Practice Update: Diabetes

VOL. 1 • NO. 2 • 2017

ISSN 2208-1488

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Improved Diet Quality Associated with Reduced Mortality

Conference American Diabetes Association Scientific Sessions 2017

JOURNAL SCAN The prognostic value of fasting plasma glucose, two-hour postload glucose, and HbA1c in patients with coronary artery disease

Prevalence of and risk factors for diabetic peripheral neuropathy in youth with type 1 and type 2 diabetes: SEARCH for Diabetes in Youth Study

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CONTENTS 3

RESEARCH Editor’s picks 4 Improved Diet Quality Associated with Reduced Mortality 5 Canagliflozin May Reduce Cardiovascular Events in Type 2 Diabetes 6 Glycemic Control Reduces Risk of Coronary Events in Men With Type 1 Diabetes 7 Higher Two-Hour Post- Load Glucose Predicts Risk for Cardiovascular Events in CAD Microvascular complications 15 Effects Of Empagliflozin on the Urinary Albumin-to- Creatinine Ratio in Patients with Type 2 Diabetes and Established CVD

Conference coverage 8 American Diabetes Association Scientific Sessions 2017 8 The PCSK9 Inhibitor in Insulin-Dependent Patients with Type 2 Diabetes 9 SGLT2 Inhibitors are Cover 4 Improved Diet Quality Associated with Reduced Mortality

PracticeUpdate is guided by a world-renowned Editorial and Advisory Board that represents community practitioners and academic specialists with cross-disciplinary expertise.

Silvio Inzucchi MD Richard Pratley MD, Deborah Wexler MD

Editor-in-Chief

Associate Editors

Editorial Contributors Lisa Parikh,

Ana Perdigoto MDPhD, Camille Powe MD

PracticeUpdate® is a registered trademark of Elsevier Inc. © 2017 Elsevier Inc. All rights reserved. ABOUT 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 www. 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. SALES Fleur Gill fleur.gill@elsevier.com Linnea Mitchell-Taverner l.mitchell@elsevier.com PRODUCTION Editorial Manager Anne Neilson anne.neilson@elsevier.com Editorial Project Manager Carolyn Ng Designer Jana Sokolovskaja

11 The PCSK9 Inhibitor Alirocumab Reduces Non-HDL Cholesterol in Patients with Type 2 Diabetes and Mixed Dyslipidaemia 12 Autoantigen GAD Vaccine is Safe for Children at High Risk of Type 1 Diabetes 13 New, Ultra-Long- Acting Insulin Degludec Demonstrates Cardiovascular Safety and Reduces Risk of Severe Hypoglycemia 14 Long-Term Metformin

Alirocumab Reduces LDL and Non-HDL Cholesterol

Associated with Reduced Cardiovascular Disease in Patients with Type 2 Diabetes Systems Prove Safe and Effective in Controlling Glucose Levels in Children and Adults with Type 2 Diabetes

10 Hybrid Closed-Loop

Diabetes 16 High Prevalence of Diabetic Peripheral Neuropathy Found in Young People with Diabetes 17 Glucose Self-Monitoring in Non-Insulin Treated Patients with Type 2 Diabetes Does Not Improve Glycemic Control

Treatment Found to Reduce Risk of Heart Disease in Adults with Type 1 Diabetes

Features 21 Dr Peter Libby on New Territory in Targeting Triglycerides 22 My Approach to the Elderly Patient with Resistant Hypertension

Cardiovascular complications 18 Differential Effects

of Dapagliflozin on Cardiovascular Risk Factors at Varying Degrees of Renal Function

19 With Aspirin and Statin Use, Diabetics Without CAD Have Same Risk for MI as Non-Diabetics Obesity 20 Physical Activity Alters Genetic Susceptibility to Long-Term Weight Gain

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VOL. 1 • NO. 2 • 2017

EDITOR’S PICKS 4

Improved Diet Quality Associated with Reduced Mortality The New England Journal of Medicine

Take-home message • Data from the Nurses’ Health Study and the Health Professionals Follow-Up Study were used to evaluate the association between changes in diet quality over 12 years and subsequent mortality risk. Individuals with the greatest improvement in diet quality had a significant decrease in risk of all-cause mortality compared with those with a relatively stable diet quality. There was a significant association between a 20-percentile increase in diet scores and a reduced risk of total and cardiovascular mortality. Maintenance of a good diet quality over the 12-year period was also associated with a lower risk of all-cause mortality. • Improvements in diet quality over time were associated with a significantly reduced mortality risk.

COMMENT By Thomas C Keyserling MD, MPH M ost lifestyle intervention stud- ies to reduce cardiovascular disease (CVD) focus on inter- mediate outcomes such as change in blood pressure, blood lipids, or weight. Few behavioral intervention studies have been large enough or conducted for a long enough period to report on firm clinical outcomes such as heart attack, stroke, and death. That is why the results from the PREDIMED rand- omized trial published in 2013 were so important. 1 When a Mediterranean diet pattern, supplemented with olive oil or nuts, was evaluated in the PRED- IMED randomized trial, there was a 30% reduction in CVD risk among par- ticipants with and without diabetes. However, there was no mortality advan- tage associated with the intervention diets. This article assesses the association of change in diet quality with total and cause-specific mortality in two large cohorts (Nurses’ Health Study and Health Professionals Follow-Up Study). Consistent with results from published meta-analyses, the authors report that improved diet quality (assessed by the Alternate Healthy Index, Alternate Mediterranean Diet, and the DASH score) over 12 years was consistently associated with a decreased risk of death. These findings further reinforce the health benefits of a dietary pattern that includes high-quality fats (vegetable and fish oils), whole grains, and plenty of fruits and vegetables. Reference 1. Estruch R, Ros E, Salas-Salvado J, et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013;368(14):1279-1290.

