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

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posted on 2020-05-04, 17:49 authored by John B Buse, Stephen C Bain, Johannes FE Mann, Michael A Nauck, Steven E Nissen, Stuart Pocock, Neil R Poulter, Richard E Pratley, Martin Linder, Tea Monk Fries, David D Ørsted, Bernard Zinman, LEADER Trial Investigators

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.

Research Design and Methods

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: HbA1c, 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 HbA1c (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 HbA1c 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.


The LEADER trial ( number: NCT01179048) and this post hoc analysis were funded by Novo Nordisk A/S.


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