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Cardiovascular Risk Reduction With Liraglutide: An Exploratory Mediation Analysis of the LEADER Trial
John B Buse1, Stephen C Bain2, Johannes F E Mann3,4
1University of North Carolina School of Medicine, Chapel Hill, NC jbuse@med.unc.edu.
Insights
Liraglutide reduces cardiovascular events in type 2 diabetes. Glycated hemoglobin (HbA1c) and urinary albumin-to-creatinine ratio (UACR) may mediate this benefit, though further research is needed.
Area of Science:
- Cardiology
- Endocrinology
- Pharmacology
Background:
- The LEADER trial showed liraglutide reduces cardiovascular (CV) events in type 2 diabetes.
- Mechanisms underlying liraglutide's CV benefit are not fully understood.
Purpose of the Study:
- To identify potential mediators of liraglutide's CV benefit in the LEADER trial.
- To explore the roles of HbA1c, body weight, UACR, and other factors.
Main Methods:
- Exploratory analyses using Cox proportional hazards and Vansteelandt methods.
- Investigated mediation by HbA1c, body weight, UACR, hypoglycemia, sulfonylurea use, insulin use, systolic blood pressure, and LDL cholesterol.
Main Results:
- HbA1c showed significant potential mediation (up to 83% via Vansteelandt method).
- UACR also showed potential mediation (up to 33% via Vansteelandt method).
- Other factors had smaller mediation effects.
Conclusions:
- HbA1c and UACR are identified as potential mediators of liraglutide's CV effects.
- Further investigation is required to determine if these are true mediators or markers of unmeasured factors.
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.
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