Abstract BACKGROUND Few studies have evaluated the relationship between changes in diet quality over time and the risk of death. METHODS We used Cox proportional-hazards models to calculate adjusted hazard ratios for total and cause-specific mortality among 47,994 women in the Nurses’ Health Study and 25,745 men in the Health Professionals Follow-up Study from 1998 through 2010. Changes in diet quality over the preceding 12 years (1986-1998) were assessed with the use of the Alternate Healthy Eating Index-2010 score, the Alternate Mediter- ranean Diet score, and the Dietary Approaches to Stop Hypertension (DASH) diet score. RESULTS The pooled hazard ratios for all-cause mortality among participants who had the greatest improvement in diet quality (13 to 33% improvement), as compared with those who had a relatively stable diet quality (0 to 3% improve- ment), in the 12-year period were the following: 0.91 (95% confidence interval [CI], 0.85 to 0.97) according to changes in the Alternate Healthy Eating Index score, 0.84 (95 CI%, 0.78 to 0.91) according to changes in the Alternate Mediter- ranean Diet score, and 0.89 (95% CI, 0.84 to 0.95) according to changes in the DASH score.

A 20-percentile increase in diet scores (indicat- ing an improved quality of diet) was significantly associated with a reduction in total mortality of 8 to 17% with the use of the three diet indexes and a 7 to 15% reduction in the risk of death from car- diovascular disease with the use of the Alternate Healthy Eating Index and Alternate Mediterra- nean Diet. Among participants who maintained a high-quality diet over a 12-year period, the risk of death from any cause was significantly lower – by 14% (95% CI, 8 to 19) when assessed with the Alternate Healthy Eating Index score, 11% (95% CI, 5 to 18) when assessed with the Alternate Mediterranean Diet score, and 9% (95% CI, 2 to 15) when assessed with the DASH score - than the risk among participants with consistently low diet scores over time. CONCLUSIONS Improved diet quality over 12 years was consistently associated with a decreased risk of death. Association of changes in diet quality with total and cause-specific mortality. N Engl J Med 2017 Jul 13;377(2)143-153, M Sotos-Prieto, SN Bhu- pathiraju, J Mattei, et al.

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Dr Keyserling is Professor in the Division of General Medicine and Clinical Epidemiology, Department of Medicine, at the University of North Carolina, Chapel Hill.

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EDITOR’S PICKS 5

Canagliflozin May Reduce Cardiovascular Events in Type 2 Diabetes The New England Journal of Medicine Take-home message • Patients with type 2 diabetes and at high cardiovascular (CV) risk were randomized to receive the SGLT2 inhibitor canagliflozin or placebo to evaluate the effect of canagliflozin on safety outcomes, particularly CV disease. The combined rate of death from CV causes, nonfatal myocardial infarction, and nonfatal stroke was significantly lower in the canagliflozin group than the placebo group (26.9 vs 31.5 participants per 1000 patient-years; P = .02 for superiority). Canagliflozin provided some renal protection by reducing the progression of albuminuria, the eGFR, the need for renal replacement therapy, and death due to renal causes; however, this did not reach statistical significance. Canagliflozin was associated with an increased risk of amputation, primarily at the level of the toe or metatarsal, but otherwise adverse effects were consistent with those reported in previous studies. • Patients with type 2 diabetes and at high CV risk may achieve a reduction in CV risk with canagliflozin, but with a higher risk of toe or metatarsal amputation.

Abstract BACKGROUND Canagliflozin is a sodium-glucose cotransporter 2 inhibitor that reduces glycemia as well as blood pressure, body weight, and albuminuria in people with diabetes. We report the effects of treatment with canagliflozin on car- diovascular, renal, and safety outcomes. METHODS The CANVAS Program integrated data from two trials involving a total of 10,142 participants with type 2 diabetes and high car- diovascular risk. Participants in each trial were randomly assigned to receive canagliflozin or placebo and were followed for a mean of 188.2 weeks. The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. RESULTS The mean age of the participants was 63.3 years, 35.8% were women, the mean dura- tion of diabetes was 13.5 years, and 65.6% had COMMENT By Silvio E Inzucchi MD T he final report from the CANVAS program (CANVAS and CANVAS-R trials) was recently published and presented simultaneously at the ADA meeting in San Diego. It showed, once again, that a member of the SGLT2 inhib- itor class (here, canagliflozin) reduced the primary CV outcome (3-point MACE) by a modest degree (14% RRR). In contrast to the well-known EMPA-REG OUTCOME study from 2015 (which tested empagli- flozin), the effect on CV mortality was not significant (HR, 0.87; 95% CI, 0.72–1.06). In EMPA-REG, the risk of this important out- come was reduced by 38%, which led to a 32% reduction in the all-cause mortal- ity risk. Consistent with the empagliflozin data, canagliflozin in CANVAS was asso- ciated with a significant 40% reduction in the composite renal outcome comprised

