetes: the Diabetes Prevention Program Outcomes Study 10-year follow-up. J Clin Endocrinol Metab 2015;100:1646–1653 51. American College of Obstetricians and Gynecologists; Task Force on Hypertension in Pregnancy. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy. Obstet Gynecol 2013;122:1122– 1131 52. Magee LA, von Dadelszen P, Rey E, et al. Less-tight versus tight control of hypertension in pregnancy. N Engl J Med 2015;372:407–417 53. Sibai BM. Treatment of hypertension in pregnant women. N Engl J Med 1996;335:257– 265 54. Kazmin A, Garcia-Bournissen F, Koren G. Risks of statin use during pregnancy: a systematic review. J Obstet Gynaecol Can 2007;29: 906–908

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14. Diabetes Care in the Hospital

American Diabetes Association

Diabetes Care 2017;40(Suppl. 1):S120–S127 | DOI: 10.2337/dc17-S017

Recommendations c c

14. DIABETES CARE IN THE HOSPITAL

c

c

c

c c

c

c

Perform an A1C for all patients with diabetes or hyperglycemia admitted to the hospital if not performed in the prior 3 months. B Insulin therapy should be initiated for treatment of persistent hyperglycemia starting at a threshold $180 mg/dL (10.0 mmol/L). Once insulin therapy is started, a target glucose range of 140–180 mg/dL (7.8–10.0 mmol/L) is recommended for the majority of critically ill patients A and noncritically ill patients. C More stringent goals, such as ,140 mg/dL (,7.8 mmol/L), may be appropriate for selected patients, as long as this can be achieved without significant hypoglycemia. C Intravenous insulin infusions should be administered using validated written or computerized protocols that allow for predefined adjustments in the insulin infusion rate based on glycemic fluctuations and insulin dose. E Basal insulin or a basal plus bolus correction insulin regimen is the preferred treatment for noncritically ill patients with poor oral intake or those who are taking nothing by mouth. An insulin regimen with basal, nutritional, and correction components is the preferred treatment for noncritically ill hospitalized patients with good nutritional intake. A Sole use of sliding scale insulin in the inpatient hospital setting is strongly discouraged. A A hypoglycemia management protocol should be adopted and implemented by each hospital or hospital system. A plan for preventing and treating hypoglycemia should be established for each patient. Episodes of hypoglycemia in the hospital should be documented in the medical record and tracked. E The treatment regimen should be reviewed and changed as necessary to prevent further hypoglycemia when a blood glucose value is ,70 mg/dL (3.9 mmol/L). C There should be a structured discharge plan tailored to the individual patient with diabetes. B

In the hospital, both hyperglycemia and hypoglycemia are associated with adverse outcomes including death (1,2). Therefore, inpatient goals should include the prevention of both hyperglycemia and hypoglycemia. Hospitals should promote the shortest, safe hospital stay and provide an effective transition out of the hospital that prevents acute complications and readmission. For in-depth review of inpatient hospital practice, consult recent reviews that focus on hospital care for diabetes (3,4). HOSPITAL CARE DELIVERY STANDARDS

High-quality hospital care for diabetes requires both hospital care delivery standards, often assured by structured order sets, and quality assurance standards for process improvement. “Best practice” protocols, reviews, and guidelines (2) are inconsistently implemented within hospitals. To correct this, hospitals have established protocols for structured patient care and structured order sets, which include computerized physician order entry (CPOE). Considerations on Admission

Initial orders should state the type of diabetes (i.e., type 1 or type 2 diabetes) or no previous history of diabetes. Because inpatient insulin use (5) and discharge orders (6) can be more effective if based on an A1C level on admission (7), perform an A1C test on all patients with diabetes or hyperglycemia admitted to the hospital if the

Suggested citation: American Diabetes Association. Diabetes care in the hospital. Sec. 14. In Standards of Medical Care in Diabetesd2017. Diabetes Care 2017;40(Suppl. 1):S120–S127 © 2017 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals .org/content/license.

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test has not been performed in the prior 3 months. In addition, diabetes selfmanagement knowledge and behaviors should be assessed on admission and diabetes self-management education (DSME) should be provided, if appropriate. DSME should include appropriate skills needed after discharge, such as taking antihyperglycemic medications, monitoring glucose, and recognizing and treating hypoglycemia (2). Computerized Physician Order Entry

The Institute of Medicine recommends CPOE to prevent medication-related errors and to increase efficiency in medication administration (8). A Cochrane review of randomized controlled trials using computerized advice to improve glucose control in the hospital found significant improvement in the percentage of time patients spent in the target glucose range, lower mean blood glucose levels, and no increase in hypoglycemia (9). Thus, where feasible, there should be structured order sets that provide computerized advice for glucose control. Electronic insulin order templates also improve mean glucose levels without increasing hypoglycemia in patients with type 2 diabetes, so structured insulin order sets should be incorporated into the CPOE (10). Diabetes Care Providers in the Hospital

Appropriately trained specialists or specialty teams may reduce length of stay, improve glycemic control, and improve outcomes, but studies are few. A call to action outlined the studies needed to evaluate these outcomes (11). Details of team formation are available from the Society of Hospital Medicine and the Joint Commission standards for programs. Quality Assurance Standards

Even the best orders may not be carried out in a way that improves quality, nor are they automatically updated when new evidence arises. To this end, the Joint Commission has an accreditation program for the hospital care of diabetes (12), and the Society of Hospital Medicine has a workbook for program development (13). GLYCEMIC TARGETS IN HOSPITALIZED PATIENTS Standard Definition of Glucose Abnormalities

Hyperglycemiainhospitalizedpatientsisdefined as blood glucose levels .140 mg/dL

Diabetes Care in the Hospital

(7.8 mmol/L). Blood glucose levels that are persistently above this level may require alterations in diet or a change in medications that cause hyperglycemia. An admission A1C value $6.5% (48 mmol/mol) suggests that diabetes preceded hospitalization (see Section 2 “Classification and Diagnosis of Diabetes”). Previously, hypoglycemia in hospitalized patients has been defined as blood glucose ,70 mg/dL (3.9 mmol/L) and severe hypoglycemia as ,40 mg/dL (2.2 mmol/L) (14). However, the American Diabetes Association (ADA) now defines clinically significant hypoglycemia as glucose values ,54 mg/dL (3.0 mmol/L), while severe hypoglycemia is defined as that associated with severe cognitive impairment regardless of blood glucose level (see Section 6 “Glycemic Targets” for additional detail on the new hypoglycemia criteria) (15). A blood glucose level of #70 mg/dL is considered an alert value and may be used as a threshold for further titration of insulin regimens. Moderate Versus Tight Glycemic Control

A meta-analysis of over 26 studies, including the Normoglycemia in Intensive Care Evaluation–Survival Using Glucose Algorithm Regulation (NICE-SUGAR) study, showed increased rates of severe hypoglycemia (blood glucose ,40 mg/dL) and mortality in tightly versus moderately controlled cohorts (16). This evidence established new standards: insulin therapy should be initiated for treatment of persistent hyperglycemia starting at a threshold $180 mg/dL (10.0 mmol/L). Once insulin therapy is started, a target glucose range of 140–180 mg/dL (7.8–10.0 mmol/L) is recommended for the majority of critically ill and noncritically ill patients (2). More stringent goals, such as ,140 mg/dL (,7.8 mmol/L), may be appropriate for selected patients, as long as this can be achieved without significant hypoglycemia. Conversely, higher glucose ranges may be acceptable in terminally ill patients, in patients with severe comorbidities, and in inpatient care settings where frequent glucose monitoring or close nursing supervision is not feasible. Clinical judgment combined with ongoing assessment of the patient’s clinical status, including changes in the trajectory of glucose measures, illness severity, nutritional status, or concomitant medications that might affect glucose levels

(e.g., glucocorticoids), should be incorporated into the day-to-day decisions regarding insulin doses (2). BEDSIDE BLOOD GLUCOSE MONITORING Indications

In the patient who is eating meals, glucose monitoring should be performed before meals. In the patient who is not eating, glucose monitoring is advised every 4–6 h (2). More frequent blood glucose testing ranging from every 30 min to every 2 h is required for patients receiving intravenous insulin. Safety standards should be established for blood glucose monitoring that prohibit the sharing of fingerstick lancing devices, lancets, and needles (17). Point-of-Care Meters

Point-of-care (POC) meters have limitations for measuring blood glucose. Although the U.S. Food and Drug Administration (FDA) has standards for blood glucose meters used by lay persons, there have been questions about the appropriateness of these criteria, especially in the hospital and for lower blood glucose readings (18). Significant discrepancies between capillary, venous, and arterial plasma samples have been observed in patients with low or high hemoglobin concentrations and with hypoperfusion. Any glucose result that does not correlate with the patient’s clinical status should be confirmed through conventional laboratory glucose tests. The FDA established a separate category for POC glucose meters for use in health care settings and has released a guidance on in-hospital use with stricter standards (19). Before choosing a device for in-hospital use, consider the device’s approval status and accuracy. Continuous Glucose Monitoring

Continuous glucose monitoring (CGM) provides frequent measurements of interstitial glucose levels, as well as direction and magnitude of glucose trends, which may have an advantage over POC glucose testing in detecting and reducing the incidence of hypoglycemia. Several inpatient studies have shown that CGM use did not improve glucose control but detected a greater number of hypoglycemic events than POC testing. However, a recent review has recommended against using CGM in adults in a hospital setting until more safety and efficacy data become available (20).

