Cardiovascular risk reduction with liraglutide: an exploratory mediation analysis of the LEADER trial

The LEADER trial (NCT01179048) demonstrated a reduced risk of cardiovascular (CV) events for patients with type 2 diabetes who received the glucagon-like peptide-1 receptor agonist liraglutide versus placebo. The mechanisms behind this CV benefit remain unclear. We aimed to identify potential mediators for the CV benefit observed with liraglutide in the LEADER trial.

We performed exploratory analyses to identify potential mediators of the effect of liraglutide on major adverse CV events (MACE: composite of CV death, non-fatal myocardial infarction or non-fatal stroke) from the following candidates: HbA_1c, body weight, urinary albumin-to-creatinine ratio (UACR), confirmed hypoglycemia, sulfonylurea use, insulin use, systolic blood pressure and LDL-cholesterol. These candidates were selected as CV risk factors on which liraglutide had an effect in LEADER such that a reduction in CV risk might result. We used two methods based on a Cox proportional hazards model, and the new Vansteelandt method designed to utilize all available information from the mediator and to control for confounding factors.

Analyses using the Cox methods and Vansteelandt method indicated potential mediation by HbA_1c (up to 41% and 83% mediation, respectively) and UACR (up to 29% and 33% mediation, respectively) on the effect of liraglutide on MACE. Mediation effects were small for other candidates.

These analyses identify HbA_1c and, to a lesser extent, UACR as potential mediators of the CV effects of liraglutide. Whether either is a marker of an unmeasured factor or a true mediator remains a key question that invites further investigation.