PracticeUpdate: Diabetes

VOL. 2 • NO. 3 • WINTER 2018

ISSN 2208-1488

OUR EXPERTS. YOUR PRACTICE.

30-Year Cost- Effectiveness Associated With Excellent Glycemic Control in Type 1 Diabetes

American Association of Clinical

Endocrinologists Annual Meeting 2018 American Diabetes Association Scientific Sessions 2018

JOURNAL SCANS Association of Metformin Use With Risk of Lactic Acidosis Across the Range of Kidney Function: A Community-Based Cohort Study

Programmed Cell Death-1 (PD-1) Inhibitor Induced Type 1 Diabetes Mellitus: Mini-Review

Unique Challenges of Cystic Fibrosis-Related Diabetes

The production and distribution of this publication is sponsored by Sanofi Australia.

EDITOR’S PICKS

PRACTICEUPDATE DIABETES BOARD PracticeUpdate is guided by a world-renowned Editorial and Advisory Board that represents community practitioners and academic specialists with cross-disciplinary expertise. Editor-in-Chief Silvio Inzucchi MD Professor of Medicine (Endocrinology); Clinical Director, Section of Endocrinology; Director, Yale Diabetes Center; Director, Endocrinology and Metabolism Fellowship, Yale School of Medicine, New Haven, Connecticut Richard Pratley MD Samuel E. Crockett MD, Chair in Diabetes Research; Director, Florida Hospital Diabetes Institute; Senior Scientist, Florida Hospital Sanford-Burnham Translational Research Institute; Adjunct Professor, Sanford-Burnham Medical Research Institute, Orlando, Florida Deborah Wexler MD, MSc Associate Professor of Medicine, Harvard Medical School; Associate Clinical Chief, Diabetes Unit; Co-Clinical Director, Massachusetts General Hospital Diabetes Center; Associate Program Director for Clinical Research, Internal Medicine Residency Program, Massachusetts General Hospital, Boston, Massachusetts Associate Editors:

PracticeUpdate® is a registered trademark of Elsevier Inc. 2018 Elsevier Inc. All rights reserved.

ABOUT For a complete listing of disclosures for each board member and editorial contributor, please refer to their profile on PracticeUpdate.com PracticeUpdate ’s mission is to help medical professionals navigate the vast array of available literature and focus on the most critical information for their patients and practice. All journal articles selected for PracticeUpdate receive a Take-Home Message designed to quickly summarize the key findings and explain the importance of that research within the specialty area. The most critical articles also receive Expert Commentaries from experts who are handpicked by the PracticeUpdate Editorial Board, providing additional context on that research for the reader. Expert Opinion pieces give special highlights to important topics and Conference Coverage captures relevant takeaways from a vast array of medical meetings throughout the year. PracticeUpdate Diabetes provides coverage of key research from leading international conferences, and a collection of top journal articles and accompanying expert commentaries in a convenient print periodical. These and more are also available online at PracticeUpdate.com PracticeUpdate and PracticeUpdate Diabetes are commercially supported by advertising, sponsorship, and educational grants. Individual access to PracticeUpdate.com is free. Premium content is available to any user who registers with the site. While PracticeUpdate is a commercially-sponsored product, it maintains the highest level of academic rigour, objectivity, and fair balance associated with all Elsevier products. No editorial content is influenced in any way by commercial sponsors or content contributors. DISCLAIMER PracticeUpdate Diabetes has been developed for specialist medical professionals. The ideas and opinions expressed in this publication do not necessarily reflect those of the Publisher. Elsevier will not assume responsibility for damages, loss, or claims of any kind arising from or related to the information contained in this publication, including any claims related to the products, drugs, or services mentioned herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. Please consult the full current Product Information before prescribing any medication mentioned in this publication. Although all advertising material is expected to conform to ethical (medical) standards, inclusion in this publication does not constitute a guarantee or endorsement of the quality or value of such product or of the claims made of it by its manufacturer. The production and distribution of this issue, PracticeUpdate Diabetes, is sponsored by Sanofi Australia. It contains content published in accordance with the editorial policies of Elsevier’s PracticeUpdate.com. Content was produced by Elsevier with no involvement by Sanofi Australia. All content printed in this publication can be found on PracticeUpdate.com. CONTENT Abstracts are available when the publisher grants permission from MEDLINE/ PubMed, a database of the US National Library of Medicine. • NLM data are produced by a US Government agency and include works of the United States Government that are not protected by US copyright law but may be protected by non-US copyright law, as well as abstracts originating from publications that may be protected by US copyright law. • NLM assumes no responsibility or liability associated with use of copyrighted material, including transmitting, reproducing, redistributing, or making commercial use of the data. NLM does not provide legal advice regarding copyright, fair use, or other aspects of intellectual property rights. Persons contemplating any type of transmission or reproduction of copyrighted material such as abstracts are advised to consult legal counsel. SALES Fleur Gill fleur.gill@elsevier.com Matthew Buttsworth m.buttsworth@elsevier.com Linnea Mitchell-Taverner l.mitchell@elsevier.com PRODUCTION Content was originally published on PracticeUpdate.com Production of this issue was executed by: Editorial Manager A nne Neilson anne.neilson@elsevier.com Editorial Project Manager Carolyn Ng • Designer Jana Sokolovskaja Cover: Conceptual sugar castle siege/gettyimages.com PracticeUpdate Diabetes is published by Elsevier Australia ISSN 2208-1488 (Print) ISSN 2208-1496 (Online)

Editorial Contributors:

Anika Anam MD Clinical Fellow in Endocrinology, Yale School of Medicine / Yale–New Haven Hospital, New Haven, Connecticut

Ana Perdigoto MD, PhD Fellow in Endocrinology, Yale New Haven Hospital, New Haven, Connecticut

Jason Sloane MD Endocrinology Fellow at Massachusetts General Hospital, Boston, Massachusetts

Editorial Boards:

Our specialty-focused KOLs meet weekly to review the Editorial Contributors’ selections and to discuss which content is truly the most impactful – identifying which items require additional expert context and commentaries.

