Abstract
Background: In DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58), the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the composite end point of cardiovascular death/hospitalization for heart failure (HHF) in a broad population of patients with type 2 diabetes mellitus. However, the impact of baseline left ventricular ejection fraction (EF) on the clinical benefit of sodium-glucose cotransporter 2 inhibition is unknown. Methods: In the DECLARE-TIMI 58 trial, baseline heart failure (HF) status was collected from all patients, and EF was collected when available. HF with reduced EF (HFrEF) was defined as EF <45%. Outcomes of interest were the composite of cardiovascular death/HHF, its components, and all-cause mortality. Results: Of 17 160 patients, 671 (3.9%) had HFrEF, 1316 (7.7%) had HF without known reduced EF, and 15 173 (88.4%) had no history of HF at baseline. Dapagliflozin reduced cardiovascular death/HHF more in patients with HFrEF (hazard ratio [HR], 0.62 [95% CI, 0.45-0.86]) than in those without HFrEF (HR, 0.88 [95% CI, 0.76-1.02]; P for interaction=0.046), in whom the treatment effect of dapagliflozin was similar in those with HF without known reduced EF (HR, 0.88 [95% CI, 0.66-1.17]) and those without HF (HR, 0.88 [95% CI, 0.74-1.03]). Whereas dapagliflozin reduced HHF both in those with (HR, 0.64 [95% CI, 0.43-0.95]) and in those without HFrEF (HR, 0.76 [95% CI, 0.62-0.92]), it reduced cardiovascular death only in patients with HFrEF (HR, 0.55 [95% CI, 0.34-0.90]) but not in those without HFrEF (HR, 1.08 [95% CI, 0.89-1.31]; P for interaction=0.012). Likewise, dapagliflozin reduced all-cause mortality in patients with HFrEF (HR, 0.59 [95% CI, 0.40-0.88;) but not in those without HFrEF (HR, 0.97 [95% CI, 0.86-1.10]; P for interaction=0.016). Conclusions: In the first sodium-glucose cotransporter 2 inhibitor cardiovascular outcome trial to evaluate patients with type 2 diabetes mellitus stratified by EF, we found that dapagliflozin reduced HHF in patients with and without HFrEF and reduced cardiovascular death and all-cause mortality in patients with HFrEF. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01730534.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2528-2536 |
| Number of pages | 9 |
| Journal | Circulation |
| Volume | 139 |
| Issue number | 22 |
| DOIs | |
| State | Published - May 28 2019 |
Keywords
- diabetes mellitus
- heart failure
- mortality
- sodium-glucose transporter 2 inhibitors
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
- Physiology (medical)
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In: Circulation, Vol. 139, No. 22, 28.05.2019, p. 2528-2536.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Effect of Dapagliflozin on Heart Failure and Mortality in Type 2 Diabetes Mellitus
AU - Kato, Eri T.
AU - Silverman, Michael G.
AU - Mosenzon, Ofri
AU - Zelniker, Thomas A.
AU - Cahn, Avivit
AU - Furtado, Remo H.M.
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 - Bonaca, Marc P.
AU - Ruff, Christian T.
AU - Desai, Akshay S.
AU - Goto, Shinya
AU - Johansson, Peter A.
AU - Gause-Nilsson, Ingrid
AU - Johanson, Per
AU - Langkilde, Anna Maria
AU - Raz, Itamar
AU - Sabatine, Marc S.
AU - Wiviott, Stephen D.
