Metformin and the Development of Age-Related Macular Degeneration.

Importance: Metformin has demonstrated protective effects in systemic diseases, including cancer, cardiovascular disease, and retinal diseases, such as diabetic retinopathy and choroidal neovascularization. Literature suggests metformin may reduce the risk of age-related macular degeneration (AMD), but a consensus has not been reached. Objective: To evaluate the association of metformin with the development of any AMD and progression to geographic atrophy and neovascular AMD using a large electronic health record (EHR) platform. Design, Setting, and Participants: This cohort study had 2 exposed cohorts of participants aged 65 years or older who were prescribed metformin: one without AMD to assess development of any AMD and the other with mild or moderate nonexudative AMD to evaluate AMD progression to geographic atrophy or neovascular AMD. Corresponding nonexposed cohorts consisted of participants not prescribed metformin. Participants were required to meet inclusion criteria at least 6 months before the outcome of interest occurred. Those who had outcomes of interest before meeting inclusion criteria were excluded from analysis. This cohort study used a federated health research platform aggregating deidentified EHR data from 70 institutions (TriNetX). Data were collected from January 2013 to June 2025 and analyzed from September 2024 to June 2025. Exposures: Participants prescribed metformin. Main Outcomes and Measures: Propensity score matching controlled for confounders, such as age, sex, race, hypertension, diabetes, and other systemic conditions. Risk ratios (RRs) with 95% CIs were calculated to compare outcomes at 5 years, 10 years, and any time after meeting criteria. Any confidence intervals that crossed 0.90 to 1.10 were considered statistically not significant. Comparisons between exposed and unexposed groups were repeated requiring a diagnosis of cataract. Results: Before propensity score matching, cohort 1 (no AMD) included 297 008 participants exposed to metformin (mean [SD] age, 74.9 [7.0] years; 157 584 [53.1%] female) and 1 269 644 participants unexposed to metformin (mean [SD] age, 76.8 [7.9] years; 738 640 [58.2%] female). Before propensity score matching in cohort 2 (early or intermediate nonexudative AMD), there were 12 843 participants exposed to metformin (mean [SD] age, 79.5 [7.2] years; 7107 [55.3%] female) and 77 279 participants unexposed to metformin (mean [SD] age, 81.6 [7.2] years; 48 491 [62.7%] female). After propensity score matching, participants prescribed metformin had comparable risk of developing any AMD relative to those not prescribed metformin (RR, 0.90; 95% CI, 0.86-0.94). When stratified by time, the risk remained similar at 5 years (RR, 0.94; 95% CI, 0.90-0.99) and 10 years (RR, 0.91; 95% CI, 0.87-0.94). Similarly, participants prescribed vs not prescribed metformin had a comparable risk of AMD progression over these time spans (RR for geographic atrophy, 0.87; 95% CI, 0.76-1.01; RR for neovascular AMD, 1.03; 95% CI, 0.91-1.17). Conclusion and Relevance: This study suggests that, overall, metformin is not associated with significant development or progression of AMD. Further studies and prospective analyses are necessary to evaluate whether dosage and longevity of metformin use are associated with AMD development or progression.