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

<b>Objective</b> <p>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.</p><b>Research Design and Methods</b> <p>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.</p><b>Results</b> <p>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.</p><b>Conclusions</b> <p>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.</p>