on behalf of the LEADER Trial Steering Committee and Investigators Severe hypoglycemia, cardiovascular outcomes and death – the LEADER experience Bernard Zinman, Steven P. Marso, Erik Christiansen, Salvatore Calanna, Søren Rasmussen, John B. Buse on behalf of the LEADER Trial Steering Committee and Investigators Presented at “Ligue Marocaine de lutte contre le diabète”, international conference on Diabetes and Nutrition , Rabat 6-8 July 2018 Presented at the American Diabetes Association 77th Scientific Sessions, 359-OR. June 12 2017, San Diego, CA, USA

LEADER: trial design Objectives Examine potential associations between severe hypoglycemia and time to: First MACE (CV death, non-fatal MI or non-fatal stroke), CV death, Non-CV death CV, cardiovascular; CVD, CV disease; HbA1c, glycated hemoglobin; LEADER, Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results; MI, myocardial infarction; QD, once daily Marso et al. Am Heart J 2013;166:823–30; Marso et al. N Engl J Med 2016;375:311–22 Presented at “Ligue Marocaine de lutte contre le diabète”, international conference on Diabetes and Nutrition , Rabat 6-8 July 2018 Presented at the American Diabetes Association 77th Scientific Sessions, 359-OR. June 12 2017, San Diego, CA, USA

CV death, non-fatal myocardial infarction, or non-fatal stroke Primary outcome Reduction of 13% of MACE with liraglutide CV death, non-fatal myocardial infarction, or non-fatal stroke Primary composite outcome in the time-to-event analysis was the first occurrence of death from CV causes, non-fatal myocardial infarction, or non-fatal stroke. Cumulative incidences were estimated with use of the Kaplan–Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. Plot is truncated at 54 months because <10% of the patients had an observation time beyond 54 months. p-values are two-sided. CI, confidence interval; CV, cardiovascular; HR, hazard ratio. Marso et al. N Engl J Med 2016;375:311–22 Presented at “Ligue Marocaine de lutte contre le diabète”, international conference on Diabetes and Nutrition , Rabat 6-8 July 2018 Presented at the American Diabetes Association 77th Scientific Sessions, 359-OR. June 12 2017, San Diego, CA, USA

Severe hypoglycemia and major adverse cardiovascular events (MACE) * p<0.05; ** p<0.001; * p<0.0001. Risk of outcome with events after severe hypolycemia based on severe hypoglycemic episodes prior to MACE, CV death or all-cause death, using a time-dependent covariate Cox regression: all events (follow-up until last contact date), follow-up within 7, 15, 30, 60, 90, 180 and 365 days. CI, confidence interval; CV, cardiovascular; hypo, hypoglycemia; MACE, major adverse cardiovascular event. * p<0.05; ** p<0.001; *** p<0.0001. Cox regression with severe hypoglycemia as a time-dependent covariate, adjusted for randomized treatment. CI, confidence interval; CV, cardiovascular; MACE, major adverse cardiovascular event Presented at “Ligue Marocaine de lutte contre le diabète”, international conference on Diabetes and Nutrition , Rabat 6-8 July 2018 Presented at the American Diabetes Association 77th Scientific Sessions, 359-OR. June 12 2017, San Diego, CA, USA

Severe hypoglycemia and CV death * p<0.05; ** p<0.001; * p<0.0001. Risk of outcome with events after severe hypolycemia based on severe hypoglycemic episodes prior to MACE, CV death or all-cause death, using a time-dependent covariate Cox regression: all events (follow-up until last contact date), follow-up within 7, 15, 30, 60, 90, 180 and 365 days. CI, confidence interval; CV, cardiovascular; MACE, major adverse cardiovascular event. * p<0.05; ** p<0.001; *** p<0.0001. Cox regression with severe hypoglycemia as a time-dependent covariate, adjusted for randomized treatment. CI, confidence interval; CV, cardiovascular Presented at “Ligue Marocaine de lutte contre le diabète”, international conference on Diabetes and Nutrition , Rabat 6-8 July 2018 Presented at the American Diabetes Association 77th Scientific Sessions, 359-OR. June 12 2017, San Diego, CA, USA

Effect of liraglutide on MACE Patients with/without severe hypoglycemia The beneficial effect of liraglutide on CV events and death appears to be independent of the lower incidence of severe hypoglycaemia †First MACE (CV death, first non-fatal myocardial infarction or stroke). CI, confidence interval; MACE, major adverse cardiovascular event (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) Presented at “Ligue Marocaine de lutte contre le diabète”, international conference on Diabetes and Nutrition , Rabat 6-8 July 2018 Presented at the American Diabetes Association 77th Scientific Sessions, 359-OR. June 12 2017, San Diego, CA, USA

Conclusions In LEADER, patients with T2D and high CV risk had a clinically relevant and significantly lower risk of severe hypoglycemia with liraglutide versus placebo Patients experiencing severe hypoglycemia were at greater risk of CV events and death It is unknown if severe hypoglycemia has a direct causal effect on CV events and death, or if the association is indirect with hypoglycemia acting as a marker for frail patients or both Patients with hypoglycemia had longer diabetes duration, greater insulin use, and higher incidence of heart failure and kidney disease at baseline The beneficial effect of liraglutide on CV events and death appears to be independent of the lower incidence of severe hypoglycaemia Nonetheless reducing severe hypoglycemia remains an important goal in the management of diabetes CV, cardiovascular; MACE, major adverse cardiovascular event (CV death, non-fatal myocardial infarction, or non-fatal stroke); T2D, type 2 diabetes Presented at “Ligue Marocaine de lutte contre le diabète”, international conference on Diabetes and Nutrition , Rabat 6-8 July 2018 Presented at the American Diabetes Association 77th Scientific Sessions, 359-OR. June 12 2017, San Diego, CA, USA