PracticeUpdate Diabetes June 2019

VOL. 3 • NO. 2 • 2019

ISSN 2208-1488

OUR EXPERTS. YOUR PRACTICE.

Morbidity &Mortality After Lifestyle Intervention for People With Impaired Glucose Tolerance

Expert Opinion NewData and New Concepts inManaging Triglycerides Interviewwith Peter Libby MD Obesity and Cardiovascular Disease in Teenagers Interviewwith Peter Libby MD

Annual Scientific & Clinical Congress of the American Association of Clinical Endocrinologists

JOURNAL SCANS Risk Factors for Retinopathy in Type 1 Diabetes: The DCCT/EDIC Study

Effect of Dapagliflozin on Heart Failure and Mortality in Type 2 Diabetes Mellitus

Early Intervention for Diabetes in Medical and Surgical Inpatients Decreases Hyperglycemia and Hospital-Acquired Infections: A Cluster Randomized Trial

* Compared with NovoRapid ® (insulin aspart) 1,2 A faster insulin response at mealtime * For adult patients with diabetes, Fiasp ® is:

2X faster into the bloodstream vs. NovoRapid ®1,3† Faster † Earlier onset of appearance in the bloodstream vs. NovoRapid ® [4.1 min vs. 8.9 min; P < 0.001] after administration in patients with type 1 diabetes. 1,3

Flexible

A faster formulation of NovoRapid ®1 – the world’s most prescribed rapid-acting insulin 4‡ Familiar

Dose within 2 minutes before or 20 minutes after the start of a meal 1

20

2

‡ IMS MIDAS (MAT December 2018 volume). 4

PBS Information: Fiasp ® is listed on the PBS for the treatment of diabetes mellitus.

Please review Product Information before prescribing. The Product Information can be accessed at www.novonordisk.com.au

Fiasp ® (insulin aspart (rys)). Indication: Treatment of diabetes mellitus in adults. Contraindications: Hypersensitivity to insulin aspart or excipients. Precautions: Fiasp ® has a distinct time action profile (see ’Pharmacology’ in full PI). If hypoglycaemia occurs, it may occur earlier after an injection/infusion when compared to other mealtime insulins. Where blood glucose is greatly improved, e.g. by intensified insulin therapy, patients may experience a change in usual warning symptoms of hypoglycaemia, and should be advised accordingly.The impact of the fast onset of action should be considered in patients with delayed gastric emptying. Inadequate dosing or discontinuation of treatment may lead to hyperglycaemia and diabetic ketoacidosis. Instruct patients to always check the insulin label before each injection to avoid accidental mix-ups between Fiasp and other insulin products. Fiasp must not be diluted or mixed with any other products except infusion fluids as described in method of administration. Pregnancy Category: A. Can be used in pregnancy (see ‘Clinical Trials’ in full PI). Paediatric use: The efficacy and safety of Fiasp in children and adolescents below 18 years of age have not been established. Use in the elderly: Close glucose monitoring is recommended and the insulin dose should be adjusted on an individual basis (see ’Pharmacology’ and ’Clinical Trials’ in full PI). Interactions: Oral hypoglycaemic agents, octreotide, lanreotide, monoamine oxidase inhibitors, non-selective, beta-adrenergic blocking agents, angiotensin converting enzyme (ACE) inhibitors, salicylates, alcohol, anabolic steroids, sulphonamides, oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics, growth hormone, danazol. Adverse Effects: Hypoglycaemia. Dosage and Administration: Dosage as determined by physician. Fiasp is an ultrafast acting insulin. Fiasp should be administered 0-2 minutes before a meal, or up to 20 minutes after the start of a meal. The pharmacokinetic profiles of Fiasp and NovoRapid ® are distinct during the first hour following administration which is of particular importance for a mealtime insulin.The earlier onset of action of Fiasp and the subsequent increased glucose lowering effect compared with NovoRapid must be considered when prescribing Fiasp. Converting from another mealtime insulin can be done on a unit-to-unit basis but must be done under medical supervision. Patients transferring from other insulins will require training. Fiasp can be used subcutaneously, intravenously or via continuous subcutaneous insulin infusion (CSII). (March 2019) References: 1. Fiasp ® Product Information. 2. NovoRapid ® Product Information. 3. Heise T, et al. Clin Pharmacokinet. 2017; 56: 551-9. 4. Internal calculations based on IQVIA IMS database. IQVIA MIDAS (Dec 2018). Abbreviation: MAT, moving annual total. Novo Nordisk Pharmaceuticals Pty. Ltd. Level 3, 21 Solent Circuit, Baulkham Hills NSW 2153 Australia. Telephone: +61 2 8858 3600 | E-mail: aunrccc@novonordisk.com Internet: www.novonordisk.com.au ®Registered trademark of Novo Nordisk A/S. AU19FSP00013. Date of Preparation: May 2019.

