Evaluating the impact of metformin targets on the risk of osteoarthritis: a mendelian randomization study

Objective To provide some causal evidence concerning the effects of metformin on osteoarthritis (OA) using two metformin targets, namely AMP-activated protein kinase (AMPK) and growth differentiation factor 15 (GDF-15) as metformin proxies. Methods This is a 2-sample Mendelian randomization design. We constructed 44 AMPK-related variants genetically predicted in HbA1c (%) as instruments for AMPK and five variants strongly predicted GDF-15 as instruments for GDF-15. Summary-level data for three OA phenotypes, including OA at any site, knee OA, and hip OA were obtained from the largest genome-wide meta-analysis across the UK Biobank and arcOGEN with 455,211 Europeans. Main analyses were conducted using the inverse-variance weighted method. Weighted median and MR-Egger were conducted as sensitivity analyses to assess the robustness of our results. Results Genetically predicted AMPK were negatively associated with OA at any site (OR: 0.60; 95% CI: 0.43–0.83) and hip OA (OR: 0.42; 95% CI: 0.22–0.80), but with not knee OA (OR: 0.85; 95% CI: 0.49–1.50). Higher levels of genetically predicted GDF-15 reduced the risk of hip OA (OR: 0.95; 95% CI: 0.90–0.99), but not OA at any site (OR: 1.00; 95% CI: 0.98–1.02) and knee OA (OR: 1.02; 95% CI: 0.98–1.07). Conclusion This study indicates that AMPK and GDF-15 can be potential therapeutic targets for OA, especially for hip OA, and metformin would be repurposed for OA therapy which needs to be verified in randomized controlled trials.