Exploring the impacts of type 2 diabetes and metformin use on Parkinson's disease: Mendelian randomization analysis and a national cohort study.

BACKGROUND: The contribution of type 2 diabetes (T2D) and metformin use to Parkinson's disease (PD) remains unclear. This study aimed to investigate both the overall and independent effects of T2D and metformin use on PD risk. METHODS: GWAS summary datasets were utilized for the Mendelian randomization (MR) analysis to explore the causal relationships between T2D, metformin use, and PD, complemented by sensitivity analyses to validate the robustness of the results. Multivariable MR (MVMR) was applied to assess the direct effects of T2D and metformin use on PD. Additionally, the FAERS database (2004 Q1-2024 Q2) was analyzed to elucidate the association of metformin use with Parkinsonism using the reporting odds ratio (ROR). RESULTS: Our MR analysis showed T2D was not associated with the risk of PD (OR: 1.02, 95% CI: 0.96-1.09, P = 0.47), while metformin use was associated with an increased risk of PD (OR: 1.08, 95% CI: 1.02-1.14, P = 0.011). The MVMR analysis demonstrated that T2D was robustly associated with a decreased risk of PD (OR: 0.63, 95% CI: 0.50-0.78, P = 5.09E-5), while metformin use was linked to a higher risk of PD (OR: 1.63, 95% CI: 1.31-2.03, P = 1.29E-5). Using FAERS, a total of 179 cases of Parkinsonism were identified from 228,283 reports of metformin-related adverse events, indicating a significant association of metformin use with Parkinsonism (ROR: 5.25). CONCLUSION: Our study reveals opposing causal effects of T2D and metformin use on PD, emphasizing the need to consider metformin's potential adverse effects in PD patients.