a history of cardiovascular disease. The rate of the primary outcome was lower with canagli- flozin than with placebo (occurring in 26.9 vs. 31.5 participants per 1000 patient-years; hazard ratio, 0.86; 95% confidence interval [CI], 0.75 to 0.97; P<0.001 for noninferiority; P=0.02 for superiority). Although on the basis of the pre- specified hypothesis testing sequence the renal outcomes are not viewed as statistically signif- icant, the results showed a possible benefit of canagliflozin with respect to the progression of albuminuria (hazard ratio, 0.73; 95% CI, 0.67 to 0.79) and the composite outcome of a sustained 40% reduction in the estimated glomerular fil- tration rate, the need for renal-replacement therapy, or death from renal causes (hazard ratio, 0.60; 95% CI, 0.47 to 0.77). Adverse reactions were consistent with the previously reported of development of macroalbuminuria, 40% reduction in GFR, need for renal replacement therapy, and renal death. A similar composite was reduced by 30% in EMPA-REG. Also, the drug reduced hos- pitalization for heart failure (HHF) by 33%, similar to the 35% reduction with empag- liflozin. Finally, two adverse effects of canagliflozin were identified: an increase in amputations and an increase in fracture rates, neither seen in the EMPA-REG trial. So, CANVAS convinces me of two things – some of the dramatic results from EMPA-REG are, in part, “class effects” – particularly those on MACE, CKD, and HHF outcomes. However, not all mem- bers of the class seem to reduce mortality to the same degree. It is unclear if this is due to intrinsic differences between the drugs or merely a reflection of study

risks associated with canagliflozin except for an increased risk of amputation (6.3 vs. 3.4 partici- pants per 1000 patient-years; hazard ratio, 1.97; 95% CI, 1.41 to 2.75); amputations were primarily at the level of the toe or metatarsal. CONCLUSIONS In two trials involving patients with type 2 diabetes and an elevated risk of cardiovascular disease, patients treated with canagliflozin had a lower risk of cardiovascular events than those who received placebo but a greater risk of amputation, primarily at the level of the toe or metatarsal. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017 Jun 12;[EPub Ahead of Print], B Neal, V Perkovic, KW Mahaffey, et al.

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methodology. For example, in CANVAS, about one-third of the participants had no known CVD (primary prevention cohort). Importantly, these patients experienced no difference in MACE (HR, 0.98). As for the new adverse effects, they are con- cerning, especially the amputation data. We should consider the totality of any drug’s effects when prescribing, particu- larly those used chronically.

Dr Inzucchi is Professor of Medicine at the Yale University School of Medicine in New Haven, Connecticut, where he serves as the Clinical Chief of the Section of Endocrinology, Program Director of the

Endocrinology and Metabolism Fellowship, and Director of the Yale Diabetes Center.

VOL. 1 • NO. 2 • 2017

EDITOR’S PICKS 6

Glycemic Control Reduces Risk of Coronary Events in MenWith Type 1 Diabetes Heart (British Cardiac Society)

This excess risk increased with younger age, female sex, worse glycae- mic control and severity of renal complications. The adjusted HR in men with T1D with updated mean haemoglobin A1c (HbA1c) <6.9% (52 mmol/ mol) and normoalbuminuria was 1.30 (95% CI 0.90 to 1.88) and in women 3.16 (95% CI 2.14 to 4.65). HRs increased to 10.7 (95% CI 8.0 to 14.3) and 31.8 (95% CI 23.6 to 42.8) in men and women, respectively, with HbA1c >9.7%and renal complications. CONCLUSIONS The excess risk of AMI in T1D is substantially lower with good glycaemic control, absence of renal complications and men compared with women. In women, the excess risk of AMI or CHD death persists even among patients with good glycaemic control and no renal complications. Glycaemic control and excess risk of major coronary events in persons with type 1 diabetes. Heart 2017 Jul 14;[EPub Ahead of Print], V Matule- viciene-Anängen, A Rosengren, AM Svensson, et al.

Take-home message • This Swedish, matched control cohort study evaluated the association between major coronary events and glycemic control and renal complications in patients with type 1 dia- betes. The results revealed a significantly higher incidence of cardiac events and death in patients with type 1 diabetes, particularly in women and in those with poor glycemic con- trol and more severe renal complications. • The authors concluded that, although glycemic control and improved renal function can reduce cardiac event risk in men with type 1 diabetes, women with type 1 diabetes remain at higher risk for cardiac events despite glycemic control and renal function. Abstract OBJECTIVE The excess risk of major coronary events (acute myocardial infarction (AMI) or death from coronary heart disease (CHD)) in individ- uals with type 1 diabetes (T1D) in relation to glycaemic control and renal complications is not known. METHODS Individuals with T1D in the Swedish National Diabetes Registry after 1 January 1998, without a previous MI (n=33170) and 164698 controls matched on age, sex and county were followed with respect to non-fatal AMI or death from CHD. Data were censored at death due to any cause until 31 December 2011. RESULTS During median follow-up of 8.3 and 8.9 years for individuals with T1D and controls, respectively, 1500 (4.5%) and 1925 (1.2%), experienced non-fatal AMI or died from CHD, adjusted HR 4.07 (95% CI 3.79 to 4.36).

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COMMENT By Robert H Eckel MD W ell known for decades is the increased risk of major coro- nary heart disease (CHD) events and related mortality in patients with type 1 diabetes (T1DM) and the added risk in patients with renal disease. Examining acute myocardial infarction (AMI) and CHD death as the specific manifestations of CHD, the paper by Matulevicien-Anängen et al is the most recent example of obser- vational data from the Swedish National Diabetes Register (NDR) of what factors contribute to risk for AMI/CHD death in patients with T1DM. In this report, hazard ratios (HR) for AMI/ CHD death were assessed in 33,170 T1DM patients and 164,698 controls, well matched for age and gender, for up to 13 years (median, 8.3 and 8.9 years,

respectively) and adjusted for multiple variables except hypertension and smok- ing (model 3). Age-dependent AMI/CHD death was approximately four times more common in T1DM than in controls, with HRs similar in T1DMmen and women; however, the marked increase in HR for women with T1DM relates to the much lower inci- dence in control women. Moreover, rates increased in relationship to levels of gly- cemia (HbA1c ≤6.9% in the 1st quintile to ≥9.7% in the 5th quintile), proteinuria, and estimated glomerular filtration rate. Thus, what is new here? Unfortunately, not much. First, how generalizable are these data, and the relationship of proteinuria and renal dysfunction to cardiovascular disease events in T1DM is well recog- nized, as is the importance of glycemia to macrovascular complications, especially

in this cohort. Although the importance of the trend in glycemia to events is con- vincing, a question arises as to whether this increased slope begins at levels of HbA1c >6.9% or >7.8%, particularly for women; and data for hypoglycemia were not included. Overall, this matter becomes quite relevant for clinical practice.