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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

Content was originally published on PracticeUpdate.com Editorial Manager A nne Neilson anne.neilson@elsevier.com Editorial Project Manager Carolyn Ng Designer Jana Sokolovskaja Cover: Insulin in action/gettyimages.com PracticeUpdate Diabetes is published by Elsevier Australia ISSN 2208-1488 (Print) ISSN 2208-1496 (Online)

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

ABN 70 001 002 357 475 Victoria Avenue Chatswood NSW 2067 Australia EMEN061901

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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For T2DM patients on insulin: The concern of hypoglycaemia is never far away 1-3

Toujeo: Lower risk of hypoglycaemia and the same HbA 1c control as insulin glargine 100 units/mL in adults with T2DM 4

Learn more about Toujeo by visiting www.mysanoficonnect.com.au

T2DM = type 2 diabetes mellitus

PBS information: Toujeo ® SoloStar ® is listed on the PBS as a long-acting insulin analogue for the treatment of adults with type 1 and type 2 diabetes.

Please review Product Information before prescribing Lantus ® . Full Product Information is available at http://products.sanofi.com.au/aus_pi_lantus.pdf or by calling 1800 818 806. Minimum Product Information: Lantus (insulin glargine 100 units/mL). Indications: Once-daily subcutaneous administration for type 1 diabetes mellitus patients (adults and children) and type 2 diabetes mellitus patients (adults) who require insulin for control of hyperglycaemia. Contraindications: Hypersensitivity to insulin glargine or any excipient. Precautions: Hypoglycaemia; hepatic, renal and visual impairment; lipodystrophy and other injection site reactions; antibody production; intercurrent conditions; not studied in children <2 years, pregnancy category B3, lactation; not intended for i.v. use; not recommended for treatment of diabetic ketoacidosis; LANTUSMUST NOT BE DILUTEDORMIXEDWITH ANY OTHER INSULINOR SOLUTION. Instruct patient to check insulin label before each injection to avoid accidental mix-ups between insulins. Interactions: Oral antidiabetic agents; cardiovascular, analgaesic, anti-inflammatory, neurological, antipsychotic agents (see full PI); antibiotics; corticosteroids, other hormonal therapies (see full PI); diuretics; protease inhibitors; sympathomimetic agents; lithium; alcohol; sympatholytics including ϐ -blockers; others, see full PI. Side effects: Hypoglycaemia; injection site reactions; visual disturbances; others, see full PI. Dosage and Administration: ≥6 years. Subcutaneous, once daily. Lantus is equipotent to human insulin. Initial dose determined depending on desired blood glucose levels and doses and timing of any antidiabetic medication. For changeover from once daily NPH or ultralente, initial dose usually not changed; for changeover from twice-daily NPH to once-daily Lantus, initial dose usually reduced by approximately 20% compared to total daily NPH dose; for initiation of type 2 patients, initial dose usually approximately 10 IU. For changeover from once daily insulin glargine 300 units/mL to once daily Lantus, recommended initial dose is approximately 80% of insulin glargine 300 units/mL that is being discontinued. Date reviewed: 04 December 2017. Reference Document: PI, 04 October 2017. References: 1. Edridge CL et al. PLoS ONE 2015;10(6):e0126427. 2. Shafiee G et al. Journal of Diabetes & Metabolic Disorders 2012;11:17. 3. Lingvay I. US Endocrinology 2011;7(2): 95-102. 4. Ritzel R et al. Diabetes Obes Metab 2018; 20(3):541–8. ® Toujeo and Lantus are registered trademarks of sanofi-aventis australia pty ltd. Sanofi-aventis australia pty ltd trading as Sanofi, ABN 31 008 558 807, Talavera Corporate Centre, Building D, 12–24 Talavera Road, Macquarie Park, NSW 2113 SAANZ.TJO.19.05.0260. Date of preparation: May 2019. Please review Product Information before prescribing Toujeo ® . Full Product Information is available at http://products.sanofi.com.au/aus_pi_toujeo.pdf or by calling 1800 818 806. Minimum Product Information: Toujeo (insulin glargine 300 units/mL). Indications: Treatment of diabetes mellitus in adults. Contraindications: Hypersensitivity to insulin glargine or any of the excipients. Precautions: Not recommended for treatment of diabetic ketoacidosis; hypoglycaemia; switching between insulin glargine 100 U/mL and Toujeo; switching between other insulins and Toujeo; intercurrent illness; insulin antibodies; insulin label must always be checked before each injection to avoid medication errors between Toujeo and other insulins; pregnancy category B3; lactation; careful glucose monitoring and dose adjustments may be necessary in elderly patients; not studied in children; renal and hepatic impairment. Interactions: Oral antidiabetic medicinal products; cardiovascular, analgaesic, anti-inflammatory, neurological, antipsychotic agents (see full PI); antibiotics; corticosteroids, other hormonal therapies (see full PI); diuretics; protease inhibitors; sympathomimetic agents; lithium; alcohol; sympatholytics including ϐ -blockers; others, see full PI. Adverse Effects: Hypoglycaemia; visual impairment; injection site reactions; others, see full PI. Dosage and Administration: Subcutaneous, once daily. Not for intravenous use. Dose adjustment may be required e.g. if patient’s weight or life-style changes or change in timing of insulin dose. The desired blood glucose levels as well as doses and timing of anti-diabetic medication must be determined and adjusted individually. Instruct patients to never re-use a needle. Toujeo must not be drawn from the cartridge of the pre-filled pen into a syringe. Insulin glargine 100 U/mL and Toujeo are not bioequivalent and are not directly interchangeable. Toujeo must not be diluted or mixed with any other insulin products. When switching from insulin glargine 100 U/mL or other basal insulin products to Toujeo, dose may need to be adjusted. Close metabolic monitoring is recommended during the switch and in the initial weeks thereafter. ≥18 years. Date reviewed: 1 July 2015 Reference Document: PI, 30 June 2015. PBS information: Lantus ® SoloStar ® and Lantus ® cartridges are listed on the PBS as a long acting insulin analogue for the treatment of type 1 and type 2 diabetes.