N1 - Funding Information: DECLARE-TIMI 58 was funded by AstraZeneca. Bristol-Myers Squibb was initially a co-sponsor as a function of the AstraZeneca/Bristol-Myers Squibb Alliance, but not a direct funder. Dr Zelniker was supported by Deutsche Forschungsge-meinschaft (ZE 1109/1-1), and Dr Furtado was supported by a grant from the Lemann Foundation Cardiovascular Research Postdoctoral Fellowship–Harvard University/Brigham and Women´s Hospital. Funding Information: DECLARE-TIMI 58 was funded by AstraZeneca. Bristol-Myers Squibb was initially a co-sponsor as a function of the AstraZeneca/Bristol-Myers Squibb Alliance, but not a direct funder. Dr Zelniker was supported by Deutsche Forschungsgemeinschaft (ZE 1109/1-1), and Dr Furtado was supported by a grant from the Lemann Foundation Cardiovascular Research Postdoctoral Fellowship-Harvard University/Brigham and Women's Hospital. Funding Information: Dr Kato reports personal fees from Daiichi Sankyo, AstraZeneca, Bristol-Myers Squibb, and Tanabe-Mitsubishi Pharma, as well as grants and personal fees from Ono Pharmaceutical. Dr Silverman reports grants from the John S. LaDue Memorial Fellowship from Harvard Medical School and the ZOLL Foundation. Dr Zelniker reports a research grant from Deutsche Forschungsgemeinschaft (ZE 1109/1-1), grants to his institution from AstraZeneca, and grants from Bristol-Myers Squibb. J. Kuder and S.A. Murphy report personal fees from Amgen and research grant support through Brigham and Women’s Hospital from Abbott Laboratories, Am-gen, 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 Wiviott reports grants from AstraZeneca, Bristol Myers Squibb, AM-GEN, 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. Dr Raz reports personal fees from Astra-Zeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Concenter BioPharma/Silkim Ltd, Eli Lilly and Company, Merck Sharp & Dohme Limited, Novo Nordisk, Inc, Or-genesis, Pfizer, Sanofi, SmartZyme Innovation Ltd, Panaxia, FuturRx Ltd, Insuline Medical, Medial EarlySign Ltd, CameraEyes, Exscopia, Dermal Biomics Inc, Johnson & Johnson, Novartis Pharma AG, Teva, Glucome Ltd, and DarioHealth. Dr Bonaca reports grants from Amgen, AstraZeneca, Merck, and Pfizer, as well as personal fees from Aralez, Amgen, AstraZeneca, Bayer, Janssen, Pfizer, and Sanofi. Dr Mosenzon reports grants and personal fees from AstraZeneca, Bristol-Myers Squibb, and NovoNordisk, plus 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, plus grants and personal fees from AstraZeneca. Dr Furtado reports grants 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 Astra-Zeneca, DalCor, Boehringer, Pfizer, Jansen, and Sanofi. 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, Ische-mix, 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, 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 GlaxoSmithKline. 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, AstraZeneca, Lexicon, Eisai Inc, Esper-ion, Metavant, Pfizer, and Applied Therapeutics. 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, AstraZeneca, 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, Mundipharma, 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 Goto received research grants from Ono, Pfizer, Sanofi, and Bristol Myer Squib and personal fees from AstraZeneca. Dr De-sai reports receiving research grants from Novartis and consulting fees from Abbott, AstraZeneca, Biofourmis, Boehringer-Ingelheim, Boston Scientific, Corvidia Therapeutics, DalCor Pharma, Novartis, Regeneron, Relypsa, Signature Medical, and Zogenix. Drs Johansson, Gause-Nilsson, Johanson, and Langkilde are employees of AstraZeneca. Dr Sabatine reports research grant support for the TIMI Study Group through Brigham and Women’s Hospital from Abbott Laboratories, Am-gen, AstraZeneca, Bayer, Daiichi-Sankyo, Eisai, Gilead, GlaxoSmithKline, Intarcia, Janssen Research and Development, The Medicines Company, MedImmune, Merck, Novartis, Poxel, Pfizer, Quark Pharmaceuticals, Roche Diagnostics, and Takeda, plus consulting fees from Alnylam, Amgen, AstraZeneca, Bristol-Myers Squibb, CVS Caremark, Dyrnamix, Esperion, IFM Therapeutics, Intarcia, Ionis, Jans-sen Research and Development, The Medicines Company, MedImmune, Merck, MyoKardia, and Novartis. Publisher Copyright: © 2019 American Heart Association, Inc.
