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.
Funding Information:
Dr Bergmark reports grant support from MedImmune and Abbott Vascular and consulting fees from Quark Pharmaceuticals, Abbott Vascular, Daiichi Sankyo, Philips, and Janssen Pharmaceuticals. Dr Bhatt reports the following: Advisory Board: Cardax, Cereno Scientific, Elsevier Practice Update Cardiology, Medscape Cardiology, PhaseBio, and Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, and TobeSoft; chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), and Population Health Research Institute; honoraria: American College of Cardiology ([ACC]; senior associate editor, Clinical Trials and News, ACC.org; vice chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (editor in chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), HMP Global (editor in chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (guest editor and associate editor), Medtelligence/ReachMD (CME steering committees), Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and US national coleader, funded by Bayer), Slack Publications (chief medical editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (secretary/treasurer), and WebMD (CME steering committees); other: Clinical Cardiology (deputy editor), NCDR-ACTION Registry Steering Committee (chair), and VA CART Research and Publications Committee (chair); research funding: Abbott, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi Aventis, Synaptic, and The Medicines Company; royalties: Elsevier (editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); site coinvestigator: Biotronik, Boston Scientific, St Jude Medical (now Abbott), and Svelte; trustee: American College of Cardiology; and unfunded research: FlowCo, Fractyl, Merck, Novo Nordisk, PLx Pharma, and Takeda. Dr McGuire reports funding from Boehringer Ingelheim, Janssen, Sanofi US, Merck Sharp and Dohme, Lilly USA, Novo Nordisk, GlaxoSmithKline, AstraZeneca, Lexicon, Eisai, Esperion, Metavant, Afim-mune, and Pfizer. Dr Cahn has served on the Advisory Board for AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Glucome, Novo Nordisk, and Sanofi; is on the speaker’s bureau for AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Merck Sharp & Dohme, Novo Nordisk, and Sanofi; and is a shareholder of Glucome. Dr Mosenzon reports speaking fees from AstraZeneca, Bristol-Myers Squibb, Novo Nordisk, Eli Lilly, Sanofi, Novartis, MSD, and Kyowa Hakko Kirin; consulting fees from Novo Nordisk, Eli Lilly, Sanofi, Novartis, As-traZeneca, BI, and Jansen; and research grants from AstraZeneca, Bristol-Myers Squibb, and Novo Nordisk. Dr Steg reports research grants from Merck, Sanofi, and Servier and speaking or consulting fees from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, CSL-Behring, Daiichi-Sankyo, GlaxoSmithKline, Janssen, Lilly, Merck Novartis, Pfizer, Regeneron, Sanofi, Servier, and The Medicines Company. Dr Raz has served on the Advisory Board for AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme Limited, Novo Nordisk, Inc, Sanofi, Orgenesis, SmartZyme Innovation Ltd, Labstyle Innovations Ltd, and Boehringer Ingelheim; as a consultant to AstraZeneca/Bristol-Myers Squibb,
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
UR - http://www.scopus.com/inward/record.url?scp=85072266890&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85072266890&partnerID=8YFLogxK
U2 - 10.1161/CIRCULATIONAHA.119.040144
DO - 10.1161/CIRCULATIONAHA.119.040144
M3 - Article
C2 - 31362530
AN - SCOPUS:85072266890
VL - 140
SP - 1004
EP - 1014
JO - Circulation
JF - Circulation
SN - 0009-7322
IS - 12
ER -