Dr Eckel is a Distinguished Alumnus of the University of Cincinnati College of Medicine and the Charles A Boettcher II Endowed Chair in Atherosclerosis, and Professor of Medicine, Division of Endocrinology,

Metabolism and Diabetes and the Division of Cardiology, and Professor of Physiology and Biophysics, University of Colorado School of Medicine Anschutz Medical Campus.

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EDITOR’S PICKS 7

Higher Two-Hour Post-Load Glucose Predicts Risk for Cardiovascular Events in CAD Diabetes Care

Take-home message • The authors of this study sought to characterize the prognostic value of three screening tools for diabetes—fasting glucose (FPG), 2-hour post-load glucose (2h-PG) from an oral glucose tolerance test, and HbA1c—in a population of patients with coronary artery disease (CAD). Researchers screened 4004 patients with CAD and no history of diabetes with all three screening tools. After 2 years, 246 patients (6.5%) experienced the primary outcome, a composite of cardiovascular mortality, nonfatal myocardial infarction, stroke, and hospitalization for heart failure. The 2h-PG test was the only screening tool that correlated with the primary outcome. Both a HbA1c of 5.7% to 6.5% and a 2h-PG of 7.8 to 11.0 mmol/L independently predicted the risk of diabetes during follow-up. • The authors conclude that, in patients with CAD, 2h-PG can provide valuable prognostic information on the risk of future cardiovascular events. In addition, increases in HbA1c and 2h-PG can signal a greater risk for diabetes.

glycemic parameters was available in 3,775 patients (94.3%), of whom246 (6.5%) experienced the primary end point. Neither FPG nor HbA1c pre- dicted the primary outcome, whereas the 2h-PG, dichotomized as <7.8 vs. ≥7.8mmol/L, was a signif- icant predictor (hazard ratio 1.38, 95% CI 1.07-1.78; P = 0.01). During follow-up, diabetes developed in 78 of the 2,609 patients (3.0%) without diabetes at baseline. A FPG between 6.1 and 6.9 mmol/L did not predict incident diabetes, whereas HbA1c 5.7-6.5% and 2h-PG 7.8-11.0mmol/L were both sig- nificant independent predictors. CONCLUSIONS The 2h-PG, in contrast to FPG and HbA1c, provides significant prognostic informa- tion regarding cardiovascular events in patients with CAD. Furthermore, elevated 2h-PG and HbA1c are significant prognostic indicators of an increased risk of incident diabetes. The prognostic value of fasting plasma glu- cose, two-hour postload glucose, and HbA1c in patients with coronary artery disease: a report from EUROASPIRE IV: a Survey from the Euro- pean Society of Cardiology Diabetes Care 2017 Jun 21;[EPub Ahead of Print], B Shahim, D De Bacquer, G De Backer, et al. profiles: is the OGTT a valid predictor of postprandial hyperglycaemia and vice versa? Diabetes Obes Metab 2009;11(3):213-222. 3. Cavalot F, Pagliarino A, Valle M, et al. Postprandial blood glucose predicts cardiovascular events and all-cause mortality in type 2 diabetes in a 14-year follow-up: lessons from the San Luigi Gonzaga Diabetes Study. Diabetes Care 2011;34(10):2237-2243. 4. Takao T, Suka M, Yanagisawa H, Iwamoto Y. The impact of postprandial hyperglycemia at clinic visits on the incidence of cardiovascular events and all-cause mortality in patients with type 2 diabetes [published online December 15, 2016]. J Diabetes Investig doi: 10.1111/jdi.12610. 5. Standl E, Schnell O, Ceriello A. Postprandial hyperglycemia and glycemic variability: should we care? Diabetes Care 2011;34(Suppl 2):S120–S127. 6. Ceriello A. Point: postprandial glucose levels are a clinically important treatment target. Diabetes Care 2010;33(8):1905-1907. Dr Ceriello is P.I. of the Research Department on Diabetes and CVD, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; and Head Diabetes Department, IRCCS MultiMedica, Milan, Italy. www.practiceupdate.com/c/55020

HbA1c were used to screen 4,004 CAD patients without a history of diabetes (age 18-80 years) for dysglycemia. The prognostic value of these tests was studied after 2 years of follow-up. The primary end point included cardiovascular mor- tality, nonfatal myocardial infarction, stroke, or hospitalization for heart failure and a secondary end point of incident diabetes. RESULTS Complete information including all three

