Metformin Treatment Is Associated with a Decreased Risk of Nonproliferative Diabetic Retinopathy in Patients with Type 2 Diabetes Mellitus: A Population-Based Cohort Study

PURPOSE: To assess the relationship between metformin use and the severity of diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM) and to investigate the effect of metformin dosage on reducing the incidence of DR. METHODS: The study population included patients with newly diagnosed T2DM, who were aged ≥20 years and prescribed with antidiabetic drug therapy lasting ≥90 days, as identified using the National Health Insurance Research Database between 2000 and 2012. We matched metformin users and nonusers by a propensity score. Cox proportional hazard regression analyses were used to compute and compare the risk of developing nonproliferative diabetic retinopathy (NPDR) in metformin users and nonusers. RESULTS: Overall, 10,044 T2DM patients were enrolled. Metformin treatment was associated with a lower risk of NPDR (aHR 0.76, 95% CI 0.68–0.87) and sight-threatening diabetic retinopathy (STDR, aHR 0.29, 95% CI 0.19–0.45); however, the reduction in risk was borderline significant for STDR progression among NPDR patients (aHR 0.54, 95% CI 0.28–1.01). Combination therapy of metformin and DPP-4i exhibited a stronger but inverse relationship with NPDR development (aHR 0.32, 95% CI 0.25–0.41), especially at early (<3 months) stages of metformin prescription. These inverse relationships were also evident at different metformin doses and in adapted Diabetes Complications Severity Index scores (aDCSI). Moreover, combination therapy of metformin with sulfonylureas was associated with an increased risk of NPDR. CONCLUSION: Metformin treatment in patients with T2DM was associated with a reduced risk of NPDR, and a potential trend was found for a reduced STDR risk in patients who had previously been diagnosed with NPDR. Combining metformin with DPP-4i seemingly had a significantly beneficial effect against NPDR risk, particularly when aDCSI scores were low, and when metformin was prescribed early after T2DM diagnosis. These results may recommend metformin for early treatment of T2DM.