TY - JOUR
T1 - Dapagliflozin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus and Previous Myocardial Infarction
T2 - Subanalysis From the DECLARE-TIMI 58 Trial
AU - Furtado, Remo H.M.
AU - Bonaca, Marc P.
AU - Raz, Itamar
AU - Zelniker, Thomas A.
AU - Mosenzon, Ofri
AU - Cahn, Avivit
AU - Kuder, Julia
AU - Murphy, Sabina A.
AU - Bhatt, Deepak L.
AU - Leiter, Lawrence A.
AU - Mcguire, Darren K.
AU - Wilding, John P.H.
AU - Ruff, Christian T.
AU - Nicolau, Jose C.
AU - Gause-Nilsson, Ingrid A.M.
AU - Fredriksson, Martin
AU - Langkilde, Anna Maria
AU - Sabatine, Marc S.
AU - Wiviott, Stephen D.
N1 - Funding Information:
The DECLARE-TIMI 58 trial was funded by a grant from AstraZeneca to Brigham and Women’s Hospital. The work of author Dr Furtado was supported by a grant from the Lemann Foundation Cardiovascular Research Postdoctoral Fellowship– Harvard University/Brigham and Women´s Hospital. The work of author Dr Zelniker was supported by the Deutsche Forschungsgemeinschaft (ZE 1109/1-1).
Funding Information:
Dr Furtado reports grant from the Lemann Foundation Cardiovascular Research Postdoctoral Fellowship and Harvard University/Brigham and Women’s Hospital; honoraria from AstraZeneca; and grants (received from his institution) from AstraZeneca, DalCor, Boehringer, Pfizer, Jansen and Sanofi. Dr Bonaca reports grants from Amgen, AstraZeneca, Merck, and Pfizer and personal fees from Aralez, Amgen, AstraZeneca, Bayer, Janssen, Pfizer, and Sanofi. Dr Raz reports personal fees from AstraZeneca, Bristol-Myers Squibb Boehringer Ingelheim, Concenter BioPharma/Silkim Ltd, Eli Lilly and Company, Merck Sharp & Dohme Limited, Novo Nordisk, Inc, Orgenesis, Pfizer, Sanofi, SmartZyme Innovation Ltd, Panaxia, FuturRx Ltd, Insuline Medical, Medial EarlySign Ltd, CameraEyes, Ex-scopia, Dermal Biomics Inc, Johnson & Johnson, Novartis Pharma AG, Teva, Glu-come Ltd, and DarioHealth. Dr Zelniker reports a research grant from Deutsche Forschungsgemeinschaft (ZE 1109/1–1), grants to his institution from AstraZen-eca, grants from Bristol-Myers Squibb. Dr Mosenzon reports grants and personal fees from AstraZeneca, Bristol-Myers Squibb, and NovoNordisk and personal fees from Eli Lilly, Sanofi, Merck Sharp & Dohme, Boehringer Ingelheim, Jansen and Jansen, and Novartis. Dr Cahn reports personal fees from NovoNordisk, Elli Lilly, Sanofi, Boehringer Ingelheim, Merck Sharp & Dohme, and Glucome, as well as grants and personal fees from AstraZeneca. J. Kuder and S.A. Murphy report research grant support through Brigham and Women’s Hospital from Abbott Laboratories, Amgen, AstraZeneca, Critical Diagnostics, Daiichi-Sankyo, Eisai, Genzyme, Gilead, GlaxoSmithKline, Intarcia, Janssen Research and Development, The Medicines Company, MedImmune, Merck, Novartis, Poxel, Pfizer, Roche Diagnostics, and Takeda. Dr Bhatt discloses the following relationships: Advisory Board: Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, 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 IDE trial [Portico Re-sheathable Transcatheter Aortic Valve System US IDE Trial], funded by St. Jude Medical, now Abbott), Cleveland Clinic, Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial [Edoxaban Compared to Standard Care After Heart Valve Replacement Using a Catheter in Patients With Atrial Fibrillation], funded by Daiichi Sankyo), and Population Health Research Institute; honoraria: American College of Cardiology (senior associate editor, Clinical Trials and News, and ACC.org; vice chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial [Evaluation of Dual Therapy With Dabigatran vs. Triple Therapy