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ANTIHYPERGLYCEMIC AGENTS IN HOSPITALIZED PATIENTS

In most instances in the hospital setting, insulin is the preferred treatment for glycemic control (2). However, in certain circumstances, it may be appropriate to continue home regimens including oral antihyperglycemic medications (21). If oral medications are held in the hospital, there should be a protocol for resuming them 1–2 days before discharge. Insulin pens are the subject of an FDA warning due to potential blood-borne diseases, and care should be taken to follow the label insert “For single patient use only.” Insulin Therapy Critical Care Setting

In the critical care setting, continuous intravenous insulin infusion has been shown to be the best method for achieving glycemic targets. Intravenous insulin infusions should be administered based on validated written or computerized protocols that allow for predefined adjustments in the infusion rate, accounting for glycemic fluctuations and insulin dose (2). Noncritical Care Setting

Outside of critical care units, scheduled insulin regimens are recommended to manage hyperglycemia in patients with diabetes. Regimens using insulin analogs and human insulin result in similar glycemic control in the hospital setting (22). The use of subcutaneous rapid- or short-acting insulin before meals or every 4–6 h if no meals are given or if the patient is receiving continuous enteral/parenteral nutrition is indicated to correct hyperglycemia (2). Basal insulin or a basal plus bolus correction insulin regimen is the preferred treatment for noncritically ill patients with poor oral intake or those who are taking nothing by mouth (NPO). An insulin regimen with basal, nutritional, and correction components is the preferred treatment for noncritically ill hospitalized patients with good nutritional intake. If the patient is eating, insulin injections should align with meals. In such instances, POC glucose testing should be performed immediately before meals. If oral intake is poor, a safer procedure is to administer the rapid-acting insulin immediately after the patient eats or to count the carbohydrates and cover the amount ingested (22). A randomized controlled trial has shown that basal-bolus treatment improved

Diabetes Care Volume 40, Supplement 1, January 2017

glycemic control and reduced hospital complications compared with sliding scale insulin in general surgery patients with type 2 diabetes (23). Prolonged sole use of sliding scale insulin in the inpatient hospital setting is strongly discouraged (2,11). While there is evidence for using premixed insulin formulations in the outpatient setting (24), a recent inpatient study of 70/30 NPH/regular versus basal-bolus therapy showed comparable glycemic control but signifcantly increased hypoglycemia in the group receiving premixed insulin. Therefore, premixed insulin regimens are not routinely recommended for in hospital use. Type 1 Diabetes

For patients with type 1 diabetes, dosing insulin based solely on premeal glucose levels does not account for basal insulin requirements or caloric intake, increasing both hypoglycemia and hyperglycemia risks and potentially leading to diabetic ketoacidosis (DKA). Typically basal insulin dosing schemes are based on body weight, with some evidence that patients with renal insufficiency should be treated with lower doses (25). Transitioning Intravenous to Subcutaneous Insulin

When discontinuing intravenous insulin, a transition protocol is associated with less morbidity and lower costs of care (26) and is therefore recommended. A patient with type 1 or type 2 diabetes being transitioned to outpatient subcutaneous insulin should receive subcutaneous basal insulin 1–2 h before the intravenous insulin is discontinued. Converting to basal insulin at 60–80% of the daily infusion dose has been shown to be effective (2,26,27). For patients continuing regimens with concentrated insulin in the inpatient setting, it is important to ensure the correct dosing by utilizing an individual pen and cartrige for each patient, meticulous pharmacist supervision of the dose administered, or other means (28,29). Noninsulin Therapies

The safety and efficacy of noninsulin antihyperglycemic therapies in the hospital setting is an area of active research. A recent randomized pilot trial in general medicine and surgery patients reported that a dipeptidyl peptidase 4 inhibitor alone or in combination with basal insulin was well tolerated and resulted in similar glucose control and frequency

of hypoglycemia compared with a basalbolus regimen (30). However, a recent FDA bulletin states that providers should consider discontinuing saxagliptin and alogliptin in people who develop heart failure (31). A review of antihyperglycemic medications concluded that glucagon-like peptide 1 receptor agonists show promise in the inpatient setting (32); however, proof of safety and efficacy await the results of randomized controlled trials (33). Moreover, the gastrointestinal symptoms associated with the glucagon-like peptide 1 receptor agonists may be problematic in the inpatinet setting. Regarding the sodium–glucose transporter 2 (SGLT2) inhibitors, the FDA includes warnings about DKA and urosepsis (34), urinary tract infections, and kidney injury (35) on the drug labels. A recent review suggested SGLT2 inhibitors be avoided in severe illness, when ketone bodies are present, and during prolonged fasting and surgical procedures (3). Until safety and effectivenss are established, SGLT2 inhibitors cannot be recommended for routine in-hospital use. HYPOGLYCEMIA

Patients with or without diabetes may experience hypoglycemia in the hospital setting. While hypoglycemia is associated with increased mortality, hypoglycemia may be a marker of underlying disease rather than the cause of increased mortality. However, until it is proven not to be causal, it is prudent to avoid hypoglycemia. Despite the preventable nature of many inpatient episodes of hypoglycemia, institutions are more likely to have nursing protocols for hypoglycemia treatment than for its prevention when both are needed. A hypoglycemia prevention and management protocol should be adopted and implemented by each hospital or hospital system. There should be a standardized hospital-wide, nurse-initiated hypoglycemia treatment protocol to immediately address blood glucose levels of #70 mg/dL [3.9 mmol/L], as well as individualized plans for preventing and treating hypoglycemia for each patient. An ADA consensus report suggested that a patient’s overall treatment regimen be reviewed when a blood glucose value of ,70 mg/dL (3.9 mmol/L) is identified because such readings often predict imminent severe hypoglycemia (2).

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Episodes of hypoglycemia in the hospital should be documented in the medical record and tracked (2). Triggering Events

Iatrogenic hypoglycemia triggers may include sudden reduction of corticosteroid dose, reduced oral intake, emesis, new NPO status, inappropriate timing of short-acting insulin in relation to meals, reduced infusion rate of intravenous dextrose, unexpected interruption of oral, enteral, or parenteral feedings, and altered ability of the patient to report symptoms. Predictors of Hypoglycemia

In one study, 84% of patients with an episode of severe hypoglycemia (,40 mg/dL [2.2 mmol/L]) had a prior episode of hypoglycemia (,70 mg/dL [3.9 mmol/L]) during the same admission (36). In another study of hypoglycemic episodes (,50 mg/dL [2.8 mmol/L]), 78% of patients were using basal insulin, with the incidence of hypoglycemia peaking between midnight and 6 A.M. Despite recognition of hypoglycemia, 75% of patients did not have their dose of basal insulin changed before the next insulin administration (37). Prevention

Common preventable sources of iatrogenic hypoglycemia are improper prescribing of hypoglycemic medications, inappropriate management of the first episode of hypoglycemia, and nutrition– insulin mismatch, often related to an unexpected interruption of nutrition. Studies of “bundled” preventative therapies including proactive surveillance of glycemic outliers and an interdisciplinary data-driven approach to glycemic management showed that hypoglycemic episodes in the hospital could be prevented. Compared with baseline, two such studies found that hypoglycemic events fell by 56% to 80% (38,39). The Joint Commission recommends that all hypoglycemic episodes be evaluated for a root cause and the episodes be aggregated and reviewed to address systemic issues. MEDICAL NUTRITION THERAPY IN THE HOSPITAL

The goals of medical nutrition therapy in the hospital are to provide adequate calories to meet metabolic demands, optimize glycemic control, address personal

Diabetes Care in the Hospital

food preferences, and facilitate creation of a discharge plan. The ADA does not endorse any single meal plan or specified percentages of macronutrients, and the term “ADA diet” should no longer be used. Current nutrition recommendations advise individualization based on treatment goals, physiological parameters, and medication use. Consistent carbohydrate meal plans are preferred by many hospitals as they facilitate matching the prandial insulin dose to the amount of carbohydrate consumed (40). Regarding enteral nutritional therapy, diabetes-specific formulas appear to be superior to standard formulas in controlling postprandial glucose, A1C and the insulin response (41). When the nutritional issues in the hospital are complex, a registered dietitian, knowledgeable and skilled in medical nutrition therapy, can serve as an individual inpatient team member. That person should be responsible for integrating information about the patient’s clinical condition, meal planning, and lifestyle habits and for establishing realistic treatment goals after discharge. Orders should also indicate that the meal delivery and nutritional insulin coverage should be coordinated, as their variability often creates the possibility of hyperglycemic and hypoglycemic events.

