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

Introduction An 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). Methods We 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. Results We 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%. Conclusion Metformin 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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This research was funded in whole, or in part, by the Wellcome Trust (grant number 222959/Z/21/Z) to KLS. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission; British Heart Foundation (grant numbers CD/14/2/30841 and RG/18/10/33842 to MJB, FD, CPN); and British Heart Foundation (grant number CH/F/22/90014) to MJB. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Please refer to the Supplementary materials of the AAAgen paper for information regarding individual studies involved in AAAgen consortium. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript. https://eur03.safelinks.protection.outlook.com/?url=https%3A%2F%2Fwww.nature.com%2Farticles%2Fs41588-023-01510-y&data=05%7C01%7Ckls46%40leicester.ac.uk%7C8f991e88d2ac454faf3808dbca7d9f2d%7Caebecd6a31d44b0195ce8274afe853d9%7C0%7C0%7C638326413104819669%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=MabkFU6hRMAc0Rd5cDyY6xStDbW2XYK7bne60DgKqDg%3D&reserved=0