Michael E Nassif1,2, Sheryl L Windsor1, Fengming Tang1, Yevgeniy Khariton1,2, Mansoor Husain3,4,5,6, Silvio E Inzucchi7, Darren K McGuire8, Bertram Pitt9, Benjamin M Scirica10, Bethany Austin1,2, Mark H Drazner8, Michael W Fong11, Michael M Givertz10, Robert A Gordon12, Rita Jermyn13, Stuart D Katz14, Sumant Lamba15, David E Lanfear16, Shane J LaRue17, JoAnn Lindenfeld18, Michael Malone19, Kenneth Margulies20, Robert J Mentz21, R Kannan Mutharasan22, Michael Pursley23, Guillermo Umpierrez24, Mikhail Kosiborod1,2,25,26. 1. Saint Luke's Mid America Heart Institute, Kansas City, MO (M.E.N., S.L.W., F.T., Y.K., B.A., M.K.). 2. University of Missouri-Kansas City, MO (M.E.N., Y.K., B.A., M.K.). 3. Toronto General Hospital Research Institute, University Health Network, Toronto, Canada (M.H.). 4. Ted Rogers Centre for Heart Research, Toronto, Canada (M.H.). 5. University of Toronto, Canada (M.H.). 6. Peter Munk Cardiac Centre, Toronto, Canada (M.H). 7. Yale University School of Medicine, New Haven, CT (S.E.I.). 8. University of Texas Southwestern Medical Center, Dallas (D.K.M., M.H.D.). 9. University of Michigan School of Medicine, Ann Arbor (B.P.). 10. Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (B.M.S., M.M.G.). 11. Keck School of Medicine of USC, University of Southern California, Los Angeles (M.W.F.). 12. NorthShore University, Evanston, IL (R.A.G.). 13. St. Francis Hospital, Roslyn, NY (R.J.). 14. New York University Langone Health, New York (S.D.K.). 15. First Coast Cardiovascular Institute, Jacksonville, FL (S.L.). 16. Henry Ford Hospital, Detroit, MI (D.E.L.). 17. Washington University School of Medicine, St. Louis, MO (S.J.L.). 18. Vanderbilt University, Nashville, TN (J.L.). 19. Charlotte Heart Group Research Center, Port Charlotte, FL (M.M.). 20. University of Pennsylvania, Philadelphia (K.M.). 21. Duke University, Durham, NC (R.J.M.). 22. Northwestern University, Chicago, IL (R.K.M.). 23. Heart Group of the Eastern Shore, Fairhope, AL (M.P.). 24. Emory University, Atlanta, GA (G.U.). 25. The George Institute for Global Health, Sydney, Australia (M.K.). 26. University of New South Wales, Sydney, Australia (M.K.).
Abstract
BACKGROUND: Outcome trials in patients with type 2 diabetes mellitus have demonstrated reduced hospitalizations for heart failure (HF) with sodium-glucose co-transporter-2 inhibitors. However, few of these patients had HF, and those that did were not well-characterized. Thus, the effects of sodium-glucose co-transporter-2 inhibitors in patients with established HF with reduced ejection fraction, including those with and without type 2 diabetes mellitus, remain unknown. METHODS: DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients with HF with Reduced Ejection Fraction) was an investigator-initiated, multi-center, randomized controlled trial of HFpatients with left ventricular ejection fraction ≤40%, New York Heart Association (NYHA) class II-III, estimated glomerular filtration rate ≥30 mL/min/1.73m2, and elevated natriuretic peptides. In total, 263 patients were randomized to dapagliflozin 10 mg daily or placebo for 12 weeks. Dual primary outcomes were (1) mean NT-proBNP (N-terminal pro b-type natriuretic peptide) and (2) proportion of patients with ≥5-point increase in HF disease-specific health status on the Kansas City CardiomyopathyQuestionnaire overall summary score, or a ≥20% decrease in NT-proBNP. RESULTS: Patient characteristics reflected stable, chronic HF with reduced ejection fraction with high use of optimal medical therapy. There was no significant difference in average 6- and 12-week adjusted NT-proBNP with dapagliflozin versus placebo (1133 pg/dL (95% CI 1036-1238) vs 1191 pg/dL (95% CI 1089-1304), P=0.43). For the second dual-primary outcome of a meaningful improvement in Kansas City CardiomyopathyQuestionnaire overall summary score or NT-proBNP, 61.5% of dapagliflozin-treated patients met this end point versus 50.4% with placebo (adjusted OR 1.8, 95% CI 1.03-3.06, nominal P=0.039). This was attributable to both higher proportions of patients with ≥5-point improvement in Kansas City CardiomyopathyQuestionnaire overall summary score (42.9 vs 32.5%, adjusted OR 1.73, 95% CI 0.98-3.05), and ≥20% reduction in NT-proBNP (44.0 vs 29.4%, adjusted OR 1.9, 95% CI 1.1-3.3) by 12 weeks. Results were consistent among patients with or without type 2 diabetes mellitus, and other prespecified subgroups (all P values for interaction=NS). CONCLUSIONS: In patients with heart failure and reduced ejection fraction, use of dapagliflozin over 12 weeks did not affect mean NT-proBNP but increased the proportion of patients experiencing clinically meaningful improvements in HF-related health status or natriuretic peptides. Benefits of dapagliflozin on clinically meaningful HF measures appear to extend to patients without type 2 diabetes mellitus. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02653482.