SELF-MANAGEMENT IN THE HOSPITAL

Diabetes self-management in the hospital may be appropriate for select youth and adult patients. Candidates include patients who successfully conduct self-management of diabetes at home, have the cognitive and physical skills needed to successfully self-administer insulin, and perform selfmonitoring of blood glucose. In addition, they should have adequate oral intake, be proficient in carbohydrate estimation, use multiple daily insulin injections or continuous subcutaneous insulin infusion (CSII) pump therapy, have stable insulin requirements, and understand sick-day management. If self-management is to be used, a protocol should include a requirement that the patient, nursing staff, and physician agree that patient selfmanagement is appropriate. If CSII is to be used, hospital policy and procedures delineating guidelines for CSII therapy including the changing of infusion sites are advised (42).

STANDARDS FOR SPECIAL SITUATIONS Enteral/Parenteral Feedings

For patients receiving enteral or parenteral feedings who require insulin, insulin should be divided into basal, nutritional, and correctional components. This is particularly important for people with type 1 diabetes to ensure that they continue to receive basal insulin even if the feedings are discontinued. One may use the patient’s preadmission basal insulin dose or a percentage of the total daily dose of insulin when the patient is being fed (usually 30 to 50% of the total daily dose of insulin) to estimate basal insulin requirements. However, if no basal insulin was used, consider using 5 units of NPH/detemir insulin subcutaneously every 12 h or 10 units of insulin glargine every 24 h (43). For patients receiving continuous tube feedings, the total daily nutritional component may be calculated as 1 unit of insulin for every 10–15 g carbohydrate per day or as a percentage of the total daily dose of insulin when the patient is being fed (usually 50 to 70% of the total daily dose of insulin) Correctional insulin should also be administered subcutaneously every 6 h using human regular insulin or every 4 h using a rapid-acting insulin such as lispro, aspart, or glulisine. For patients receiving enteral bolus feedings, approximately 1 unit of regular human insulin or rapid-acting insulin should be given per 10–15 g carbohydrate subcutaneously before each feeding. Correctional insulin coverage should be added as needed before each feeding. For patients receiving continuous peripheral or central parenteral nutrition, regular insulin may be added to the solution, particularly if .20 units of correctional insulin have been required in the past 24 h. A starting dose of 1 unit of human regular insulin for every 10 g dextrose has been recommended (44), to be adjusted daily in the solution. Correctional insulin should be administered subcutaneously. For full enteral/parenteral feeding guidance, the reader is encouraged to consult review articles (2,45) and see Table 14.1. Glucocorticoid Therapy

Glucocorticoid type and duration of action must be considered in determining insulin treatment regimens. Once-aday, short-acting glucocorticoids such as prednisone peak in about 4 to 8 h

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Table 14.1—Insulin dosing for enteral/parenteral feedings Situation

Basal/nutritional

Correctional

Continuous enteral feedings

Continue prior basal or, if none, calculate from TDD or consider 5 units NPH/detemir every 12 h or 10 units glargine daily Nutritional: regular insulin every 6 h or rapid-acting insulin every 4 h, starting with 1 unit per 10–15 g of carbohydrate; adjust daily

SQ regular insulin every 6 h or rapid-acting insulin every 4 h for hyperglycemia

Bolus enteral feedings

Continue prior basal or, if none, calculate from TDD or consider 5 units NPH/detemir every 12 h or 10 units glargine daily Nutritional: give regular insulin or rapid-acting insulin SQ before each feeding, starting with 1 unit per 10– 15 g of carbohydrate; adjust daily

SQ regular insulin every 6 h or rapid-acting insulin every 4 h for hyperglycemia

Parenteral feedings

Add regular insulin to TPN IV solution, starting with 1 unit per 10 g of carbohydrate; adjust daily

SQ regular insulin every 6 h or rapid-acting insulin every 4 h for hyperglycemia

IV, intravenous; SQ, subcutaneous; TDD, total daily dose; TPN, total parenteral nutrition.

(46), so coverage with intermediateacting insulin (NPH) may be sufficient. For long-acting glucocorticoids such as dexamethasone or multidose or continuous glucocorticoid use, long-acting insulin may be used (21,45). For higher doses of glucocorticoids, increasing doses of prandial and supplemental insulin may be needed in addition to basal insulin (47). Whatever orders are started, adjustments based on anticipated changes in glucocorticoid dosing and POC glucose test results are critical. Perioperative Care

Many standards for perioperative care lack a robust evidence base. However, the following approach (48) may be considered: 1. Target glucose range for the perioperative period should be 80– 180 mg/dL (4.4–10.0 mmol/L). 2. Perform a preoperative risk assessment for patients at high risk for ischemic heart disease and those with autonomic neuropathy or renal failure. 3. Withold metformin 24 h before surgery. 4. Withhold any other oral hypoglycemic agents the morning of surgery or procedure and give half of NPH dose or 60–80% doses of a long-acting analog or pump basal insulin. 5. Monitor blood glucose at least every 4–6 h while NPO and dose with shortacting insulin as needed. A review found that perioperative glycemic control tighter than 80–180 mg/dL (4.4–10.0 mmol/L) did not improve outcomes and was associated with more hypoglycemia (49); therefore, in general, tighter glycemic targets are not advised.

In noncardiac general surgery patients, basal insulin plus premeal regular or short-acting insulin (basal-bolus) coverage has been associated with improved glycemic control and lower rates of perioperative complications compared with the traditional sliding scale regimen (regular or short-acting insulin coverage only with no basal dosing) (23,50). Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic State

There is considerable variability in the presentation of DKA and hyperosmolar hyperglycemic state, ranging from euglycemia or mild hyperglycemia and acidosis to severe hyperglycemia, dehydration, and coma; therefore, treatment individualization based on a careful clinical and laboratory assessment is needed (51). Management goals include restoration of circulatory volume and tissue perfusion, resolution of hyperglycemia, and correction of electrolyte imbalance and ketosis. It is also important to treat any correctable underlying cause of DKA such as sepsis. In critically ill and mentally obtunded patients with DKA or hyperosmolar hyperglycemic state, continuous intravenous insulin is the standard of care. However, there is no significant difference in outcomes for intravenous regular insulin versus subcutaneous rapid-acting analogs when combined with aggressive fluid management for treating mild or moderate DKA (52). Patients with uncomplicated DKA may sometimes be treated with subcutanous insulin in the emergency department or step-down units (53), an approach that may be safer and more cost-effective than treatment

with intravenous insulin (54). If subcutaneous administration is used, it is important to provide adequate fluid replacement, nurse training, frequent bedside testing, infection treatment if warranted, and appropriate follow-up to avoid recurrant DKA. Several studies have shown that the use of bicarbonate in patients with DKA made no difference in resolution of acidosis or time to discharge, and its use is generally not recommended (55). For further information, regarding treatment, refer to recent in-depth reviews (3,56). TRANSITION FROM THE ACUTE CARE SETTING

A structured discharge plan tailored to the individual patient may reduce length of hospital stay, readmission rates, and increase patient satisfaction (57). Therefore, there should be a structured discharge plan tailored to each patient. Discharge planning should begin at admission and be updated as patient needs change. Transition from the acute care setting is a risky time for all patients. Inpatients may be discharged to varied settings including home (with or without visiting nurse services), assisted living, rehabilitation, or skilled nursing facilities. For the patient who is discharged to home or to assisted living, the optimal program will need to consider diabetes type and severity, effects of the patient’s illness on blood glucose levels, and the patient’s capacities and desires. An outpatient follow-up visit with the primary care provider, endocrinologist, or diabetes educator within 1 month of discharge is advised for all patients

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having hyperglycemia in the hospital. If glycemic medications are changed or glucose control is not optimal at discharge, an earlier appointment (in 1–2 weeks) is preferred, and frequent contact may be needed to avoid hyperglycemia and hypoglycemia. A recent discharge algorithm for glycemic medication adjustment based on admission A1C found that the average A1C in patients with diabetes after discharge was significantly improved (6). Therefore, if an A1C from the prior 3 months is unavailable, measuring the A1C in all patients with diabetes or hyperglycemia admitted to the hospital is recommended. Clear communication with outpatient providers either directly or via hospital discharge summaries facilitates safe transitions to outpatient care. Providing information regarding the cause of hyperglycemia (or the plan for determining the cause), related complications and comorbidities, and recommended treatments can assist outpatient providers as they assume ongoing care. The Agency for Healthcare Research and Quality (AHRQ) recommends that at a minimum, discharge plans include the following (58): Medication Reconciliation ○



The patient’s medications must be cross-checked to ensure that no chronic medications were stopped and to ensure the safety of new prescriptions. Prescriptions for new or changed medication should be filled and reviewed with the patient and family at or before discharge.

Structured Discharge Communication ○





Information on medication changes, pending tests and studies, and follow-up needs must be accurately and promptly communicated to outpatient physicians. Discharge summaries should be transmitted to the primary physician as soon as possible after discharge. Appointment-keeping behavior is enhanced when the inpatient team schedules outpatient medical followup prior to discharge.

