Metabolic Improvement Mediates the Causal Relationship Between GLP-1 Receptor Agonists and Myocardial Infarction: A Mendelian Randomization and Mediation Analysis Study
Authors' conclusion
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.
Study context
- Population
- European-ancestry genome-wide association studies (GWAS) data: metabolic traits from the Million Veteran Program; T2D from DIAGRAM; Myocardial infarction (MI) from UK Biobank/CARDIoGRAMplusC4D
- Comparison
- Genetically proxied GLP-1RA
- Outcome
- Causal association of GLP-1R expression (proxying GLP-1RAs) with MI and mediation by metabolic traits
Methodological detailstwo-step mendelian randomization (MR), multivariate MR, European ancestry GWAS data
- Two-step MR
- Multivariate MR
- European ancestry GWAS data
Main finding
As reported in the abstract
- Higher GLP-1R expression and MI, OR
- 0.97 [0.95, 1.00] (95% CI)
- Proportion mediated by HbA1c
- 36.67% [3.89, 69.44]
- Proportion mediated by BMI
- 28.86% [2.62, 55.10]
- Proportion mediated by TG
- 18.52% [1.47, 35.57]
- Proportion mediated by HDL-C
- 18.28% [1.45, 35.12]
- Proportion mediated by systolic blood pressure
- 11.55% [0.33, 22.76]
- Direct effect of GLP-1R expression on MI after adjusting for metabolic traits (multivariate Mendelian randomization (MVMR)): none observed
- β = −0.003, P = 0.12
Further findings
- Higher GLP-1R expression and T2D, OR
- 0.94 [0.92, 0.97] (95% CI)
Original publication
Metabolic Improvement Mediates the Causal Relationship Between GLP-1 Receptor Agonists and Myocardial Infarction: A Mendelian Randomization and Mediation Analysis Study. Diabetes Care. Published 19 November 2025. doi:10.
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