RCT Entities:
BACKGROUND: Outcome trials in patients with type 2 diabetes mellitus have demonstrated reduced hospitalizations for heart failure (HF) with sodium-glucose co-transporter-2 inhibitors. However, few of these patients had HF, and those that did were not well-characterized. Thus, the effects of sodium-glucose co-transporter-2 inhibitors in patients with established HF with reduced ejection fraction, including those with and without type 2 diabetes mellitus, remain unknown. METHODS: DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients with HF with Reduced Ejection Fraction) was an investigator-initiated, multi-center, randomized controlled trial of HF patients with left ventricular ejection fraction ≤40%, New York Heart Association (NYHA) class II-III, estimated glomerular filtration rate ≥30 mL/min/1.73m2, and elevated natriuretic peptides. In total, 263 patients were randomized to dapagliflozin 10 mg daily or placebo for 12 weeks. Dual primary outcomes were (1) mean NT-proBNP (N-terminal pro b-type natriuretic peptide) and (2) proportion of patients with ≥5-point increase in HF disease-specific health status on the Kansas City Cardiomyopathy Questionnaire overall summary score, or a ≥20% decrease in NT-proBNP. RESULTS: Patient characteristics reflected stable, chronic HF with reduced ejection fraction with high use of optimal medical therapy. There was no significant difference in average 6- and 12-week adjusted NT-proBNP with dapagliflozin versus placebo (1133 pg/dL (95% CI 1036-1238) vs 1191 pg/dL (95% CI 1089-1304), P=0.43). For the second dual-primary outcome of a meaningful improvement in Kansas City Cardiomyopathy Questionnaire overall summary score or NT-proBNP, 61.5% of dapagliflozin-treated patients met this end point versus 50.4% with placebo (adjusted OR 1.8, 95% CI 1.03-3.06, nominal P=0.039). This was attributable to both higher proportions of patients with ≥5-point improvement in Kansas City Cardiomyopathy Questionnaire overall summary score (42.9 vs 32.5%, adjusted OR 1.73, 95% CI 0.98-3.05), and ≥20% reduction in NT-proBNP (44.0 vs 29.4%, adjusted OR 1.9, 95% CI 1.1-3.3) by 12 weeks. Results were consistent among patients with or without type 2 diabetes mellitus, and other prespecified subgroups (all P values for interaction=NS). CONCLUSIONS: In patients with heart failure and reduced ejection fraction, use of dapagliflozin over 12 weeks did not affect mean NT-proBNP but increased the proportion of patients experiencing clinically meaningful improvements in HF-related health status or natriuretic peptides. Benefits of dapagliflozin on clinically meaningful HF measures appear to extend to patients without type 2 diabetes mellitus. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02653482.
Entities:
Keywords:
SGLT2 inhibitors; biomarkers; health status; heart failure; outcomes
Authors: Sandeep R Das; Brendan M Everett; Kim K Birtcher; Jenifer M Brown; James L Januzzi; Rita R Kalyani; Mikhail Kosiborod; Melissa Magwire; Pamela B Morris; Joshua J Neumiller; Laurence S Sperling Journal: J Am Coll Cardiol Date: 2020-08-05 Impact factor: 24.094
Authors: Mark C Petrie; Subodh Verma; Kieran F Docherty; Silvio E Inzucchi; Inder Anand; Jan Belohlávek; Michael Böhm; Chern-En Chiang; Vijay K Chopra; Rudolf A de Boer; Akshay S Desai; Mirta Diez; Jaroslaw Drozdz; Andre Dukát; Junbo Ge; Jonathan Howlett; Tzvetana Katova; Masafumi Kitakaze; Charlotta E A Ljungman; Béla Merkely; Jose C Nicolau; Eileen O'Meara; Pham Nguyen Vinh; Morten Schou; Sergey Tereshchenko; Lars Køber; Mikhail N Kosiborod; Anna Maria Langkilde; Felipe A Martinez; Piotr Ponikowski; Marc S Sabatine; Mikaela Sjöstrand; Scott D Solomon; Per Johanson; Peter J Greasley; David Boulton; Olof Bengtsson; Pardeep S Jhund; John J V McMurray Journal: JAMA Date: 2020-04-14 Impact factor: 56.272