It is recommended that the following areas of knowledge be reviewed and addressed prior to hospital discharge: ○



Identify the health care provider who will provide diabetes care after discharge. Level of understanding related to the diabetes diagnosis, self-monitoring of

Diabetes Care in the Hospital







○ ○

blood glucose, explanation of home blood glucose goals, and when to call the provider. Definition, recognition, treatment, and prevention of hyperglycemia and hypoglycemia. Information on consistent nutrition habits. If relevant, when and how to take blood glucose–lowering medications, including insulin administration. Sick-day management. Proper use and disposal of needles and syringes.

It is important that patients be provided with appropriate durable medical equipment, medications, supplies (e.g., insulin pens), and prescriptions along with appropriate education at the time of discharge in order to avoid a potentially dangerous hiatus in care. PREVENTING ADMISSIONS AND READMISSIONS Preventing Hypoglycemic Admissions in Older Adults

Insulin-treated patients 80 years of age or older are more than twice as likely to visit the emergency department and nearly five times as likely to be admitted for insulin-related hypoglycemia than those 45–64 years of age (59). However, older adults with type 2 diabetes in long-term care facilities taking either oral antihyperglycemic agents or basal insulin have similar glycemic control (60), suggesting that oral therapy may be used in place of insulin to lower the risk of hypoglycemia for some patients. In addition, many older adults with diabetes are overtreated (61), with half of those maintaining an A1C ,7% being treated with insulin or a sulfonlyurea, which are associated with hypoglycemia. To further lower the risk of hypoglycemiarelated admissions in older adults, providers may, on an individual basis, relax A1C targets to ,8% or ,8.5% in patients with shortened life expectancies and significant comorbidities (refer to Section 11 “Older Adults” for detailed criteria). Preventing Readmissions

In patients with diabetes, the readmission rate is between 14% and 20% (62). Risk factors for readmission include lower socioeconomic status, certain racial/ethnic minority groups, comorbidities, urgent admission, and recent prior hospitalization

(62). Of interest, 30% of patients with two or more hospital stays account for over 50% of hospitalizations and their accompanying hospital costs (63). While there is no standard to prevent readmissions, several successful strategies have been reported, including an intervention program targeting ketosisprone patients with type 1 diabetes (64), initiating insulin treatment in patients with admission A1C .9% (65), and a transitional care model (66). For people with diabetic kidney disease, patientcentered medical home collaboratives may decrease risk-adjusted readmission rates (67). References 1. Clement S, Braithwaite SS, Magee MF, et al.; American Diabetes Association Diabetes in Hospitals Writing Committee. Management of diabetes and hyperglycemia in hospitals. Diabetes Care 2004;27:553–591 2. Moghissi ES, Korytkowski MT, DiNardo M, et al.; American Association of Clinical Endocrinologists; American Diabetes Association. American Association of Clinical Endocrinologists and American Diabetes Association consensus statement on inpatient glycemic control. Diabetes Care 2009;32:1119–1131 3. Umpierrez G, Korytkowski M. Diabetic emergencies - ketoacidosis, hyperglycaemic hyperosmolar state and hypoglycaemia. Nat Rev Endocrinol 2016;12:222–232 4. Bogun M, Inzucchi SE. Inpatient management of diabetes and hyperglycemia. Clin Ther 2013;35:724–733 5. Pasquel FJ, Gomez-Huelgas R, Anzola I, et al. Predictive value of admission hemoglobin A1c on inpatient glycemic control and response to insulin therapy in medicine and surgery patients with type 2 diabetes. Diabetes Care 2015;38: e202–e203 6. Umpierrez GE, Reyes D, Smiley D, et al. Hospital discharge algorithm based on admission HbA1c for the management of patients with type 2 diabetes. Diabetes Care 2014;37:2934–2939 7. Carpenter DL, Gregg SR, Xu K, Buchman TG, Coopersmith CM. Prevalence and impact of unknown diabetes in the ICU. Crit Care Med 2015; 43:e541–e550 8. Institute of Medicine. Preventing Medication Errors. Aspden P, Wolcott J, Bootman JL, Cronenwett LR, Eds.Washington, DC, The National Academies Press, 2007 9. Gillaizeau F, Chan E, Trinquart L, et al. Computerized advice on drug dosage to improve prescribing practice. Cochrane Database Syst Rev 2013;11:CD002894 10. Wexler DJ, Shrader P, Burns SM, Cagliero E. Effectiveness of a computerized insulin order template in general medical inpatients with type 2 diabetes: a cluster randomized trial. Diabetes Care 2010;33:2181–2183 11. Draznin B, Gilden J, Golden SH, et al.; PRIDE investigators. Pathways to quality inpatient management of hyperglycemia and diabetes: a call to action. Diabetes Care 2013;36:1807–1814

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12. Arnold P, Scheurer D, Dake AW, et al. Hospital Guidelines for Diabetes Management and the Joint Commission-American Diabetes Association Inpatient Diabetes Certification. Am J Med Sci 2016;351:333–341 13. Society of Hospital Medicine. Clinical Tools | Glycemic Control Implementation Toolkit [Internet]. Available from http://www.hospitalmedicine .org/Web/Quality_Innovation/Implementation_ Toolkits/Glycemic_Control/Web/Quality___ Innovation/Implementation_Toolkit/Glycemic/ Clinical_Tools/Clinical_Tools.aspx. Accessed 25 August 2015 14. Seaquist ER, Anderson J, Childs B, et al. Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. Diabetes Care 2013; 36:1384–1395 15. International Hypoglycaemia Study Group. Glucose concentrations of less than 3.0 mmol/L (54 mg/dL) should be reported in clinical trials: a joint position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2017;40: 155–157 16. NICE-SUGAR Study Investigators, Finfer S, Chittock DR, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med 2009;360:1283–1297 17. Cobaugh DJ, Maynard G, Cooper L, et al. Enhancing insulin-use safety in hospitals: practical recommendations from an ASHP Foundation expert consensus panel. Am J Health Syst Pharm 2013;70:1404–1413 18. Boyd JC, Bruns DE. Quality specifications for glucose meters: assessment by simulation modeling of errors in insulin dose. Clin Chem 2001; 47:209–214 19. U.S. Food and Drug Administration. Blood Glucose Monitoring Test Systems for Prescription Point-of-Care Use: Guidance for Industry and Food and Drug Administration Staff [Internet], 2016. Available from http://www.fda.gov/downloads/ medicaldevices/deviceregulationandguidance/ guidancedocuments/ucm380325.pdf. Accessed 21 November 2016 20. Gomez AM, Umpierrez GE. Continuous glucose monitoring in insulin-treated patients in non-ICU settings. J Diabetes Sci Technol 2014; 8:930–936 21. Maynard G, Wesorick DH, O’Malley C, Inzucchi SE; Society of Hospital Medicine Glycemic Control Task Force. Subcutaneous insulin order sets and protocols: effective design and implementation strategies. J Hosp Med 2008; 3(Suppl.):29–41 22. Bueno E, Benitez A, Rufinelli JV, et al. Basalbolus regimen with insulin analogues versus human insulin in medical patients with type 2 diabetes: a randomized controlled trial in Latin America. Endocr Pract 2015;21:807–813 23. Umpierrez GE, Smiley D, Jacobs S, et al. Randomized study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes undergoing general surgery (RABBIT 2 surgery). Diabetes Care 2011;34: 256–261 24. Giugliano D, Chiodini P, Maiorino MI, Bellastella G, Esposito K. Intensification of insulin therapy with basal-bolus or premixed insulin regimens in type 2 diabetes: a systematic review

