Hypoglycemia, cardiovascular outcomes, and death: The LEADER experience

OBJECTIVE: In the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) cardiovascular (CV) outcomes trial (NCT01179048), liraglutide significantly reduced the risk of CV events (by 13%) and hypoglycemia versus placebo. This post hoc analysis examines the associations between hypoglycemia and CV outcomes and death. RESEARCH DESIGN AND METHODS: Patients with type 2 diabetes and high risk for CV disease (n = 9, 340) were randomized 1:1 to liraglutide or placebo, both in addition to standard treatment, and followed for 3.5-5 years. The primary end point was time to first major adverse cardiovascular event (MACE) (1, 302 first events recorded), and secondary end points included incidence of hypoglycemia. We used Cox regression to analyze time to first MACE, CV death, non-CV death, or all-cause death with hypoglycemia as a factor or time-dependent covariate. RESULTS: A total of 267 patients experienced severe hypoglycemia (liraglutide n = 114, placebo n = 153; rate ratio 0.69; 95% CI 0.51, 0.93). These patients had longer diabetes duration, higher incidence of heart failure and kidney disease, and used insulin more frequently at baseline than those without severe hypoglycemia. In combined analysis (liraglutide and placebo), patients with severe hypoglycemia were more likely to experience MACE, CV death, and all-cause death, with higher risk shortly after hypoglycemia. The impact of liraglutide on risk of MACE was similar in patients with and without severe hypoglycemia (P-interaction = 0.90). CONCLUSIONS: Patients experiencing severe hypoglycemia were at greater risk of CV events and death, particularly shortly after the hypoglycemic episode. While causality remains unclear, reducing hypoglycemia remains an important goal in diabetes management.