Abstract OBJECTIVES Three tests are recommended for identifying dysglycemia: fasting glucose (FPG), 2-h postload glucose (2h-PG) from an oral glucose tolerance test (OGTT), and glycated hemoglobin A1c (HbA1c). This study explored the prognostic value of these screening tests in patients with coronary artery disease (CAD). RESEARCH DESIGN AND METHODS FPG, 2h-PG, and COMMENT By Antonio Ceriello MD, MPH T his study confirms, in a large cohort of people with CAD and without diabetes, the role of 2-hour glyce- mia during an oral glucose tolerance test (OGTT) as an independent risk factor for a future cardiovascular event. What can be the clinical impact of this new evidence? Some epidemiological evi- dence in the past led to the hypothesis that postprandial glycemia (PPG) should be considered an independent risk fac- tor for CVD, 1 but that OGTT could not be considered equivalent to a meal. This con- cern was overcome by the demonstration of the existence of a direct correlation, at any time, between the values of glycemia during OGTT and those during standard meals and home blood glucose monitor- ing in individuals with or without impaired glucose tolerance or overt diabetes. 2 Furthermore, the San Luigi Gonzaga Dia- betes Study confirmed, after a very long follow-up of people with type 2 diabetes,

that 2-hour PPG is an independent pre- dictor of CVD 3 —evidence more recently confirmed. 4 At the same time, results from specific intervention trials are inconclu- sive. 5 In this respect, however, it should be noted that perhaps no trial has yet been well-designed specifically for this purpose. 6 Several, if not almost all, current guide- lines suggest controlling PPG for the optimal management of diabetes and its complications; therefore, in my opinion, this study is further stressing the need for controlling PPG in people with diabetes to reduce the risk of CVD. References 1. Ceriello A, Hanefeld M, Leiter L, et al. Postprandial glucose regulation and diabetic complications. Arch Intern Med 2004;164(19):2090-2095. 2. Meier JJ, Baller B, Menge BA, et al. Excess glycaemic excursions after an oral glucose tolerance test compared with a mixed meal challenge and self-measured home glucose

VOL. 1 • NO. 2 • 2017

CONFERENCE COVERAGE 8

American Diabetes Association Scientific Sessions 2017 9–13 JUNE 2017 • SAN DIEGO, CALIFORNIA, USA

© ADA/Monica Almeida 2017

The PCSK9 Inhibitor Alirocumab Reduces LDL and Non-HDL Cholesterol in Insulin-Dependent Patients with Type 2 Diabetes In the first dedicated trial of a PCSK9

Lawrence Leiter, MD, of the Li Ka Shing Knowledge Institute at St. Michael’s Hos- pital, and the University of Toronto, Ontario, Canada, explained that patients with dia- betes are predisposed to abnormal cholesterol levels. He said, “Despite the current standard of care for lipid-lowering therapy, many indi- viduals with diabetes have persistent lipid abnormalities resulting in increased resid- ual cardiovascular risk. For people with diabetes, cardiovascular risk increases with advanced duration of diabetes, particularly in insulin-treated patients.”

The PCSK9 protein inhibits the activity of hepatic receptors that bind to and allow metabolism of cholesterol. Alirocumab is an approved monoclonal antibody that pre- vents PCSK9 protein from impairing hepatic receptors. More cholesterol is metabolized by the liver, lowering cholesterol levels. The ODYSSEY DM-Insulin Trial was con- ducted at 108 centers across the US and Europe. The trial enrolled insulin-treated patients with types 1 and 2 diabetes who were at high cardiovascular risk and were hypercholesterolemic despite maximum tolerated statin therapy.

inhibitor in patients with type 2 diabetes, alirocumab has been shown to reduce LDL and non-HDL cholesterol in insulin-dependent patients. T his outcome of the international phase 3, randomized, double-blind, placebo-controlled ODYSSEY-DM Insulin Trial was reported at the American Diabetes Association’s 77th Scientific Ses- sions, from June 9–13.

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ADA 2017 9

SGLT2 Inhibitors are Associated with Reduced Cardiovascular Disease in Patients with Type 2 Diabetes The new medication class, sodium-glucose transporter-2 (SGLT2) inhibitors, has been associated with lower rates of death and hospitalization for heart failure in patients with type 2 diabetes, both with and without existing cardiovascular disease, and regardless of the specific SGLT2 inhibitor used. T his outcome of the population-based Hospitalization for Heart Failure and Death inNewUsers of SGLT2 Inhibitors

matching, baseline characteristics were balanced between groups, and 306,156 patients, >150,000 person years (100,947 person years for SGLT2 inhibitors; 89,208 person years for other glucose-lowering drugs) and 950 new heart failure events were analyzed. Hazard ratios for heart fail- ure, death, and the composite of death or heart failure were estimated by country and pooled as a weighted average. An association between SGLT2 inhibitors and lower rates of death due to heart fail- ure and hospitalization for heart failure was seen in all five participating countries. Fur- thermore, the benefits of SGLT2 inhibitor treatments were consistent regardless of the type of SGLT2 inhibitor used, which var- ied from country to country. SGLT2 inhibitors vs other glucose-lowering drugs were associated with 31% lower rates of heart failure in patients with existing and 45% without existing cardiovascular dis- ease (hazard ratio 0.69, 95% confidence interval 0.59–0.80; hazard ratio 0.55, 95% confidence interval 0.34–0.88). Similar results were seen for death and death due to heart failure regardless of whether patients had a history of cardiovascular disease. All patients treatedwith SGLT2 inhib- itors were less likely to suffer heart failure or subsequent death vs patients receiving other glucose-lowering drugs. Dr Cavender concluded, “Results of this study offer further evidence regarding the to week 24 and adverse events. At 24-weeks, alirocumab reduced LDL-C significantly, by 49% vs placebo and improved other lipid parameters as well. Further, 80% of patients reached rec- ommended target LDL-C levels with alirocumab 75 mg. Dr Leiter concluded that co-administration of alirocumab and insulin was safe and the incidence of adverse events was generally similar between alirocumab and placebo. Additionally, alirocumab was well tolerated and did not affect glucose control. Results were comparable to those seen in previ- ous ODYSSEY trials. This study also evaluated the effect of ali- rocumab on some newer lipid parameters that will enable a better understanding of