Diabetes Care Volume 40, Supplement 1, January 2017

and meta-analysis of randomized controlled trials. Endocrine 2016;51:417–428 25. Baldwin D, Zander J, Munoz C, et al. A randomized trial of two weight-based doses of insulin glargine and glulisine in hospitalized subjects with type 2 diabetes and renal insufficiency. Diabetes Care 2012;35:1970–1974 26. Schmeltz LR, DeSantis AJ, Thiyagarajan V, et al. Reduction of surgical mortality and morbidity in diabetic patients undergoing cardiac surgery with a combined intravenous and subcutaneous insulin glucose management strategy. Diabetes Care 2007;30:823–828 27. Shomali ME, Herr DL, Hill PC, Pehlivanova M, Sharretts JM, Magee MF. Conversion from intravenous insulin to subcutaneous insulin after cardiovascular surgery: transition to target study. Diabetes Technol Ther 2011;13:121–126 28. Tripathy PR, Lansang MC. U-500 regular insulin use in hospitalized patients. Endocr Pract 2015;21:54–58 29. Lansang MC, Umpierrez GE. Inpatient hyperglycemia management: a practical review for primary medical and surgical teams. Cleve Clin J Med 2016;83(Suppl. 1):S34–S43 30. Umpierrez GE, Gianchandani R, Smiley D, et al. Safety and efficacy of sitagliptin therapy for the inpatient management of general medicine and surgery patients with type 2 diabetes: a pilot, randomized, controlled study. Diabetes Care 2013;36:3430–3435 31. U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA adds warnings about heart failure risk to labels of type 2 diabetes medicines containing saxagliptin and alogliptin [Internet]. Available from http:// www.fda.gov/Drugs/DrugSafety/ucm486096 .htm. Accessed 7 October 2016 32. Mendez CE, Umpierrez GE. Pharmacotherapy for hyperglycemia in noncritically ill hospitalized patients. Diabetes Spectr 2014;27: 180–188 33. Umpierrez GE, Korytkowski M. Is incretinbased therapy ready for the care of hospitalized patients with type 2 diabetes?: Insulin therapy has proven itself and is considered the mainstay of treatment. Diabetes Care 2013;36:2112– 2117 34. U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections [Internet]. Available from http://www.fda.gov/Drugs/DrugSafety/ ucm475463.htm. Accessed 7 October 2016 35. U.S. Food and Drug Administration. FDA strengthens kidney warnings for diabetes medicines canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR) [Internet]. Available from http://www.fda.gov/drugs/ drugsafety/drugsafetypodcasts/ucm507785 .htm. Accessed 7 October 2016 36. Dendy JA, Chockalingam V, Tirumalasetty NN, et al. Identifying risk factors for severe hypoglycemia in hospitalized patients with diabetes. Endocr Pract 2014;20:1051–1056 37. Ulmer BJ, Kara A, Mariash CN. Temporal occurrences and recurrence patterns of hypoglycemia during hospitalization. Endocr Pract 2015;21:501–507 38. Maynard G, Kulasa K, Ramos P, et al. Impact of a hypoglycemia reduction bundle and a

systems approach to inpatient glycemic management. Endocr Pract 2015;21:355–367 39. Milligan PE, Bocox MC, Pratt E, Hoehner CM, Krettek JE, Dunagan WC. Multifaceted approach to reducing occurrence of severe hypoglycemia in a large healthcare system. Am J Health Syst Pharm 2015;72:1631–1641 40. Curll M, Dinardo M, Noschese M, Korytkowski MT. Menu selection, glycaemic control and satisfaction with standard and patient-controlled consistent carbohydrate meal plans in hospitalised patients with diabetes. Qual Saf Health Care 2010;19:355–359 41. Ojo O, Brooke J. Evaluation of the role of enteral nutrition in managing patients with diabetes: a systematic review. Nutrients 2014;6: 5142–5152 42. Houlden RL, Moore S. In-hospital management of adults using insulin pump therapy. Can J Diabetes 2014;38:126–133 43. Umpierrez GE. Basal versus sliding-scale regular insulin in hospitalized patients with hyperglycemia during enteral nutrition therapy. Diabetes Care 2009;32:751–753 44. Pichardo-Lowden AR, Fan CY, Gabbay RA. Management of hyperglycemia in the nonintensive care patient: featuring subcutaneous insulin protocols. Endocr Pract 2011;17: 249–260 45. Corsino L, Dhatariya K, Umpierrez G. Management of diabetes and hyperglycemia in hospitalized patients. In Endotext [Internet]. Available from http://www.ncbi.nlm.nih.gov/ books/NBK279093/. Accessed 21 November 2016 46. Kwon S, Hermayer KL. Glucocorticoidinduced hyperglycemia. Am J Med Sci 2013; 345:274–277 47. Brady V, Thosani S, Zhou S, Bassett R, Busaidy NL, Lavis V. Safe and effective dosing of basal-bolus insulin in patients receiving high-dose steroids for hyper-cyclophosphamide, doxorubicin, vincristine, and dexamethasone chemotherapy. Diabetes Technol Ther 2014;16:874–879 48. Smiley DD, Umpierrez GE. Perioperative glucose control in the diabetic or nondiabetic patient. South Med J 2006;99:580–589 49. Buchleitner AM, Mart´ınez-Alonso M, Hern´andez M, Sol`a I, Mauricio D. Perioperative glycaemic control for diabetic patients undergoing surgery. Cochrane Database Syst Rev 2012; 9:CD007315 50. Umpierrez GE, Smiley D, Hermayer K, et al. Randomized study comparing a basal-bolus with a basal plus correction insulin regimen for the hospital management of medical and surgical patients with type 2 diabetes: Basal Plus trial. Diabetes Care 2013;36:2169–2174 51. Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with diabetes. Diabetes Care 2009;32:1335–1343 52. Andrade-Castellanos CA, Colunga-Lozano LE, Delgado-Figueroa N, Gonzalez-Padilla DA. Subcutaneous rapid-acting insulin analogues for diabetic ketoacidosis. Cochrane Database Syst Rev 2016;1:CD011281 53. Kitabchi AE, Umpierrez GE, Fisher JN, Murphy MB, Stentz FB. Thirty years of personal experience in hyperglycemic crises: diabetic ketoacidosis and hyperglycemic hyperosmolar

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state. J Clin Endocrinol Metab 2008;93:1541– 1552 54. Umpierrez GE, Latif K, Stoever J, et al. Efficacy of subcutaneous insulin lispro versus continuous intravenous regular insulin for the treatment of patients with diabetic ketoacidosis. Am J Med 2004;117:291–296 55. Duhon B, Attridge RL, Franco-Martinez AC, Maxwell PR, Hughes DW. Intravenous sodium bicarbonate therapy in severely acidotic diabetic ketoacidosis. Ann Pharmacother 2013; 47:970–975 56. Gosmanov AR, Gosmanova EO, Kitabchi AE. Hyperglycemic crises: diabetic ketoacidosis (DKA), and hyperglycemic hyperosmolar state (HHS). In Endotext [Internet]. Available from http://www.ncbi.nlm.nih.gov/books/NBK279052/. Accessed 7 October 2016 57. Shepperd S, Lannin NA, Clemson LM, McCluskey A, Cameron ID, Barras SL. Discharge

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planning from hospital to home. Cochrane Database Syst Rev 2016;1:CD000313 58. Agency for Healthcare Research and Quality. Adverse events after hospital discharge [article online], 2010. Available from http:// psnet.ahrq.gov/primer.aspx?primerID511. Accessed 21 November 2016 59. Bansal N, Dhaliwal R, Weinstock RS. Management of diabetes in the elderly. Med Clin North Am 2015;99:351–377 60. Pasquel FJ, Powell W, Peng L, et al. A randomized controlled trial comparing treatment with oral agents and basal insulin in elderly patients with type 2 diabetes in long-term care facilities. BMJ Open Diabetes Res Care 2015;3: e000104 61. Lipska KJ, Ross JS, Miao Y, Shah ND, Lee SJ, Steinman MA. Potential overtreatment of diabetes mellitus in older adults with tight glycemic control. JAMA Intern Med 2015;175:356–362

62. Rubin DJ. Hospital readmission of patients with diabetes. Curr Diab Rep 2015;15:17 63. Jiang HJ, Stryer D, Friedman B, Andrews R. Multiple hospitalizations for patients with diabetes. Diabetes Care 2003;26:1421–1426 64. Maldonado MR, D’Amico S, Rodriguez L, Iyer D, Balasubramanyam A. Improved outcomes in indigent patients with ketosis-prone diabetes: effect of a dedicated diabetes treatment unit. Endocr Pract 2003;9:26–32 65. Wu EQ, Zhou S, Yu A, et al. Outcomes associated with post-discharge insulin continuity in US patients with type 2 diabetes mellitus initiating insulin in the hospital. Hosp Pract (1995) 2012;40:40–48 66. Hirschman KB, Bixby MB. Transitions in care from the hospital to home for patients with diabetes. Diabetes Spectr 2014;27:192–195 67. Tuttle KR, Bakris GL, Bilous RW, et al. Diabetic kidney disease: a report from an ADA Consensus Conference. Diabetes Care 2014;37:2864–2883

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15. Diabetes Advocacy

American Diabetes Association

15. DIABETES ADVOCACY

Diabetes Care 2017;40(Suppl. 1):S128–S129 | DOI: 10.2337/dc17-S018

Managing the daily health demands of diabetes can be challenging. People living with diabetes should not have to face additional discrimination due to diabetes. By advocating for the rights of those with diabetes at all levels, the American Diabetes Association (ADA) can help to ensure that they live a healthy and productive life. A strategic goal of the ADA is that more children and adults with diabetes live free from the burden of discrimination. One tactic for achieving this goal is to implement the ADA’s Standards of Care through advocacy-oriented position statements. The ADA publishes evidence-based, peer-reviewed statements on topics such as diabetes and employment, diabetes and driving, and diabetes management in certain settings such as schools, child care programs, and correctional institutions. In addition to the ADA’s clinical position statements, these advocacy position statements are important tools in educating schools, employers, licensing agencies, policymakers, and others about the intersection of diabetes medicine and the law. ADVOCACY POSITION STATEMENTS

Partial list, with most recent publications appearing first Diabetes Care in the School Setting (1)

First publication: 1998 (revised 2015) A sizeable portion of a child’s day is spent in school, so close communication with and cooperation of school personnel are essential to optimize diabetes management, safety, and academic opportunities. See the ADA position statement “Diabetes Care in the School Setting” (http://care.diabetesjournals.org/content/38/10/ 1958.full). Care of Young Children With Diabetes in the Child Care Setting (2)

