Deciphering the Role of Metformin in Abdominal Aortic Aneurysm Progression: Insights from Two-Step Mendelian Randomization and Colocalization Analysis

Objective: Our research sought to investigate the relationship between metformin and abdominal aortic aneurysm (AAA) risk. We aimed to contribute to the current understanding of metformin's potential as a pharmaceutical intervention for AAA and explore the genetic facets influencing its effect. Methods: The methods encompassed meta-analysis, Mendelian Randomization (MR) and colocalization analysis. Meta-analysis facilitated a robust review and synthesis of the current literature. MR could investigate the causal relationship between metformin treatment and AAA incidence, and the mediating effects of certain factors. Colocalization analysis results are used as a supplement to MR analysis. Results: Meta-analysis suggest that metformin prescription is associated with a clinically important significant reduction in both growth in people with AAA. MR analysis results indicated the negative correlation between metformin treatment and AAA (OR = 0.0108, 95% CI: 0.000204 - 0.572, P = 0.0254), and the reduction of total cholesterol levels (mediation effect 25.17%, OR=0.3199, 95% CI: 0.159 - 0.644) mediated the protective effect of metformin against AAA, and the main role may be played by low-density lipoprotein levels (mediation effect 28.84%, OR = 0.271, 95% CI: 0.133 - 0.552). Colocalization analysis identified 9 significant genes, notably GPD2, associated with both metformin treatment and reduced AAA risk. Conclusions: Metformin treatment is associated with a significant reduction in AAA incidence, potentially mediated by its effects on blood lipid levels. These findings support further investigation into metformin as a therapeutic option for AAA, emphasizing the importance of integrating pharmacological and genetic approaches in cardiovascular disease management.