CONTENTS 3

RESEARCH 4 Morbidity and Mortality After Lifestyle Intervention for People With Impaired Glucose Tolerance Comment by Deborah Wexler MD, MSc 5 Risk Factors for Retinopathy in Type 1 Diabetes 6 Effect of Dapagliflozin on Heart Failure and Mortality in Type 2 Diabetes Mellitus Comment by James L. Januzzi MD

COVER 4

Morbidity and Mortality After Lifestyle Intervention for People With Impaired Glucose Tolerance Comment by Deborah Wexler MD, MSc

EXPERT OPINION 12 New Data and New Concepts in Managing Triglycerides Interview with Peter Libby MD by Aman Shah MD

14 Obesity and Cardiovascular Disease in Teenagers Interview with Peter Libby MD by Aman Shah MD

7 Canagliflozin Improves Renal Outcomes in Type 2 Diabetes Comment by Steven G. Coca DO, MS 8 Early Intervention for Diabetes Inpatients Decreases Hyperglycemia and Hospital- Acquired Infections Comment by Mary Korytkowski MD and Esra Karslioglu-French MD

CONFERENCE 16 28 th Annual Scientific & Clinical Congress of the American Association of Clinical Endocrinologists By the PracticeUpdate Editorial Team 16 A “Hypo-Triad” and Comprehensive Glucose Paragon Demonstrate Superior Improvement in Glycemic Control 17 Synacthen Testing Identifies Adrenal Insufficiency 18 Proptosis of Thyroid Eye Disease Is Reduced With Teprotumumab 18 Dulaglutide Monotherapy Improves Glycemic Outcomes and Helps Control Body Weight in Obese Adults With Prediabetes 19 Estimation of Von Willebrand Factor a Possible Diagnostic Aid in Identifying CV Risk Factors in Patients With Type 2 Diabetes 20 Stage of Cardiometabolic Disease Proves Predictive of Incident Diabetes

9 Diuretics May Increase Risk of Lower Limb Events in Type 2 Diabetes 10 Deintensification in Older Patients With Type 2 Diabetes Comment by Peter Lin MD, CCFP

VOL. 3 • NO. 2 • 2019

EDITOR’S PICKS 4

Morbidity and Mortality After Lifestyle Intervention for People With Impaired Glucose Tolerance The Lancet Diabetes & Endocrinology Take-home message • In this longitudinal study of patients with impaired glucose intolerance (n=577), the authors evaluated the long-termeffects of lifestyle interventions on diabetes incidence, complications, and overall mortality. Over a 30-year follow-up after initial implementation of lifestyle interventions, the authors determined that themedian delay in diabetes onset compared with controls was 3.96 years. Also, patients in the initial treatment group experienced fewer cardiovascular disease events, fewer microvascular complications, as well as fewer cardiovascular disease-specific and overall deaths. • Lifestyle interventions for patients with impaired glucose tolerance improved overall morbidity and mortality risk and increased life expectancy by an average of 1.44 years. Lifestyle interventions should remain a strong focus in the treatment of glucose intolerance and type 2 diabetes. COMMENT By Deborah Wexler MD, MSc

I n 1986, in Da Qing, China, 577 adults with impaired glucose tolerance (of 110,660 screened) enrolled in a cluster randomized trial of lifestyle intervention. Clinics were assigned to no intervention or to deliver one of three lifestyle interventions: • dietary intervention aimed at increasing vegetable intake and decreasing alcohol and sugar intake; • exercise intervention aimed at increasing leisure time activity; or • both. All lifestyle intervention groups empha- sized the importance of weight loss and reduced caloric intake for patients who were overweight (BMI >25 kg/m 2 , which was close to the mean BMI in this popu- lation). Active intervention was carried out over 6 years and showed a reduced risk of diabetes in all intervention arms com- pared with control. Gong et al report the 30-year (!) outcomes of this cohort. For the 30-year analysis, intervention participants were combined (n=438) and compared with control partici- pants (n=138) in intention-to-treat analyses adjusting for clinic site, with over 90% out- come ascertainment (most participants still live in Da Qing, and the majority receive their secondary and tertiary care at a sin- gle regional hospital).

