Metformin Use and Clinical Outcomes Among Patients With Diabetes Mellitus With or Without Heart Failure or Kidney Dysfunction: Observations From the SAVOR-TIMI 53 Trial

Brian A Bergmark; Deepak L Bhatt; Darren K McGuire; Avivit Cahn; Ofri Mosenzon; Ph Gabriel Steg; KyungAh Im; Estella Kanevsky; Yared Gurmu; Itamar Raz; Eugene Braunwald; Benjamin M Scirica; SAVOR-TIMI 53 Steering Committee and Investigators

doi:10.1161/CIRCULATIONAHA.119.040144

Metformin Use and Clinical Outcomes Among Patients With Diabetes Mellitus With or Without Heart Failure or Kidney Dysfunction: Observations From the SAVOR-TIMI 53 Trial

Circulation. 2019 Sep 17;140(12):1004-1014. doi: 10.1161/CIRCULATIONAHA.119.040144. Epub 2019 Jul 31.

Authors

Brian A Bergmark^{1

2}, Deepak L Bhatt^{1

2}, Darren K McGuire³, Avivit Cahn⁴, Ofri Mosenzon⁴, Ph Gabriel Steg^{5

6

7

8}, KyungAh Im^{1

2}, Estella Kanevsky^{1

2}, Yared Gurmu^{1

2}, Itamar Raz⁴, Eugene Braunwald^{1

2}, Benjamin M Scirica^{1

2}; SAVOR-TIMI 53 Steering Committee and Investigators

Affiliations

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.).

PMID: 31362530
DOI: 10.1161/CIRCULATIONAHA.119.040144

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 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.

Keywords: cardiovascular system; diabetes mellitus; metformin; mortality; risk.

Publication types

Clinical Trial
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Biomarkers
Cohort Studies
Diabetes Mellitus, Type 2 / drug therapy*
Diabetes Mellitus, Type 2 / mortality
Female
Follow-Up Studies
Heart Failure / drug therapy*
Heart Failure / mortality
Humans
Hypoglycemic Agents / therapeutic use*
Kidney Diseases / drug therapy*
Kidney Diseases / mortality
Male
Metformin / therapeutic use*
Middle Aged
Risk
Survival Analysis
Treatment Outcome

Substances

Biomarkers
Hypoglycemic Agents
Metformin

Associated data

ClinicalTrials.gov/NCT01107886