potential of SGLT2 inhibitors to improve outcomes in patients with diabetes. While our results were striking in their similar- ity to a prior randomized study evaluating the benefit of SGLT2 inhibitors in patients with diabetes and known cardiovascular disease, the results went one step further to show that SGLT2 inhibition may benefit patients with diabetes regardless of whether they harbor known cardiovascular disease. It is also important to note the significant difference in the particular SGLT2-inhib- itor used in each country. This difference suggested that benefits seen with SGLT2 inhibitors were likely a class effect. Research has shown that patients with diabetes are at 30% higher risk of heart failure vs patients without diabetes. These findings suggested that use of SGLT2 inhibitors may provide the opportunity to reduce the incidence of heart failure among patients with diabetes.” Ongoing randomized clinical trials with SGLT2 inhibitors are likely to provide con- siderable additional information regarding their clinical effectiveness. As a follow-up to this study, the effectiveness of SGLT2 inhib- itors on other important clinical events are being further evaluated. Such evaluation will broaden the study’s focus on associations between other drugs for patients with diabe- tes and a history of cardiovascular events. www.practiceupdate.com/c/54675 the effect of alirocumab on atherogenic diabetic dyslipidemia. Atherogenic diabetic dyslipidemia is caused by insulin resist- ance primarily, and is characterized by high serum triglycerides, elevated LDL levels, low HDL levels, and postprandial lipemia. Dr Leiter concluded, “Results of the ODYS- SEY DM-Insulin study provided valuable information on the efficacy and safety of alirocumab in this high cardiovascular risk group and will help guide clinical deci- sion-making beyond statin therapy.” Results on the efficacy and safety of aliro- cumab in patients with type 1 diabetes will be reported at a later date. www.practiceupdate.com/c/54540 PracticeUpdate Editorial team.

in Patients With and Without Cardiovascular Disease (CVD-REAL) trial was reported at This outcome of the international phase 3, rand- omized, double-blind, placebo-controlled ODYSSEY-DM Insulin Trial was reported at the American Diabetes Association’s 77th Scientific Sessions, from June 9–13. Matthew A. Cavender, MD, MPH, of the University of North Carolina School of Med- icine in Chapel Hill, explained that SGLT2 is a protein responsible for glucose regula- tion. SGLT2 inhibitors reduce renal glucose reabsorption by causing excess blood glu- cose to be expelled through urine. The CVD-REAL study analyzed outcomes of 306,156 patients with type 2 diabetes from the US, UK, Norway, Sweden, and Denmark who were treated with SGLT2 inhibitors. Using data from clinical practice, Dr Cav- ender and colleagues compared rates of heart failure and death in patients with and without prior cardiovascular disease vs heart failure rates in new users of SGLT2 inhibitors and other glucose-lowering drugs. Data on heart failure and subse- quent death rates were collected using medical records, medical claims, electronic health records, and national registers. Propensity scores were used to match patients treated with SGLT2 inhibitors and other glucose-lowering drugs. After Dr Leiter presented results of patients with type 2 diabetes (n = 441, LDL-C ≥70 mg/dL (1.81 mmoL/L). They were taking either tak- ing the maximum tolerated statin dose or were unable to tolerate any statin. Addi- tionally, they harbored atherosclerotic cardiovascular disease or at least one other cardiovascular risk factor. Patients were randomized to either an injection of 75 mg of alirocumab (n = 294) or placebo (n = 147) injection once every 2 weeks. Patients in the alirocumab group whose LDL-C was ≥70 mg/dL at 8 weeks received a blinded dose increase to 150 mg at week 12. Primary endpoints were the difference between treatment arms in percentage change of calculated LDL-C from baseline

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Hybrid Closed-Loop Systems Prove Safe And Effective in Controlling Glucose Levels in Children and Adults with Type 1 Diabetes Results of two trials demonstrated safety and efficacy, and reduction in exercise-induced hypokalemia, using closed- loop systems in children and adults with type 1 diabetes. Results of the two trials were reported at the American Diabetes Association’s 77th Scientific Sessions, from June 9–13. C ontinuous glucose monitoring devices provide around-the-clock information on blood glucose lev- 4% of readings <70 mg/dL when at home and not using the hybrid-closed loop sys- tem. Mean fasting glucose level following overnight use of the closed-loop system was 136 ± 24 mg/dL. closed-loop system that responds to phys- ical activity automatically.

The study included 20 adults with type 1 diabetes who used wearable, wireless sen- sors including heart rate and accelerometer sensors to detect the onset of aerobic exercise automatically and communicate, calculate, and deliver the appropriate insu- lin and/or glucagon dose needed to avoid hypoglycemia. In random order, participants used various systems, including: • A single-hormone closed-loop system that doses insulin only • A dual-hormone closed-loop system that doses both insulin and glucagon • A predictive, low-glucose suspend system that shuts off insulin if glucose is predicted to go too low • Patients’ usual current standard of care whereby they controlled their glucose levels using their own methods Participants attended four, 4-day outpa- tient visits at which they exercised for 45 minutes at 60% VO2max on days 1 and 4 in a human performance lab. They com- pleted at least one at-home exercise session to determine the amount of time in hypoglycemia. Subjects entered estimated carbohy- drate intake into the insulin pump, which automatically delivered a portion of the

