PracticeUpdate Diabetes March 2019

VOL. 3 • NO. 1 • 2019

ISSN 2208-1488

OUR EXPERTS. YOUR PRACTICE.

More Top Stories in 2018 The ASCEND Study

Expert Opinion Disordered Eating Behaviors in Adolescents With Type 1 Diabetes By Elizabeth A. Doyle DNP, APRN, BC-ADM, CDE Management of Hyperglycemia in Type 2 Diabetes, 2018: Consensus Report by ADA and EASD By Silvio E. Inzucchi MD

JOURNAL SCANS State of Type 1 Diabetes Management and Outcomes From the T1D Exchange in 2016–2018

Excess Risk of Hospitalisation for Heart Failure Among People With Type 2 Diabetes

Incretin Based Drugs and Risk of Cholangiocarcinoma Among Patients With Type 2 Diabetes: Population Based Cohort Study

PBS Information: This product is not listed on the PBS. Please review full Product Information before prescribing. Product Information available on request from iNova Pharmaceuticals, Toll-free 1800 630 056.

Minimum Product Information. CONTRAVE ® 8/90 (naltrexone hydrochloride and bupropion hydrochloride extended release tablets). Indications: CONTRAVE is indicated, as an adjunct to a reduced-calorie diet and increased physical activity, for the management of weight in adult patients ( ≥ 18 years) with an initial Body Mass Index (BMI) of ≥ 30 kg/ m 2 (obese) or ≥ 27 kg/m 2 to <30 kg/m 2 (overweight) in the presence of one or more weight-related co-morbidities (e.g., type 2 diabetes, dyslipidaemia, or controlled hypertension). Treatment with CONTRAVE should be discontinued after 16 weeks if patients have not lost at least 5% of their initial body weight. Contraindications: Hypersensitivity to bupropion, naltrexone or any of the excipients, uncontrolled hypertension, seizure disorder or a history of seizures, patients with a known central nervous system tumour, patients undergoing acute alcohol or benzodiazepine withdrawal, patients with a history of bipolar disorder, use of concomitant treatment containing bupropion or naltrexone, current or previous diagnosis of bulimia or anorexia nervosa, patients currently dependent on chronic opioids or opiate agonists, or patients in acute opiate withdrawal, pregnancy, patients with severe hepatic impairment, patients with end-stage renal failure, and in concomitant administration with monoamine oxidase inhibitors (MAOI). At least 14 days should elapse between discontinuation of MAOI and initiation of treatment with CONTRAVE. Starting CONTRAVE in a patient treated with reversible MAOIs is also contraindicated, Precautions: Safety and tolerability should be assessed at regular intervals. Safety and efficacy of CONTRAVE for longer than a year has not been established. Suicidal ideation has been reported in post marketing reports with CONTRAVE and patients should be supervised closely. There is a small increase in the risk of seizure. In patients requiring intermittent opiate treatment, CONTRAVE should be temporarily discontinued and lower doses of opioids may be needed. A patient should stop taking CONTRAVE and consult a doctor if experiencing any allergic symptoms during treatment. Use with caution in those with controlled

hypertension, predisposing factors that increase the likelihood of seizing, reduced renal clearance, underlying liver disease, history of mania and patients aged greater than 65. Caution in performing activities requiring mental alertness e.g. driving and operating machinery. Interactions: Contraindicated in use with MAOIs, drugs containing bupropion, chronic opioid use or opiate agonist therapy. CONTRAVE may increase the availability of other medicines metabolised by CYP2D6 substrate. Medicines metabolised by the CYP2B6 isozyme may interact with CONTRAVE. Use with caution with drugs that lower the seizure threshold and dopaminergic drugs. Avoid or minimise the use of alcohol. Adverse Reactions: Decreased lymphocyte count, palpitations, tinnitus, vertigo, nausea, constipation, vomiting, dry mouth, toothache, upper abdominal pain, feeling jittery, dizziness, tremor, dysgeusia, disturbance in attention, lethargy, hot flush, hyperhidrosis, pruritus and alopecia. Dosage and Administration : Swallow tablets whole with water, and preferably with food. Dose should be escalated over a 4-week period from initiation. The recommended starting dose is 1 tablet in the morning for 1 week, increasing to 1 tablet in the morning and 1 at night in the second week, 2 tablets in the morning and 1 tablet at night in the third week. The maintenance dose from week 4 onward is 2 tablets in the morning and 2 at night. References: 1. World Health Organization. Obesity: preventing and managing the global epidemic. Technical Report 894. 2000. 2. Billes SK et al. Pharmacol Res 2014;84:1–11. 3. Contrave Product Information. 4. Zyban (bupropion) Product Information. 5. Revia (naltrexone) Product Information. 6. Therapeutic Goods Administration. ARTG search of ‘bupropion, naltrexone’. 3 October 2018. Available at: tga.gov.au. 7. Greenway FL et al. Lancet 2010;376(9741):595–605. © 2018 iNova Pharmaceuticals (Australia) Pty Limited. ABN 13 617 871 539. Level 10, 12 Help Street Chatswood NSW 2067, Australia. p. 1800 630 056. www. inovapharma.com.au. INP0176/EL/FP. SSW. January 2019. AU-2018-12-0040 EXP 02 2020.

