Metformin use and the risk of incident immune-mediated diseases in patients with type 2 diabetes: a population-based cohort study.

Objectives: To investigate the association between metformin use and risks of incident immune-mediated diseases (IMDs) among patients with type-2 diabetes mellitus (T2DM). Methods: We conducted a retrospective cohort study using the National Health Insurance Research Database, including patients newly diagnosed with T2DM between 2000 and 2017 and followed until the end of 2018. Patients receiving metformin for ≥28 days were identified as users, and propensity score matching (1:1) was applied to balance baseline characteristics. The primary outcome was incident IMDs. Secondary outcomes included IMD-related hospitalization and all-cause mortality. Dose-response analyses were performed according to cumulative metformin exposure (<182 days, 182-364 days, >364 days). Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. Results: After propensity score matching, 20,460 metformin users and 20,460 non-users were included. Metformin use was associated with a higher risk of incident IMDs (adjusted HR 2.36, 95%CI 2.09-2.67). Metformin users also had a higher risk of IMD-related hospitalization (adjusted HR 2.44, 95%CI 1.94-3.05), but a lower observed risk of all-cause mortality (adjusted HR 0.64, 95%CI 0.60-0.68) compared with non-users. Longer cumulative metformin exposure was associated with progressively higher risks of IMDs and IMD-related hospitalization, whereas all-cause mortality decreased with longer use. Conclusion: In patients with T2DM, metformin use was associated with increased risks of incident IMDs and IMD-related hospitalization but a lower observed risk of all-cause mortality. These findings highlight the dual immunometabolic effects of metformin and underscore the need for individualized monitoring and further mechanistic research.