Advisory Boards: Expert physician Advisory Boards oversee subspecialty areas within each broader topic and provide guidance and context for that content for each specialty area. Editorial Contributors: Each week these teams of specialty-specific physicians scan all of the available literature and hand-select the most impactful and practice changing content for the Editorial Boards to review. Guest Advisors: Experts invited by our boards to contextualize and provide commentary on featured articles.

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CONTENTS 5

RESEARCH Editor’s picks 6 30-Year Cost-Effectiveness Associated With Excellent Glycemic Control in Type 1 Diabetes Comment by Pooyan Kazemian PhD 7 Association of Metformin Use With Risk of Lactic Acidosis Across the Range of Kidney Function

COVER 6 30-Year Cost-Effectiveness Associated With Excellent Glycemic Control in Type 1 Diabetes Comment by Pooyan Kazemian PhD

CONFERENCE 18

17 Hypertension and Lipids in Diabetic Patients With CVD Interview with Benjamin Morgan Scirica MD Glycemic Variability Throughout the Night By the PracticeUpdate Editorial Team 23 Youth With Type 1 Diabetes Can Have Insulin Resistance By the PracticeUpdate Editorial Team 24 Testing for Gestational Diabetes Mellitus Early in Pregnancy Is Necessary By the PracticeUpdate Editorial Team 24 Enteroendocrine Function of the Intestine By Jason Sloane MD 25 Intensive Glycemic Control During Pregnancy By Jason Sloane MD 26 Inpatient Diabetes Management Guidelines – Use of the Insulin Pump and CGM By Jason Sloane MD 26 Long-Term Implantable Continuous Glucose Monitoring System Safe and Accurate in Teens With Type 1 Diabetes By the PracticeUpdate Editorial Team 22 American Diabetes Association 78th Scientific Sessions 22 Use of Insulin Analogs Provides Less

American Association of Clinical Endocrinologists Annual Meeting By the PracticeUpdate Editorial Team

8 Add-On Antihypertensive Medications to Angiotensin–Aldosterone System Blockers in Diabetes Comment by Jan N. Basile MD 9 Natural History of Diabetic Coronary Atherosclerosis by Quantitative Measurement of Serial Coronary CTA 10 PD-1 Inhibitor-Induced Type 1 Diabetes Comment by Jason Sloane MD 11 Cognitive Function Deficits Associated With Long-Duration Type 1 Diabetes and Vascular Complications Comment by Naomi Sage Chaytor PhD, ABPP 12 Decreasing Rates of Major Lower-Extremity Amputation in People With Diabetes By Michael T. Watkins MD, FACS, FAHA 13 Diabetes in Individuals With Cystic Fibrosis: A Review Comment by Melissa S. Putman MD, MSc

EXPERT OPINION 16 Sequencing Injectable Therapies in Type 2 Diabetes Interview with John (Jack) L. Leahy MD by Jason Sloane MD 18 Type 2 Diabetes Patients Respond to Hydroxychloroquine 19 High Incidence of Ipilimumab-Induced Hypophysitis Documented in Large Cohort Study of Patients With Metastatic Melanoma 20 Thyroid Nodule Location a Predictive Risk Factor for Malignancy 20 Nodule Size Not Linked to Risk of Thyroid Cancer 21 Patients With Low PTH and Calcium Levels After Total Thyroidectomy at Higher Risk for Developing Hypocalcemia and Permanent Hypoparathyroidism

14 Reduced Risk of Heart Failure With

Intensified Multifactorial Intervention in Individuals With T2D and Microalbuminuria

15 Canagliflozin and Renal Outcomes in Type 2 Diabetes 15 Hypoglycemia Associated With Risk of

Cardiac Arrhythmia in Patients With Diabetes Mellitus

VOL. 2 • NO. 3 • 2018

EDITOR’S PICKS 6

30-Year Cost-Effectiveness Associated With Excellent Glycemic Control in

Type 1 Diabetes Journal of Diabetes and Its Complications

" Although maintaining excellent glycemic control can be costly, such cost is offset by cost savings from averting

Take-home message • The authors investigated the costs involved in intensive and conventional treat- ments of type 1 diabetes (T1D). Over a 30-year period, the following observations were reported. Diabetes Control and Complications Trial (DCCT) intensive therapy vs DCCT conventional therapy resulted in a cost of $127,500 to $181,600 more per patient. Modern intensive therapy vs modern basic therapy cost between $87,700 and as much as $409,000 more per patient. Approximately $90,900 was saved in costs through excellent glycemic control as a result of averting complications, and approximately 1.62 quality-adjusted life-years were added per patient over this period. • Value for money is apparent when utilizing the least expensive intensive therapy option that can achieve treatment goals in patients with T1D. T he current studies shed light on the benefits and costs of long-term intensive glycemic control for patients with type 1 diabetes mellitus (T1DM). 1,2 The authors conducted a post hoc analysis of DCCT/EDIC and demonstrated that 30 years of excellent (HbA1c ~ 7%) compared with poor (HbA1c ~ 9%) glycemic control substan- tially reduces the risk of end-stage renal disease, retinopathy, neuropathy, myocardial infarction, stroke, and death, as well as increases quality-adjusted life years. 1 A 30-year Monte Carlo simulation informed by DCCT/EDIC results revealed that achieving the HbA1c target of 7% using multiple daily injection therapy is cost-saving and using insu- lin pump therapy is cost-effective. 2 However, modern pump therapy with continuous glucose monitoring (CGM) may not be cost-effective. These results support the use of intensive therapy to achieve HbA1c ~ 7% for patients with T1DM. Although maintaining excellent glycemic control can be costly, such cost is offset by cost savings from averting downstream diabetes-related complications, comorbidities, and death. Also, current studies do not support pump therapy with CGM as first-line treatment for all T1DM patients due to its notably greater cost, although it can be an appropriate therapy for a subset of patients who are at increased risk of hypoglycemia or have poor glycemic control. References 1. Herman WH, Braffett BH, Kuo S, et al. What Are the Clinical, Quality-of-Life, and Cost Consequences of 30 Years of Excellent vs Poor Glycemic Control in Type 1 Diabetes? [Published online June 12, 2018]. J Diabetes Complicat Doi: 10.1016/j.jdiacomp.2018.05.007. 2. Herman WH, Braffett BH, Kuo S, et al. The 30-Year Cost-Effectiveness of Alternative Strategies to Achieve Excellent Glycemic Control in Type 1 Diabetes: An Economic Simulation Informed by the Results of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) [published online June 12, 2018]. J Diabetes Complicat Doi: 10.1016/j. jdiacomp.2018.06.005. COMMENT By Pooyan Kazemian PhD

