Safety of metformin in chronic kidney disease and type 2 diabetes mellitus: a systematic review and meta-analysis

Metformin is the mainstay treatment for type 2 diabetes mellitus (T2DM), but its use in chronic kidney disease (CKD) remains controversial because of concerns about lactic acidosis. Previous meta-analyses have been limited by heterogeneous comparator groups and lack of CKD-stage stratification. To assess the association between metformin use and the risk of all-cause mortality, major cardiovascular events (MACE), end-stage renal disease (ESRD) and lactic acidosis in population with CKD and T2DM. A systematic search was conducted using Medline, Scopus, Web of Science and the Cochrane Library from inception to September 2025. Observational studies evaluating these associations in populations with CKD and T2DM were included. The associations were expressed as Hazard Ratios (HR) with 95% confidence intervals (95% CI). Meta-analyses were performed with subgroup analyses according to CKD stage. Twelve studies were included. Metformin use was associated with a reduction in both all-cause mortality (HR = 0.76, 95% CI: 0.64, 0.90) and ESRD (HR = 0.61, 95% CI: 0.49, 0.76). However, there was a trend towards an increased lactic acidosis risk in stage 4 (HR = 1.93, 95% CI: 0.95, 3.87). Metformin use was not associated with MACE. In this updated meta-analysis, based on observational evidence with very low certainty, metformin was inversely associated with all-cause mortality and ESRD. However, the results were inconsistent, and a potential increase in lactic acidosis risk in stage 4 was observed. Future studies examining the effect of dosage on these associations are required. • Metformin use in patients with Type 2 Diabetes Mellitus and Chronic Kidney Disease was associated with a 24% lower all-cause mortality and a 39% reduced risk of progression to End-Stage Renal Disease. • Overall lactic acidosis risk was not increased, but the risk increased in advanced Chronic Kidney Disease, particularly in stage 4. • No consistent effect on major adverse cardiovascular events, although a 19% risk reduction was observed in stages 3-4. • Findings support stage-adjusted dosing clinical trials and pharmacokinetic studies to define a safe metformin therapeutic window.