HELP THEM OUTRUN HUNGER, CRAVINGS AND THE DANGERS OF OBESITY 1–3

*BMI ≥ 27 kg/m² to <30 kg/m² in the presence of one or more weight-related comorbidities. † As an adjunct to reduced-calorie diet and increased physical activity. oral, dual-acting Contrave is a unique combination of well-established molecules. 3–6 Help patients who are overweight * or have obesity to break the hold of hunger and cravings, lose weight and sustain weight loss while they’re on therapy . †3,7 NEW

CONTENTS 3

TOP STORIES 2018 5 The ASCEND Study By Richard E. Pratley MD

EXPERT OPINION 20

Disordered Eating Behaviors in Adolescents With Type 1 Diabetes By Elizabeth A. Doyle DNP, APRN, BC-ADM, CDE

RESEARCH Editor’s picks 6 Type 1 Diabetes Management and Outcomes Comment by William V. Tamborlane MD and Michelle A. Van Name MD 7 Effect of Metformin in Addition to Dietary and Lifestyle Advice for Pregnant Women Who Are Overweight or Obese

12 Incretin-Based Drugs and Risk of Cholangiocarcinoma Among Patients With Type 2 Diabetes Comment by Michael Nauck MD 13 Neurocognitive and Hormonal Correlates of Voluntary Weight Loss in Humans 14 Carbohydrate Quality and Human Health: A Series of Systematic Reviews and Meta-Analyses Comment by Mark A. Pereira PhD 15 Association of Biochemical Hypoglycemia With the Subsequent Risk of a Severe Hypoglycemic Event 16 Maternal Glycemia and Childhood Glucose Metabolism Comment by Christina S. Han MD 17 Risk Factors for Readmission of Inpatients With Diabetes Comment by Enrico Cagliero MD 17 A Dose–Response Relationship Between Insulin Glargine 100 Units/mL and Glycemic Control 18 Adiposity and Risk of Decline in Glomerular Filtration Rate Comment by F. Perry Wilson MD, MSCE

21 Effects of Dapagliflozin on Circulating Markers of Phosphate Homeostasis By Simeon I. Taylor MD, PhD 22 Management of Hyperglycemia in Type 2 Diabetes, 2018: Consensus Report by ADA and EASD By Silvio E. Inzucchi MD

8 Change in Albuminuria as a Surrogate

Endpoint for Progression of Kidney Disease Comment by Keith C. Norris MD, PhD

9 Analysis of HbA1c as a Risk Factor for Coronary Artery Disease 10 Excess Risk of Hospitalization for Heart Failure Among People With Type 2 Diabetes Comment by Kenneth W. Mahaffey MD 11 Decreasing Cumulative Incidence of End- Stage Renal Disease in Young Patients With Type 1 Diabetes in Sweden Comment by Neera K. Dahl MD, PhD

19 Impact of Birth Weight on Metabolic Syndrome in Adolescents Comment by Nicola Santoro MD, PhD

VOL. 3 • NO. 1 • 2019

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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 printing and distribution of this publication has been made possible through paid advertising. The editorial content herein is independently produced by Elsevier with no involvement by the advertiser. It contains content published in accordance with the editorial policies of Elsevier’s PracticeUpdate.com. All content printed in this publication can be found on PracticeUpdate.com. CONTENT Abstracts are available when the publisher grants permission to 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 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: Atherosclerosis/gettyimages.com PracticeUpdate Diabetes is published by Elsevier Australia ISSN 2208-1488 (Print) ISSN 2208-1496 (Online)

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

Associate Editors

Richard E. Pratley MD Senior Investigator, Florida Hospital/Sanford–Burnham Translational Research Institute for Metabolism and Diabetes; Medical Director, Florida Hospital Diabetes Institute, Orlando, Florida

Deborah Wexler MD, MSc Associate Professor of Medicine, Harvard Medical School; Associate Clinical Chief of the Diabetes Unit, Clinical Director, Massachusetts General Hospital Diabetes Center; Associate Program Director for Clinical Research, Internal Medicine Residency Program, Massachusetts General Hospital, Boston, Massachusetts

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, Massachusetts General Hospital, Boston, Massachusetts

CARDIOMETABOLIC DISEASE AND DIABETES FACULTY Our center of excellence in the treatment of cardiometabolic disease and diabetes leverages technology to create a collaborative and comprehensive way to improve patient care. This unique center has the key advantages of a real world academic center as well as the features and enhancements that only PracticeUpdate and Elsevier can provide to foster an expert-led team approach that helps you stay ahead. Editor-in-Chief Silvio E. 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

Associate Editors

Richard E. Pratley MD Senior Investigator, Florida Hospital/Sanford–Burnham Translational Research Institute for Metabolism and Diabetes; Medical Director, Florida Hospital Diabetes Institute, Orlando, Florida

Deborah Wexler MD, MSc Associate Professor of Medicine, Harvard Medical School; Associate Clinical Chief of the Diabetes Unit, Clinical Director, Massachusetts General Hospital Diabetes Center; Associate Program Director for Clinical Research, Internal Medicine Residency Program, Massachusetts General Hospital, Boston, Massachusetts

Advisory Board

Kathleen Dungan MD, MPH Assistant Professor of Internal Medicine, Division of Endocrinology, Diabetes & Metabolism, The Ohio State University, Columbus, Ohio

Peter Libby MD Mallinckrodt Professor of Medicine, Harvard Medical School, Boston, Massachusetts

Benjamin Morgan Scirica MD Cardiologist and Director, Innovation, Cardiovascular Division, Brigham and Women's Hospital; Associate Professor of Medicine, Harvard Medical School; Senior Investigator, TIMI Study Group, Boston, Massachusetts