and treating clinics may have continued after the study ended (indeed, sustained behavior change on the part of both patients and providers may be considered a goal of lifestyle intervention). Finally, it is possible that the benefit observed was not due to the lifestyle intervention itself, but to something else, possibly a stronger therapeutic alliance between patients and providers that was engendered by life- style intervention, which, if true, could also count as a plus for lifestyle intervention. What is incontrovertible is that lifestyle intervention focused on dietary modi- fication, exercise, or both, coupled with weight loss among those who are over- weight, sustained over time, yields myriad health benefits, at relatively low cost. Although not all participants are willing to engage in lifestyle change, for those who do, new habits may be lasting and even, as Da Qing illustrates and multiple observational trials suggest, prolong both lifespan and health span. Taken together with other trials showing benefit (Diabetes Prevention Program, Look AHEAD, Finn- ish Diabetes Prevention Study), lifestyle intervention should be the foundation of management of people with impaired glucose tolerance and cardiometabolic disease.

The authors extend earlier reports of the benefit of lifestyle intervention based on more accumulated events, reporting significant reductions of 26% in cardio- vascular events, including stroke, 35% in microvascular complications, 33% in car- diovascular deaths, and 26% in all-cause mortality among lifestyle compared with control participants, corresponding to an increase of 4.82 years in median sur- vival and a mean increase of 1.44 years in life expectancy. The number needed to treat (over the 6 years of the interven- tion, measured at 30 years) to prevent diabetes, CVD death, or the composite microvascular disease outcome was 10 for each outcome. Results this strong have not been seen in other lifestyle intervention studies, even with relatively long follow-up. What is different about the Da Qing Diabetes Prevention Study? Da Qing has the long- est duration of follow-up, and differences in non-diabetes event rates began to emerge only 12 years after randomiza- tion. Background medical therapy or risk factors, such as smoking, may have been less favorable in Da Qing than those in other contexts, allowing the benefit of life- style intervention to become evident in this cohort. Also, the lifestyle intervention was long – 6 years – and both participants

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EDITOR’S PICKS 5

Risk Factors for Retinopathy in Type 1 Diabetes Take-home message • In this study of participants in the DCCT/EDIC studies, retinopathy risk factors were evaluated using data from more than 30 years of follow-up. The rate of ocular events per 1000 person-years was 12 for proliferative diabetic retinopathy, 14.5 for clinically significant macular edema, and 7.6 for ocular surgeries. The greatest risk factors for proliferative diabetic retinopathy were higher mean HbA1c levels, longer duration of type 1 diabetes, elevated albumin excretion rate, and higher average diastolic blood pressure. Risk factors for clinically signifi- cant macular edema were higher average HbA1c levels, longer duration of type 1 diabetes, older age, and higher average diastolic blood pressure. Risk factors for ocular surgeries were higher average HbA1c levels, older age, and longer diabetes duration. • HbA1c levels, elevated albumin excretion rate, and higher average diastolic blood pressure are modifiable risk factors, in addition to glycemic control, associated with retinopathy progression. Abstract OBJECTIVE The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive therapy reduced the development and progression of retinopathy in type 1 diabetes (T1D) compared with con- ventional therapy. The Epidemiology of Diabetes Interventions and Complications (EDIC) study observational follow-up showed persis- tent benefits. In addition to glycemia, we now examine other potential retinopathy risk factors (modifiable and nonmodifiable) over more than 30 years of follow-up in DCCT/EDIC. RESEARCH DESIGN AND METHODS The retinopathy outcomes were prolif- erative diabetic retinopathy (PDR), clinically significant macular edema (CSME), and ocular surgery. The survival (event-free) probability was estimated using the Kaplan-Meier method. Cox proportional hazards models assessed the association between risk factors and subsequent risk of retinopathy. Both forward- and backward-selection approaches determined the multivariable models. RESULTS Rate of ocular events per 1,000 person-years was 12 for PDR, 14.5 for CSME, and 7.6 for ocular surgeries. Approximately 65%, 60%, and 70% of participants remained free of PDR, CSME, and ocular surgery, respectively. The greatest risk factors for PDR in descend- ing order were higher mean HbA1c, longer duration of T1D, elevated albumin excretion rate (AER), and higher mean diastolic blood pres- sure (DBP). For CSME, risk factors, in descending order, were higher mean HbA1c, longer duration of T1D, and greater age and DBP, and for ocular surgeries were higher mean HbA1c, older age, and longer duration of T1D. CONCLUSIONS Mean HbA1c was the strongest risk factor for the progres- sion of retinopathy. Although glycemic control is important, elevated AER and DBP were other modifiable risk factors associated with the progression of retinopathy. Risk Factors for Retinopathy in Type 1 Diabetes: The DCCT/ EDIC Study. Diabetes Care 2019 Mar 04;[EPub Ahead of Print], DP Hainsworth, I Bebu, LP Aiello, et al. www.practiceupdate.com/c/80729 Diabetes Care