With Warfarin in Patients With AF That Undergo a PCI With Stenting] steering committee funded by Boehringer Ingelheim), 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, associate editor), Population Health Research Institute (for the COMPASS [Cardiovascular Outcomes for People Using Anticoagulation Strategies] 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), WebMD (CME steering committees); other: Clinical Cardiology (deputy editor), NCDR-ACTION Registry Steering Committee (chair), and Veterans Administration Clinical Assessment Reporting and Tracking Research and Publications Committee (chair); research funding: Abbott, Amarin, Amgen, AstraZeneca (including for the DECLARE-TIMI 58 Executive Committee), Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, 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: Bio-tronik, Boston Scientific, St. Jude Medical (now Abbott), and Svelte; trustee: American College of Cardiology; and unfunded research: FlowCo, Merck, Novo Nordisk, PLx Pharma, and Takeda. Dr Leiter reports grants and personal fees from AstraZeneca, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, and Sanofi; personal fees from Servier; and grants from Glaxo-SmithKline. Dr McGuire reports personal fees from AstraZeneca, Boehringer Ingelheim, Janssen Research and Development LLC, Sanofi US, Merck Sharp and Dohme Corp, Eli Lilly and Company, Novo Nordisk, GlaxoSmithKline, Astra-Zeneca, Lexicon, Eisai Inc, Esperion, Metavant, Pfizer, and Applied Therapeutics. Dr Wilding reports personal fees and other from Brigham and Women’s Hospital; grants, personal fees, and consultancy fees (paid to his institution) from AstraZeneca, Novo Nordisk, and Takeda; personal fees and consultancy fees (paid to his institution) from Boehringer Ingelheim, Lilly, Janssen, Napp, Mundi-pharma, and Sanofi; and consultancy fees (paid to his institution) from Wilmington Healthcare. Dr Ruff reports research grants through his institution from Boehringer Ingelheim, Daiichi Sankyo, MedImmune, and the National Institutes of Health, as well as honoraria for scientific advisory boards and consulting from Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Jans-sen, MedImmune, Pfizer, and Portola. Dr Nicolau reports research grants from Amgen Inc, Bayer Healthcare Pharmaceuticals, Bristol-Myers Squibb Co, Dal-Cor, Janssen Pharmaceuticals Inc, Sanofi-Aventis, Astra Zeneca, Boehringer In-gelheim, Novartis, and Pfizer Inc, as well as consultant/advisory board fees from Sanofi-Aventis. Drs Gause-Nilsson, Fredriksson, and Langkilde are employees of AstraZeneca. Dr Sabatine reports research grant support through Brigham and Women’s Hospital from Abbott Laboratories, Amgen, AstraZeneca, Bayer, Daiichi-Sankyo, Eisai, Gilead, GlaxoSmithKline, Intarcia, Janssen Research and Development, The Medicines Company, MedImmune, Merck, Novartis, Pox-el, Pfizer, Quark Pharmaceuticals, Roche Diagnostics, and Takeda, as well as consulting fees from Alnylam, Amgen, AstraZeneca, Bristol-Myers Squibb, CVS Caremark, Dyrnamix, Esperion, IFM Therapeutics, Intarcia, Ionis, Janssen Research and Development, The Medicines Company, MedImmune, Merck, MyoKardia, and Novartis. Dr Wiviott reports grants from AstraZeneca, Bristol Myers Squibb, AMGEN, and Sanofi Aventis; grants and personal fees from Arena, Daiichi Sankyo, Eisai, Eli Lilly, and Janssen; grants, personal fees, and other from Merck; and personal fees from Aegerion, Allergan, Angelmed, Boehringer Ingelheim, Boston Clinical Research Institute, Icon Clinical, Lexicon, St. Jude Medical, Xoma, Servier, AstraZeneca, and Bristol Myers Squibb.
