Metformin, the most common first-line therapy for type 2 diabetes, is used frequently in patients with moderate and severe chronic kidney disease (CKD), despite concerns regarding lactic acidosis. We aim to provide evidence on the cardiovascular and renal safety of metformin in CKD3-4.
MATERIALS AND METHODS
This posthoc analysis compared participants with eGFR 15-59 mL/min/1.73m2 in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) and the Saxagliptin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus (SAVOR)-TIMI 53 trials taking metformin, with those not exposed to metformin during these trials, using a propensity-matching approach. Adjusted Cox proportional hazards models were used to assess risk of major adverse cardiovascular events (MACE) and all-cause mortality (ACM). Metformin effect on eGFR slope was calculated using a mixed model-repeated measures (MMRM) analysis, and the number of lactic acidosis events was tabulated.
No strong trend for lower metformin doses with lower eGFR values was observed in either EXSCEL or SAVOR. In the 1745 metformin-using participants matched to non-metformin users, metformin had neutral effects on MACE (hazard ratio 0.91, 95%CI 0.76-1.08, p = 0.28) and ACM (0.86, 0.70-1.07, p = 0.18), with no interaction by CKD stage, or with use of exenatide or saxagliptin. An improvement in eGFR slope was observed with metformin in the CKD stage 3B cohort in SAVOR, but not in other groups.
This analysis of participants with CKD3-4 from two cardiovascular outcomes trials supports the cardiorenal safety of metformin but does not suggest a consistent benefit on MACE, ACM, or eGFR slope across this population.