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TOP STORIES 2018 5

The ASCEND Study By Richard E. Pratley MD

For years, diabetes has been described as a “cardiovascular disease equivalent” based upon evidence from several observational studies and clinical trials demonstrating that the risk for cardiovascular events is comparable among patients with diabetes who do not have prior cardiovascular disease (CVD) and those without diabetes who have had a prior CV event. S ince daily aspirin has been shown to decrease the risk of recurrent events among patients with CVD, it is rea-

prevention of CVD in patients with diabetes. While the ASCEND study providesmore pre- cision around the benefit/risk ratio, it is not likely to change this recommendation. As Dr. Paul Ridker stated in an accompanying editorial “For secondary prevention, in which risk is determined largely by the extent of ath- erosclerotic disease, the benefits of aspirin outweigh the risks of bleeding. In contrast, for primary prevention, in which risk is deter- mined largely by age and the presence or absence of diabetes, the benefit–risk ratio for prophylactic aspirin in current practice is exceptionally small.” 4 References 1. Belch J, MacCuish A, Campbell I, et al. The Prevention of Progression of Arterial Disease and Diabetes (POPADAD) trial: Factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. BMJ 2008;337:a1840-a1840. 2. Ogawa H, Nakayama M, Morimoto T, et al. Low-dose aspirin for primary prevention of atherosclerotic events in patientswith type 2 diabetes: a randomized controlled trial. JAMA 2008;300:2134-2141. 3. ASCEND Study Collaborative Group, Bowman L, MafhamM, Wallendszus K, et al. Effects of aspirin for primary prevention in persons with diabetes mellitus. N Engl J Med 2018 Oct 18;379(16):1529-1539. 4. Ridker PM. Should aspirin be used for primary prevention in the post-statin era? N Engl J Med 2018 Oct 18;379(16):1572-1574. www.practiceupdate.com/c/77381

sight-threatening bleeding event in the eye, gastrointestinal bleeding, or other seri- ous bleeding) occurred in more patients assigned to aspirin (314 subjects, 4.1%) than placebo (245 subjects, 3.2%) for a rate ratio of 1.29 (95% CI, 1.09 to 1.52; P = .003). Most major bleeding events were gastro- intestinal/extracranial in nature. Intracranial hemorrhage events were relatively infre- quent and not significantly different in patients randomized to aspirin vs. placebo (55 participants, 0.7% vs 45 participants, 0.6%, respectively, RR 1.22, 95% CI 0.82– 1.81). Furthermore, fatal bleeding events were rare and occurred with a similar inci- dence among subjects assigned to aspirin (19 participants, 0.2%) vs. placebo (16 par- ticipants, 0.2%). All-cause mortality was not significantly different between groups (748 [9.7%] vs 792 [10.2%] in subjects assigned to aspirin vs. placebo, respectively; RR 0.94 [95% CI 0.88–1.04]). Finally, no difference in the incidence of gastrointestinal tract can- cer was noted between groups. How do these data change clinical practice? For patients with diabetes but no evidence of CVD, the benefit of aspirin to decrease the risk of vascular events needs to be balanced against the increased risk of major bleed- ing which is similar in magnitude. Currently, aspirin is not recommended for the primary

sonable to ask whether aspirin would also decrease the risk in those with diabetes who have a comparably high CVD risk. To date, the data have been mixed. Two small trials, one in Scotland and one in Japan, did not provide strong evidence for the use of aspirin in the primary prevention of CVD among patients with diabetes. 1,2 To address this important knowledge gap, investigators from the UK undertook the ASCEND study, a large pragmatic trial test- ing the effects of aspirin for the primary prevention of CVD in patients with diabe- tes. 3 A group of 15,480 adults with diabetes (94% of whom had type 2 diabetes), but no evidence of CVD, were randomized to receive aspirin (100 mg daily) or matching placebo. Subjects were followed for a mean of 7.4 years. The primary endpoint (myocar- dial infarction, stroke or transient ischemic attack, or death from any vascular cause) occurred in 658 subjects (8.5%) assigned to aspirin vs. 743 (9.6%) subjects assigned to placebo (rate ratio [RR], 0.88; 95% confi- dence interval, 0.79 to 0.97; P = .01). Counterbalancing this benefit, major bleeding events (intracranial hemorrhage,

VOL. 3 • NO. 1 • 2019

EDITOR’S PICKS 6

Type 1 Diabetes Management and Outcomes Diabetes Technology & Therapeutics

Take-home message • Data from the Type 1 Diabetes Exchange Clinic-based Registry regarding diabetes management and general clinical outcomes from 22,697 registry participants from 2016 until 2018 were compared with similar data collected from 2010 until 2012. Mean HbA1c in 2016–2018 increased from 8.1% at the age of 5 years to 9.3% between ages 15 and 18 years, with a decrease to 8% by age 28 years and 7.5–7.9% beyond age 30 years. Children and adolescents achieved an HbA1c level of <7.5% only 17% of the time, and only 21% of adults achieved an HbA1c level of <7%. Insulin pump use increased from 57% in 2010–2012 to 63% in 2016–2018, and continuous glucose monitoring (CGM) use increased from 7% in 2010–2012 to 30% in 2016–2018. Glycemic control was significantly closer to goal in those patients who used CGM. • Results of this analysis indicate that only a minority of children, adolescents, and adults achieve the goals of care established by the American Diabetes Association. Individuals using CGM technology were able to achieve better glycemic control overall compared with people who did not use the technology, a finding supported by other large studies. Jason Sloane MD

" Because increases in insulin pump and CGM use individually have not

Abstract OBJECTIVE To provide a snapshot of the profile of adults and youth with type 1 diabetes (T1D) in the United States and assessment of longitu- dinal changes in T1D management and clinical outcomes in the T1D Exchange registry. RESEARCH DESIGN AND METHODS Data on diabe- tes management and outcomes from 22,697 registry participants (age 1-93 years) were col- lected between 2016 and 2018 and compared with data collected in 2010-2012 for 25,529 reg- istry participants. RESULTS Mean HbA1c in 2016-2018 increased from 65mmol/mol at the age of 5 years to 78mmol/mol between ages 15 and 18, with a decrease to 64 mmol/mol by age 28 and 58-63mmol/mol beyond age 30. The Ameri- can Diabetes Association (ADA) HbA1c goal of <58mmol/mol for youth was achieved by only 17% and the goal of <53mmol/mol for adults by only 21%. Mean HbA1c levels changed lit- tle between 2010-2012 and 2016-2018, except in adolescents who had a higher mean HbA1c in 2016-2018. Insulin pump use increased from 57% in 2010-2012 to 63% in 2016-2018. Contin- uous glucose monitoring (CGM) increased from 7% in 2010-2012 to 30% in 2016-2018, rising >10-fold in children <12 years old. HbA1c levels were lower in CGM users than nonusers. Severe hypoglycemia was most frequent in participants ≥50 years old and diabetic ketoacidosis was most common in adolescents and young adults. Racial differences were evident in use of pumps and CGM and HbA1c levels. CONCLUSIONS Data from the T1D Exchange reg- istry demonstrate that only a minority of adults and youth with T1D in the United States achieve ADA goals for HbA1c. State of Type 1 Diabetes Management and Out- comes From the T1D Exchange in 2016–2018. Diabetes Technol Ther 2019 Jan 18;[EPub Ahead of Print], NC Foster, RW Beck, KM Miller, et al. www.practiceupdate.com/c/79012 improved overall metabolic control, our next hope is that integrated, automatic, or semi- automatic artificial pancreas systems that link pumps and sensors will be able to move HbA1c levels downward. "

