Diabetes CareHeart & CardiovascularJanuary 1, 2026

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

Tong J, Li N, Hu F, Yue Y

Key Finding

GLP-1 receptor agonists prevent heart attacks entirely through metabolic improvements like better blood sugar (37% contribution) and weight loss (29% contribution), with no direct protective effect on the heart itself.

What This Study Found

Think of GLP-1 medications like a master key that opens multiple doors to better health - but this study reveals they protect your heart by walking through those doors, not by magic. Researchers used a clever genetic approach called Mendelian randomization, which is like using your DNA as a natural experiment to avoid the usual bias problems in studies. They found that people with genetic variants that naturally boost GLP-1 receptor activity had a 6% lower risk of type 2 diabetes and a 3% lower risk of heart attacks. Here's the fascinating part: when researchers traced exactly HOW these medications prevent heart attacks, they discovered it's entirely through the boring but effective metabolic improvements. Better blood sugar control accounted for 37% of the heart protection, weight loss contributed 29%, and improvements in triglycerides, HDL cholesterol, and blood pressure made up the rest. It's like discovering that a fancy sports car only goes fast because of its excellent engine, transmission, and aerodynamics - there's no secret turbo boost.

Statistics Decoded

The odds ratio of 0.94 for diabetes means 6% lower risk (like reducing risk from 100 to 94 people out of 1,000). The MI odds ratio of 0.97 means 3% lower heart attack risk. The mediation percentages show how much each factor contributes: HbA1c accounts for 36.67% of heart protection (confidence interval 3.89-69.44% means we're pretty sure it's at least some contribution, possibly much more). BMI contributes 28.86% (2.62-55.10% range). The P = 0.12 for direct effect means there's about a 12% chance this result happened by luck - not strong enough evidence to claim a direct effect (we usually want less than 5%).

Why This Matters

This settles a major debate about whether GLP-1 drugs have some mysterious direct heart protection or work through the metabolic improvements we can measure - it's entirely the latter. For doctors, this means focusing on maximizing the metabolic benefits (weight loss, blood sugar control, lipid improvements) rather than expecting additional cardiovascular magic, and it validates treating the whole metabolic picture rather than just one aspect.

Original Abstract

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. 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. 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). 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.