1. 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 , San Diego, CA, USA

2. 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 , San Diego, CA, USA

3. 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 , San Diego, CA, USA

4. Severe hypoglycemia and major adverse cardiovascular events (MACE)
* p<0.05; ** p<0.001; * p<
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< 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 , San Diego, CA, USA

5. Severe hypoglycemia and CV death
* p<0.05; ** p<0.001; * p<
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< 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 , San Diego, CA, USA

6. 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 , San Diego, CA, USA

7. 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 , San Diego, CA, USA