Metformin Use and Clinical Outcomes among Patients with Diabetes with or without Heart Failure or Kidney Dysfunction: Observations from the SAVOR-TIMI 53 Trial.

BACKGROUND Metformin is first line therapy for type 2 diabetes mellitus (T2DM) although its effects on the cardiovascular (CV) system are unproved. METHODS In this post hoc analysis, patients in SAVOR-TIMI 53 with baseline biomarker samples (n=12,156) were classified as Ever versus Never taking metformin during the trial period. Associations between metformin exposure and outcomes were estimated using inverse probability of treatment weighting (IPTW) Cox modeling for the composite end point of CV death, myocardial infarction (MI), or ischemic stroke as well as CV death and all-cause mortality with inclusion of biomarkers as covariates. Additional sensitivity analyses included propensity score matching and Cox multivariable models. RESULTS Of the 12,156 patients with baseline biomarker samples, 8,971 (74%) had metformin exposure, 1,611 (13%) had prior HF, and 1,332 (11%) had at least moderate CKD (eGFR ≤45 mL/min/1.73m2). Metformin use was associated with no difference in risk for the composite end point (HRIPTW 0.92; 95% CI 0.76-1.11), but lower risk of all-cause mortality (HRIPTW 0.75; 95% CI 0.59-0.95). There was no significant relationship between metformin use and these end points in patients with prior HF or moderate to severe CKD. CONCLUSIONS In a cohort of 12,156 patients with T2DM and high CV risk, metformin use was associated with lower rates of all-cause mortality, including after adjustment for clinical variables and biomarkers, but not lower rates of the composite endpoint of CV death, MI, or ischemic stroke. This association was most apparent in patients without prior HF or moderate to severe CKD. CLINICAL TRIAL REGISTRATION URL: https://clinicaltrials.gov Unique Identifier: NCT01107886.