Metabolic Improvement Mediates the Causal Relationship Between GLP-1 Receptor Agonists and Myocardial Infarction: A Mendelian Randomization and Mediation Analysis Study

Nov 19, 2025Diabetes care

Metabolic improvements may explain how GLP-1 receptor drugs reduce heart attack risk

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Abstract

Higher GLP-1 receptor expression is associated with a lower risk of myocardial infarction (MI) (odds ratio 0.97 [0.95, 1.00]).

GLP-1 receptor agonists may reduce the risk of type 2 diabetes mellitus (T2DM) as indicated by an odds ratio of 0.94 [0.92, 0.97].
Metabolic improvements are linked to the relationship between GLP-1 receptor expression and MI risk.
The contributions of various metabolic traits to the protective effect include HbA1c (36.67% contribution), BMI (28.86%), triglycerides (18.52%), HDL-cholesterol (18.28%), and systolic blood pressure (11.55%).
No direct effect of GLP-1 receptor expression on MI risk was found after accounting for metabolic traits (β = -0.003, P = 0.12).
The findings suggest a focus on metabolic improvements to mitigate cardiovascular risk associated with GLP-1 receptor agonists.

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OBJECTIVE: Glucagon-like peptide 1 receptor agonists (GLP-1RAs) have cardiovascular benefits, but whether this is via metabolic improvements or direct effect remains controversial. This study aimed to explore the causal link between GLP-1RAs and myocardial infarction (MI) and quantify the contribution of metabolic improvements.

RESEARCH DESIGN AND METHODS: Mendelian randomization (MR) was applied to assess the causal relationship between GLP-1RAs and MI, and two-step MR analysis was applied to quantify the mediating role of metabolic traits. The direct effect of GLP-1RAs on MI was evaluated by multivariate Mendelian randomization (MVMR). Genetic variants associated with GLP-1 receptor (GLP-1R) expression (proxying GLP-1RAs) were used as instrumental variables. Genome-wide association studies (GWAS) data for metabolic traits glycated hemoglobin (HbA1c), BMI, lipid profile, and blood pressure were sourced from the Million Veteran Program, serving as mediators. GWAS data for type 2 diabetes mellitus (T2DM) were obtained from the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium, and data for MI were sourced from the UK Biobank/Coronary ARtery DIsease Genome wide Replication and Meta-analysis plus The Coronary Artery Disease (CARDIoGRAMplusC4D), serving as outcomes. All GWAS data were restricted to European ancestry.

RESULTS: Higher GLP-1R expression was correlated with a lower risk of T2DM (odds ratio 0.94 [95% CI 0.92, 0.97]) and MI (0.97 [0.95, 1.00]). Metabolic improvements mediated this association: HbA1c (36.67% [3.89, 69.44]), BMI (28.86% [2.62, 55.10]), triglycerides (18.52% [1.47, 35.57]), HDL-cholesterol (18.28% [1.45, 35.12]), and systolic blood pressure (11.55% [0.33, 22.76]). No direct effect of GLP-1R expression on MI was observed after adjusting for metabolic traits (β = -0.003, P = 0.12).

CONCLUSIONS: GLP-1RAs protect against MI primarily through metabolic improvements, with no direct effect independent of these pathways. These findings support prioritizing metabolic improvements to reduce cardiovascular risk with GLP-1RAs.

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Metabolic Improvement Mediates the Causal Relationship Between GLP-1 Receptor Agonists and Myocardial Infarction: A Mendelian Randomization and Mediation Analysis Study

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