The EMPEROR-Preserved trial showed that the sodium-glucose co-transporter 2 inhibitor empagliflozin significantly reduces the risk of cardiovascular death or hospitalization for heart failure (HHF) in heart failure patients with left ventricular ejection fraction (LVEF) > 40%. Here, we report the results of a pre-specified analysis that separately evaluates these patients stratified by LVEF: preserved (≥ 50%) (n = 4,005; 66.9%) or mid-range (41-49%). In patients with LVEF ≥ 50%, empagliflozin reduced the risk of cardiovascular death or HHF (the primary endpoint) by 17% versus placebo (hazard ratio (HR) 0.83; 95% confidence interval (CI): 0.71-0.98, P = 0.024). For the key secondary endpoint, the HR for total HHF was 0.83 (95%CI: 0.66-1.04, P = 0.11). For patients with an LVEF of 41-49%, the HR for empagliflozin versus placebo was 0.71 (95%CI: 0.57-0.88, P = 0.002) for the primary outcome (Pinteraction = 0.27), and 0.57 (95%CI: 0.42-0.79, P < 0.001) for total HHF (Pinteraction = 0.06). These results, together with those from the EMPEROR-Reduced trial in patients with LVEF < 40%, support the use of empagliflozin across the full spectrum of LVEF in heart failure.

1st Department of Medicine Faculty of Medicine Mannheim University of Heidelberg Mannheim Germany

Argentine Catholic University Buenos Aires Argentina

Baylor Scott and White Research Institute Dallas TX USA

Boehringer Ingelheim International Ingelheim Germany

Boehringer Ingelheim Pharma GmbH and Co KG Biberach Germany

Boehringer Ingelheim Pharmaceuticals Inc Ridgefield CT USA

Cardiology Department University Hospital CIBERCV Santiago de Compostela Spain

Cardiology Service Fundación Valle del Lili Universidad Icesi Cali Cali Colombia

Cardiovascular Department Cardiology Division Papa Giovanni XXIII Hospital Bergamo Italy

Cardiovascular Research and Development Center Department of Surgery and Physiology Faculty of Medicine of the University of Porto Porto Portugal

Central Michigan University Mount Pleasant MI USA

Department of Cardiology partner site Berlin Charité Universitätsmedizin Berlin Berlin Germany

Department of Cardiovascular Diseases University Hospitals Leuven Leuven Belgium

Department of Cardiovascular Medicine Faculty of Medical Sciences Kyushu University Fukuoka Japan

Department of Medicine Seoul National University Bundang Hospital Seoul South Korea

FLENI and IADT Institute Buenos Aires Argentina

Heart and Vascular Center Semmelweis University Budapest Hungary

Heart Failure Center Fuwai Hospital Chinese Academy of Medical Science and Peking Union Medical College Beijing China

Heart Failure Clinics Instituto do Coracao Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo Sao Paulo Brazil

Institute of Heart Diseases Wrocław Medical University Wrocław Poland

Internal Cardiology Department St Ann University Hospital and Masaryk University Brno Brno Czech Republic

London School of Hygiene and Tropical Medicine London UK

Maastricht University Medical Center Maastricht the Netherlands

Massachusetts General Hospital and Baim Institute for Clinical Research Boston MA USA

Max Superspeciality Hospital Saket New Delhi India

McGill University Health Centre Montreal Quebec Canada

National and Kapodistrian University of Athens School of Medicine Athens Greece

National Heart Centre Singapore Singapore Singapore

National Institute of Cardiology Mexico City Mexico

NIHR Biomedical Research Centre University of Leicester Glenfield Hospital Leicester UK

School for Cardiovascular Disease CARIM Maastricht the Netherlands

St Michael's Hospital University of Toronto Toronto Ontario Canada

Università di Pisa Pisa Italy

Universitätsklinikum des Saarlandes Homberg Saar Germany

Université de Lorraine INSERM Centre d'Investigations Cliniques Plurithématique 1433 and INSERM U1116 CHRU F CRIN INI CRCT Nancy France

Université de Lorraine INSERM INI CRCT CHRU Nancy France

University and Emergency Hospital Bucharest Romania

University of Medicine and Pharmacy Carol Davila Bucharest Romania

University of Mississippi Jackson MS USA

University of Mississippi Medical Center Jackson MS USA

Victorian Heart Institute Monash University Melbourne Victoria Australia

Wrocław Medical University Wrocław Poland

See more in PubMed

Kelly JP, et al. Patient selection in heart failure with preserved ejection fraction clinical trials. J. Am. Coll. Cardiol. 2015;65:1668–1682. doi: 10.1016/j.jacc.2015.03.043. PubMed DOI PMC

Ponikowski P, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur. J. Heart Fail. 2016;18:891–975. doi: 10.1002/ejhf.592. PubMed DOI

