{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T06:26:24Z","timestamp":1773901584367,"version":"3.50.1"},"reference-count":22,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2021,1,11]],"date-time":"2021-01-11T00:00:00Z","timestamp":1610323200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100001003","name":"Boehringer Ingelheim","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001003","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004312","name":"Eli Lilly and Company","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004312","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,2,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>We evaluated the influence of sacubitril\/valsartan on the effects of sodium-glucose cotransporter 2 (SGLT2) inhibition with empagliflozin in patients with heart failure and a reduced ejection fraction.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>The EMPEROR-Reduced trial randomized 3730 patients with heart failure and an ejection fraction \u226440% to placebo or empagliflozin (10\u2009mg\/day), in addition to recommended treatment for heart failure, for a median of 16\u2009months. A total of 727 patients (19.5%) received sacubitril\/valsartan at baseline. Analysis of the effect of neprilysin inhibition was 1 of 12 pre-specified subgroups. Patients receiving a neprilysin inhibitor were particularly well-treated, as evidenced by lower systolic pressures, heart rates, N-terminal prohormone B-type natriuretic peptide, and greater use of cardiac devices (all P\u2009&amp;lt;\u20090.001) when compared with those not receiving sacubitril\/valsartan. Nevertheless, when compared with placebo, empagliflozin reduced the risk of cardiovascular death or hospitalization for heart failure in patients receiving or not receiving sacubitril\/valsartan [hazard ratio 0.64 (95% CI 0.45\u20130.89), P\u2009=\u20090.009 and hazard ratio 0.77 (95% CI 0.66\u20130.90), P\u2009=\u20090.0008, respectively, interaction P\u2009=\u20090.31]. Empagliflozin slowed the rate of decline in estimated glomerular filtration rate by 1.92\u2009\u00b1\u20090.80\u2009mL\/min\/1.73 m2\/year in patients taking a neprilysin inhibitor (P\u2009=\u20090.016) and by 1.71\u2009\u00b1\u20090.35\u2009mL\/min\/1.73 m2\/year in patients not taking a neprilysin inhibitor (P\u2009&amp;lt;\u20090.0001), interaction P\u2009=\u20090.81. Combined inhibition of SGLT2 and neprilysin was well-tolerated.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>The effects on empagliflozin to reduce the risk of heart failure and renal events are not diminished in intensively treated patients who are receiving sacubitril\/valsartan. Combined treatment with both SGLT2 and neprilysin inhibitors can be expected to yield substantial additional benefits.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/eurheartj\/ehaa968","type":"journal-article","created":{"date-parts":[[2020,11,12]],"date-time":"2020-11-12T04:15:26Z","timestamp":1605154526000},"page":"671-680","source":"Crossref","is-referenced-by-count":118,"title":["Influence of neprilysin inhibition on the efficacy and safety of empagliflozin in patients with chronic heart failure and a reduced ejection fraction: the EMPEROR-Reduced trial"],"prefix":"10.1093","volume":"42","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1828-2387","authenticated-orcid":false,"given":"Milton","family":"Packer","sequence":"first","affiliation":[{"name":"Baylor Heart and Vascular Institute, Baylor University Medical Center , 621 N. Hall Street, Dallas, TX, USA"},{"name":"Imperial College , London, UK"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3331-7314","authenticated-orcid":false,"given":"Stefan D","family":"Anker","sequence":"additional","affiliation":[{"name":"Department of Cardiology (CVK), and Berlin Institute of Health Center for Regenerative Therapies, German Centre for Cardiovascular Research Partner Site Berlin, Charit\u00e9 Universit\u00e4tsmedizin , Berlin, Germany"}]},{"given":"Javed","family":"Butler","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Mississippi School of Medicine , Jackson, MS, USA"}]},{"given":"Gerasimos","family":"Filippatos","sequence":"additional","affiliation":[{"name":"National and Kapodistrian, University of Athens School of Medicine, Athens University Hospital Attikon , Athens, Greece"}]},{"given":"Joao Pedro","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Lorraine, Inserm INI-CRCT, CHRU , Nancy, France"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2212-4007","authenticated-orcid":false,"given":"Stuart J","family":"Pocock","sequence":"additional","affiliation":[{"name":"Department of Medical Statistics, London School of Hygiene and Tropical Medicine , London, UK"}]},{"given":"Hans-Peter Brunner-La","family":"Rocca","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Maastricht University Medical Center , Maastricht, The Netherlands"}]},{"given":"Stefan","family":"Janssens","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Hospital Gasthuisberg of Leuven , Leuven, Belgium"}]},{"given":"Hiroyuki","family":"Tsutsui","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Kyushu University , Higashi-ku, Fukuoka, Japan"}]},{"given":"Jian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing, People\u2019s Republic of China"}]},{"given":"Martina","family":"Brueckmann","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim International GmbH and Faculty of Medicine Mannheim, University of Heidelberg , Mannheim, Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9133-8450","authenticated-orcid":false,"given":"Waheed","family":"Jamal","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim International GmbH , Ingelheim, Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1411-7993","authenticated-orcid":false,"given":"Daniel","family":"Cotton","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim Pharmaceuticals, Inc , Ridgefield, CT, USA"}]},{"given":"Tomoko","family":"Iwata","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim Pharma GmbH & Co. KG , Biberach, Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6041-5839","authenticated-orcid":false,"given":"Janet","family":"Schnee","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim Pharmaceuticals, Inc , Ridgefield, CT, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7456-1570","authenticated-orcid":false,"given":"Faiez","family":"Zannad","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Lorraine, Inserm INI-CRCT, CHRU , Nancy, France"}]},{"name":"for the EMPEROR-Reduced Trial Committees and Investigators","sequence":"additional","affiliation":[]}],"member":"286","published-online":{"date-parts":[[2021,1,11]]},"reference":[{"key":"2022102513281331900_ehaa968-B1","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1056\/NEJMoa1409077","article-title":"Angiotensin-neprilysin inhibition versus enalapril in heart failure","volume":"371","author":"McMurray","year":"2014","journal-title":"N Engl J Med"},{"key":"2022102513281331900_ehaa968-B2","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1056\/NEJMoa1911303","article-title":"DAPA-HF Trial Committees and Investigators. 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