els in patients with type 1 diabetes. Insulin pumps allow insulin to be administered subcutaneously throughout the day. Over the recent past, researchers com- bined the technology of continuous glucose monitoring and insulin pumps to form closed-loop systems, which allow for continuous insulin delivery through a pump throughout the day and night based on glucose measurements provided every 5 minutes by the continuous glucose monitor. Hybrid closed-loop indicates that the system is continuously adjusting insulin delivery. At mealtime, however, the patient enters the amount of carbohydrates being consumed, and the insulin pump deter- mines the meal dose of insulin. Hybrid Closed-Loop System in Children Age 6–12 Years With Type 1 Diabetes Using a Personalized Model Predictive Control Algorithm Bruce A. Buckingham, MD, of the Lucile Salter Packard Children’s Hospital, Stanford University in Stanford, California, explained that children with type 1 diabetes are more sensitive to insulin than adolescents and adults, and are at increased risk of severe hypoglycemia overnight. Dr Buckingham and colleagues performed an inpatient research center study to eval- uate the safety and feasibility of a new hybrid closed-loop system. They combined a patch pump with Bluetooth-enabled sensor built into the receiver and a person- alized model predictive control algorithm. The study included 12 children aged 6-12 years with type 1 diabetes whose average age was 9 years and average diabetes duration was 4 years. The trial consisted of a 36-h, inpatient, closed-loop assess- ment with meals ranging from 30-90 g of carbohydrates and limited physical activity to examine glycemic outcomes. Continuous monitoring data indicated that 69.2% of overall glucose values were between the desired range of 70-180 mg/ dL. Overnight, 82% of values were within range. Participants’ average glucose level was 157 mg/dL, and 2% of readings were <70 mg/dL using the system compared to

Dr Buckingham concluded that the auto- mated glucose control algorithm performed well and was safe during day and night use in children with type 1 diabetes. “Hybrid closed-loop systems do a great job improving glucose control overnight, low- ering the risk of hypoglycemia significantly, and allowing patients and their families to get a good night’s sleep,” he said. “These systems also assist patients dur- ing the day in decreasing the magnitude of both high- and low-glucose fluctuations,” he added. “Many patients prefer wearing an ‘untethered’ patch pump, which pro- vides more flexibility to enjoy physical activities without worrying about infusion set detachments.” He continued, “The hybrid system provides additional protection against hypoglyce- mia, resulting in improved quality of life for children with diabetes. Longer outpa- tient studies are needed in subjects using the system under their home living condi- tions. The device is being tested in many age groups and under many different conditions.” Single and Dual-Hormone Closed-Loop Glucose Control with Automated Exercise Detection to Prevent Hypoglycemia in Type 1 Diabetes Peter G. Jacobs, PhD, of Oregon Health & Science University in Portland, explained that patients with type 1 diabetes encounter difficulty in controlling their blood glucose levels while exercising. Aerobic exercise can cause sharp drops in blood sugar, leading to hypoglycemia. Single- and dual-hormone closed-loop systems automate the dosing of insulin, or insulin plus glucagon, to help these patients avoid exercise-induced hypoglycemia by reducing insulin delivery and increasing glucagon in response to exercise. Dr Jacobs and colleagues developed and evaluated single- and dual-hor- mone closed-loop systems. They set out to determine whether exercise-related hypoglycemia can be reduced through a

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estimated premeal insulin dose. Blood glucose levels were measured four times daily. Incorporating glucagon and insulin into automated dosing during and after exercise reduced exercise-induced hypoglycemia from 6.3 t to 1.0% vs insulin-only usage. The dual-hormone closed-loop systemwas also more effective than both the predictive low-glu- cose-suspend dosing system and current-care therapy. Results across all 4 days from a subset of the 20 adult subjects from 17 visits showed that time spent in hypoglycemia (<70 mg/ dL) was 1.0% for the dual-hormone system; 3.4% for single-hor- mone; 1.2% for the predictive low-glucose-suspend system; and 2.1% for current care. Participants undergoing current care, however, prevented exer- cise-induced hypoglycemia by keeping their blood sugar levels significantly higher leading up to the start of exercise. Mean glucose level after exercise was significantly lower for single- than with dual-hormone, 67 ± 6 and 100 ± 9 mg/dL, respectively. Dr Jacobs concluded, “Our findings showed that fully automated insulin and glucagon delivery, combined with wearable physical activity sensors that detected exercise, controlled glucose levels effectively, reduced exercise-induced hypoglycemia, and were used safely in a home environment. The results suggested that a dual-hormone closed-loop system with automated detection of aerobic exercise can be used as a tool to adjust insulin and glucagon dosing during and after exercise.” He added, “We plan to explore migrating our system from a smartphone platform to a smart watch, where exercise can be detected more easily. These exercise-enabled automated dosing systems may soon be able to help people with type 1 diabetes exercise safely without fear of hypoglycemia.” www.practiceupdate.com/c/54688 significantly, and allowing patients and their families to get a good night’s sleep. Hybrid closed-loop systems do a great job improving glucose control overnight, lowering the risk of hypoglycemia