COMMENT By William V. Tamborlane MD and Michelle A. Van Name MD

I n 2015, the Type 1 Diabetes (T1D) Exchange published its first report of the state of type 1 diabetes treatment in the US between 2010 and 2012. That study included >25,000 T1D patients across all age groups at leading diabe- tes treatment centers who were enrolled in the T1D Exchange Registry. 1 The current report compares data in the first study with new data collected by the Regis- try between 2016 and 2018 in >22,000 patients. To paraphrase Dickens, the current report indicates that it is the best of times and still the worst of times for patients with T1D in the US. The good news is that more patients are using advanced dia- betes technologies, with more than 60% on insulin pump therapy and a dramatic increase in use of continuous glucose monitoring (CGM) from 7% to 30%, most markedly in youth under 12 years of age. Moreover, HbA1c levels were as low in CGM users using injection therapy as CGM users on insulin pumps (7.3% and 7.4%, respectively) in adults aged 26 years and older. The bad news is that minority patients still lagged well behind non-Hispanic whites in the use of pumps and sensors, and, across all age groups, there was little or no improvement in overall metabolic

control. Indeed, HbA1c levels actually increased in adolescents between 15 and 18 years of age. It is noteworthy, how- ever, that the majority of adolescents in the 2016–2018 cohort were also preteens who were enrolled in the 2010–2012 cohort. Consequently, increases in HbA1c in this group over time can be amplified by physiologic changes including dimin- ished endogenous insulin secretion and increases in insulin resistance that nor- mally accompany puberty. Because increases in insulin pump and CGM use individually have not improved overall metabolic control, our next hope is that integrated, automatic, or semi- automatic artificial pancreas systems that link pumps and sensors will be able to move HbA1c levels downward. Outcomes beyond glycemic control related to technology use should also be considered. Reference 1. Miller KM, Foster NC, Beck RW, et al. Current state of type 1 diabetes treatment in the US: Updated data from the T1D Exchange clinic registry. Diabetes Care 2015;38(6):971-978. Dr. Tamborlane is Professor and Chief of Pediatric Endocrinology at Yale School of Medicine in New Haven, Connecticut. Dr. Van Name is Assistant Professor of Pediatric Endocrinology at Yale School of Medicine in New Haven, Connecticut.

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EDITOR’S PICKS 7

Effect of Metformin in Addition to Dietary and Lifestyle Advice for Pregnant Women Who Are Overweight or Obese The Lancet Diabetes & Endocrinology

Take-home message • In this randomized, double-blind, placebo-controlled study (n=524), the authors evaluated the efficacy of metformin on pregnancy outcomes in overweight or obese women imple- menting antenatal dietary and lifestyle interventions. The authors determined that infant birthweight >4000 g was not associated with metformin vs placebo. While average weekly gestational weight gain was lower in the metformin group, total gestational weight gain, outcomes, maternal diet, physical activity, and quality of life did not differ between themetformin- and placebo-treated groups. • The authors concluded that antenatal metformin treatment does not improve overall pregnancy or birth outcomes in overweight or obese women. Abstract BACKGROUND Maternal overweight and obesity are associated with well recognised pregnancy complications. Antenatal dietary and lifestyle interventions have a modest effect on gesta- tional weight gain without affecting pregnancy outcomes. We aimed to assess the effects on maternal and infant outcomes of antenatal met- formin given in addition to dietary and lifestyle advice among overweight and obese pregnant women. METHODS GRoW was a multicentre, randomised, double-blind, placebo-controlled trial in which pregnant women at 10–20 weeks’ gestation with a BMI of 25 kg/m 2 or higher were recruited from three public maternity units in Adelaide, SA, Australia. Women were randomly assigned (1:1) via a computer-generated schedule to receive either metformin (to a maximum dose of 2000 mg per day) or matching placebo. Participants, their antenatal care providers, and research staff (including outcome assessors) were masked to treatment allocation. All women received an antenatal dietary and lifestyle intervention. The primary outcome was the proportion of infants with birthweight greater than 4000 g. Second- ary outcomes included measures of maternal weight gain, maternal diet and physical activ- ity, maternal pregnancy and birth outcomes, maternal quality of life and emotional wellbe- ing, and infant birth outcomes. Outcomes were analysed on an intention-to-treat basis (includ- ing all randomly assigned women who did not

withdraw consent to use their data, and who did not have a miscarriage or termination of preg- nancy before 20 weeks’ gestation, or a stillbirth). FINDINGS Of 524 women who were randomly assigned between May, 28 2013 and April 26, 2016, 514 were included in outcome analyses (256 in the metformin group and 258 in the pla- cebo group). Median gestational age at trial entry was 16·29 weeks (IQR 14·43–18·00) and median BMI was 32·32 kg/m 2 (28·90–37·10); 167 (32%) participants were overweight and 347 (68%) were obese. There was no significant differ- ence in the proportion of infants with birthweight greater than 4000 g (40 [16%] with metformin vs 37 [14%] with placebo; adjusted risk ratio [aRR] 0·97, 95% CI 0·65 to 1·47; p=0·899). Women receiving metformin had lower average weekly gestational weight gain (adjusted mean differ- ence −0·08 kg, 95% CI −0·14 to −0·02; p=0·007) and were more likely to have gestational weight gain below recommendations (aRR 1·46, 95% CI 1·10 to 1·94; p=0·008). Total gestational weight gain, pregnancy and birth outcomes, maternal diet and physical activity, and maternal quality of life and emotional wellbeing did not differ sig- nificantly between groups. Similar numbers of women in both treatment groups (76% [159/208] in the metformin group and 73% [144/196] in the placebo group) reported side-effects including nausea, diarrhoea, and vomiting. Two stillbirths