PY - 2019/5/28
Y1 - 2019/5/28
N2 - Background: In DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58), the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the composite end point of cardiovascular death/hospitalization for heart failure (HHF) in a broad population of patients with type 2 diabetes mellitus. However, the impact of baseline left ventricular ejection fraction (EF) on the clinical benefit of sodium-glucose cotransporter 2 inhibition is unknown. Methods: In the DECLARE-TIMI 58 trial, baseline heart failure (HF) status was collected from all patients, and EF was collected when available. HF with reduced EF (HFrEF) was defined as EF <45%. Outcomes of interest were the composite of cardiovascular death/HHF, its components, and all-cause mortality. Results: Of 17 160 patients, 671 (3.9%) had HFrEF, 1316 (7.7%) had HF without known reduced EF, and 15 173 (88.4%) had no history of HF at baseline. Dapagliflozin reduced cardiovascular death/HHF more in patients with HFrEF (hazard ratio [HR], 0.62 [95% CI, 0.45-0.86]) than in those without HFrEF (HR, 0.88 [95% CI, 0.76-1.02]; P for interaction=0.046), in whom the treatment effect of dapagliflozin was similar in those with HF without known reduced EF (HR, 0.88 [95% CI, 0.66-1.17]) and those without HF (HR, 0.88 [95% CI, 0.74-1.03]). Whereas dapagliflozin reduced HHF both in those with (HR, 0.64 [95% CI, 0.43-0.95]) and in those without HFrEF (HR, 0.76 [95% CI, 0.62-0.92]), it reduced cardiovascular death only in patients with HFrEF (HR, 0.55 [95% CI, 0.34-0.90]) but not in those without HFrEF (HR, 1.08 [95% CI, 0.89-1.31]; P for interaction=0.012). Likewise, dapagliflozin reduced all-cause mortality in patients with HFrEF (HR, 0.59 [95% CI, 0.40-0.88;) but not in those without HFrEF (HR, 0.97 [95% CI, 0.86-1.10]; P for interaction=0.016). Conclusions: In the first sodium-glucose cotransporter 2 inhibitor cardiovascular outcome trial to evaluate patients with type 2 diabetes mellitus stratified by EF, we found that dapagliflozin reduced HHF in patients with and without HFrEF and reduced cardiovascular death and all-cause mortality in patients with HFrEF. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01730534.
AB - Background: In DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58), the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the composite end point of cardiovascular death/hospitalization for heart failure (HHF) in a broad population of patients with type 2 diabetes mellitus. However, the impact of baseline left ventricular ejection fraction (EF) on the clinical benefit of sodium-glucose cotransporter 2 inhibition is unknown. Methods: In the DECLARE-TIMI 58 trial, baseline heart failure (HF) status was collected from all patients, and EF was collected when available. HF with reduced EF (HFrEF) was defined as EF <45%. Outcomes of interest were the composite of cardiovascular death/HHF, its components, and all-cause mortality. Results: Of 17 160 patients, 671 (3.9%) had HFrEF, 1316 (7.7%) had HF without known reduced EF, and 15 173 (88.4%) had no history of HF at baseline. Dapagliflozin reduced cardiovascular death/HHF more in patients with HFrEF (hazard ratio [HR], 0.62 [95% CI, 0.45-0.86]) than in those without HFrEF (HR, 0.88 [95% CI, 0.76-1.02]; P for interaction=0.046), in whom the treatment effect of dapagliflozin was similar in those with HF without known reduced EF (HR, 0.88 [95% CI, 0.66-1.17]) and those without HF (HR, 0.88 [95% CI, 0.74-1.03]). Whereas dapagliflozin reduced HHF both in those with (HR, 0.64 [95% CI, 0.43-0.95]) and in those without HFrEF (HR, 0.76 [95% CI, 0.62-0.92]), it reduced cardiovascular death only in patients with HFrEF (HR, 0.55 [95% CI, 0.34-0.90]) but not in those without HFrEF (HR, 1.08 [95% CI, 0.89-1.31]; P for interaction=0.012). Likewise, dapagliflozin reduced all-cause mortality in patients with HFrEF (HR, 0.59 [95% CI, 0.40-0.88;) but not in those without HFrEF (HR, 0.97 [95% CI, 0.86-1.10]; P for interaction=0.016). Conclusions: In the first sodium-glucose cotransporter 2 inhibitor cardiovascular outcome trial to evaluate patients with type 2 diabetes mellitus stratified by EF, we found that dapagliflozin reduced HHF in patients with and without HFrEF and reduced cardiovascular death and all-cause mortality in patients with HFrEF. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01730534.
KW - diabetes mellitus
KW - heart failure
KW - mortality
KW - sodium-glucose transporter 2 inhibitors
UR - http://www.scopus.com/inward/record.url?scp=85063963517&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85063963517&partnerID=8YFLogxK
U2 - 10.1161/CIRCULATIONAHA.119.040130
DO - 10.1161/CIRCULATIONAHA.119.040130
M3 - Article
C2 - 30882238
AN - SCOPUS:85063963517
SN - 0009-7322
VL - 139
SP - 2528
EP - 2536
JO - Circulation
JF - Circulation
IS - 22
ER -