TY - JOUR
T1 - Metformin Use and Clinical Outcomes among Patients with Diabetes Mellitus with or Without Heart Failure or Kidney Dysfunction
T2 - Observations from the SAVOR-TIMI 53 Trial
AU - Bergmark, Brian A.
AU - Bhatt, Deepak L.
AU - McGuire, Darren K.
AU - Cahn, Avivit
AU - Mosenzon, Ofri
AU - Steg, Ph Gabriel
AU - Im, Kyungah
AU - Kanevsky, Estella
AU - Gurmu, Yared
AU - Raz, Itamar
AU - Braunwald, Eugene
AU - Scirica, Benjamin M.
N1 - Funding Information:
SAVOR-TIMI 53 was sponsored by AstraZeneca and Bristol-Myers Squibb. Executive Committee: Dr Braunwald (study chair), Dr Bhatt (coprincipal investigator), Dr Raz (coprincipal investigator), Jaime A. Davidson, Robert Frederich (nonvoting), Boaz Hirshberg (nonvoting), and Dr Steg.
Publisher Copyright:
© 2019 American Heart Association, Inc.
PY - 2019/9/17
Y1 - 2019/9/17
N2 - 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.
AB - 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.
KW - cardiovascular system
KW - diabetes mellitus
KW - metformin
KW - mortality
KW - risk
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U2 - 10.1161/CIRCULATIONAHA.119.040144
DO - 10.1161/CIRCULATIONAHA.119.040144
M3 - Article
C2 - 31362530
AN - SCOPUS:85072266890
SN - 0009-7322
VL - 140
SP - 1004
EP - 1014
JO - Circulation
JF - Circulation
IS - 12
ER -