(placebo group) and one neonatal death (met- formin group) occurred; none of the perinatal deaths were determined to be attributable to participation in the trial. INTERPRETATION For pregnant women who are overweight or obese, metformin given in addi- tion to dietary and lifestyle advice initiated at 10–20 weeks’ gestation does not improve preg- nancy and birth outcomes. Effect of Metformin in Addition to Dietary and Lifestyle Advice for Pregnant Women Who Are Overweight or Obese: The GRoW Randomised, Double-Blind, Placebo-Controlled Trial. Lancet Diabetes Endocrinol 2018 Dec 04;[EPub Ahead of Print], JM Dodd, J Louse, AR Deussen, et al. treatment does not improve overall pregnancy or birth outcomes in overweight or obese women. " " …antenatal metformin

www.practiceupdate.com/c/77231

VOL. 3 • NO. 1 • 2019

EDITOR’S PICKS 8

Change in Albuminuria as a Surrogate Endpoint for Progression of Kidney Disease The Lancet Diabetes & Endocrinology Take-home message • The authors performed a meta-analysis to determine whether albuminuria may be a surrogate endpoint for progression of chronic kidney disease in future randomized controlled trials. Patient-level data were available for 29,979 participants (71% with diabetes) from 41 eligible randomized trials. With a mean follow-up of 3.4 years, 3935 participants (13%) reached the composite clinical endpoint of treated end-stage kidney disease, eGFR <15 mL/min per 1.73 m 2 , and doubling of serum creatinine. The authors demonstrated, with a meta-regression analysis (slope, 0.89), that hazard ratios for the clinical endpoint were 27% lower for each 30% decrease in geometric mean albuminuria. • The results indicate that albuminuria may be a useful surrogate endpoint for the progression of chronic kidney disease, and it is of particular value among patients with high baseline albuminuria. I ncreased levels of urinary albumin excretion are a hallmark of many forms of kid- ney disease. One challenge for the renal community and for clinicians has been the need to have robust data supporting the reduction of albuminuria to improve kidney outcomes. Coresh and colleagues examined the association between albuminuria and devel- opment of end-stage kidney disease (ESKD) in nearly 700,000 individuals from 28 observational cohort studies. 1 In patients with a baseline albumin to creatinine ratio of 300 mg/g or higher, they found that a 30% reduction in albuminuria over 1, 2, or 3 years was linked to an approximate 20% relative reduction in ESKD. This is greater than a 1% absolute reduction in the 10-year risk of ESKD. The companion study led by Dr. Heerspink performed a similar analysis on nearly 30,000 individuals entered into randomized studies and found very similar results. 2 A 30% decrease in albuminuria with treatment led to a 27% reduction in a pooled out- come of ESKD, estimated glomerular filtration rate of <15 mL/min/1.73m 2 , or doubling of serum creatinine. They found the higher the baseline level of albuminuria, the greater the protective effect of lowering albuminuria was on the pooled clinical outcomes. The results of these two large meta-analyses examining both observation and rand- omized study results provide high confidence that lowering albuminuria is a prudent clinical approach to reducing the risk of progressive kidney disease. References 1. Coresh J, Heerspink HJL, Sang Y, et al. Change in albuminuria and subsequent risk of end-stage kidney disease: an individual participant-level consortiummeta-analysis of observational studies. Lancet Diabetes Endocrinol 2019 Jan 8. doi: 10.1016/S2213-8587(18)30313-9. [Epub ahead of print.] 2. Heerspink HJL, Greene T, Tighiouart H, et al. Change in albuminuria as a surrogate endpoint for progression of kidney disease: a meta-analysis of treatment effects in randomised clinical trials. Lancet Diabetes Endocrinol 2019 Jan 8. doi: 10.1016/S2213-8587(18)30314-0. [Epub ahead of print.] COMMENT By Keith C. Norris MD, PhD

Abstract BACKGROUND Change in albuminuria has strong biological plausibility as a surrogate endpoint for progression of chronic kidney disease, but empirical evidence to support its validity is lack- ing. We aimed to determine the association between treatment effects on early changes in albuminuria and treatment effects on clinical endpoints and surrogate endpoints, to inform the use of albuminuria as a surrogate endpoint in future randomised controlled trials. METHODS In this meta-analysis, we searched PubMed for publications in English from Jan 1, 1946, to Dec 15, 2016, using search terms including “chronic kidney disease”, “chronic renal insufficiency”, “albuminuria”, “proteinuria”, and “randomized controlled trial”; key inclu- sion criteria were quantifiable measurements of albuminuria or proteinuria at baseline and within 12 months of follow-up and information on the incidence of end-stage kidney disease. We requested use of individual patient data from the authors of eligible studies. For all studies that the authors agreed to participate and that had sufficient data, we estimated treatment effects on 6-month change in albuminuria and the com- posite clinical endpoint of treated end-stage kidney disease, estimated glomerular filtration rate of less than 15 mL/min per 1·73 m 2 , or dou- bling of serum creatinine. We used a Bayesian mixed-effects meta-regression analysis to relate the treatment effects on albuminuria to those on the clinical endpoint across studies and devel- oped a prediction model for the treatment effect on the clinical endpoint on the basis of the treat- ment effect on albuminuria.