Abstract OBJECTIVE To simulate the cost-effectiveness of historical and modern treatment scenarios that achieve excellent vs. poor glycemic control in type 1 diabetes (T1DM). RESEARCH DESIGN ANDMETHODS We describe and compare the costs of intensive and conven- tional therapies for T1DM as performed during DCCT, and modern intensive and basic therapy scenarios using insulin analogs, pens, pumps, and continuous glucose monitoring (CGM) to achieve excellent or poor glycemic control. We then assess the differences in treatment costs and the costs of outcomes over 30 years and report incremental cost-effectiveness ratios. RESULTS Over 30 years, DCCT intensive therapy cost $127,500 to $181,600 more per participant than DCCT conventional therapy, and modern intensive therapy cost $87,700 to $409,000more per individual thanmodern basic therapy. Excellent glycemic control averted as much as $90,900 in costs from complications and added ~ 1.62 qual- ity-adjusted life-years (QALYs) per participant over 30 years. When costs and QALYs were dis- counted at 3% annually, DCCT intensive therapy and modern intensive therapies that use multiple daily injections (MDI) or pumps are cost-saving or cost-effective (<$100,000/QALY-gained). If applied to all patients with T1DM, modern intensive ther- apy using pumps and CGM is not cost-effective (>$250,000/QALY-gained) but would be more cost-effective if associated with less hypoglyce- mia, better glycemic control, fewer complications, or improved health-related quality-of-life. CONCLUSIONS Use of the least expensive inten- sive therapy needed to safely achieve treatment goals for patients with T1DM represents a good value for money. The 30-Year Cost-Effectiveness of Alternative Strategies to Achieve Excellent Glycemic Con- trol in Type 1 Diabetes: An Economic Simulation Informed by the Results of the Diabetes Control and Complications Trial/Epidemiology of Dia- betes Interventions and Complications (DCCT/ EDIC). J Diabetes Complicat 2018 Jun 12;[EPub Ahead of Print], WH Herman, BH Braffett, S Kuo, et al. www.practiceupdate.com/c/69637 downstream diabetes- related complications, comorbidities, and death. "

Dr. Kazemian is a Research Scientist at Medical Practice Evaluation Center of the Division of General Internal Medicine, Massachusetts General Hospital, and Instructor in Medicine at Harvard Medical School in Boston, Massachusetts.

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EDITOR’S PICKS 7

Association of Metformin Use With Risk of Lactic Acidosis Across the Range of Kidney

Function JAMA Internal Medicine

Take-home message • In this community-based cohort study of 75,413 people with diabetes, the association between metformin use and hospitalization with acidosis across the range of estimated glomerular filtration rate (eGFR) was investigated. Over a median of 5.7 years of follow-up, 2335 hospitalizations with acidosis were reported. No associations were reported between time-dependent metformin use and overall incident acidosis or in patients with eGFR between 30 and 59 mL/min/1.73 m 2 . Metformin use was associated with an increased acidosis risk in patients with eGFR below 30 mL/min/1.73 m 2 . • These findings support cautious use of metformin in individuals with type 2 diabetes and an eGFR above 30 mL/min/1.73 m 2 . Abstract

in Geisinger Health System, with time-depend- ent assessment of eGFR stage from January 2004 until January 2017. Results were replicated in 67 578 new metformin users and 14 439 new sulfonylurea users from 2010 to 2015, sourced from 350 private US health systems. EXPOSURES Metformin use. MAIN OUTCOMES AND MEASURES Hospitalization with acidosis (International Classification of Dis- eases, Ninth Revision, Clinical Modification code of 276.2). RESULTS In the primary cohort (n = 75 413), mean (SD) patient age was 60.4 (15.5) years, and 51% (n = 38 480) of the participants were

IMPORTANCE Approximately 1 million patients in the United States with type 2 diabetes mellitus and mild-to-moderate kidney disease do not receive guideline-directed therapy with met- formin. This may reflect uncertainty regarding the risk of acidosis in patients with chronic kid- ney disease. OBJECTIVE To quantify the association between metformin use and hospitalization with acidosis across the range of estimated glomerular filtra- tion rate (eGFR), accounting for change in eGFR stage over time. DESIGN, SETTING, AND PARTICIPANTS Communi- ty-based cohort of 75 413 patients with diabetes

