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 May;23(5):1101-1110. doi: 10.1111/dom.14313. Epub 2021 Feb 2.


Aim: To provide evidence on the cardiovascular and renal safety of metformin in chronic kidney disease (CKD) stages 3 to 4.

Materials and methods: This post hoc analysis compared participants with an estimated glomerular filtration rate (eGFR) of 15 to 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 analysis, and the number of lactic acidosis events was tabulated.

Results: No strong trend for lower metformin doses with lower eGFR values was observed in either the EXSCEL or SAVOR-TIMI 53 trials. In the 1745 metformin-using participants matched to non-metformin users, metformin had neutral effects on MACE (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.76-1.08; P = 0.28) and ACM (HR 0.86, 95% CI 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-TIMI 53, but not in other groups.

Conclusions: This analysis of participants with CKD stages 3 to 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.

Keywords: cardiovascular disease; metformin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cardiovascular Diseases* / epidemiology
  • Cardiovascular Diseases* / prevention & control
  • Diabetes Mellitus, Type 2* / complications
  • Diabetes Mellitus, Type 2* / drug therapy
  • Glomerular Filtration Rate
  • Humans
  • Kidney
  • Metformin* / adverse effects
  • Renal Insufficiency, Chronic* / complications
  • Renal Insufficiency, Chronic* / epidemiology


  • Metformin

Grant support