Abstract BACKGROUND Lifestyle interventions can delay the onset of type 2 dia- betes in people with impaired glucose tolerance, but whether this leads subsequently to fewer complications or to increased longevity is uncer- tain. We aimed to assess the long-term effects of lifestyle interventions in people with impaired glucose tolerance on the incidence of diabetes, its complications, and mortality. METHODS The original study was a cluster randomised trial, started in 1986, in which 33 clinics in Da Qing, China, were randomly assigned to either be a control clinic or provide one of three interventions (diet, exercise, or diet plus exercise) for 6 years for 577 adults with impaired glucose toler- ance who usually receive their medical care from the clinics. Subsequently, participants were followed for up to 30 years to assess the effects of intervention on the incidence of diabetes, cardiovascular disease events, composite microvascular complications, cardiovascular disease death, all- cause mortality, and life expectancy. FINDINGS Of the 577 participants, 438 were assigned to an intervention group and 138 to the control group (one refused baseline examination). After 30 years of follow-up, 540 (94%) of 576 participants were assessed for outcomes (135 in the control group, 405 in the intervention group). During the 30-year follow-up, compared with control, the combined inter- vention group had a median delay in diabetes onset of 3·96 years (95% CI 1·25 to 6·67; p=0·0042), fewer cardiovascular disease events (hazard ratio 0·74, 95% CI 0·59-0·92; p=0·0060), a lower incidence of microvascular complications (0·65, 0·45-0·95; p=0·025), fewer cardiovascular disease deaths (0·67, 0·48-0·94; p=0·022), fewer all-cause deaths (0·74, 0·61-0·89; p=0·0015), and an average increase in life expectancy of 1·44 years (95% CI 0·20-2·68; p=0·023). INTERPRETATION Lifestyle intervention in people with impaired glucose tol- erance delayed the onset of type 2 diabetes and reduced the incidence of cardiovascular events, microvascular complications, and cardiovascu- lar and all-cause mortality, and increased life expectancy. These findings provide strong justification to continue to implement and expand the use of such interventions to curb the global epidemic of type 2 diabetes and its consequences. Morbidity and Mortality After Lifestyle Intervention for People With Impaired Glucose Tolerance: 30-year Results of the Da Qing Diabe- tes Prevention Outcome Study. Lancet Diabetes Endocrinol 2019 Apr 26;[EPub Ahead of Print], Q Gong, P Zhang, J Wang, et al. www.practiceupdate.com/c/82928

VOL. 3 • NO. 2 • 2019

EDITOR’S PICKS 6

Effect of Dapagliflozin on Heart Failure and Mortality in Type 2 Diabetes Mellitus Circulation

COMMENT By James L. Januzzi MD S odium/glucose cotransporter-2 (SGLT2) inhibitors reduced car- diovascular events in outcomes trials of patients with type 2 diabetes (T2D) and a hemoglobin A1c above 7.0%, with an early and particularly strong impact on heart failure (HF) hos- pitalization. It remains unclear whether the benefits of SGLT2 inhibitors vary depending on left ventricular ejection fraction (LVEF). Given that heart failure with preserved EF (HFpEF) is a diagno- sis lacking defined treatments, a benefit from SGLT2 inhibitors would be of great importance. In the present analysis from the Dapagliflozin Effect on CardiovascuLAR Events (DECLARE) TIMI-58 trial, Kato and colleagues sought to evaluate effects of dapagliflozin on risk for cardiovascular death or hospitalization for HF relative to presence of HF with reduced EF (HFrEF; defined somewhat unusually as an LVEF ≤45% compared with the usual cut-off of 40% in most studies), “HF without known reduced EF” (a mixture of HFpEF and HF without available LVEF data), and no history of HF at study entry. The investigators found that dapagliflozin reduced cardiovascular death/HF hospitalization along with all- cause death most in those with HFrEF, with less obvious benefit in patients with HFpEF (where HF hospitalization was reduced but mortality was less obviously affected). These results should be considered hypothesis-generating only as they are based on historical LVEF categorized using an unorthodox cut-point for “HFrEF.” Understanding regarding the effect of SGLT2 inhibitors across the spectrum of LVEF will be definitively addressed by ongoing randomized studies enrolling carefully phenotyped patients with HF.

Take-home message • In this study, the authors evaluated data from patients with heart failure with reduced ejection fraction (HFrEF) from the DECLARE-TIMI 58 trial in order to determine the efficacy of the SGLT2 inhibitor dapagliflozin for reducing cardiovascular (CV) death and hospitalization for HF (HHF). The use of dapagliflozin was associated with a greater reduction in the CV death/HHF composite in patients with HFrEF compared with patients without HFrEF. Further analysis revealed that dapagliflozin reduced HHF in all subgroups, but reduced CV death and all-cause mortality only in the HFrEF group. • The authors concluded that dapagliflozin shows promise for reducing overall HHF and reducing CV and all-cause mortality in patients with HFrEF.