Dr. Norris is a Professor in the Division of General Internal Medicine at David Geffen School of Medicine at UCLA in Los Angeles, California.

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Analysis of HbA1c as a Risk Factor for Coronary Artery Disease Diabetes Care

Take-home message • The authors sought to determine whether genet- ically elevated HbA1c is causally associated with coronary artery disease (CAD), using Mendelian randomization. Upon including 50 HbA1c-asso- ciated variants from a GWAS study of 159,940 participants, the authors found that CAD risk was increased among those with HbA1c variants resulting in increased HbA1c levels (OR, 1.61; P = 6.9 × 10 −12 ). This finding remained significant when looking at either glycemic or erythrocytic variants alone (OR, 2.23 and 1.30, respectively). • The authors conclude that these results suggest a causal relationship between elevated HbA1c levels and risk of CAD, which is driven by both glycemic and nonglycemic factors. Abstract OBJECTIVE Observational studies show that higher hemoglo- bin A1c (A1C) predicts coronary artery disease (CAD). It remains unclear whether this association is driven entirely by glycemia. We used Mendelian randomization (MR) to test whether A1C is causally associated with CAD through glycemic and/or nong- lycemic factors. RESEARCHDESIGNANDMETHODS To examine the association of A1C with CAD, we selected 50 A1C-associated variants (log10 Bayes factor ≥6) from an A1C genome-wide association study (GWAS; n = 159,940) and performed an inverse-variance weighted average of variant-specific causal estimates from CAD GWAS data (CAR- DIoGRAMplusC4D; 60,801 CAD case subjects/123,504 control subjects). We then replicated results in UK Biobank (18,915 CAD case subjects/455,971 control subjects) and meta-analyzed all results. Next, we conducted analyses using two subsets of var- iants, 16 variants associated with glycemic measures (fasting or 2-h glucose) and 20 variants associated with erythrocyte indices (e.g., hemoglobin [Hb]) but not glycemic measures. In additional MR analyses, we tested the association of Hb with A1C and CAD. RESULTS Genetically increased A1C was associated with higher CAD risk (odds ratio [OR] 1.61 [95% CI 1.40, 1.84] per %-unit, P = 6.9 × 10 −12 ). Higher A1C was associated with increased CAD risk when using only glycemic variants (OR 2.23 [1.73, 2.89], P = 1.6 × 10 −9 ) and when using only erythrocytic variants (OR 1.30 [1.08, 1.57], P = 0.004). Genetically decreased Hb, with concom- itantly decreased mean corpuscular volume, was associated with higher A1C (0.30 [0.27, 0.33] %-unit, P = 2.9 × 10 −6 ) per g/dL and higher CAD risk (1.18 [1.04, 1.33], P = 0.009). CONCLUSIONS Genetic evidence supports a causal link between higher A1C and higher CAD risk. This relationship is driven not only by glycemic but also by erythrocytic, glycemia-independ- ent factors. Mendelian Randomization Analysis of Hemoglobin A1c as a Risk Factor for Coronary Artery Disease. Diabetes Care 2019 Jan 18;[EPub Ahead of Print], A Leong, J Chen, E Wheeler, et al.

FINDINGS We identified 41 eligible treatment comparisons from randomised trials (referred to as studies) that provided sufficient patient-level data on 29 979 par- ticipants (21 206 [71%] with diabetes). Over a median follow-up of 3·4 years (IQR 2·3–4·2), 3935 (13%) participants reached the composite clinical endpoint. Across all studies, with a meta-regression slope of 0·89 (95% Bayesian credible interval [BCI] 0·13–1·70), each 30% decrease in geometric mean albuminuria by the treat- ment relative to the control was associated with an average 27% lower hazard for the clinical endpoint (95% BCI 5–45%; median R 2 0·47, 95% BCI 0·02–0·96). The association strengthened after restricting analyses to patients with base- line albuminuria of more than 30 mg/g (ie, 3·4 mg/mmol; R 20·72, 0·05–0·99]). For future trials, the model predicts that treatments that decrease the geometric mean albuminuria to 0·7 (ie, 30% decrease in albuminuria) relative to the con- trol will provide an average hazard ratio (HR) for the clinical endpoint of 0·68, and 95% of sufficiently large studies would have HRs between 0·47 and 0·95. INTERPRETATION Our results support a role for change in albuminuria as a sur- rogate endpoint for the progression of chronic kidney disease, particularly in patients with high baseline albuminuria; for patients with low baseline levels of albuminuria this association is less certain. Change in Albuminuria as a Surrogate Endpoint for Progression of Kidney Disease: A Meta-Analysis of Treatment Effects in Randomised Clinical Trials. Lancet Diabetes Endocrinol 2019 Jan 08;[EPub Ahead of Print], HJL Heerspink, results provide high confidence that lowering albuminuria is a prudent clinical approach to reducing the risk of progressive kidney disease. " " The results of these two large meta-analyses examining both observation and randomized study

T Greene, H Tighiouart, et al. www.practiceupdate.com/c/78482

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Excess Risk of Hospitalization for Heart Failure Among People With Type 2 Diabetes Diabetologia Take-home message • Previous studies have shown an association between heart failure and type 2 diabetes (T2D). Some researchers have hypothe- sized that this relationship is causal; therefore, improved glycemic control may improve cardiovascular outcomes in heart failure patients. This study was among the largest ever to assess associations between heart failure and T2D using patient data from the Swedish National Diabetes Register along with data from age-, gender-, and county-matched individuals without diabetes from the population registry. The final dataset contained information from 266,305 individuals with T2D and 1,323,504 matched controls. The results of this study demonstrated that men and women with T2D who were younger than 55 years of age had hazard ratios for hospitalization for heart failure of 2.07 and 4.59, respectively. In addition, younger age (<55 years old), poorer glycemic control, and deteriorating renal function were all associated with increased excess risk of heart failure in those with T2D compared with the control group. Interestingly individuals with T2D who were >75 years old had risk similar to that of matched controls. • This study is important for clinicians to understand because it provides more evidence that T2D is associated with heart failure hospitalizations. This association provides some explanation for why the SGLT2 class of diabetes medications can offer benefits in reducing cardiovascular events, especially heart failure hospitalizations. Jason Sloane MD Abstract

