PMID- 31524498 OWN - NLM STAT- MEDLINE DCOM- 20200617 LR - 20210504 IS - 1524-4539 (Electronic) IS - 0009-7322 (Linking) VI - 140 IP - 18 DP - 2019 Oct 29 TI - Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart Failure With Reduced Ejection Fraction: The DEFINE-HF Trial. PG - 1463-1476 LID - 10.1161/CIRCULATIONAHA.119.042929 [doi] AB - 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 /=30 mL/min/1.73m(2), 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. FAU - Nassif, Michael E AU - Nassif ME AD - Saint Luke's Mid America Heart Institute, Kansas City, MO (M.E.N., S.L.W., F.T., Y.K., B.A., M.K.). AD - University of Missouri-Kansas City, MO (M.E.N., Y.K., B.A., M.K.). FAU - Windsor, Sheryl L AU - Windsor SL AD - Saint Luke's Mid America Heart Institute, Kansas City, MO (M.E.N., S.L.W., F.T., Y.K., B.A., M.K.). FAU - Tang, Fengming AU - Tang F AD - Saint Luke's Mid America Heart Institute, Kansas City, MO (M.E.N., S.L.W., F.T., Y.K., B.A., M.K.). FAU - Khariton, Yevgeniy AU - Khariton Y AD - Saint Luke's Mid America Heart Institute, Kansas City, MO (M.E.N., S.L.W., F.T., Y.K., B.A., M.K.). AD - University of Missouri-Kansas City, MO (M.E.N., Y.K., B.A., M.K.). FAU - Husain, Mansoor AU - Husain M AD - Toronto General Hospital Research Institute, University Health Network, Toronto, Canada (M.H.). AD - Ted Rogers Centre for Heart Research, Toronto, Canada (M.H.). AD - University of Toronto, Canada (M.H.). AD - Peter Munk Cardiac Centre, Toronto, Canada (M.H). FAU - Inzucchi, Silvio E AU - Inzucchi SE AD - Yale University School of Medicine, New Haven, CT (S.E.I.). FAU - McGuire, Darren K AU - McGuire DK AD - University of Texas Southwestern Medical Center, Dallas (D.K.M., M.H.D.). FAU - Pitt, Bertram AU - Pitt B AD - University of Michigan School of Medicine, Ann Arbor (B.P.). FAU - Scirica, Benjamin M AU - Scirica BM AD - Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (B.M.S., M.M.G.). FAU - Austin, Bethany AU - Austin B AD - Saint Luke's Mid America Heart Institute, Kansas City, MO (M.E.N., S.L.W., F.T., Y.K., B.A., M.K.). AD - University of Missouri-Kansas City, MO (M.E.N., Y.K., B.A., M.K.). FAU - Drazner, Mark H AU - Drazner MH AD - University of Texas Southwestern Medical Center, Dallas (D.K.M., M.H.D.). FAU - Fong, Michael W AU - Fong MW AD - Keck School of Medicine of USC, University of Southern California, Los Angeles (M.W.F.). FAU - Givertz, Michael M AU - Givertz MM AD - Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (B.M.S., M.M.G.). FAU - Gordon, Robert A AU - Gordon RA AD - NorthShore University, Evanston, IL (R.A.G.). FAU - Jermyn, Rita AU - Jermyn R AD - St. Francis Hospital, Roslyn, NY (R.J.). FAU - Katz, Stuart D AU - Katz SD AD - New York University Langone Health, New York (S.D.K.). FAU - Lamba, Sumant AU - Lamba S AD - First Coast Cardiovascular Institute, Jacksonville, FL (S.L.). FAU - Lanfear, David E AU - Lanfear DE AD - Henry Ford Hospital, Detroit, MI (D.E.L.). FAU - LaRue, Shane J AU - LaRue SJ AD - Washington University School of Medicine, St. Louis, MO (S.J.L.). FAU - Lindenfeld, JoAnn AU - Lindenfeld J AD - Vanderbilt University, Nashville, TN (J.L.). FAU - Malone, Michael AU - Malone M AD - Charlotte Heart Group Research Center, Port Charlotte, FL (M.M.). FAU - Margulies, Kenneth AU - Margulies K AD - University of Pennsylvania, Philadelphia (K.M.). FAU - Mentz, Robert J AU - Mentz RJ AD - Duke University, Durham, NC (R.J.M.). FAU - Mutharasan, R Kannan AU - Mutharasan RK AD - Northwestern University, Chicago, IL (R.K.M.). FAU - Pursley, Michael AU - Pursley M AD - Heart Group of the Eastern Shore, Fairhope, AL (M.P.). FAU - Umpierrez, Guillermo AU - Umpierrez G AD - Emory University, Atlanta, GA (G.U.). FAU - Kosiborod, Mikhail AU - Kosiborod M AD - Saint Luke's Mid America Heart Institute, Kansas City, MO (M.E.N., S.L.W., F.T., Y.K., B.A., M.K.). AD - University of Missouri-Kansas City, MO (M.E.N., Y.K., B.A., M.K.). AD - The George Institute for Global Health, Sydney, Australia (M.K.). AD - University of New South Wales, Sydney, Australia (M.K.). LA - eng SI - ClinicalTrials.gov/NCT02653482 GR - P30 DK111024/DK/NIDDK NIH HHS/United States PT - Clinical Trial PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190916 PL - United States TA - Circulation JT - Circulation JID - 0147763 RN - 0 (Benzhydryl Compounds) RN - 0 (Biomarkers) RN - 0 (Glucosides) RN - 1ULL0QJ8UC (dapagliflozin) SB - IM MH - Aged MH - Benzhydryl Compounds/*pharmacology MH - Biomarkers/analysis MH - Diabetes Mellitus, Type 2/complications/*drug therapy MH - Female MH - Glucosides/*pharmacology MH - Heart Failure/*drug therapy/physiopathology MH - Humans MH - Male MH - Middle Aged MH - Stroke Volume/*drug effects MH - Ventricular Dysfunction, Left/*drug therapy MH - Ventricular Function, Left/drug effects OTO - NOTNLM OT - SGLT2 inhibitors OT - biomarkers OT - health status OT - heart failure OT - outcomes EDAT- 2019/09/17 06:00 MHDA- 2020/06/18 06:00 CRDT- 2019/09/17 06:00 PHST- 2019/09/17 06:00 [pubmed] PHST- 2020/06/18 06:00 [medline] PHST- 2019/09/17 06:00 [entrez] AID - 10.1161/CIRCULATIONAHA.119.042929 [doi] PST - ppublish SO - Circulation. 2019 Oct 29;140(18):1463-1476. doi: 10.1161/CIRCULATIONAHA.119.042929. Epub 2019 Sep 16.