First publication: 2014 Very young children (aged ,6 years) with diabetes have legal protections and can be safely cared for by child care providers with appropriate training, access to resources, and a system of communication with parents and the child’s diabetes provider. See the ADA position statement “Care of Young Children With Diabetes in the Child Care Setting” (http://care.diabetesjournals.org/content/37/10/2834). Diabetes and Driving (3)

First publication: 2012 People with diabetes who wish to operate motor vehicles are subject to a great variety of licensing requirements applied by both state and federal jurisdictions, which may lead to loss of employment or significant restrictions on a person’s license. Presence of a medical condition that can lead to significantly impaired consciousness or cognition may lead to drivers being evaluated for fitness to drive. People with diabetes should be individually assessed by a health care professional knowledgeable in diabetes if license restrictions are being considered, and patients should be counseled about detecting and avoiding hypoglycemia while driving. See the ADA position statement “Diabetes and Driving” (http://care.diabetesjournals.org/content/37/Supplement_1/S97). Diabetes and Employment (4)

First publication: 1984 (revised 2009) Any person with diabetes, whether insulin treated or noninsulin treated, should be eligible for any employment for which he or she is otherwise qualified. Employment decisions should never be based on generalizations or stereotypes regarding the effects of diabetes. When questions arise about the medical fitness of a person with diabetes for a particular job, a health care professional with expertise in treating diabetes should perform

Suggested citation: American Diabetes Association. Diabetes advocacy. Sec. 15. In Standards of Medical Care in Diabetesd2016. Diabetes Care 2017;40(Suppl. 1):S128–S129 © 2017 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals .org/content/license.

care.diabetesjournals.org

an individualized assessment. See the ADA position statement “Diabetes and Employment” (http://care.diabetesjournals .org/content/37/Supplement_1/S112). Diabetes Management in Correctional Institutions (5)

First publication: 1989 (revised 2008) People with diabetes in correctional facilities should receive care that meets national standards. Because it is estimated that nearly 80,000 inmates have diabetes, correctional institutions should

Diabetes Advocacy

have written policies and procedures for the management of diabetes and for training of medical and correctional staff in diabetes care practices. See the ADA position statement “Diabetes Management in Correctional Institutions” (http://care.diabetesjournals.org/content/ 37/Supplement_1/S104). References 1. Jackson CC, Albanese-O’Neill A, Butler KL, et al. Diabetes care in the school setting: a position statement of the American Diabetes

Association. Diabetes Care 2015;38:1958– 1963 2. Siminerio LM, Albanese-O’Neill A, Chiang JL, et al. Care of young children with diabetes in the child care setting: a position statement of the American Diabetes Association. Diabetes Care 2014;37:2834–2842 3. American Diabetes Association. Diabetes and driving. Diabetes Care 2014;37:(Suppl. 1):S97–S103 4. American Diabetes Association. Diabetes and employment. Diabetes Care 2014;37(Suppl. 1): S112–S117 5. American Diabetes Association. Diabetes management in correctional institutions. Diabetes Care 2014;37(Suppl. 1):S104–S111

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PROFESSIONAL PRACTICE COMMITTEE DISCLOSURES

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Professional Practice Committee Disclosures Diabetes Care 2017;40(Suppl. 1):S130–S131 | DOI: 10.2337/dc17-S019

Committee members disclosed the following financial or other conflicts of interest covering the period 12 months before December 2016 Member William H. Herman, MD, MPH (Co-Chair) Rita R. Kalyani, MD, MHS, FACP (Co-Chair) Andrea L. Cherrington, MD, MPH Donald R. Coustan, MD

Ian de Boer, MD, MS Robert James Dudl, MD Hope Feldman, CRNP, FNP-BC Hermes J. Florez, MD, PhD, MPH Suneil Koliwad, MD, PhD Melinda Maryniuk, MEd, RD, CDE Joshua J. Neumiller, PharmD, CDE, FASCP Joseph Wolfsdorf, MB, BCh Erika Gebel Berg, PhD (Staff) Sheri Colberg-Ochs, PhD (Staff)

Employment

Research grant

Other research support

University of Michigan, Ann Arbor, MI

None

None

Johns Hopkins University, Baltimore, MD

None

None

University of Alabama, Birmingham, AL

Boehringer Ingelheim, Merck Sharp & Dohme None

None

The Warren Alpert Medical School of Brown University and Women & Infants’ MaternalFetal Medicine, Providence, RI

None

University of Washington, Seattle, WA

University of Washington

None

Kaiser Permanente, La Jolla, CA

None

None

Abbottsford-Falls Family Practice & Counseling, Philadelphia, PA

None

None

University of Miami Miller School of Medicine, Miami, FL

None

None

University of California, San Francisco, San Francisco, CA Joslin Diabetes Center, Boston, MA

None

None

None

None

Washington State University, Spokane, WA

None

None

Boston Children’s Hospital and Harvard Medical School, Boston, MA

None

None

American Diabetes Association, Arlington, VA American Diabetes Association, Virginia Beach, VA

None None

None None

Alicia H. McAuliffe-Fogarty, PhD, CPsychol (Staff)

American Diabetes Association, Arlington, VA

None

None

Sacha Uelmen, RDN, CDE (Staff)

American Diabetes Association, Arlington, VA

None

None

Robert E. Ratner, MD, FACP, FACE (Staff)

American Diabetes Association, Arlington, VA

None

None

ADA, American Diabetes Association; DSMB, Data and Safety Monitoring Board; MEDCAC, Medicare Evidence Development & Coverage Advisory Committee. *$$10,000 per year from company to individual.

care.diabetesjournals.org

Professional Practice Committee

Speakers’ bureau/ honoraria

Ownership interest

Consultant/advisory board

Other

W.H.H.

None

None

Merck Sharp & Dohme (Chair, DSMB),* Lexicon Pharmaceuticals (Chair, DSMB, Travel), RTI International (Member, Ad Board, Travel)

National Committee for Quality Assurance (Chair, Diabetes Panel), Centers for Medicare & Medicaid Services (member, MEDCAC), Diabetic Medicine (former Editor for the Americas), Diabetes Care (ad hoc Editor in Chief)

R.R.K.

None

None

Diabetes Care (Editorial Board)

A.L.C.

None

None

Novo Nordisk, Johns Hopkins School of Medicine Continuing Medical Education None

D.R.C.

None

None

None

None

I.d.B.

Boehringer Ingelheim, Bayer, Janssen

None

None

University of Washington research grant from the ADA

R.J.D. H.Fe.

None None

None None

None None

None None

Member

Connection Health (Board President)

H.Fl.

None

None

None

None

S.K.

None

None

Yes Health

Yes Health (Equity Holder, Advisor)

M.M.

None

None

None

None

J.J.N.

Novo Nordisk

None

Sanofi, Eli Lilly

Diabetes Spectrum (Editor in Chief)

J.W.

None

None

None

Diabetes Care (Editorial Board)

E.G.B.

None

None

None

None

S.C.-O. A.H.M.-F.

None None

None None

None None

None None

S.U.

None

None

None

None

R.E.R.

None

None

None

None

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Diabetes Care Volume 40, Supplement 1, January 2017

INDEX

Index

A1C. see also glycemic control age in, S12 CGM and, S49 confirmation testing, S13 CVD and, S51–S52 diagnostic criteria, S13 ethnic, pediatric differences, S50 exercise benefits, S37 glycemic targets and, S52–S53 goals, S50–S52 hemoglobinopathies, S13 in HIV, S28–S29 limitations, S50 mean glucose and, S50, S51 medical nutrition therapy effects on, S34 microvascular complications and, S50–S51 prediabetes, S13–S14, S28 in pregnancy, S115–S116 race/ethnicity in, S12 red blood cell turnover, S13 resistance training, S37–S38 SMBG and, S49 testing, S12–S13, S49–S50 acarbose, S68, S71 ACCORD study, S28, S51, S52, S54, S76, S81, S90 ACE inhibitors, S76–S78, S88, S91, S92, S108 acylated human glucagon-like peptide 1 receptor agonist, S60 ADAG trial, S50 ADA Position Statement, S1 ADA Scientific Statement, S1 ADVANCE-BP trial, S76–S77 ADVANCE-ON study, S77 ADVANCE study, S51, S52 advocacy, S128–S129 Affordable Care Act, S8 a-glucosidase inhibitors, S68, S71 AIM-HIGH trial, S81 albiglutide, S69, S71 albuminuria, S88–S91, S109 alcohol, S35, S37 Alli (orlistat), S60 alogliptin, S59, S65, S68, S71, S84 amlodipine, S78 amylin mimetics, S65, S68, S71 angiotensin receptor blockers (ARBs), S76–S78, S88, S91, S92, S108 antihyperglycemics, S59, S84, S122 antihypertensive therapy, S78, S90–S91 antioxidants supplementation, S37 antiplatelets, S81–S83, S92 antipsychotics, S30 Antithrombotic Trialists (ATT), S82 anti-VEGF, S92–S93 anxiety disorders, S29 ARV-associated hyperglycemia, S28–S29 aspart, S72 ASPIRE trial, S49 aspirin, S81–S83, S92 aspirin resistance, S83 atherosclerotic cardiovascular disease (ASCVD), S75. see also cardiovascular disease atorvastatin, S80 autoimmune diseases, S26–S27, S107 autonomic neuropathy, S38, S93–S95

