SRS220 - Evidence of a protective effect of metformin on abdominal aortic aneurysm risk: Insights from an observational study and Mendelian randomisation analysis using putative Metformin targets

Abstract Background There is currently no proven treatment to prevent the growth or rupture of abdominal aortic aneurysm (AAA). Metformin, a commonly prescribed drug for type 2 diabetes, has been linked in observational studies to a reduced risk of AAA, although causality has not been established. We investigated this association in an observational analysis using the UK Biobank cohort, and tested for a causal relationship using Mendelian randomisation (MR), a genomic approach that infers causality from genetic variation. Methods Logistic regression was used to test the association between AAA and self-reported metformin use in 2972 AAA cases and 89 160 propensity matched controls from UK Biobank. MR analyses were conducted using genetic variants at putative metformin targets to proxy drug effects. Results In the observational analysis, metformin was significantly associated with lower AAA risk (OR 0.49, 95% c.i.: 0.41–0.59, P = 3.15x10−14). MR analysis supported a causal effect, estimating a 43% risk reduction per standard deviation (OR = 0.57, 95% c.i.: 0.38–0.88 P = 0.010) per standard deviation decrease in HbA1c via metformin gene targets, equivalent to the effect of a prescribed dose of metformin. Conclusions Both observational and MR analyses found strong evidence that metformin use reduces the risk of developing AAA, supporting our findings that there is evidence of a potential causal association. Clinical trials are warranted to assess the efficacy of metformin to reduce the risk of aneurysm growth and rupture in people with AAA.