The PCSK9 Inhibitor Alirocumab Reduces Non-HDL Cholesterol in Patients with Type 2 Diabetes and Mixed Dyslipidaemia The PCSK9 inhibitor alirocumab has been shown to reduce non-HDL cholesterol in patients with type 2 diabetes and mixed dyslipidaemia. This outcome of the randomized, open-label, parallel group ODYSSEY DM – DYSLIPIDEMIA Study was reported at the American Diabetes Association’s 77th Scientific Sessions, from June 9–13. R obert R. Henry, MD, of the University of California, Veterans Administration Medical Center, San Diego, said, “Cardiovas- cular disease is a significant cause of morbidity and mortality in patients with type 2 diabetes. Mixed dyslipidemia is present commonly in these patients and further increases their cardio- vascular risk.” Dr Henry and colleagues evaluated alirocumab vs standard care (either no additional lipid-lowering therapy or ezetimibe, fenofi- brates, omega-3 fatty acids, or nicotinic acid) in patients with type 2 diabetes and mixed dyslipidemia who were at high cardiovascular risk (established atherosclerotic cardiovascular disease or at least one other cardiovascular risk factor) with non-HDL- C inadequately controlled with the maximum tolerated dosage of statin therapy. Mixed dyslipidemia was defined as elevations in non-HDL cho- lesterol and triglyceride levels, often accompanied by low levels of HDL cholesterol. The study enrolled 413 patients with type 2 diabetes from 110 centers from the US, Europe, South America, the Middle East, Australia, and the UK. The trial consisted of a 24-week treatment period, and a safety follow-up period of 8weeks. Patients were randomized to either 75 mg of alirocumab (adminis- tered via an autoinjector every 2 weeks for 24 weeks); or standard care in a 2:1 ratio. Patients randomized to alirocumab, but who did not achieve adequate reduction in non-HDL-cholesterol after 12 weeks of follow-up were titrated to 150 mg in a blinded manner. The primary endpoint was the difference between treatment arms in percentage change of non-HDL-C from baseline to week 24. After 24 weeks of treatment, alirocumab reduced the non-HDL-C significantly, by 32.5% vs usual care. Non-HDL-C is considered a better predictor of cardiovascular risk than LDL-C levels, par- ticularly in patients with type 2 diabetes with mixed dyslipidemia. Additionally, patients who received alirocumab improved in other lipid parameters vs those who received usual care. Themajority of patients in the alirocumab group reached the recom- mended lipid levels with the 75 mg dose. The number of adverse events was similar between the two treatment arms. Further, aliro- cumab was well tolerated and did not affect glucose control. Dr Henry concluded, “The ODYSSEY-DM-DYSLIPIDEMIA Study was the first trial to compare a PCSK9 inhibitor vs usual care in patients with type 2 diabetes with lipid disturbances. The results will help cli- nicians manage mixed dyslipidemia, a persistent clinical challenge

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in patients with type 2 diabetes.” www.practiceupdate.com/c/54541

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Autoantigen GADVaccine is Safe for Children at High Risk of Type 1 Diabetes Treatment with autoantigen-specific therapies such as alum-formulated glutamic acid decarboxylase is safe in children at increased risk of developing type 1 diabetes, yet the vaccine does not prevent the development of the disease. This conclusion, based on results of a randomized, double-blind, investigator-initiated trial, was presented at the American Diabetes Association’s 77th Scientific Sessions, from June 9–13. H elena Elding Larsson, MD, PhD, of Lund University, Sweden, explained that glutamate decarboxylase, or participants receiving placebo vs alum-for- mulated glutamic acid decarboxylase.

every 3 months for 5 years, with the oral glucose tolerance test repeated every 6 months and the intravenous glucose tol- erance test repeated at each annual visit during the study. Oral glucose tolerance tests were also performed annually, and intravenous and oral glucose tolerance tests were alternated every 6 months. Results indicated that it is safe to administer alum-formulated glutamic acid decarbox- ylase to children at high risk of type 1 diabetes. No significant preventive effect was observed, however, in the small study sample. The group was composed of children with both normal and impaired glucose toler- ance on enrollment. These subjects were known to progress to type 1 diabetes at different rates, so it was not possible to perform specific subgroup analyses. No difference in adverse events or serious adverse events were observed between

Dr Larsson concluded, “Since our study showed that alum-formulated glutamic acid decarboxylase treatment is safe, we want to explore this treatment further, either in different doses or in combination with other drugs, in prevention studies that may impact patient care. For example, an option is to use repeated, increasingly small doses, as is common in classic immune tolerance treatment for allergic symptoms.” She added, “We collected a large number of immunological samples from the study that have yet to be analyzed to under- stand the possible mechanistic effects of alum-formulated glutamic acid decarbox- ylase. These results will be important to consider in developing new studies with combination therapies.” www.practiceupdate.com/c/54557

glutamic acid decarboxylase, is an enzyme targeted by autoantibodies in individuals who go on to develop type 1 diabetes. Research has reported that injections of glutamic acid decarboxylase may preserve some insulin production for 30 months in those with type 1 diabetes, yet this insulin preservation had not been confirmed in larger-scale studies. Dr Larsson and colleagues set out to eval- uate the effect of alum-formulated glutamic acid decarboxylase on progression to type 1 diabetes in children with ongoing persis- tent beta-cell autoimmunity as indicated by multiple positive islet cell autoantibodies. Diabetes Prevention-Immune Tolerance (DIAPREV-IT) was the first prevention study where alum-formulated glutamic acid decarboxylase was given before the onset of type 1 diabetes. Its goal was to determine whether alum-formulated glu- tamic acid decarboxylase is safe in children at high risk of developing type 1 diabetes, as an attempt to induce immune tolerance earlier during the autoimmune process, preventing or delaying the process lead- ing to clinical type 1 diabetes. Known risk factors for type 1 diabetes include family history, genetics, geogra- phy and age, with the highest incidence of onset occurring in children 4 to 7 and 10 to 14 years of age. The study was conducted from 2009 to 2017. The trial enrolled 50 children age 4-18 years, without type 1 diabetes, and who harboured positive glutamic acid decarbox- ylase antibodies and at least one additional type 1 diabetes-associated autoantibody (IA-2Ab, ZnT8R/W/QAb, or IAA). The children were randomized to either two injections of the previously tested dose of 20 μg alum-formulated glutamic acid decarboxylase administered as a prime- and-boost at days 1 and 30 (no serious adverse reactions have been observed with this regimen) or two injections of placebo. Both intravenous and oral glucose toler- ance tests were performed before the first injection. Follow-up visits were conducted

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