AIMS/HYPOTHESIS Type 2 diabetes is an estab- lished risk factor for heart failure, but age-specific data are sparse. We aimed to determine excess risk of heart failure, based on age, glycaemic control and kidney function in comparison with COMMENT By Kenneth W. Mahaffey MD T he current study is a large obser- vational study of over 250,000 individuals with diabetes and over 1 million controls from Sweden from a national data repository. Diabetes was associated with a significantly increased risk of heart failure, with important obser- vations about subgroups of patients at even higher risk than others, including younger patients with poor glycemic control. These data are quite relevant and timely given the recent revelation of marked improvements in heart failure hospitalizations in patients with type 2 diabetes at increased risk for cardiovas- cular outcomes studied in the published EMPA-REG and CANAVAS programs. 1-3 Marked ~ 40% reductions in hospitaliza- tion for heart failure were observed with SGLT2 inhibitors in the two trials, includ- ing subgroups with or without prior heart failure and in patients with and without known coronary artery disease. The precise mechanism(s) of benefit with these agents is unclear. Leveraging data from large observational registries like

age- and sex-matched control individuals from the general population. METHODS Individuals with type 2 diabetes regis- tered in the Swedish National Diabetes Registry 1998-2012 (n = 266,305) were compared with

age-, sex- and county-matched control individu- als without diabetes (n=1,323,504), and followed over a median of 5.6 years until 31 December 2013. RESULTS We identified 266,305 individuals with type 2 diabetes (mean age 62.0 years, 45.3% women) and 1,323,504 control individuals. Of the individuals with type 2 diabetes and control individuals, 18,715 (7.0%) and 50,157 (3.8%) were hospitalised with a diagnosis of heart failure, respectively. Comparing individuals with diabe- tes with those in the control group, men and women with type 2 diabetes who were younger than 55 years of age had HRs for hospitalisa- tion for heart failure of 2.07 (95% CI 1.73, 2.48) and 4.59 (95% CI 3.50, 6.02), respectively, using analyses adjusted for socioeconomic variables and associated conditions. Younger age, poorer glycaemic control and deteriorating renal func- tion were all associated with increased excess risk of heart failure in those with type 2 diabe- tes compared with the control group. However, people with diabetes who were ≥75 years and without albuminuria or with good glycaemic con- trol (HbA1c ≤52 mmol/mol [≤6.9%]) had a similar risk of hospitalisation for heart failure as control individuals in the same age group. CONCLUSIONS/INTERPRETATION Men and women aged <55 years with type 2 diabetes are at markedly elevated excess risk of heart failure. The excess risk declined with age, but persisted even with good glycaemic control. However, among those who were 75 years and older, dia- betic individuals with well controlled glucose levels or without albuminuria had a risk of heart failure that was on a par with individuals with- out diabetes. Excess Risk of Hospitalisation for Heart Fail- ure Among People With Type 2 Diabetes. Diabetologia 2018 Nov 01;61(11)2300-2309, A Rosengren, J Edqvist, A Rawshani, et al. www.practiceupdate.com/c/75570

that presented by Rosengren and col- leagues in combination with data from rigorous clinical trials is needed to better understand the heart failure risk, iden- tify groups at greatest risk, and promote better understanding of mechanisms and treatment options. References 1. NealB,PerkovicV,MahaffeyKW,etal.Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377(7):644-657. 2. Mahaffey KW, Neal B, Perkovic V, et al. Canagliflozin for primary and secondary prevention of cardiovascular events: results from the CANVAS program (Canagliflozin Cardiovascular Assessment Study). Circulation 2017;137(4):323-334. 3. Zinman B, Lachin JM, Inzucchi SE. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2016;374(11):1094.

Dr. Mahaffey is a Professor at Stanford University School of Medicine, Vice Chair of Clinical Research in the Department of Medicine and Director at the Stanford Center for Clinical Research (SCCR) in Stanford, California.

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Decreasing Cumulative Incidence of End-Stage Renal Disease in Young Patients With Type 1 Diabetes in Sweden Diabetes Care

1977-1984 and 1985-1990, independently of dia- betes duration. CONCLUSIONS The risk of developing ESRD in Sweden in this population is still low and also seems to decrease with time. Decreasing Cumulative Incidence of End-Stage Renal Disease in Young Patients With Type 1 Diabetes in Sweden: A 38-Year Prospective Nationwide Study. Diabetes Care 2019 Jan 01;42(1)27-31, C Toppe, A Möllsten, I Waernbaum, et al. www.practiceupdate.com/c/77730 Dr. Dahl is Director of the Nephrology Clinical Trials Program, and Associate Professor of Medicine in the Section of Nephrology at Yale University School of Medicine in New Haven, Connecticut. COMMENT By Neera K. Dahl MD, PhD T he present study continues to define the changing epidemi- ology of ESRD due to diabetic nephropathy in young patients with type 1 diabetes. The incidence of type 1 diabetes mellitus is high in Scandina- via, and the long-term ability to track patients is excellent. The study popu- lation is comprised of three datasets, including the Swedish Childhood Dia- betes Register (SCDR) started in 1977, the Diabetes Incidence Study in Swe- den (DISS) started in 1983, and the National Diabetes Register, started in 1996, comprising almost 19,000 unique patients. Cases of ESRD were identified using the Swedish Renal Registry (SRR). The risk of ESRD was lower in patients with diabetes onset in 1991–2001 compared with either 1977–1984 or 1985–1990. Patients with diabetes onset before the age of 10 had a lower risk of ESRD than those diagnosed at an older age. Patients with ESRD had a 12-fold higher risk of death compared with patients without ESRD. This study supports the consensus that improved diabetes care has reduced the risk of ESRD. It also points to the need to con- sider patients with type 1 diabetes and ESRD as an extremely vulnerable pop- ulation.

