Evaluating the impact of metformin targets on the risk of heart failure: a Mendelian randomization study

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Abstract Background With conflicting findings in observational studies, the efficacy of metformin in improving heart failure outcomes remains inconclusive. This study employs a two-sample Mendelian randomization design, using AMP-activated protein kinase (AMPK) and growth differentiation factor 15 (GDF-15) as pharmacological targets of metformin, to simulate impact of metformin use on heart failure outcomes. Methods The exposure factors AMPK and GDF-15 data used in this study were sourced from large genome-wide association study meta-analyses. 40 single-nucleotide polymorphisms (SNPs) were utilized as instrumental variables for AMPK, while 4 SNPs were employed as instrumental variables for GDF-15. The heart failure outcome data were extracted from the largest genome-wide association study meta-analyses, encompassing 977,323 participants of European descent. The primary method for MR analysis was the inverse-variance weighted method. Additionally, sensitivity analyses were conducted using the weighted median, MR-Egger, simple mode, and weighted mode methods to assess result robustness. Results Genetically predicted AMPK (OR: 1.22; 95% CI: 0.81–1.86, P = 0.34) and genetically predicted GDF-15 (OR: 1.01; 95% CI: 0.97–1.05; P = 0.57) were not found to have a causal association with the risk of HF. Conclusion No convincing evidence supports that metformin reduces the risk of heart failure by activating the AMPK pathway or increasing GDF-15 expression. Further investigation is needed to explore whether metformin can mitigate heart failure -related risks through alternative pathways or biological mechanisms.

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