Metformin Use and Risk of All-Cause Mortality and Cardiovascular Events in Patients With Chronic Kidney Disease—A Systematic Review and Meta-Analysis

BACKGROUND: To evaluate whether metformin use assuredly alters overall all-cause death in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). METHODS: Pubmed, Web of Science, Embase, and Cochrane Central Register of Controlled Trials were systematically searched from inception to Feb. 29, 2020 with no language restriction. All related articles comparing all-cause death of T2DM and CKD patients after metformin use (monotherapy or combination) versus non-metformin treatment were identified. Pooled risk ratios (RR) and 95% confidence intervals (CI) were computed using random-effects models regardless of the heterogeneity quantified by Cochrane χ(2) and I(2) statistics. RESULTS: Totally 13 studies (9 cohort studies [CSs], 3 subanalyses or post-hoc analyses of randomized controlled trials [RCTs], and 1 nested case-control article) involving 303,540 patients were included. Metformin-based treatments relative to any other measure displayed significantly lower risks of all-cause mortality (Pooled RRs 0.71, 95%CI 0.61 to 0.84; I(2 =) 79.0%) and cardiovascular events (Pooled RRs 0.76, 95%CI 0.60 to 0.97; I(2 =) 87.0%) in CKD patients at stage G1-3, with substantial heterogeneity. Metformin use was not significantly related with these end points in advanced CKD patients. CONCLUSIONS: Metformin use is connected with significantly less risks of all-cause mortality and cardiovascular events in patients with T2DM and mild/moderate CKD. However, RCTs with large sample sizes are warranted in the future to assess whether these key benefits extend to later stages of CKD by dose adjustment.