Beyond A1C. Non-glycemic Effects of GLP-1 Receptor Agonists. Olga Astapova MD, PhD Luis Chavez MD URMC Endocrinology Fellows

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1 Beyond A1C Non-glycemic Effects of GLP-1 Receptor Agonists Olga Astapova MD, PhD Luis Chavez MD URMC Endocrinology Fellows

2 Disclosures No conflicts of interest.

3 Learning Objectives 1. Understand the physiological role of our gut hormones in glucagon inhibition, glucose dependent insulin secretion, appetite regulation and gastric motility. 2. Understand the effectiveness of this class of medication to reduce hyperglycemia and weight. 3. Learn about cardiovascular benefits of GLP1 receptor agonists. 4. Become familiar with adverse effects and cost of GLP1 receptor agonists.

4 Diabetes Treatment Goals Avoiding imminent death Alleviating symptoms of hyperglycemia Preventing complications 1920s Insulin Tolbutamide 1950s 1970s Fingerstick BG meters Hemoglobin A1C 2000s Framingham DCCT / EDIC UKPDS

5 JAMA. 2015;314(1):52-60;2. World Heart Federation. Cardiovascular disease risk factors

6 Action to Control Cardiovascular Risk in Diabetes (ACCORD) HbA1C 6.4% HbA1C 7.5% N Engl J Med 2008; 358:

7 Sponsors should establish an independent cardiovascular endpoints committee to prospectively adjudicate, in a blinded fashion, cardiovascular events during all phase 2 and phase 3 trials.

8 GLP1 Receptor Agonists

9 Saraiva and Sposito Cardiovascular Diabetology 2014, 13:142

10 Exenatide (Byetta) Lixisenatide (Adlyxin) Insulin Liraglutide (Victoza) Albiglutide (Tanzeum) Dulaglutide (Trulicity) Semaglutide (Ozempic) Albèr et al. Diabetes Obes Metab Jul;19(7):

11 LEADER Among patients with T2DM at increased risk for CV events, does daily liraglutide reduce CV mortality, nonfatal MI, or nonfatal strokes when compared to placebo? Liraglutide (plus standard care) Placebo (plus standard care) 9340 patients 50 years old Type 2 diabetes Mean 12.8 years diabetes duration Mean HbA1C 8.7% High CV risk: > 70% had CV disease N Engl J Med 2016; 375:

12 LEADER Hemoglobin A1C and Weight Reduction WEIGHT 2.3 KG N Engl J Med 2016; 375:

13 LEADER Primary Composite Outcome cardiovascular death nonfatal myocardial infarction nonfatal stroke 14.9% 13.0% N Engl J Med 2016; 375:

14 LEADER Renal Benefit N Engl J Med 2016; 375:

15 LEADER Adverse Events N Engl J Med 2016; 375:

16 LEADER Adverse Events N Engl J Med 2016; 375:

17 LEADER Adverse Events N Engl J Med 2016; 375:

18 LEADER Adverse Events N Engl J Med 2016; 375:

19 LEADER Among patients with T2DM at increased risk for CV events, does daily liraglutide reduce CV mortality, nonfatal MI, or nonfatal strokes when compared to placebo? YES N Engl J Med 2016; 375:

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21 Exenatide (Byetta) Lixisenatide (Adlyxin) Liraglutide (Victoza) Albiglutide (Tanzeum) Dulaglutide (Trulicity) Semaglutide (Ozempic) Albèr et al. Diabetes Obes Metab Jul;19(7):

22 SUSTAIN-6 In patients with type 2 DM at high CV risk, is semaglutide non-inferior to placebo in terms of CV safety? Semaglutide (plus standard care) Placebo (plus standard care) 3297 patients Mean age: 65 Type 2 diabetes Mean 13.9 years diabetes duration Mean HbA1C 8.7% High CV risk 60% ischemic heart disease 93% hypertension N Engl J Med 2016; 375:

23 SUSTAIN-6 Hemoglobin A1C Reduction N Engl J Med 2016; 375:

24 SUSTAIN-6 Weight Reduction N Engl J Med 2016; 375:

25 SUSTAIN-6 Primary Composite Outcome cardiovascular death nonfatal myocardial infarction nonfatal stroke 8.9% 6.6% N Engl J Med 2016; 375:

26 SUSTAIN-6 N Engl J Med 2016; 375: Adverse Events

27 SUSTAIN-6 In patients with type 2 DM at high CV risk, semaglutide is superior to placebo in terms of CV safety.

28 GLP-1 Receptor Agonists: CV Outcomes Compared with Placebo Lixisenatide Liraglutide Semaglutide Exenatide Lixisenatide Liraglutide Semaglutide Exenatide Lancet Diabetes Endocrinol Feb;6(2):

29 Ongoing Clinical Trials Ther Adv Chronic Dis 2018, Vol. 9(1) 33 50

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31 GLP1 Receptor Agonists Decision Making PROS HbA1C Weight Cardiovascular events Overall mortality CONS Nausea Heart burn Gallstones Cost

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33 Take Home Points Fundamental paradigm shift in T2D management. Several classes of glucose lowering medications improve CV outcomes in RCTs. These emerging data should shift focus of T2D Rx from A1C alone to comprehensive CV risk reduction. We now have options to treat T2DM that have beneficial outcomes beyond A1C reduction.

34 ~ Your friendly neighborhood endocrinology fellows ~