Could Metformin use reduce abdominal aortic aneurysm risk? A Mendelian randomisation study using known Metformin targets

IntroductionAn abdominal aortic aneurysm (AAA) is a swelling of the main artery in the body estimated to affect 0.92% of adults (aged 30-79) worldwide. Rupture is often fatal and surgical intervention may be offered if the risk of rupture is high. There is no treatment to prevent AAA or to slow aneurysm growth aside from dietary and lifestyle recommendations. Metformin, a drug prescribed to treat type 2 diabetes, has previously been associated with a potential reduction in AAA disease risk but no causal link has been shown. Here we investigate the causal link between Metformin and AAA risk through Mendelian randomisation (MR). MethodsWe conducted a two-sample MR analysis using genetic variants associated with gene expression of five Metformin drug targets that also show a genetic association with decreased glycated haemoglobin (HbA1c) levels. Effect sizes are obtained from within UK Biobank for HbA1c, and within AAAgen for AAA risk, a multi-ancestry meta-GWAS analysis of 39,221 cases and 1,086,107 controls. ResultsWe identified statistically significant evidence of a causal association between a genetic proxy for Metformin action and a decrease in AAA risk, OR=0.58 (95%CI: 0.37-0.90 p=0.015). We estimate that on average a one standard deviation decrease in HbA1c, measured via Metformin gene targets, reduces AAA risk by over 40%. ConclusionMetformin use in those at increased risk of AAA may reduce incidence of disease. Clinical trials are required to assess the efficacy of Metformin in reducing disease risk.