Eri T Kato1, Michael G Silverman2, Ofri Mosenzon3, Thomas A Zelniker4, Avivit Cahn3, Remo H M Furtado4, Julia Kuder4, Sabina A Murphy4, Deepak L Bhatt4, Lawrence A Leiter5, Darren K McGuire6, John P H Wilding7, Marc P Bonaca8, Christian T Ruff4, Akshay S Desai9, Shinya Goto10, Peter A Johansson11, Ingrid Gause-Nilsson11, Per Johanson11, Anna Maria Langkilde11, Itamar Raz3, Marc S Sabatine4, Stephen D Wiviott4. 1. Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Japan (E.T.K.). 2. Cardiology Division, Massachusetts General Hospital, Boston (M.G.S.). 3. Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Medical Center, Hebrew University of Jerusalem, Faculty of Medicine, Jerusalem, Israel (O.M., A.C., I.R.). 4. TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (T.A.Z., R.H.M.F., J.K., S.A.M., D.L.B., C.T.R., M.S.S., S.D.W.). 5. Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Ontario, Canada (L.A.L.). 6. Division of Cardiology, University of Texas Southwestern Medical Center, Dallas (D.K.M.). 7. Institute of Ageing and Chronic Disease, University of Liverpool, UK (J.P.H.W.). 8. CPC Clinical Research, University of Colorado, Denver (M.P.B.). 9. Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (A.S.D.). 10. Department of Medicine (Cardiology), Tokai University, Isehara, Japan (S.G.). 11. AstraZeneca, Gothenburg, Sweden (P.A.J., I.G.-N., P.J., A.M.L.).
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.
RCT Entities:
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.
Authors: Mahmoud Al Rifai; Xiaoming Jia; Mouaz H Al-Mallah; Michael D Miedema; Seth S Martin; Salim S Virani Journal: Curr Atheroscler Rep Date: 2019-05-24 Impact factor: 5.113
Authors: Javed Butler; Milton Packer; Stephen J Greene; Mona Fiuzat; Stefan D Anker; Kevin J Anstrom; Peter E Carson; Lauren B Cooper; Gregg C Fonarow; Adrian F Hernandez; James L Januzzi; Mariell Jessup; Rita R Kalyani; Sanjay Kaul; Mikhail Kosiborod; JoAnn Lindenfeld; Darren K McGuire; Marc S Sabatine; Scott D Solomon; John R Teerlink; Muthiah Vaduganathan; Clyde W Yancy; Norman Stockbridge; Christopher M O'Connor Journal: Circulation Date: 2019-12-16 Impact factor: 29.690
Authors: Anna Norhammar; Johan Bodegard; Thomas Nyström; Marcus Thuresson; Klas Rikner; David Nathanson; Jan W Eriksson Journal: Diabetes Obes Metab Date: 2019-08-26 Impact factor: 6.577