PY - 2019/5/28
Y1 - 2019/5/28
N2 - Background: Sodium glucose transporter-2 inhibitors reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus and a history of atherosclerotic cardiovascular disease. Because of their baseline risk, patients with previous myocardial infarction (MI) may derive even greater benefit from sodium glucose transporter-2 inhibitor therapy. Methods: DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58) randomized 17 160 patients with type 2 diabetes mellitus and either established atherosclerotic cardiovascular disease (n=6974) or multiple risk factors (n=10 186) to dapagliflozin versus placebo. The 2 primary end points were composite of MACE (cardiovascular death, MI, or ischemic stroke) and the composite of cardiovascular death or hospitalization for heart failure. Those with previous MI (n=3584) made up a prespecified subgroup of interest. Results: In patients with previous MI (n=3584), dapagliflozin reduced the relative risk of MACE by 16% and the absolute risk by 2.6% (15.2% versus 17.8%; hazard ratio [HR], 0.84; 95% CI, 0.72-0.99; P=0.039), whereas there was no effect in patients without previous MI (7.1% versus 7.1%; HR, 1.00; 95% CI, 0.88-1.13; P=0.97; P for interaction for relative difference=0.11; P for interaction for absolute risk difference=0.048), including in patients with established atherosclerotic cardiovascular disease but no history of MI (12.6% versus 12.8%; HR, 0.98; 95% CI, 0.81-1.19). There seemed to be a greater benefit for MACE within 2 years after the last acute event (P for interaction trend=0.007). The relative risk reductions in cardiovascular death/hospitalization for heart failure were more similar, but the absolute risk reductions tended to be greater: 1.9% (8.6% versus 10.5%; HR, 0.81; 95% CI, 0.65-1.00; P=0.046) and 0.6% (3.9% versus 4.5%; HR, 0.85; 95% CI, 0.72-1.00; P=0.055) in patients with and without previous MI, respectively (P interaction for relative difference=0.69; P interaction for absolute risk difference=0.010). Conclusions: Patients with type 2 diabetes mellitus and previous MI are at high risk of MACE and cardiovascular death/hospitalization for heart failure. Dapagliflozin appears to robustly reduce the risk of both composite outcomes in these patients. Future studies should aim to confirm the large clinical benefits with sodium glucose transporter-2 inhibitors we observed in patients with previous MI. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01730534.
AB - Background: Sodium glucose transporter-2 inhibitors reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus and a history of atherosclerotic cardiovascular disease. Because of their baseline risk, patients with previous myocardial infarction (MI) may derive even greater benefit from sodium glucose transporter-2 inhibitor therapy. Methods: DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58) randomized 17 160 patients with type 2 diabetes mellitus and either established atherosclerotic cardiovascular disease (n=6974) or multiple risk factors (n=10 186) to dapagliflozin versus placebo. The 2 primary end points were composite of MACE (cardiovascular death, MI, or ischemic stroke) and the composite of cardiovascular death or hospitalization for heart failure. Those with previous MI (n=3584) made up a prespecified subgroup of interest. Results: In patients with previous MI (n=3584), dapagliflozin reduced the relative risk of MACE by 16% and the absolute risk by 2.6% (15.2% versus 17.8%; hazard ratio [HR], 0.84; 95% CI, 0.72-0.99; P=0.039), whereas there was no effect in patients without previous MI (7.1% versus 7.1%; HR, 1.00; 95% CI, 0.88-1.13; P=0.97; P for interaction for relative difference=0.11; P for interaction for absolute risk difference=0.048), including in patients with established atherosclerotic cardiovascular disease but no history of MI (12.6% versus 12.8%; HR, 0.98; 95% CI, 0.81-1.19). There seemed to be a greater benefit for MACE within 2 years after the last acute event (P for interaction trend=0.007). The relative risk reductions in cardiovascular death/hospitalization for heart failure were more similar, but the absolute risk reductions tended to be greater: 1.9% (8.6% versus 10.5%; HR, 0.81; 95% CI, 0.65-1.00; P=0.046) and 0.6% (3.9% versus 4.5%; HR, 0.85; 95% CI, 0.72-1.00; P=0.055) in patients with and without previous MI, respectively (P interaction for relative difference=0.69; P interaction for absolute risk difference=0.010). Conclusions: Patients with type 2 diabetes mellitus and previous MI are at high risk of MACE and cardiovascular death/hospitalization for heart failure. Dapagliflozin appears to robustly reduce the risk of both composite outcomes in these patients. Future studies should aim to confirm the large clinical benefits with sodium glucose transporter-2 inhibitors we observed in patients with previous MI. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01730534.
KW - myocardial infarction
KW - sodium-glucose transporter 2 inhibitors
KW - type 2 diabetes mellitus
UR - http://www.scopus.com/inward/record.url?scp=85067266385&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85067266385&partnerID=8YFLogxK
U2 - 10.1161/CIRCULATIONAHA.119.039996
DO - 10.1161/CIRCULATIONAHA.119.039996
M3 - Article
C2 - 30882239
AN - SCOPUS:85067266385
VL - 139
SP - 2516
EP - 2527
JO - Circulation
JF - Circulation
SN - 0009-7322
IS - 22
ER -