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

<p dir="ltr">Objective</p><p dir="ltr">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 causal link between GLP-1RAs and myocardial infarction (MI) and quantify contribution of metabolic improvements.</p><p dir="ltr">Research Design and Methods</p><p dir="ltr">Mendelian randomization (MR) was applied to assess causal relationship between GLP-1RAs and MI, and two-steps 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 (GLP1R) expression (proxying GLP-1RAs) were used as instrumental variables. Genome-wide association studies (GWAS) data for metabolic traits (HbA1c, BMI, lipid profile, blood pressure) were sourced from the Million Veteran Program, serving as mediators. GWAS data for T2DM were obtained from the DIAGRAM consortium, and data for MI were sourced from the UK Biobank/CARDIoGRAMplusC4D, serving as outcomes. All GWAS data were restricted to European ancestry.</p><p dir="ltr">Results</p><p dir="ltr">Higher GLP1R expression was correlated with a lower risk of T2DM (OR 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]), high-density lipoprotein cholesterol (HDL-c,18.28% [1.45,35.12]), and systolic blood pressure (SBP,11.55% [0.33,22.76]). No direct effect of GLP1R expression on MI was observed after adjusting for metabolic traits (β -0.003, P=0.12).</p><p dir="ltr">Conclusions</p><p dir="ltr">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.</p><p><br></p>