Mastery of Medicine in Diabetes Management Video Roundtable

Part I: Cardiovascular Disease and Diabetes Moderator: David M. Nathan, MD Panelists: Carol J. Levy, MD, CDE Anne L. Peters, MD

Slide 1. Prediction of Cardiovascular Events in Type 2 Diabetes by Means of a Genetic Risk Score1 N = 5360 self-reported white subjects with type 2 diabetes Genetic risk score: derived by adding the effect size-weighted number of risk alleles at 40 cardiovascular disease loci previously identified within the general population Scores ranged from 27 to 62 Each unit increase associated with a 3% additional risk of a major adverse cardiovascular event (OR 1.03, P = .002) Effect attenuated by adjustment for clinical predictors (OR 1.42) Addition of genetic risk profile to clinical risk score led to 9% increase in the ability to correctly reclassify individuals with major adverse cardiovascular events, and 4% increase in the ability to correctly reclassify individuals with nonevents Morieri M, et al. American Diabetes Association 77th Scientific Session: Presentation 2-OR/2.

Slide 2. All-Cause Mortality in Randomized Controlled Trials of Type 2 Diabetes2 33 randomized, controlled trials: 175,310 patients and 693,665 patient-years of follow-up Advanced chronic kidney disease associated with highest mortality rates Barkoudah E, et al. American Diabetes Association 77th Scientific Session: Presentation 427-P.

Slide 3. DEFENCE Study3 16 week multicenter, prospective, open-label, randomized parallel study Type 2 diabetic patients randomized to 750 mg metformin + 5 mg dapagliflozin 1500 mg metformin Results Flow-mediated dilation (marker of vascular endothelial function): comparable between groups, although with a trend favoring dapagliflozin Hemoglobin A1c, fasting plasma glucose, plasma glucagon, and body weight significantly decreased in both groups Urine 8-OHdG (biomarker of oxidative stress) significantly decreased with dapagliflozin compared with metformin alone Shigiyama F, et al. American Diabetes Association 77th Scientific Session: Presentation 12-LB.

Slide 4. EMPA-REG OUTCOME Trial4,5 Patients with type 2 diabetes and established cardiovascular disease randomized to receive standard of care plus Empagliflozin 10 mg or 25 mg Placebo All study endpoints adjusted for control of blood pressure (systolic blood pressure <140 mm Hg and diastolic blood pressure <90 mm Hg), LDL-C (<100 mg/dL), and hemoglobin A1c (<7.5%) Results HR for hospitalizations for heart failure: 0.64-0.67 33%-36% reduction in hospitalizations for heart failure with empagliflozin HR for cardiovascular death: 0.59-0.62 38%-41% reduction in cardiovascular death with empagliflozin HR for all-cause mortality: 0.66-0.67 33%-34% reduction in all-cause mortality with empagliflozin Conclusion Empagliflozin reduces the risk of hospitalization for heart failure, cardiovascular death, and all-cause mortality even when analyses are adjusted for control of blood pressure, LDL-C, and hemoglobin A1c, suggesting that the risk reduction with empagliflozin is irrespective of these conventional risk factors Zinman B, et al. American Diabetes Association 77th Scientific Session: Presentation 1173-P. Fitchett D, et al. American Diabetes Association 77th Scientific Session: Presentation 1172-P.

Part II: GLP-1 Receptor Agonists Moderator: David M. Nathan, MD Panelists: Carol J. Levy, MD, CDE Anne L. Peters, MD

Slide 5. Changes in Insulin Dosing Induced by Adding Liraglutide6 26-week randomized, placebo-controlled trial 44 overweight C-peptide negative adults with insulin-pump treated type 1 diabetes and suboptimal glycemic control 1.8 mg liraglutide vs placebo RESULTS Liraglutide significantly reduced hemoglobin A1c compared with placebo (-0.6% vs 0.2%, P <.001) Liraglutide significantly reduced body weight compared with placebo (-6.4 kg vs -0.6 kg, P <.001) Basal/bolus insulin distributions similar between 2 groups Daily carbohydrate intake constant in both groups Insulin:carbohydrate intake ratios increased significantly at mid-day and evening hours in the liraglutide group compared with the placebo group (P <.05) Insulin:carbohydrate intake ratio in the morning was unchanged between the 2 groups Schmidt S, et al. American Diabetes Association 77th Scientific Session: Presentation 72-OR.

Slide 6. DUAL VII Trial8 26-week open-label trial 506 patients with type 2 diabetes uncontrolled on metformin and 20-50 U insulin glargine U100 Insulin degludec + liraglutide vs basal-bolus (insulin glargine U100 + insulin aspart up to 4 times per day) RESULTS Mean hemoglobin A1c decreased from 8.2% to 6.7% in both arms, confirming noninferiority of insulin degludec + liraglutide A similar proportion of patients in each arm achieved hemoglobin A1c targets Total daily insulin dose lower with insulin degludec + liraglutide (40.4 U vs 84.1 U, P <.0001) Body weight decreased with insulin degludec + liraglutide and increased with basal-bolus treatment Rate of hypoglycemic episodes was lower with insulin degludec + liraglutide (P <.0001) Billings LK, et al. American Diabetes Association 77th Scientific Session: Presentation 136-OR.

Part III: New Insulin Therapies in Diabetes Moderator: David M. Nathan, MD Panelists: Carol J. Levy, MD, CDE Anne L. Peters, MD

Slide 7. Potential Uses for Ultra-Rapid Insulins Pediatric patients Geriatric patients Artificial pancreas systems Patients with type 1 diabetes and poor insulin control in the morning (breakfast)

Slide 8. Insulin Glargine U300 vs Insulin Degludec9 Comparison of steady-state pharmacokinetic and pharmacodynamic profiles Insulin glargine U300 (0.4 and 0.6 U/kg/day) Insulin degludec (0.4 and 0.6 U/kg/day) Primary endpoint: within-day variability of smoothed glucose infusion rate of 24-hour dosing period 20% lower with glargine U300 or than with degludec 0.4 U/kg/day (P = .047) but similar to degludec 0.6 U/kg/day Other endpoints Relative degree of serum insulin concentration 24-hour fluctuation 13% lower with glargine U300 than with degludec 0.4 U/kg/day 17% lower with glargine U300 than with degludec 0.6 U/kg/day Area under the INS time curve Distribution more even with glargine than both doses of degludec Bailey TS, et al. American Diabetes Association 77th Scientific Session: Presentation 985-P.

Slide 9. SWITCH 1 and 2 Trials10 64-week, double-blind, treat-to-target cross-over trials Type 1 diabetes (SWITCH 1) Type 2 diabetes (SWITCH 2) Insulin degludec once daily vs Insulin glargine U100 once daily Hemoglobin A1c noninferiority confirmed in both trials Reduction in hypoglycemia Significant reductions across all definitions of hypoglycemia with degludec vs glargine U100 in SWITCH 1 Significant reductions with degludec vs glargine U100 in SWITCH 2 in most definitions of hypoglycemia, except severe hypoglycemia Wysham CH, et al. American Diabetes Association 77th Scientific Session: Presentation 974-P.