" …findings support cautious use of metformin in individuals

with type 2 diabetes and an eGFR above 30 mL/min/1.73 m 2 . "

female. There were 2335 hospitalizations with acidosis over a median follow-up of 5.7 years (interquartile range, 2.5-9.9 years). Compared with alternative diabetes management, time-de- pendent metformin use was not associated with incident acidosis overall (adjusted hazard ratio [HR], 0.98; 95% CI, 0.89-1.08) or in patients with eGFR 45 to 59 mL/min/1.73 m 2 (adjusted HR, 1.16; 95% CI, 0.95-1.41) and eGFR 30 to 44 mL/ min/1.73 m 2 (adjusted HR, 1.09; 95% CI, 0.83- 1.44). On the other hand, metformin use was associated with an increased risk of acidosis at eGFR less than 30 mL/min/1.73 m 2 (adjusted HR, 2.07; 95% CI, 1.33-3.22). Results were consistent when newmetformin users were compared with new sulfonylurea users (adjusted HR for eGFR 30-44 mL/min/1.73 m 2 , 0.77; 95% CI, 0.29-2.05), in a propensity-matched cohort (adjusted HR for eGFR 30-44 mL/min/1.73 m 2 , 0.71; 95% CI, 0.45- 1.12), when baseline insulin users were excluded (adjusted HR for eGFR 30-44 mL/min/1.73 m 2 , 1.16; 95% CI, 0.87-1.57), and in the replication cohort (adjusted HR for eGFR 30-44 mL/min/1.73 m 2 , 0.86; 95% CI, 0.37-2.01). CONCLUSIONS AND RELEVANCE In 2 real-world clinical settings, metformin use was associated with acidosis only at eGFR less than 30 mL/ min/1.73 m 2 . Our results support cautious use of metformin in patients with type 2 diabetes and eGFR of at least 30 mL/min/1.73 m 2 . Association of Metformin Use With Risk of Lactic Acidosis Across the Range of Kidney Function: A Community-Based Cohort Study. JAMA Intern Med 2018 Jun 04;[EPub Ahead of Print], B Lazarus, A Wu, JI Shin, et al. www.practiceupdate.com/c/69282

VOL. 2 • NO. 3 • 2018

EDITOR’S PICKS 8

Add-On Antihypertensive Medications to Angiotensin– Aldosterone System Blockers in Diabetes Clinical journal of the American Society of Nephrology: CJASN Take-home message • This observational, multicenter, cohort study examined outcomes in 21,897 peoplewith diabetes in the Surveillance, Prevention, and Effectiveness of Management of Diabetes cohort treated with ACE inhibitors or ARBs who added a variety of antihypertensive medications. These add-on medications include dihydropyridine calcium channel blockers, β-blockers, thiazide diuretics, and loop diuretics. Almost half (45%) of the participants began the study taking thiazide diuretics. β-blockers, calcium channel blockers, and loop diuretics were taken by 34%, 12%, and 10% of patients, respectively. Those taking thiazide diuretics had a greater risk of a significant kidney event compared with those taking calcium channel blockers or β-blockers. However, the risk of a sig- nificant kidney event was greater for those taking loop diuretics than for those taking thiazide diuretics. There was a higher risk of death in the loop diuretic group than in the thiazide diuretic group. The β-blocker and loop diuretic groups had a greater risk of cardiovascular events compared with the thiazide diuretic group. • This study suggests that there may be a benefit in using calcium channel blockers in patients with diabetes taking angiotensin-converting enzyme inhibitors or angi- otensin II receptor blockers. Calcium channel blockers may be associated with lower risk of cardiovascular events and of significant kidney events compared with thiazide diuretics in these patients. Abstract

BACKGROUND AND OBJECTIVES In individuals with diabetes, the comparative effectiveness of add-on antihypertensive medications added to an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker on the risk of sig- nificant kidney events is unknown. COMMENT By Jan N. Basile MD P atients with hypertension and dia- betes often require 2 or more antihypertensive medications to con- trol their BP. In a comparative effectiveness study from 4 large integrated health care systems, almost 22,000 individuals with diabetes were followed for up to 5 years to determine which antihypertensive class of agent was associated with best renal and cardiovascular (CV) outcomes on an initial background of ACE inhibitor or ARB monotherapy. With a BP > 130/80 mm Hg, the observers used propensity matched scoring to compare the addition of dihy- dropyridine calcium channel blockers (DCCBs), β-blockers, and loop diuretics to the largest group, thiazide diuretics.

enzyme inhibitors or angiotensin II receptor blockers. We examined the hazard of signifi- cant kidney events, cardiovascular events, and death using Cox proportional hazard models with propensity score weighting. The composite significant kidney event end point was defined

DESIGN, SETTING PARTICIPANTS, & MEASUREMENTS We used an observational, multicenter cohort of 21,897 individuals with diabetes to compare individuals who added β-blockers, dihydropyri- dine calcium channel blockers, loop diuretics, or thiazide diuretics to angiotensin-converting

DCCBs were associated with a lower risk of renal events, a similar risk of CV events, and a trend toward a lower risk of death than thiazide diuretics. While β-block- ers were associated with a lower risk of renal events, they increased the risk of CV events compared to thiazide diuret- ics. Loop diuretics were associated with a greater risk of renal events than thiazide diuretics. All other events were not com- paratively different. In this observational study with a strong potential for residual confounding and bias, DCCBs and thiazide diuretics are associ- ated with improved outcomes when added to an initial RAS-blocking agent. These find- ings remain in agreement with the recently

published 2017 ACC/AHA Clinical Practice Guideline on Hypertension and with the 2018 ADA Standards of Medical Care in diabetes which promote calcium channel blocking agents, thiazide diuretics, and ACE inhibitors or ARBs (but not both) as the first three classes of antihypertensive agents recommended in individuals with diabetes and hypertension unless a com- pelling situation dictates otherwise. Dr. Basile is with the Seinsheimer Cardiovascular Health Program at Medical University of South Carolina and the Ralph H Johnson VA Medical Center, both in Charleston, South Carolina. He is also President-Elect of the American Society of Hypertension 2018–2020.

