Glaucoma Risk with Metformin and Sulfonylurea Therapies in Type 2 Diabetes: A Retrospective Cohort Study

Background: Research on metformin, sulfonylureas, and open-angle glaucoma risk in type 2 diabetes mellitus (T2DM) has yielded inconsistent findings. This study examined associations between hypoglycemic treatments and glaucoma diagnosis rates. Methods: This retrospective cohort study analyzed electronic health records of newly diagnosed T2DM patients from the Merative™ Explorys ® Therapeutic Dataset (2010– 2022), comparing three groups: metformin monotherapy, sulfonylureas plus metformin combination, and untreated controls. Propensity score matching balanced demographics, glycemic control, body mass index, blood pressure, lipid levels, and comorbidities. Cox proportional hazards models calculated adjusted hazard ratios for incident glaucoma. Results: After 1:1 propensity score matching, metformin monotherapy (N=100,387) showed a non-significant trend toward higher glaucoma diagnosis rates compared to matched controls (HR 1.106, 95% CI 1.014– 1.207, p=0.023; adjusted HR 1.076, 95% CI 0.995– 1.163, p=0.067). Patients receiving combination therapy with sulfonylureas and metformin (N=38,692) demonstrated statistically significantly higher glaucoma diagnosis rates relative to matched controls (HR 1.235, 95% CI 1.077– 1.417, p=0.002; adjusted HR 1.194, 95% CI 1.075– 1.326, p=0.001). Direct comparison between combination therapy and metformin monotherapy did not reach statistical significance (adjusted HR 1.084, 95% CI 0.973– 1.207, p=0.144). Conclusion: This observational study found associations between diabetes medications and increased glaucoma diagnosis rates but cannot establish causality. Multiple competing explanations exist: reverse causation (clinicians preferentially prescribing metformin to diabetic patients with emerging glaucoma based on prior protective literature), confounding by indication (sicker patients requiring medication having inherently higher glaucoma risk), and detection bias (differential surveillance patterns). The non-significant metformin monotherapy finding (p=0.067) aligns with recent meta-analyses showing no association. While the statistically significant combination therapy association warrants investigation, it should not be interpreted as definitive causation. Prospective studies controlling for disease severity, surveillance patterns, and treatment indication are needed to disentangle these explanations and inform clinical practice. Keywords: glaucoma, metformin, sulfonylureas, type 2 diabetes mellitus, retrospective cohort study