Cardiovascular Risk Reduction With Liraglutide: An Exploratory Mediation Analysis of the LEADER Trial

John B Buse, Stephen C Bain, Johannes F E 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, John B Buse, Stephen C Bain, Johannes F E 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

Abstract

Objective: The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial (ClinicalTrials.gov reg. no. 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, nonfatal myocardial infarction, or nonfatal stroke) from the following candidates: glycated hemoglobin (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 use all available information from the mediator and to control for confounding factors.

Results: 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.

Conclusions: 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.

© 2020 by the American Diabetes Association.

Figures

Figure 1
Figure 1
Probability of no MACE occurring in patients treated with liraglutide and placebo and with adjustment for HbA1c as a candidate mediator using the Vansteelandt method.

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Source: PubMed

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