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EDITOR’S PICKS 9

Natural History of Diabetic Coronary Atherosclerosis by QuantitativeMeasurement of Serial Coronary CTA JACC: Cardiovascular Imaging Take-home message • Patients with and without diabetes mellitus (DM) underwent serial coronary computed tomography angiography over 24 months to evaluate plaque progression (PP), changes in plaque features, and clinical predictors of PP in patients with DM. DM was a significant independent risk factor for PP. In patients with DM, other independent risk factors were male gender and mean plaque burden at baseline ≥75%. Patients with DM showed significantly greater changes in overall plaque volume and necrotic core volume than those without. In addition, patients with DM showed significantly greater frequency of spotty calcification, positive remodeling, and burden of low-attenuation plaque compared with patients without. • Compared with patients without DM, individuals with DM are at risk of greater PP particularly affecting adverse plaque. Abstract OBJECTIVES This study aimed to determine the rate and extent of plaque progression (PP), changes in plaque features, and clinical predictors of PP in patients with diabetes mellitus (DM). BACKGROUND The natural history of coronary PP in patients with DM is not well established. METHODS A total of 1,602 patients (age 61.3 ± 9.0 years; 60.3% men; median scan interval 3.8 years) who underwent serial coronary computed tomog- raphy angiography over a period of at least 24 months were enrolled and analyzed from the PARADIGM (Progression of Atherosclerotic Plaque Determined by Computed Tomographic Angiography Imaging) trial. Study endpoints were changes in plaque features in diabetics with PP and risk fac- tors for PP by serial coronary computed tomography angiography between patients with and without DM. PP was defined if plaque volume at follow-up minus plaque volume at baseline was >0. RESULTS DM was an independent risk factor for PP (84.6%; 276 of 326 patients with PP) in multivariate analysis (odds ratio [OR]: 1.526; 95% con- fidence interval [CI]: 1.100 to 2.118; p = 0.011). Independent risk factors for PP in patients with DM were male sex (OR: 1.485; 95% CI: 1.003 to 2.199; p = 0.048) and mean plaque burden at baseline ≥75% (OR: 3.121; 95% CI: 1.701 to 5.725; p ≤ 0.001). After propensity matching, percent changes in overall plaque volume (30.3 ± 36.9% in patients without DM and 36.0 ± 29.7% in those with DM; p = 0.032) and necrotic core volume (-7.0 ± 35.8% in patients without DM and 21.5 ± 90.5% in those with DM; p = 0.007) were significantly greater in those with DM. The frequency of spotty calcification, positive remodeling, and burden of low-attenuation plaque were signifi- cantly greater in patients with DM. CONCLUSIONS People with DM experience greater PP, particularly significantly greater progression in adverse plaque, than those without DM. Male sex and mean plaque burden >75% at baseline were identified as independ- ent risk factors for PP. Natural History of Diabetic Coronary Atherosclerosis by Quantitative Meas- urement of Serial Coronary Computed Tomographic Angiography: Results of the PARADIGM Study (Progression of Atherosclerotic Plaque Determined by Computed Tomographic Angiography Imaging). JACC Cardiovasc Imag- ing 2018 May 11;[EPub Ahead of Print], U Kim, JA Leipsic, SL Sellers, et al. www.practiceupdate.com/c/68414

" These findings remain in agreement with the recently published 2017 ACC/ AHA Clinical Practice Guideline on Hypertension and with the 2018 ADA Standards of Medical Care in diabetes… "

as the first occurrence of a ≥30% decline in eGFR to an eGFR<60 ml/ min per 1.73 m 2 , initiation of dialysis, or kidney transplant. The compos- ite cardiovascular event end point was defined as the first occurrence of hospitalization for acute myocardial infarction, acute coronary syn- drome, stroke, or congestive heart failure; coronary artery bypass grafting; or percutaneous coronary intervention, and it was only exam- ined in those free of cardiovascular disease at baseline. RESULTS Over a maximum of 5 years, there were 4707 significant kid- ney events, 1498 deaths, and 818 cardiovascular events. Compared with thiazide diuretics, hazard ratios for significant kidney events for β-blockers, calcium channel blockers, and loop diuretics were 0.81 (95% confidence interval, 0.74 to 0.89), 0.67 (95% confidence interval, 0.58 to 0.78), and 1.19 (95% confidence interval, 1.00 to 1.41), respectively. Compared with thiazide diuretics, hazard ratios of mor- tality for β-blockers, calcium channel blockers, and loop diuretics were 1.19 (95% confidence interval, 0.97 to 1.44), 0.73 (95% confidence interval, 0.52 to 1.03), and 1.67 (95% confidence interval, 1.31 to 2.13), respectively. Compared with thiazide diuretics, hazard ratios of cardi- ovascular events for β-blockers, calcium channel blockers, and loop diuretics compared with thiazide diuretics were 1.65 (95% confidence interval, 1.39 to 1.96), 1.05 (95% confidence interval, 0.80 to 1.39), and 1.55 (95% confidence interval, 1.05 to 2.27), respectively. CONCLUSIONS Compared with thiazide diuretics, calcium channel block- ers were associated with a lower risk of significant kidney events and a similar risk of cardiovascular events. Add-On Antihypertensive Medications to Angiotensin-Aldosterone System Blockers in Diabetes: A Comparative Effectiveness Study. Clin J Am Soc Nephrol 2018 May 07;13(5)727-734, EB Schroeder,

M Chonchol, SM Shetterly, et al. www.practiceupdate.com/c/68937

VOL. 2 • NO. 3 • 2018

EDITOR’S PICKS 10

PD-1 Inhibitor-Induced Type 1 Diabetes The Journal of Clinical Endocrinology and Metabolism

