Potential the relationship between clinical use metformin and frailty index:a Mendelian randomization study

Background: Observational studies present conflicting evidence regarding the association between metformin use and the risk of an increase in the Frailty Index. Some studies suggest a significant increase, while others indicate the opposite. Objective: This study aims to explore the causal relationship between metformin use and an increased risk of the Fraility Index . Methods: We conducted a two-sample Mendelian randomization (MR) analysis using various methods: inverse-variance weighted (IVW), weighted median, MR-Egger regression, simple mode, and weighted mode. Publicly available summary statistics datasets from genome-wide association studies (GWAS) meta-analyses were utilized. These datasets focused on metformin use in individuals of European descent (n = 462933) as the exposure variable, and a GWAS on doctor-diagnosed frailty index increase in individuals from the UK Biobank (n =175226) as the outcome variable. Additionally, we validated the outcomes using data from another group of metformin patients. Results: We identified 61 single nucleotide polymorphisms (SNPs) associated with metformin use at genome-wide significance as instrumental variables (P<1e-5; linkage disequilibrium r2 <0.001). The IVW (b = 2.646518, SE = 0.3763135, P = 2.03E-12), MR-Egger regression (b = 1.986775, SE = 1.4747723, P = 1.83E-01), simple mode (b = 3.450373, SE = 1.0903862, P = 2.44E-03), weighted median (b = 2.388585, SE = 0.4366406, P =4.49E-08), and Weighted mode (b = 3.08067, SE = 0.9913658, P =2.88E-03) methods all indicated a potential causal relationship between metformin use and the frailty index. Cochran’s Q test and funnel plot analysis showed no evidence of heterogeneity or asymmetry, suggesting no directional pleiotropy. Similar trends were observed in both forward and reverse validation within an additional 49 datasets. Conclusion: Our MR analysis findings suggest a potential causal relationship between metformin use and an increase risk of frailty index.