balance training, S37 bariatric surgery, S59–S61 BARI 2D trial, S94 Belviq (lorcaserin), S60 benazepril, S78 biguanides, S68, S71. see also metformin bile acid sequestrants, S69, S71 bromocriptine, S69, S71 canagliflozin, S69, S71 cancer, S27 carbohydrates, carbohydrate counting, S36 cardiac autonomic neuropathy, S94 cardiovascular disease A1C and, S51–S52 children and adolescents, S108–S109 CKD management and, S90–S91 hypertension/blood pressure control, S75–S78 lipid management, S79–S81 prevention, S46 proteins, S35, S36 revisions summary, S5 cardiovascular outcome trials (CVOTs), S70–S71 celiac disease, S107–S108 children and adolescents A1C, blood glucose goals, S107 A1C differences in, S50 autoimmune conditions, S107 celiac disease, S107–S108 comorbidities, S110 CVD risk management, S108–S109 DSME/DSMS, S7, S8, S33–S34, S46, S105 dyslipidemia, S108–S109 exercise, S37–S38 glycemic control, S106–S107 kidney disease (nephropathy), S109 neuropathy, S109–S110 pediatric to adult care transition, S111 psychosocial issues, S106 retinopathy, S109 revisions summary, S5 school, child care, S106 smoking, S109 thyroid disease, S107 type 1 diabetes, S54, S105–S110 type 2 diabetes, S18, S110 cholesterol management, S79–S81 chronic care model, S6–S8 chronic kidney disease, S36, S38, S78, S88–S91, S109 classification, S4, S11 cognitive impairment/dementia, S27–S28, S81, S100 colesevelam, S69, S71 community screening, S17 comorbidities children and adolescents, S110 comprehensive medical evaluation, S25–S27 immunizations, S25–S26 initial management referrals, S27–S28 patient-centered approach, S25 protocol, S26–S30 revisions summary, S4 consensus reports, S1

continuous glucose monitoring (CGM), S49, S121 contraception, S117 Contrave (naltrexone/bupropion), S60 coronary heart disease, S83–S84 cystic fibrosis–related diabetes, S21–S22 dapagliflozin, S69, S71 DASH diet, S34 DASH study, S77 degludec, S72 dental practices, screening in, S17–S18 depression, S29–S30 detemir, S72 Diabetes Control and Complications Trial (DCCT), S50–S51, S54, S64, S90, S107 diabetes distress, S29, S39–S40 Diabetes Prevention Program, S14, S44–S45 Diabetes Prevention Program Outcomes Study (DPPOS), S37, S45, S46 diabetes self-management education (DSME), S7, S8, S33–S34, S46, S105, S123 diabetes self-management support (DSMS), S33–S34, S46 diabetic ketoacidosis (DKA), S11, S16, S122, S124 diagnosis. see also specific types of diabetes A1C, S12–S13 confirmation, S13 criteria, S13 FPG testing, S12, S13 2-h PG testing, S12, S13 monogenic syndromes, S20–S21 psychosocial issues, S39–S40 revisions summary, S4 testing, S12–S14 dipeptidyl peptidase (DPP) 4 inhibitors, S59, S65, S68, S71, S73, S84, S90, S102, S122 disordered eating behaviors, S30 disparity reduction access to care, S8 ethnic, cultural, sex differences, S8 food insecurity, S8–S9 homelessness, S9 language barriers, S9 recommendations, S8 revisions summary, S4 treatment tailoring, S8–S9 dopamine-2 agonists, S69, S71 dulaglutide, S69, S71 duloxetine, S94 dyslipidemia, S79–S81, S108–S109 e-cigarettes, S38–S39, S109 EDIC study, S51, S54, S90 empagliflozin, S69–S71, S84 EMPA-REG OUTCOME, S70–S71, S84 end of life care, S103 energy balance, S35 enteral/parenteral feedings, S123, S124 eplerenone, S91 erectile dysfunction, S94, S95 estimated glomerular filtration rate (eGFR), S88–S90 EXAMINE study, S84 exenatide, S69, S71

care.diabetesjournals.org

exercise, S37–S38, S45 ezetimibe, S81 fasting plasma glucose testing, S12, S13 fat (dietary), S35, S36 fatty liver disease, S28 fibrates, S81 finerenone, S91 flexibility training, S37 fluvastatin, S80 food insecurity, S8–S9 foot care, S5, S95–S96 fractures, S28 gastrointestinal neuropathies, S94 gastroparesis, S95 GCK-MODY, S20, S21 genitourinary disturbances, S94 gestational diabetes mellitus (GDM). see also pregnancy classification, S11 definition, S14, S18 diagnosis, S18–S20 management, S116–S117 one-step strategy, S18–S19 pharmacology, S46 pharmacotherapy, S116–S118 prevalence, S115 recommendations, S19 two-step strategy, S19–S20 glargine, S72 glimepiride, S68, S71 glipizide, S8–S9, S68, S71 GLP-1 receptor agonists, S69, S71, S73, S84, S90, S102 glucagon, S54 glucagon-like peptide 1 (GLP-1), S65 glucocorticoids, S123–S124 glulisine, S72 glyburide, S68, S71 glycemic control. see also A1C children and adolescents, S106–S107 in CKD management, S90 continuous glucose monitoring, S49, S121 control, assessment of, S48 CVD and, S51–S52 hospital care, S121 intercurrent illness and, S54–S55 mean glucose, S50, S51 neuropathy, S38, S93–S95 in older adults, S100 pregnancy, S115–S116 recommendations, S48, S52, S54 revisions summary, S5 self-monitoring of blood glucose, S48–S49 health promotion care delivery systems, S6 chronic care model, S6–S8 patient-centered care, S6 recommendations, S6 revisions summary, S4 hearing impairment, S28 heart failure, S84 hemoglobinopathies, S13 hepatitis B vaccination, S26 herbal supplements, S35, S37 HIV, S28–S29 HNF1A-MODY, S20, S21 HNF4A-MODY, S20, S21 HNF1B-MODY, S20, S21

Index

homelessness, S9 hospital care acute care setting, transition from, S124–S125 admission considerations, S120–S121 antihyperglycemics, S59, S84, S122 care providers, S121 delivery standards, S120–S121 discharge communications, S125 DSME, S123 enteral/parenteral feedings, S123, S124 glucocorticoids, S123–S124 glycemic control, S121 hypoglycemia, S121–S123 medical nutrition therapy, S123 medication reconciliation, S125 perioperative care, S124 physician order entry, computerized, S121 quality assurance, S121 readmissions, prevention, S125 recommendations, S120 revisions summary, S5 HOT trial, S76, S77 human regular insulin, S72 hydrochlorothiazide, S78 hyperglycemia antihyperglycemic therapy, S59 cognitive function and, S28 hospital care, S121 management, S53 hyperosmolar hyperglycemic state, S124 hypertension/blood pressure control, S75–S78, S88, S90–S91, S108 hypertriglyceridemia, S81 hypoglycemia characterization, S53–S54 classification, S54 cognitive function and, S28, S54 CVD and, S52 exercise, S38 glucose monitoring, bedside, S121 hospital care, S121–S123 nocturnal, S49, S78 in older adults, S100, S102–S103 predictors of, S123 prevention, S54, S123, S125 recommendations, S53 treatment, S54 unawareness, S29, S53, S54 immune-mediated diabetes, S14–S16 immunizations, S25–S26 IMPROVE-IT trial, S81 incretin-based therapies, S59, S65, S102 indapamide, S78 influenza vaccination, S26 inhaled insulin, S72, S73 injection-related anxiety, S29 insulin basal, S72, S73 bolus, S72 carbohydrate intake and, S36 CGM and, S49 children and adolescents, S110 combination, S67–S70, S73 concentrated preparations, S72–S73 exercise hypoglycemia, S38 food insecure patients, S9 gestational diabetes mellitus, S116 hospital care, S122 inhaled, S72, S73 median cost of, S72