Take-home message • The authors of this study sought to determine the incidence rate of end-stage renal disease (ESRD) among Swedish patients with type 1 diabetes (T1D). Among participants who had diabetes onset between birth and 34 years of age, and longer than 14 years since disease onset, the incidence was 5.6%. The most recent cohort (onset between 1991 and 2001) had a lower incidence than earlier cohorts (1977–1990). • The results indicate that the incidence of ESRD in individuals with T1D is low in Sweden and may be declining in more recent years.

Abstract OBJECTIVE Diabetic nephropathy is a serious complication of type 1 diabetes. Recent studies indicate that end-stage renal disease (ESRD) incidence has decreased or that the onset of ESRD has been postponed; therefore, we wanted to analyze the incidence and time trends of ESRD in Sweden. RESEARCH DESIGN AND METHODS In this study, patients with duration of type 1 diabetes >14 years and age at onset of diabetes 0-34 years were included. Three national diabetes registers were used: the Swedish Childhood Diabetes Register, the Diabetes Incidence Study in Swe- den, and the National Diabetes Register. The Swedish Renal Registry, a national register on renal replacement therapy, was used to identify patients who developed ESRD.

" It also points to the need to consider patients with type 1 diabetes and ESRD as an extremely vulnerable population. "

RESULTS We found that the cumulative incidence of ESRD in Sweden was low after up to 38 years of diabetes duration (5.6%). The incidence of ESRD was lower in patients with type 1 diabe- tes onset in 1991-2001 compared to onset in

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Incretin-Based Drugs and Risk of Cholangiocarcinoma Among Patients With Type 2 Diabetes British Medical Journal Take-home message • The GLP-1 incretin hormone has been shown to have proliferative and anti-apoptotic effects on cholangiocytes, which raises the possibility that the incretin-based DPP-4 inhibitors and GLP-1 receptor agonists could increase the risk of cholangiocarci- noma. The authors of this population-based cohort study sought to determine whether DPP-4 inhibitors and GLP-1 receptor agonists were associated with an increased risk of cholangiocarcinoma in adults with type 2 diabetes. Study partic- ipants were 154,162 adults newly treated with antidiabetic drugs from March 2007 to March 2017 and followed until March 2018. During 614,274 person-years of follow-up, 105 incident cholangiocarcinoma events were observed. Use of DPP-4 inhibitors was associated with a near doubling of the risk of cholangiocarcinoma. A similar association was observed with GLP-1 receptor agonists but was not statistically significant. • Incretin-based drugs may be associated with an increased risk of cholangiocarci- noma in people with type 2 diabetes. Michael Allen MD

COMMENT By Michael Nauck MD

I ncretin-based glucose-lowering medications now are widely used. DPP-4 inhibitors are – broadly speaking – safe (includ- ing cardiovascular safety) and almost free from a class-specific profile of clinical adverse events. GLP-1 receptor agonists have the potential to prevent cardiovascular events and premature death. Both classes had been incremented to be associated with acute pancreatitis, but current analyses of large-scale car- diovascular trials attest of their safety in this respect. Now, the current publication reports a signal regarding chol- angiocarcinoma to be associated with a new prescription of DPP-4 inhibitors (significant) and GLP-1 receptor agonists (trend). The overall number of events is small (0.02 % per year), and the difference in DPP-4 inhibitor- and GLP-1 receptor agonist treated patients increased the risk by 0.01% and 0.004% per year. This results in numbers needed to harm of 10,000 and 25,000, respectively. Thus, the results of the present manuscript, even if confirmed, would not impact much on the estimated benefit–risk relationship estimated for either class. Are the results plausible? It may appear difficult to comprehend that a median duration of new use of DPP-4 inhibitors or GLP-1 receptor agonists of less than 2 years will result in clinical cholangiocarcinoma. Recent data, however, confirm an interaction of GLP-1 receptor stimulation with the biliary system: gallbladder disease and bil- iary obstruction was more prevalent with liraglutide treatment in the LEADER trial, 1 and GLP-1 receptor stimulation (the mechanism

common to DPP-4 inhibitors and GLP-1 receptor agonists) results in changes in gallbladder, and perhaps, biliary tract motility. 2 A mechanism has been suggested recently. 3 Based on the small numbers of events, the relatively short duration of follow-up, and lack of details regarding clinical presentation and conse- quences, the current signals need to be viewed as preliminary. They do, however, open our eyes to watch out for this and other rare adverse events that can only be detected with large cohorts followed for prolonged periods of time. References 1. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375(4):311-322. 2. Keller J, Trautmann ME, Haber H, et al. Effect of exenatide on cholecystokinin- induced gallbladder emptying in fasting healthy subjects. Regul Pept 2012;179(1-3):77-83. 3. Rehfeld JF, Knop FK, Asmar A, Madsbad S, Holst JJ, Asmar M. Cholecystokinin secretion is suppressed by glucagon-like peptide-1: clue to the mechanism of the adverse gallbladder events of GLP-1-derived drugs. Scand J Gastroenterol 2018 Nov 19:1-4. doi: 10.1080/00365521.2018.1530297. [Epub ahead of print]

Dr. Nauck is Head of Clinical Research at Diabetes Center Bochum-Hattingen, St. Josef Hospital, Ruhr-University Bochum in Bochum, Germany.

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