Take-home message • This systematic review includes 42 published cases of PD-1 inhibitor-induced type 1 diabetes mellitus. Potential patho- genic mechanisms, prognostic markers, clinical presentation, and a treatment and screening protocol are discussed. • Clinicians must be aware of diabetic ketoacidosis as a rare but serious side effect of immunotherapy use. COMMENT By Jason Sloane MD A s more and more case reports surface related to checkpoint inhibitor-induced autoimmune diabetes, this review comes at a fitting time. Although autoimmune diabetes remains one of the rarer immune-related adverse events, it is important to recognize this endocrinopathy as early as possible because acute complications of diabetes can be life-threatening. So far, there have been 42 reported cases of checkpoint inhibitor- associated autoimmune diabetes, and diabetic ketoacidosis (DKA) has been the most common presenting symptom in 30 of those. Most of the reported cases of autoimmune diabetes are asso- ciated with the PD-1 and PD-L1 humanized antibody checkpoint inhibitor cancer drugs. As reported in this review, the proposed mechanism for the induction of autoimmune diabetes is activat- ing T cells and blocking the PD-1 receptor on pancreatic beta cells to eventually induce cell death. Studies have shown that patients with type 1 diabetes mellitus have less PD-1 recep- tor expression on CD4+ T cells, which may contribute to the unchecked immune response that causes beta-cell destruction. It is not surprising that those individuals who have glutamic acid decarboxylase antibodies (GADA) or insulin receptor antibodies (IA2) prior to the initiation of checkpoint inhibitor therapy have a much higher chance of developing autoimmune diabetes and at a much faster rate than those patients without the mutation. This brings us to the most important concept presented in this review, that of establishing screening criteria so that autoim- mune diabetes can be diagnosed early, and hopefully before DKA. Although there are currently no consensus guidelines, I would agree with some of the ideas put forth in this review. Prior to the initiation of checkpoint inhibitor therapy, particularly PD-1 or PD-L1 antibodies, patients should be screened for GADA, IA2, have a baseline HbA1c, and a baseline fasting serum glucose. I would also agree with the review recommendation that patients on checkpoint inhibitor therapy should be screenedwith anHbA1c and fasting serumglucose prior to each cycle of treatment. There should also be education prior to therapy initiation to make sure that patients understand the hallmark symptoms of diabetes. Patients should also be able to check their capillary blood glucose levels at home on a glucometer and have some understanding of what glucose levels should be concerning. Once there are labo- ratory findings or clinical symptoms concerning for diabetes, it is too late to start any immunosuppressive therapy, so it is critical to have a basic understanding of insulin therapy. Oncologists should know it is always acceptable to ask for help if needed from endo- crinology colleagues to coordinate and initiate the proper therapy for diabetes in a timely and safe manner.

Abstract CONTEXT Pembrolizumab (Keytruda) is a humanized IgG4 monoclonal antibody used in cancer immunotherapy. It targets the programmed cell death-1 (PD-1) receptor which is important in maintaining self-toler- ance. However, immune checkpoint blockade is associated with a risk for immune-related adverse events (irAE) potentially affecting the endocrine organs. Type 1 diabetes mellitus is a rare irAE of PD-1 inhibitors, occur- ring in 0.2% of cases. EVIDENCE ACQUISITION Systematic search of 4 databases (Medline, Embase, Web of Science and Cochrane Library) using the search terms “diabetes” or “ketoacidosis” and “pembrolizumab”, “nivolumab”, “PD-1 inhibitor” or “immunotherapy. Included were articles published in English between January 1, 2012 and January 1, 2018. The search was supplemented by bib- liographic searches of the complete reference lists of all included papers. EVIDENCE SYNTHESIS We provide an overview of all published cases (n=42) of programmed cell death-1 (PD-1) inhibitor induced type 1 diabetes melli- tus to date, including a well-characterized novel case of islet cell antibody (ICA) and glutamic acid decarboxylase antibody (GADA) positive diabetes mellitus, in a patient with a diabetes prone HLA genotype. She presented with diabetic ketoacidosis (DKA) during pembrolizumab therapy for a met- astatic uveal melanoma. Furthermore, we discuss potential pathogenic mechanisms, clinical presentation, prognostic markers (beta-cell antibod- ies, HLA type), a treatment and a screening protocol. CONCLUSIONS Since the use of immunotherapy will increase, it is essen- tial that all clinicians are aware of diabetic ketoacidosis as a rare and life-threatening side effect of immunotherapy. Blood glucose monitoring during anti-PD-1 therapy is necessary. Programmed Cell Death-1 (PD-1) Inhibitor Induced Type 1 Diabetes Mel- litus: Mini-Review. J Clin Endocrinol Metab 2018 Jun 27;[EPub Ahead of Print], K Clotman, K Janssens, P Specenier, et al. www.practiceupdate.com/c/70201

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Cognitive Function Deficits AssociatedWith Long-Duration Type 1 Diabetes and Vascular Complications Diabetes Care Take-home message • In this study, 82 individuals with at least 50 years of T1D, 31 age-matched participants with T2D, and 30 age-matched participants without diabetes were included to assess complications with cognition. Worse performance on immediate and delayed recall was reported in patients with T1D and T2D compared with controls. Additionally, patients with T1D and T2D had significantly worse psychomotor speed in both hands and a trend toward worse executive function compared with controls. Cardiovascular disease was associated with worse executive function, and proliferative diabetic retinopathy was associated with slower psychomotor speed in individuals with at least 50 years of T1D. • These findings demonstrate the importance of cognitive evaluation and implementation of behavior modification in patients with T1D. Abstract

