Metformin has cardiorenal safety in diabetics with CKD but may not decrease MACE

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.

Therefore, Lindsay E Clegg and colleagues from the Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, Gaithersburg, USA aimed to provide evidence on the cardiovascular and renal safety of metformin in CKD3-4.

The authors 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.

The following results were observed-

a. No strong trend for lower metformin doses with lower eGFR values was observed in either EXSCEL or SAVOR.

b. 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.

c. An improvement in eGFR slope was observed with metformin in the CKD stage 3B cohort in SAVOR, but not in other groups.

Hence, it was concluded that "the 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."

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Clegg LE, Jing Y, Penland RC, Boulton DW, Hernandez AF, Holman RR, Vora J. Cardiovascular and renal safety of metformin in patients with diabetes and moderate or severe chronic kidney disease: observations from the EXSCEL and SAVOR-TIMI 53 cardiovascular outcomes trials. Diabetes Obes Metab. 2021 Jan 4. doi: 10.1111/dom.14313.