{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T02:35:10Z","timestamp":1792722910738,"version":"4.5.0"},"reference-count":30,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"18","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2019,10,29]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      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 \u226440%, New York Heart Association (NYHA) class II-III, estimated glomerular filtration rate \u226530 mL\/min\/1.73m\n                      <jats:sup>2<\/jats:sup>\n                      , 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 \u22655-point increase in HF disease-specific health status on the Kansas City Cardiomyopathy Questionnaire overall summary score, or a \u226520% decrease in NT-proBNP.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      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\u20131238) vs 1191 pg\/dL (95% CI 1089\u20131304),\n                      <jats:italic>P<\/jats:italic>\n                      =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\n                      <jats:italic>P<\/jats:italic>\n                      =0.039). This was attributable to both higher proportions of patients with \u22655-point improvement in Kansas City Cardiomyopathy Questionnaire overall summary score (42.9 vs 32.5%, adjusted OR 1.73, 95% CI 0.98\u20133.05), and \u226520% reduction in NT-proBNP (44.0 vs 29.4%, adjusted OR 1.9, 95% CI 1.1\u20133.3) by 12 weeks. Results were consistent among patients with or without type 2 diabetes mellitus, and other prespecified subgroups (all\n                      <jats:italic>P<\/jats:italic>\n                      values for interaction=NS).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical Trial Registration:<\/jats:title>\n                    <jats:p>\n                      URL:\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.clinicaltrials.gov\">https:\/\/www.clinicaltrials.gov<\/jats:ext-link>\n                      . Unique identifier: NCT 02653482.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.119.042929","type":"journal-article","created":{"date-parts":[[2019,9,16]],"date-time":"2019-09-16T10:40:07Z","timestamp":1568630407000},"page":"1463-1476","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":379,"title":["Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart Failure With Reduced Ejection Fraction"],"prefix":"10.1161","volume":"140","author":[{"given":"Michael E.","family":"Nassif","sequence":"first","affiliation":[{"name":"Saint Luke\u2019s Mid America Heart Institute, Kansas City, MO (M.E.N., S.L.W., F.T., Y.K., B.A., M.K.)."},{"name":"University of Missouri-Kansas City, MO (M.E.N., Y.K., B.A., M.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheryl L.","family":"Windsor","sequence":"additional","affiliation":[{"name":"Saint Luke\u2019s Mid America Heart Institute, Kansas City, MO (M.E.N., S.L.W., F.T., Y.K., B.A., M.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengming","family":"Tang","sequence":"additional","affiliation":[{"name":"Saint Luke\u2019s Mid America Heart Institute, Kansas City, MO (M.E.N., S.L.W., F.T., Y.K., B.A., M.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yevgeniy","family":"Khariton","sequence":"additional","affiliation":[{"name":"Saint Luke\u2019s Mid America Heart Institute, Kansas City, MO (M.E.N., S.L.W., F.T., Y.K., B.A., M.K.)."},{"name":"University of Missouri-Kansas City, MO (M.E.N., Y.K., B.A., M.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mansoor","family":"Husain","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network, Toronto, Canada (M.H.)."},{"name":"Ted Rogers Centre for Heart Research, Toronto, Canada (M.H.)."},{"name":"University 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