COMMENT By Naomi Sage Chaytor PhD, ABPP

OBJECTIVE Patients with type 1 diabetes now live long enough to experience cognitive decline. During middle age, they show mild cognitive deficits, but it is unknown whether severity increases with aging or whether cognitive pro- files are similar to those of age-matched peers with and without diabetes. RESEARCH DESIGN AND METHODS We tested and compared cognition in 82 individuals with 50 or more years of type 1 diabetes (Medalists), 31 age- matched individuals with type 2 diabetes, and 30 age-matched control subjects without diabe- tes. Medical histories and biospecimens were collected. We also evaluated the association of complications with cognition in Medalists only. RESULTS Compared with control subjects, both individuals with type 1 diabetes and individu- als with type 2 diabetes performed worse on immediate and delayed recall (P ≤ 0.002) and psychomotor speed in both hands (P ≤ 0.01) and showed a trend toward worse executive function (P = 0.05). In Medalists, cardiovascular disease was associated with decreased executive func- tion and proliferative diabetic retinopathy with slower psychomotor speed. CONCLUSIONS Both patients with type 1 and patients with type 2 diabetes showed overall worse cognition than control subjects. Further, in Medalists, a relationship between complications and cognition was seen. Although both groups with diabetes showed similar deficit patterns, the underlying mechanisms may be different. Now that patients with type 1 diabetes are liv- ing longer, efforts should be made to evaluate cognition and to identify modifying behaviors to slow decline. Cognitive Function Deficits Associated With Long-Duration Type 1 Diabetes and Vascu- lar Complications. Diabetes Care 2018 Jun 05;[EPub Ahead of Print], G Musen, LJ Tinsley, KA Marcinkowski, et al. www.practiceupdate.com/c/69353

A lthough type 2 diabetes has become an established risk factor for cognitive decline and dementia, the impact of type 1 diabetes on cognitive functioning is less clear. This is particularly true in older adults, who may have had type 1 diabetes for most of their lives and who have a higher burden of diabetes-related complications that carry additional cognitive risk. The recent case-control study by Musen and colleagues published in Diabetes Care characterizes the cognitive status of adults who have had type 1 diabetes for over 50 years. They compared 82 “50- year Medalists” with 31 age-matched adults with type 2 diabetes and 30 age-matched adults without diabetes. This study adds to a nascent literature on cognition in older adults with type 1 diabetes. There are, however, features of the study design that limit the conclusions that can be drawn. First, although the authors matched the groups on age, they were not matched on education, which is an important determinant of cognitive performance. Furthermore, all groups had intelligence scores that were well above average for the general population, with the normal control group scoring the highest (in the superior range). Although IQ was controlled for statistically in some analyses, the groups are likely different in other important respects. For example, there may be an interaction between IQ and vulnerability to the cognitive effects of diabetes, as it is well known that “cognitive reserve” is an important buffer to decline secondary to aging and dementia. Consistent with this, the type 1 diabetes cohort produced scores that were well within normal limits across all measures, despite being statistically lower than the controls’ above-average memory test scores. Although there were likely some individuals who had clinically meaningful cognitive impairment, this was not reported in the manuscript. This tempers the authors’ conclusion that those with long-duration diabetes have cognitive function deficits. Lastly, comparisons between the two dia- betes groups, which generally found no differences, were confounded by duration of diabetes (19 vs 55 years). These limitations aside, perhaps the most important take- away from this paper is how well this select group is doing, particularly those who have avoided diabetes-related complications. It remains to be seen if this will be rep- resentative of most people with type 1 diabetes as they age.

Dr. Chaytor is a Board-Certified Clinical Neuropsychologist and Associate Professor in the Elson S. Floyd College of Medicine at Washington State University in Spokane, Washington.

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Decreasing Rates of Major Lower-Extremity Amputation in People With Diabetes Diabetologia Take-home message • In prior studies, outcomes data have demonstrated a significant decrease in lower-extremity amputations (LEAs) due to diabetes after institution of multidisciplinary interventions, including better wound care, access to foot specialists, and improvements in HbA1c. In this study, the authors investigated the annual rates of LEA in people with and without diabetes in Belgium to determine the prevalence and the factors in that time period that may have contributed to any changes. Results of this population study showed that, throughout the observational period (2009–2013), the risk of major amputation was six times higher in people with diabetes compared with those without. In people with diabetes, the rates of amputation declined significantly from 42.3 per 100,000 person-years in 2009 to 29.9 in 2013, but there was no such significant decline in patients without diabetes. There was a similar significant decrease in minor LEA in patients with diabetes, although the effect was less profound than that seen with major LEA. • This is a countrywide association study of over 11,000 individuals with and without diabetes that clearly demonstrated a signif- icant decline in both major and minor LEA. Although these results are similar to those reported in prior population studies, the significant decrease in this instance can be traced back to stronger national efforts in Belgium to establish multidisciplinary foot care in patients with diabetes. It could benefit other countries, therefore, to consider a similar approach to help decrease the rates of LEA in people with diabetes. Jason Sloane MD Abstract

AIMS/HYPOTHESIS The reduction of major low- er-extremity amputations (LEAs) is one of the main goals in diabetes care. Our aim was to estimate annual LEA rates in individuals with and without diabetes in Belgium, and correspond- ing time trends. METHODS Data for 2009-2013 were provided by the Belgian national health insurance funds, covering more than 99% of the Belgian popu- lation (about 11 million people). We estimated the age-sex standardised annual amputation rate (first per year) in the populations with and without diabetes for major and minor LEAs, and the corresponding relative risks. To test for time trends, Poisson regression models were fitted.

and without diabetes (5% and 3% annual reduc- tion, respectively, p<0.001). CONCLUSIONS/INTERPRETATION In this nationwide study, the risk of undergoing a major LEA in Belgium gradually declined for individuals with diabetes between 2009 and 2013. However, continued efforts should be made to further reduce the number of unnecessary amputations. Decreasing Rates of Major Lower-Extremity Amputation in People With Diabetes but Not in Those Without: A Nationwide Study in Belgium. Diabetologia 2018 Jun 16;[EPub Ahead of Print], H Claessen, H Avalosse, J Guillaume, et al. www.practiceupdate.com/c/69788