Abstract BACKGROUND In DECLARE-TIMI 58, the sodium glucose co-transporter 2 inhibitor (SGLT2i) dapagliflozin reduced the composite endpoint of cardiovascular (CV) death/ hospitalization for heart failure (HHF) in a broad population of patients with T2DM. However, the impact of baseline left ventricular ejection fraction (EF) on the clinical benefit of SGLT2i is unknown. METHODS In the DECLARE-TIMI 58 trial, baseline HF status was collected from all patients and EF where available. HF with reduced EF (HFrEF) was defined as EF <45%. Outcomes of interest were the composite of CV death/HHF, its com- ponents, and all-cause mortality (ACM). RESULTS Of 17,160 patients, 671 (3.9%) had HFrEF, 1316 (7.7%) had HF without known reduced EF and 15,173 (88.4%) had no history of HF at baseline. Dapagliflozin reduced CV death/HHF more in patients with HFrEF (HR 0.62, 95% CI 0.45-0.86) than in those without HFrEF (HR 0.88, 95% CI 0.76-1.02; P-interaction 0.046), in whom the treat- ment effect of dapagliflozin was similar in those

with HF without known reduced EF (HR 0.88, 95% CI 0.66-1.17) and those without HF (HR 0.88, 95% CI 0.74-1.03). Whereas dapagliflozin reduced HHF both in those with (HR 0.64, 95%CI 0.43-0.95) and without HFrEF (HR 0.76, 95%CI 0.62-0.92), it reduced CV death only in patients with HFrEF (HR 0.55, 95% CI 0.34-0.90) but not in those with- out HFrEF (HR 1.08, 95%CI 0.89-1.31, P-interaction 0.012). Likewise, dapagliflozin reduced ACM in patients with HFrEF (HR 0.59, 95% CI 0.40-0.88), but not in those without HFrEF (HR 0.97, 95% CI 0.86-1.10, P-interaction 0.016). CONCLUSIONS In the first SGLT2i CV outcome trial to evaluate T2DM patients stratified by EF, we found that dapagliflozin reduced HHF in patients with and without HFrEF, and reduced CV death and ACM in patients with HFrEF. Effect of Dapagliflozin on Heart Failure and Mortality in Type 2 Diabetes Mellitus. Circula- tion 2019 Mar 18;[EPub Ahead of Print], ET Kato, MG Silverman, O Mosenzon, et al. www.practiceupdate.com/c/81405

Dr. Januzzi is a Physician in the Cardiology Division of Massachusetts General Hospital and Hutter Family Professor of Medicine at Harvard Medical School in Boston, Massachusetts.

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Canagliflozin Improves Renal Outcomes in Type 2 Diabetes The New England Journal of Medicine

Take-home message • In this study, 4401 patients with type 2 diabetes and albuminuric chronic kidney disease were randomized to receive canagliflozin or placebo to investigate renal outcomes. At a median follow-up of 2.62 years, the relative risk of a composite of end-stage kidney disease, a doubling of the serum creatinine level, and death from renal or cardiovascular disease was 30% lower in patients receiving canag- liflozin compared with placebo. These patients also had a significantly lower risk of cardiovascular death, myocardial infarction and stroke, and a significantly lower risk of hospitalization for heart failure. • These findings demonstrate that canagliflozin treatment leads to a lower risk of kidney failure and cardiovascular events in patients with type 2 diabetes and kidney disease.

Abstract BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are avail- able. In cardiovascular trials of inhibitors of sodium-glucose cotransporter 2 (SGLT2), explor- atory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m 2 of body-sur- face area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin-angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m 2 ), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommenda- tion of the data and safety monitoring committee. At that time, 4401 patients had undergone ran- domization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kid- ney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitali- zation for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the can- agliflozin group than in the placebo group at a median follow-up of 2.62 years. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med 2019 Apr 14;[EPub Ahead of Print], V Perkovic, MJ Jar- dine, B Neal, et al. www.practiceupdate.com/c/82411

COMMENT By Steven G. Coca DO, MS T he CREDENCE trial results provide a major accomplishment for patients with diabetic kidney disease (DKD) and for nephrology. Since the IDNT and RENAAL trials of angiotensin receptor blockers were published in 2001, there had not been a single positive phase III clinical trial of any new agent – including bardoxolone (BEACON), sulodexide (Sun-MACRO), aliskiren (ALTITUDE) – or strategies (dual RAAS blockade [VA NEPHRON-Daswell as theaforementioned ALTITUDE trial]) in patients with DKD. CREDENCE enrollment began in 2014, and, in the intervening time, there has been simmering hope for patients with DKD. In the EMPA-REG Outcome, CANVAS Program, and DECLARE TIMI- 58 trials, there were strong signals for kidney protection in patients with type 2 diabetes and high cardiovascular risk. 1-3 Kidney-related endpoints were reduced by 40% to 50% in these three large trials of different SGLT2 inhibitors. In these three trial populations, however, the baseline eGFR was 74 to 85 and median UACR was 12 to 18 mg/g. Only 9% to 26% of participants had a baseline eGFR <60 and only 7% to 11% had UACR >300 mg/g. Thus, although there was optimism for this class, there was still trepidation of how the SGLT2 inhibitors would fare in patients with overt DKD (UACR >300 mg/g). The CREDENCE results did not disap- point. The effect sizes for canagliflozin versus placebo were robust for every