older adults, S102 omission in disordered eating, S30 physiology, in pregnancy, S115 premixed, S72 principles of use, S71–S72 pump, S123 SMBG and, S49 type 1 diabetes, S64–S65, S122 insulin secretagogues, S38, S102 insurance, S8 kidney disease (nephropathy), S36, S38, S78, S88–S91, S109 Kumamoto Study, S51 language barriers, S9 laser photocoagulation therapy, S91–S93 LEADER trial, S71, S84 lifestyle management cost-effectiveness, S45 DSME/DSMS, S7, S8, S33–S34, S46 exercise, S37–S38, S45 gestational diabetes mellitus, S116 hypertension/blood pressure control, S77, S108 nutrition therapy, S34–S36 pharmacology in, S46, S66 prevention/delay, type 2 diabetes, S44–S46 psychosocial issues, S39–S40 revisions summary, S4 smoking cessation, S38–S39 technology platforms, S45 weight loss, S34–S36, S44–S45, S57–S60 linagliptin, S59, S65, S68, S71 lipase inhibitors, S60 lipid management, S79–S81, S108–S109 liraglutide (Saxenda), S60, S69, S71, S84 lispro, S72, S73 lixisenatide, S69 long-term care, S102–S103 Look AHEAD trial, S29, S58 lorcaserin (Belviq), S60 loss of protective sensation, S95, S96 lovastatin, S80 macronutrient distribution, eating patterns and, S35 macular edema, S92–S93 maturity-onset diabetes of the young (MODY), S20–S21 meal planning, S36 mean glucose, S50, S51 medical nutrition therapy (MNT), S34, S35, S123 Medicare reimbursement, DSME/DSMS, S34 medications. see pharmacotherapy Mediterranean diet, S28, S34 meglitinides (glinides), S68, S71 mental health referral, S39, S40 mental illness, serious, S30, S39–S40 metabolic surgery, S59–S61 metformin children and adolescents, S110 in CKD management, S90 exercise and, S37 gestational diabetes mellitus, S116 lifestyle management, S45–S46 older adults, S102 principles of use, guidelines, S65–S68, S71, S73

S133

S134

Index

metoclopramide, S95 micronutrients, S35, S37 microvascular complications A1C and, S50–S51 foot care, S5, S95–S96 kidney disease, S36, S38, S78, S88–S91, S109 neuropathy, S38, S93–S95 retinopathy, S38, S91–S93, S109 revisions summary, S5 miglitol, S68, S71 mineralocorticoid receptor antagonists, S91 naltrexone/bupropion (Contrave), S60 nateglinide, S68, S71 neonatal diabetes, S20, S21 neuropathic pain, S94 neuropathy, S38, S93–S95, S109–S110 niacin, S81 nonnutritive sweeteners, S35, S37 NPH insulin, S72 nucleoside reverse transcriptase inhibitors (NRTIs), S28 nutrition in CKD management, S90 in cognitive function, S28 in diabetes prevention, S45 gastroparesis, S95 in obesity management, S57–S58 therapy, S34–S36 obesity, type 2 diabetes assessment of, S57 diet, S57–S58 interventions, S57–S58 lifestyle interventions, S57–S58 management benefits, S57, S58 metabolic surgery, S59–S61 pharmacotherapy, S58–S60 revisions summary, S5 obstructive sleep apnea, S29 older adults cognitive impairment/dementia, S27–S28, S81, S100 end of life care, S103 epidemiology, S99–S100 glycemic control in, S100 hypoglycemia in, S100, S102–S103 pharmacotherapy, S102 recommendations, S99 treatment goals, S100–S101 treatment in LTC settings, S102–S103 opioid antagonist/aminoketone antidepressant combination, S60 orlistat (Alli), S60 orlistat (Xenical), S60 orthostatic hypotension, S95 pancreas, islet transplantation, S65 Patient-Centered Medical Home, S7–S8 PCSK9 inhibitors, S81 perindopril, S78 periodontal disease, S29 peripheral arterial disease (PAD), S96 peripheral neuropathy, S38, S93–S95 pharmacotherapy. see also specific drugs by name ACE inhibitors/ARBs, S76–S78, S88, S91, S92, S108 antihyperglycemics, S59, S84 antihypertensives, S78 antiplatelets, S81–S83, S92

Diabetes Care Volume 40, Supplement 1, January 2017

cardiovascular outcome trials, S70–S71 combination, S67–S70, S78, S81 concomitant, S59 as diabetes risk, S17 gestational diabetes mellitus, S116–S118 glucocorticoids, S123–S124 hypertension/blood pressure control, S77–S78, S108 in lifestyle management, S46, S66 mineralocorticoid receptor antagonists, S91 obesity, S58–S60 older adults, S102 prevention/delay, type 2 diabetes, S45–S46 type 1 diabetes, S64–S65 type 2 diabetes, S65–S73 phentermine/topiramate ER (Qsymia), S60 physical activity, S37–S38, S45 pioglitazone, S68, S71 pitavastatin, S80 plate method, S36 pneumococcal pneumonia vaccination, S26 pneumonia vaccination, S26 point-of-care (POC) meters, S121 posttransplantation diabetes mellitus, S22 pramlintide, S65, S68, S71 pravastatin, S80 prediabetes, S13–S14, S28 pregabalin, S94 pregnancy. see also gestational diabetes mellitus (GDM) antihypertensive therapy, S78 contraception, S117 diabetes prevalence, S115 drugs contraindicated, S78, S114 glycemic control, S115–S116 hypertension/blood pressure control, S75–S78 lactation, S117 pharmacotherapy, S116–S118 postpartum care, S117 preconception counseling, S115 preexisting diabetes management, S116–S117 recommendations, S114 retinopathy, S38, S91–S93 revisions summary, S5 prevention/delay, type 2 diabetes Diabetes Prevention Program, S44–S45 nutrition in, S45 pharmacologic interventions, S45–S46 recommendations, S44 revisions summary, S4–S5 Professional Practice Committee (PPC), S3 protease inhibitors (PIs), S28 proteins, S35, S36 psychosis, S30 psychosocial/emotional disorders, S29 psychosocial issues, S39–S40 P2Y12 receptor antagonists, S83 Qsymia (phentermine/topiramate ER), S60 repaglinide, S68, S71 resistance training, S37–S38 retinal photography, S91, S92 retinopathy, S38, S91–S93, S109 revisions summary, S4–S5 rosiglitazone, S68, S71 rosuvastatin, S80 Roux-en-Y gastric bypass, S61

SAVOR-TIMI 53 study, S84 saxagliptin, S59, S65, S68, S71, S84 Saxenda (liraglutide), S60, S69, S71, S84 scientific evidence grading, S1–S2 screening. see diagnosis self-monitoring of blood glucose (SMBG), S48–S49 serotonin receptor agonists, S60 sexual dysfunction, S94, S95 SGLT2 inhibitors, S65, S69–S71, S73, S84, S90, S102, S122 shoes/footwear, S96 simvastatin, S80 sitagliptin, S59, S65, S68, S71 smoking cessation, S38–S39, S109 sodium, S35, S36 spironolactone, S91 SPRINT trial, S76, S77 statins, S28, S79–S80 sulfonylureas, S8–S9, S68, S71, S73, S116 sympathomimetic amine anorectic/antiepileptic combination, S60 tai chi, S37 tapentadol, S94 TECOS study, S84 testosterone, S29 thyroid disease, S107 tobacco, S38–S39, S109 TODAY study, S110 2-h plasma glucose testing, S12, S13 type 1 diabetes autoimmune diseases, S26–S27, S107 celiac disease, S107–S108 children and adolescents, S105–S110 CKD management, S89–S90 classification, S11 CVD and, S51–S52 diagnosis, S14–S16 hypoglycemia in, S54 idiopathic, S16 immune-mediated, S14–S16 insulin, S122 pancreas, islet transplantation, S65 pathophysiology, S11–S12 pharmacotherapy, S64–S65 pregnancy, S116–S117 recommendations, S14 retinopathy, S38, S91–S93, S109 risk testing, S16 staging, S12 statins, S80 thyroid disease, S107 type 2 diabetes age, screening, S14, S17 asymptomatic adults, screening, S14, S15, S17 BMI/ethnicity, screening, S14, S17 cancer and, S27 characterization, S16–S17 children and adolescents, S18, S110 children and adolescents, screening, S18 CKD management, S90 classification, S11 community screening, S17 CVD and, S52 dental practices, screening in, S17–S18 diagnosis, S16–S18 fat (dietary), S35, S36 hyperglycemia, S28 hypoglycemia, S28

care.diabetesjournals.org

obesity management (see obesity, type 2 diabetes) pharmacotherapy, S65–S73 pregnancy, S116–S117 prevention/delay (see prevention/delay, type 2 diabetes) proteins, S35, S36 recommendations, S16 retinopathy, S38, S91–S93 risk assessment, S15

Index

risk factors, S29–S30 staging, S12 statins, S80 TZDs, S68, S71, S73, S84, S102 UK Prospective Diabetes Study (UKPDS), S51, S52 urinary albumin–to–creatinine ratio (UACR), S89

VADT study, S51, S52 vitamin B12 deficiency, S37 weight management, S34–S36, S44–S45, S57–S60. see also obesity, type 2 diabetes Xenical (orlistat), S60 yoga, S37

S135

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STANDARDS OF MEDICAL CARE IN DIABETES—2017

TH E J O U R NAL O F C LI N ICA L A N D A PPLI ED R ESEA RC H A N D EDU CATI O N VOLUME 40 | SUPPLEMENT 1 WWW.DIABETES.ORG/DIABETESCARE LEME 1 T...

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