Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart Failure With Reduced Ejection Fraction: The DEFINE-HF Trial

Michael E. Nassif, Sheryl L. Windsor, Fengming Tang, Yevgeniy Khariton, Mansoor Husain, Silvio E. Inzucchi, Darren K. Mc-Guire, Bertram Pitt, Benjamin M. Scirica, Bethany Austin, Mark H. Drazner, Michael W. Fong, Michael M. Givertz, Robert A. Gordon, Rita Jermyn, Stuart D. Katz, Sumant Lamba, David E. Lanfear, Shane J. LaRue, Jo Ann LindenfeldMichael Malone, Kenneth Margulies, Robert J. Mentz, R. Kannan Mutharasan, Michael Pursley, Guillermo Umpierrez, Mikhail Kosiborod

Research output: Contribution to journalArticle

5 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)1463-1476
Number of pages14
JournalCirculation
Volume140
Issue number18
DOIs
StatePublished - Oct 29 2019

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Heart Failure
Biomarkers
Natriuretic Peptides
Type 2 Diabetes Mellitus
Sodium-Glucose Transporter 2
Cardiomyopathies
Symporters
Placebos
2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol
Health Status
Glomerular Filtration Rate
Stroke Volume
Heart Diseases
Hospitalization
Randomized Controlled Trials
Research Personnel
Clinical Trials

Keywords

  • SGLT2 inhibitors
  • biomarkers
  • health status
  • heart failure
  • outcomes

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Nassif, Michael E. ; Windsor, Sheryl L. ; Tang, Fengming ; Khariton, Yevgeniy ; Husain, Mansoor ; Inzucchi, Silvio E. ; Mc-Guire, Darren K. ; Pitt, Bertram ; Scirica, Benjamin M. ; Austin, Bethany ; Drazner, Mark H. ; Fong, Michael W. ; Givertz, Michael M. ; Gordon, Robert A. ; Jermyn, Rita ; Katz, Stuart D. ; Lamba, Sumant ; Lanfear, David E. ; LaRue, Shane J. ; Lindenfeld, Jo Ann ; Malone, Michael ; Margulies, Kenneth ; Mentz, Robert J. ; Mutharasan, R. Kannan ; Pursley, Michael ; Umpierrez, Guillermo ; Kosiborod, Mikhail. / Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart Failure With Reduced Ejection Fraction : The DEFINE-HF Trial. In: Circulation. 2019 ; Vol. 140, No. 18. pp. 1463-1476.
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title = "Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart Failure With Reduced Ejection Fraction: The DEFINE-HF Trial",
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 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.",
keywords = "SGLT2 inhibitors, biomarkers, health status, heart failure, outcomes",
author = "Nassif, {Michael E.} and Windsor, {Sheryl L.} and Fengming Tang and Yevgeniy Khariton and Mansoor Husain and Inzucchi, {Silvio E.} and Mc-Guire, {Darren K.} and Bertram Pitt and Scirica, {Benjamin M.} and Bethany Austin and Drazner, {Mark H.} and Fong, {Michael W.} and Givertz, {Michael M.} and Gordon, {Robert A.} and Rita Jermyn and Katz, {Stuart D.} and Sumant Lamba and Lanfear, {David E.} and LaRue, {Shane J.} and Lindenfeld, {Jo Ann} and Michael Malone and Kenneth Margulies and Mentz, {Robert J.} and Mutharasan, {R. Kannan} and Michael Pursley and Guillermo Umpierrez and Mikhail Kosiborod",
year = "2019",
month = "10",
day = "29",
doi = "10.1161/CIRCULATIONAHA.119.042929",
language = "English (US)",
volume = "140",
pages = "1463--1476",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "18",

}

Nassif, ME, Windsor, SL, Tang, F, Khariton, Y, Husain, M, Inzucchi, SE, Mc-Guire, DK, Pitt, B, Scirica, BM, Austin, B, Drazner, MH, Fong, MW, Givertz, MM, Gordon, RA, Jermyn, R, Katz, SD, Lamba, S, Lanfear, DE, LaRue, SJ, Lindenfeld, JA, Malone, M, Margulies, K, Mentz, RJ, Mutharasan, RK, Pursley, M, Umpierrez, G & Kosiborod, M 2019, 'Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart Failure With Reduced Ejection Fraction: The DEFINE-HF Trial', Circulation, vol. 140, no. 18, pp. 1463-1476. https://doi.org/10.1161/CIRCULATIONAHA.119.042929

Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart Failure With Reduced Ejection Fraction : The DEFINE-HF Trial. / Nassif, Michael E.; Windsor, Sheryl L.; Tang, Fengming; Khariton, Yevgeniy; Husain, Mansoor; Inzucchi, Silvio E.; Mc-Guire, Darren K.; Pitt, Bertram; Scirica, Benjamin M.; Austin, Bethany; Drazner, Mark H.; Fong, Michael W.; Givertz, Michael M.; Gordon, Robert A.; Jermyn, Rita; Katz, Stuart D.; Lamba, Sumant; Lanfear, David E.; LaRue, Shane J.; Lindenfeld, Jo Ann; Malone, Michael; Margulies, Kenneth; Mentz, Robert J.; Mutharasan, R. Kannan; Pursley, Michael; Umpierrez, Guillermo; Kosiborod, Mikhail.

In: Circulation, Vol. 140, No. 18, 29.10.2019, p. 1463-1476.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart Failure With Reduced Ejection Fraction

T2 - The DEFINE-HF Trial

AU - Nassif, Michael E.

AU - Windsor, Sheryl L.

AU - Tang, Fengming

AU - Khariton, Yevgeniy

AU - Husain, Mansoor

AU - Inzucchi, Silvio E.

AU - Mc-Guire, Darren K.

AU - Pitt, Bertram

AU - Scirica, Benjamin M.

AU - Austin, Bethany

AU - Drazner, Mark H.

AU - Fong, Michael W.

AU - Givertz, Michael M.

AU - Gordon, Robert A.

AU - Jermyn, Rita

AU - Katz, Stuart D.

AU - Lamba, Sumant

AU - Lanfear, David E.

AU - LaRue, Shane J.

AU - Lindenfeld, Jo Ann

AU - Malone, Michael

AU - Margulies, Kenneth

AU - Mentz, Robert J.

AU - Mutharasan, R. Kannan

AU - Pursley, Michael

AU - Umpierrez, Guillermo

AU - Kosiborod, Mikhail

PY - 2019/10/29

Y1 - 2019/10/29

N2 - 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.

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 ≤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.

KW - SGLT2 inhibitors

KW - biomarkers

KW - health status

KW - heart failure

KW - outcomes

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