Brian A Bergmark1,2, Deepak L Bhatt1,2, Darren K McGuire3, Avivit Cahn4, Ofri Mosenzon4, Ph Gabriel Steg5,6,7,8, KyungAh Im1,2, Estella Kanevsky1,2, Yared Gurmu1,2, Itamar Raz4, Eugene Braunwald1,2, Benjamin M Scirica1,2. 1. Thrombolysis in Myocardial Infarction (TIMI) Study Group (B.A.B., D.L.B., K.I., E.K., Y.G., E.B., B.M.S.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA. 2. Cardiovascular Division, Heart and Vascular Center (B.A.B., D.L.B., K.I., E.K., Y.G., E.B., B.M.S.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA. 3. Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas (D.K.M.). 4. Diabetes Unit, Division of Internal Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, The Faculty of Medicine, Israel (A.C., O.M., I.R.). 5. FACT (French Alliance for Cardiovascular Clinical Trials), Département Hospitalo-Universitaire FIRE (Fibrosis, Inflammation, Remodelling), Université de Paris, Sorbonne Paris-Cité, France (P.G.S.). 6. Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, France (P.G.S.). 7. INSERM U-1148, Paris, France (P.G.S.). 8. National Heart and Lung Institute, Imperial College, Royal Brompton Hospital, London, UK (P.G.S.).
Abstract
BACKGROUND:Metformin is first-line therapy for type 2 diabetes mellitus, although its effects on the cardiovascular system are unproved. METHODS: In this post hoc analysis, patients in SAVOR-TIMI 53 (Saxagliptin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus) with baseline biomarker samples (n=12 156) were classified as ever versus never takingmetformin during the trial period. Associations between metformin exposure and outcomes were estimated with inverse probability of treatment weighting Cox modeling for the composite end point of cardiovascular death, myocardial infarction, or ischemic stroke, as well as cardiovascular death and all-cause mortality, with biomarkers included as covariates. Additional sensitivity analyses included propensity score matching and Cox multivariable models. RESULTS:Of the 12 156 patients with baseline biomarker samples, 8971 (74%) had metformin exposure, 1611 (13%) had prior heart failure, and 1332 (11%) had at least moderate chronic kidney disease (estimated glomerular filtration rate ≤45 mL·min-1·1.73 m-2). Metformin use was associated with no difference in risk for the composite end point (hazard ratio for inverse probability of treatment weighting, 0.92 [95% CI, 0.76-1.11]) but lower risk of all-cause mortality (hazard ratio for inverse probability of treatment weighting, 0.75 [95% CI, 0.59-0.95]). There was no significant relationship between metformin use and these end points in patients with prior heart failure or moderate to severe chronic kidney disease. CONCLUSIONS: In a cohort of 12 156 patients with type 2 diabetes mellitus and high cardiovascular 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 end point of cardiovascular death, myocardial infarction, or ischemic stroke. This association was most apparent in patients without prior heart failure or moderate to severe chronic kidney disease. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01107886.
RCT Entities:
BACKGROUND:Metformin is first-line therapy for type 2 diabetes mellitus, although its effects on the cardiovascular system are unproved. METHODS: In this post hoc analysis, patients in SAVOR-TIMI 53 (Saxagliptin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus) 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 with inverse probability of treatment weighting Cox modeling for the composite end point of cardiovascular death, myocardial infarction, or ischemic stroke, as well as cardiovascular death and all-cause mortality, with biomarkers included as covariates. Additional sensitivity analyses included propensity score matching and Cox multivariable models. RESULTS: Of the 12 156 patients with baseline biomarker samples, 8971 (74%) had metformin exposure, 1611 (13%) had prior heart failure, and 1332 (11%) had at least moderate chronic kidney disease (estimated glomerular filtration rate ≤45 mL·min-1·1.73 m-2). Metformin use was associated with no difference in risk for the composite end point (hazard ratio for inverse probability of treatment weighting, 0.92 [95% CI, 0.76-1.11]) but lower risk of all-cause mortality (hazard ratio for inverse probability of treatment weighting, 0.75 [95% CI, 0.59-0.95]). There was no significant relationship between metformin use and these end points in patients with prior heart failure or moderate to severe chronic kidney disease. CONCLUSIONS: In a cohort of 12 156 patients with type 2 diabetes mellitus and high cardiovascular 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 end point of cardiovascular death, myocardial infarction, or ischemic stroke. This association was most apparent in patients without prior heart failure or moderate to severe chronic kidney disease. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01107886.
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