kidney-related outcome (and cardiovas- cular outcomes). In fact, the consistency in the effect sizes across the SGLT2 inhibitor trials, the lack of interactions by baseline characteristics, including baseline eGFR or albuminuria, the flattening of eGFR slopes over time, and the lack of a consist- ent signal for significant adverse events suggest none other than the following statement: SGLT2 inhibitors represent a “game-changing” breakthrough therapy in patients in early and later phases of type 2 diabetes for safely reducing the risk of inci- dent and prevalent kidney disease. References 1. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016;375(4):323-334. 2. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377(7):644-657. 3. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380(4):347-357. Dr. Coca is Associate Chair for Clinical and Translational Research, Department of Internal Medicine and Associate Professor of Medicine at Icahn School of Medicine in Mount Sinai, New York. later phases of type 2 diabetes for safely reducing the risk of incident and prevalent kidney disease. " " SGLT2 inhibitors represent a ‘game-changing’ breakthrough therapy in patients in early and

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Early Intervention for Diabetes Inpatients Decreases Hyperglycemia and Hospital- Acquired Infections Diabetes Care Take-home message • This study of 1002 consecutive adult inpatients with diabetes or new hypergly- cemia was designed to assess whether early electronic identification and bedside management improves glycemic control. A cluster-randomized trial was conducted on eight wards, and individuals were randomized to a 12-week active period of early intervention or usual care. Significantly more patients who received early intervention received specialist diabetes management and new insulin treatment compared with those who received usual care. Furthermore, the number of adverse glycemic days, overt hyperglycemia, and hospital-acquired infections significantly decreased in patients who received early intervention. • These results demonstrate that early identification and management of inpatients with diabetes contributes to a decrease in hyperglycemia and hospital-acquired infections.

COMMENT By Mary Korytkowski MD and Esra Karslioglu-French MD I t is well-known that poor inpatient glycemic control is asso- ciated with adverse events. This is the first randomized trial to investigate the effect of early intervention by an inpatient diabetes team (IDT) on blood glucose (BG) control measured as adverse glucose days (AGDs; defined as patient days with BG values <72 or >270 mg/dL) and adverse clinical outcomes (hospital-acquired infections, AKI, MI, unplanned critical care admission, and mortality). IDT members received training in inpa- tient glycemic management by a senior diabetologist prior to the intervention. Patients with diabetes or new hyperglycemia hospitalized on one of eight hospital units (four medical, four surgical) were identified using electronic surveillance of capillary BG measures from net- worked meters. Cluster randomization was performed according to hospital unit. Patients (n=270) admitted to units in the control arm received usual diabetes care with consultation by the IDT only upon request of the primary team. Patients (n=291) admit- ted to units in the intervention arm were seen and managed by the IDT within 24 hours of hospital admission. Compared with AGDs measured on the same units during a 10-week baseline period, patients hospitalized on the interven- tion units decreased AGDs by 24% at the cluster level and 28% at the individual level (both, P < .001) without an increase in hypogly- cemia. There was no difference in AGDs in the control group. The reduction in AGDs was associated with a significant reduction in hospital-acquired infections, but not other adverse outcomes. These favorable results following early IDT intervention occurred despite similar mean BG in the control and intervention arms, suggesting that focusing on preventing extreme glycemic

excursions may be more important than targeting specific BG targets in hospitalized patients, where testing is often affected by timing of meals, glucose-containing IV fluids, or timing of insu- lin dosing. These results also call into question the practice of providing IDT consultation only by request, which often occurs when there are multiple AGDs resulting in delays in achieving glycemic stability. A barrier to changing to proactive glycemic interventions is the need for the IDT to justify their existence with adequate numbers of billing events, which, as Kyi et al demon- strate, may not be the best way of ensuring optimal outcomes for hospitalized patients with diabetes. events …may not be the best way of ensuring optimal outcomes for hospitalized patients with diabetes. " " A barrier to changing to proactive glycemic interventions is the need for the IDT to justify their existence with adequate numbers of billing

Dr. Korytkowski is Professor of Medicine at the University of Pittsburgh School of Medicine in Pittsburgh, Pennsylvania.

Dr. Karslioglu-French is Clinical Assistant Professor of Medicine and Clinical Lead of the Inpatient Diabetes Program at the University of Pittsburgh in Pittsburgh, Pennsylvania.

