Dose-Dependent Association of Long-Term Metformin Use and Diabetic Nephropathy Risk in Patients with Type 2 Diabetes Mellitus: A Nationwide Population-Based Study in Taiwan

BACKGROUND: Diabetic nephropathy (DN) is one of the most serious chronic microvascular complications of diabetes. Animal and clinical studies on the renoprotective effects of metformin have reported inconsistent results. OBJECTIVE: This study investigated the relationship between long-term metformin use and DN risk in patients with type 2 diabetes mellitus (T2DM), to determine whether this relationship exhibits a dose-dependent pattern. METHODS: This was a retrospective cohort study using data from a nationally representative database in Taiwan. Patients given a diagnosis of new-onset T2DM between 2002 and 2013 were divided into 2 groups: metformin and sulfonylurea treatment. We evaluated DN risk after a 5-year follow-up period. Using the Cox proportional hazard model, we estimated DN risk in correlation with the cumulative defined daily dose (cDDDs) of metformin, with adjustment for sex, age, income, urbanization level, diabetes severity, and various comorbidities. RESULTS: In the metformin-treated group, the DN incidence rates were 7.02%, 8.09%, 9.24%, and 10.75% for metformin administered at cDDDs of < 3 0, 30 to 120, 120 to 240, and > 240, respectively. After adjustments for relevant variables, relative to sulfonylurea-treated patients, patients who received metformin at cDDDs of < 30, 30 to 120, 120 to 240, and > 240 exhibited adjusted hazard ratios (95% CIs) for DN of 1.06 (1.03-1.09), 1.24 (1.21-1.27), 1.45 (1.41-1.49), and 1.72 (1.65-1.80), respectively. CONCLUSIONS: In patients with T2DM, metformin treatment exhibited a dose-dependent relationship with an increased DN risk after 5 years of follow-up. Further large-scale prospective studies are warranted to confirm these findings and elucidate the biological mechanisms underlying this observed association.