RESULTS A total of 5438 individuals (52.1% with diabetes) underwent a major LEA, 2884 people with above- and 3070 with below-the-kneemajor amputations. A significant decline in the major amputation rate was observed in people with diabetes (2009: 42.3; 2013: 29.9 per 100,000 per- son-years, 8% annual reduction, p<0.001), which was particularly evident for major amputations above the knee. The annual major amputa- tion rate remained stable in individuals without diabetes (2009: 6.1 per 100,000 person-years; 2013: 6.0 per 100,000 person-years, p=0.324) and thus the relative risk reduced from 6.9 to 5.0 (p<0.001). A significant but weaker decrease was observed for minor amputation in individuals with

COMMENT By Michael T. Watkins MD, FACS, FAHA T he article by Classen et al provides information to indicate that concerted nationwide efforts to address diabetic foot care have had an impact on the incidence of amputation in diabetic but not nondiabetic patients in Belgium. This was accomplished through an Initiative for Quality Improvement and Epidemiology in Multidisciplinary Diabetic Foot Clinics. The authors met their aim, which was to analyze the major and minor lower-extremity amputation (LEA) rates in people with and without diabetes. It is important to note that, although there was a statistically sig- nificant decrease in LEA in the diabetic patient population vs the nondiabetic patient population, the major overall risk remained more than six times higher in the people with diabetes in the study period. Another significant finding was that the LEA rate was twice as high in men vs women; however, the reduction in LEA rate was greater in women. The authors have undertaken a descriptive statistical tour de force assessing both above- and below-knee amputations along with minor amputations in diabetic and nondiabetic patients. What is

missing in their analysis and the analysis of others 1,2 who have studied this important topic is what specific indications for ampu- tation have been impacted over the study period in diabetic and nondiabetic patients. Until we know how interventions modify the indications for amputations in these patient populations, the kind of operations they receive will be less relevant. References 1. Kennon B, Lesse GP, Cochrane L, et al. Reduced incidence of lower- extremity amputations in people with diabetes in Scotland. Diabetes Care 2012;35(12):2588-2590. 2. Kayssi A, de Mestral C, Forbes TL, Roche-Nagle G. A Canadian population- based description of the indications for lower extremity amputations and outcomes. Can J Surg 2016;59(2):99-106.

Dr. Watkins is the Director of Vascular Surgery Basic Science Laboratory at the Massachusetts General Hospital, Associate Professor of Surgery at Harvard Medical School, and the Isenberg Scholar in Academic Surgery at Massachusetts General Hospital in Boston, Massachusetts.

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Diabetes in Individuals With Cystic Fibrosis: A Review Diabetic Medicine: A Journal of the British Diabetic Association Take-home message • This review describes the unique form of diabetes that occurs in individuals with cystic fibrosis. • The authors describe the pattern of insulin and metabolic abnormalities that develop in individuals with cystic fibrosis as they age, and how these changes can affect lung function and other aspects of the cystic fibrosis disease process. The authors also discuss treatment strategies in this unique patient population.

COMMENT By Melissa S. Putman MD, MSc P atients with cystic fibrosis (CF) are living longer than ever due to significant improvements in available treatments and clinical care over the past several decades. As life expectancy improves, non-pulmonary complications are becoming increas- ingly prevalent and burdensome, including CF-related diabetes (CFRD). This comprehensive review by Bridges et al summarizes the unique challenges faced by this patient population based on a symposium held at the Diabetes UK Professional Conference. CFRD affects up to 20% of adolescents and 35% to 50% of adults with CF, and the development of CFRD is associated with clinical deterioration, including worsening pulmonary function, com- promised nutrition, and increased mortality. Insulin is the treatment of choice for CFRD and has been shown to improve clinical status and decrease mortality. However, diabetes adds to what is already a significant medical burden these patients must carry. New CF treatments, including cystic fibrosis transmembrane receptor (CFTR) mod- ulators, and new technologic advances in diabetes management may have sig- nificant potential for improving glycemic control in patients with CFRD.

Dr. Putman is Assistant Professor in Pediatrics at Harvard Medical School, Attending Physician in Adult and Pediatric

Endocrinology at Boston Children’s Hospital and Massachusetts General Hospital, and Endocrinologist for the MGH and BCH Cystic Fibrosis Centers in Boston, Massachusetts.

Abstract Individuals with cystic fibrosis and pancreatic insufficiency have a gradual decline in insulin secretion over time, which results in an increase in the prevalence of diabetes with age; up to 50% of adults with cystic fibrosis aged over 35 years have diabetes. Cystic fibrosis-related diabetes differs from Type 1 and Type 2 diabetes in sev- eral ways; there is a pattern of insulin deficiency with reduced and delayed insulin response to carbohydrates but a sparing of basal insulin that results in glucose abnormalities, which are frequently characterized by normal fasting glu- cose and postprandial hyperglycaemia. Insulin deficiency and hyperglycaemia, even at levels which do not reach the threshold for a diag- nosis of diabetes, have an adverse impact on

lung function and clinical status in people with cystic fibrosis. Although the risk of microvas- cular complications occurs as in other forms of diabetes, the main reason for treatment is to pre- vent deterioration in lung function and weight loss; treatment may therefore be required at an earlier stage than for other types of diabetes. Treatment is usually with insulin, but manage- ment needs to take into account all the other medical issues that arise in cystic fibrosis. Unique Challenges of Cystic Fibrosis-Related Diabetes. Diabet Med 2018 Apr 23;[EPub Ahead of Print], N Bridges, R Rowe, RIG Holt. www.practiceupdate.com/c/68232

" New CF treatments, including cystic fibrosis transmembrane receptor (CFTR) modulators, and new technologic advances in diabetes management may have significant potential for improving glycemic control in patients with CFRD. "

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