PRACTICEUPDATE DIABETES

EDITOR’S PICKS 9

Diuretics May Increase Risk of Lower Limb Events in Type 2 Diabetes Take-home message • These authors used data from the SURDIAGENE prospective observational cohort study (n=1459) to inves- tigate whether diuretic use increased the risk of lower limb amputation (LLA) in people with type 2 diabetes. After comparing LLA risk in patients with and without diuretic treatment over a 7.1-year follow-up, the authors determined that the incidence of lower limb events (LLE) was 1.80 per 100 patient-years in diuretic users compared with 1.00 in non-users. The hazard ratio for LLE in diuretic users versus non-users was 2.08, which was significant even after multivariable adjustments. • Based on the results of this trial, the authors suggest that diuretic use increases the risk of LLE including LLA in patients with type 2 diabetes. This may help explain the increased risk of LLA in people with type 2 diabetes who use an SGLT2 inhibitor like canagliflozin. Clinicians should emphasize the importance of hydration in patients treated with SGLT2 inhibitors. Jason Sloane MD Abstract AIMS/HYPOTHESIS Recently, safety data signalled an increased risk of amputations in people taking canagliflozin, a sodium-glucose cotrans- porter 2 (SGLT2) inhibitor. If this side effect is due to drug-induced hypovolaemia, diuretics should also increase that risk. The aim of this study was to analyse the association between diuretic use and the risk of lower limb events (LLEs) in people with type 2 diabetes. METHODS SURDIAGENE (SUivi Rénal, DIAbète de type 2 et GENEti- que) is a prospective observational cohort that includes people with type 2 diabetes enrolled from 2002 to 2012 and followed-up until onset of LLE, death or 31 December 2015, whichever came first. Pri- mary outcome was the first occurrence of LLE, a composite of lower limb amputation (LLA) and lower limb revascularisation (LLR). The rates of primary outcome were compared between participants taking and not taking diuretics at baseline in a Cox-adjusted model. RESULTS At baseline, of the 1459 participants included, 670 were tak- ing diuretics. In participants with and without diuretics, the mean ages were 67.1 and 62.9 years and 55.8% and 59.8% were men, respectively. During a median follow-up of 7.1 years, the incidence of LLE was 1.80 per 100 patient-years in diuretic users vs 1.00 in non-users (p<0.001). The HR for LLE in users vs non-users was 2.08 (95% CI 1.49, 2.93), p <0.001. This association remained significant in a multivariable-ad- justed model (1.49 [1.01, 2.19]; p=0.04) and similar after considering death as a competing risk (subhazard ratio 1.89 [1.35, 2.64]; p<0.001). When separated, LLA but not LLR, was associated with the use of diuretics: 2.01 (1.14, 3.54), p=0.02 and 1.05 (0.67, 1.64), p=0.84, respec- tively, in the multivariable-adjusted model. CONCLUSIONS/INTERPRETATION Among people with type 2 diabetes treated with diuretics, there was a significant increase in the risk of LLE, predominantly in the risk of LLA. Lower Limb Events in Individuals With Type 2 Diabetes: Evidence for an Increased Risk Associated With Diuretic Use. Diabetologia 2019 Feb 26;[EPub Ahead of Print], L Potier, R Roussel, G Velho, et al. www.practiceupdate.com/c/81051 Diabetologia

Abstract OBJECTIVE To investigate if early electronic identification and bedside management of inpatients with diabetes improves glycemic control in noncritical care. RESEARCH DESIGN AND METHODS We investigated a proactive or early inter- vention model of care (whereby an inpatient diabetes team electronically identified individuals with diabetes and aimed to provide bedside manage- ment within 24 h of admission) compared with usual care (a referral-based consultation service). We conducted a cluster randomized trial on eight wards, consisting of a 10-week baseline period (all clusters received usual care) followed by a 12-week active period (clusters randomized to early intervention or usual care). Outcomes were adverse glycemic days (AGDs) (patient-days with glucose <4 or >15 mmol/L [<72 or >270 mg/dL]) and adverse patient outcomes. RESULTS We included 1,002 consecutive adult inpatients with diabetes or new hyperglycemia. More patients received specialist diabetes manage- ment (92% vs. 15%, P < 0.001) and new insulin treatment (57% vs. 34%, P = 0.001) with early intervention. At the cluster level, incidence of AGDs decreased by 24% from 243 to 186 per 1,000 patient-days in the interven- tion arm (P < 0.001), with no change in the control arm. At the individual level, adjusted number of AGDs per person decreased from a mean 1.4 (SD 1.6) to 1.0 (0.9) days (-28% change [95% CI -45 to -11%], P = 0.001) in the intervention arm but did not change in the control arm (1.8 [2.0] to 1.5 [1.8], -9% change [-25 to 6%], P = 0.23). Early intervention reduced overt hyperglycemia (55% decrease in patient-days with mean glucose >15 mmol/L, P < 0.001) and hospital-acquired infections (odds ratio 0.20 [95% CI 0.07-0.58], P = 0.003). CONCLUSIONS Early identification and management of inpatients with dia- betes decreased hyperglycemia and hospital-acquired infections. Early Intervention for Diabetes in Medical and Surgical Inpatients Decreases Hyperglycemia and Hospital-Acquired Infections: A Clus- ter Randomized Trial. Diabetes Care 2019 Mar 28;[EPub Ahead of Print], M Kyi, PG Colman, PR Wraight, et al. www.practiceupdate.com/c/81683

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