Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart Failure With Reduced Ejection Fraction
Authors: Nassif Michael E. , Windsor Sheryl L. , Tang Fengming , Khariton Yevgeniy , Husain Mansoor , Inzucchi Silvio E. , McGuire 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 JoAnn , Malone Michael , Margulies Kenneth , Mentz Robert J. , Mutharasan R. Kannan , Pursley Michael , Umpierrez Guillermo , Kosiborod Mikhail ,   On behalf of the DEFINE-HF Investigators, Malik Ali O. , Wenger Nannette , Ogunniyi Modele , Vellanki Priyathama , Murphy Brenda , Newman Jonathan , Hartupee Justin , Gupta Charu , Goldsmith Marcela , Baweja Paramdeep , Montero Manuel , Gottlieb Stephen S. , Costanzo Maria Rosa , Hoang Thanh , Warnock Alicia , Allen Larry , Tang Wilson , Chen Horng H. , Cox John M. 
Published: September 2019

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/1.73m
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: NCT 02653482.