Bozkurt B, et al. Universal definition and classification of heart failure: a report of the Heart Failure Society of America, Heart Failure Association of the European Society of Cardiology, Japanese Heart Failure Society and Writing Committee of the Universal Definition of Heart Failure. J. Card. Fail. 2021;27:387–413. doi: 10.1016/j.cardfail.2021.01.022. PubMed DOI

McDonagh TA, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur. Heart J. 2021;42:3599–3726. doi: 10.1093/eurheartj/ehab368. PubMed DOI

Solomon SD, et al. Angiotensin–neprilysin inhibition in heart failure with preserved ejection fraction. N. Engl. J. Med. 2019;381:1609–1620. doi: 10.1056/NEJMoa1908655. PubMed DOI

Pitt B, et al. Spironolactone for heart failure with preserved ejection fraction. N. Engl. J. Med. 2014;370:1383–1392. doi: 10.1056/NEJMoa1313731. PubMed DOI

Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet. 2003;362:777–781. doi: 10.1016/S0140-6736(03)14285-7. PubMed DOI

Solomon SD, et al. Influence of ejection fraction on outcomes and efficacy of spironolactone in patients with heart failure with preserved ejection fraction. Eur. Heart J. 2016;37:455–462. doi: 10.1093/eurheartj/ehv464. PubMed DOI PMC

Lund LH, et al. Heart failure with mid-range ejection fraction in CHARM: characteristics, outcomes and effect of candesartan across the entire ejection fraction spectrum. Eur. J. Heart Fail. 2018;20:1230–1239. doi: 10.1002/ejhf.1149. PubMed DOI

Anker SD, et al. Empagliflozin in heart failure with a preserved ejection fraction. N. Engl. J. Med. 2021;385:1451–1461. doi: 10.1056/NEJMoa2107038. PubMed DOI

Butler J, et al. Empagliflozin, health status, and quality of life in patients with heart failure and preserved ejection fraction: the EMPEROR-Preserved trial. Circulation. 2022;145:184–193. doi: 10.1161/CIRCULATIONAHA.121.057812. PubMed DOI PMC

Solomon SD, et al. Sacubitril/valsartan across the spectrum of ejection fraction in heart failure. Circulation. 2020;141:352–361. doi: 10.1161/CIRCULATIONAHA.119.044586. PubMed DOI

Packer M, Zannad F, Anker SD. Heart failure and a preserved ejection fraction: a side-by-side examination of the PARAGON-HF and EMPEROR-Preserved trials. Circulation. 2021;144:1193–1195. doi: 10.1161/CIRCULATIONAHA.121.056657. PubMed DOI

Packer M, et al. Effect of empagliflozin on worsening heart failure events in patients with heart failure and preserved ejection fraction: EMPEROR-Preserved trial. Circulation. 2021;144:1284–1294. doi: 10.1161/CIRCULATIONAHA.121.056824. PubMed DOI PMC

Butler J, et al. Effect of empagliflozin in patients with heart failure across the spectrum of left ventricular ejection fraction. Eur. Heart J. 2022;43:416–426. doi: 10.1093/eurheartj/ehab798. PubMed DOI PMC

Bhatt, D. et al. Benefits of SGLT1/2 inhibition with sotagliflozin in heart failure with preserved ejection fraction. In The American College of Cardiology (ACC) 70th Annual Scientific Session & Expo Virtual Experience; May 15–17, 2021https://www.acc.org/education-and-meetings/image-and-slide-gallery/~/media/B0EE906FD2D34B6AA29900BCE0681B8E.pdf (2021).

Nassif ME, et al. The SGLT2 inhibitor dapagliflozin in heart failure with preserved ejection fraction: a multicenter randomized trial. Nat. Med. 2021;27:1954–1960. doi: 10.1038/s41591-021-01536-x. PubMed DOI PMC

Solomon SD, et al. Dapagliflozin in heart failure with preserved and mildly reduced ejection fraction: rationale and design of the DELIVER trial. Eur. J. Heart Fail. 2021;23:1217–1225. doi: 10.1002/ejhf.2249. PubMed DOI PMC

Lam CS, Solomon SD. The middle child in heart failure: heart failure with mid-range ejection fraction (40–50%) Eur. J. Heart Fail. 2014;16:1049–1055. doi: 10.1002/ejhf.159. PubMed DOI

Butler J, Anker SD, Packer M. Redefining heart failure with a reduced ejection fraction. JAMA. 2019;322:1761–1762. doi: 10.1001/jama.2019.15600. PubMed DOI

Anker SD, et al. Evaluation of the effects of sodium-glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality in patients with chronic heart failure and a preserved ejection fraction: rationale for and design of the EMPEROR-Preserved Trial. Eur. J. Heart Fail. 2019;21:1279–1287. doi: 10.1002/ejhf.1596. PubMed DOI

Mishra RK, et al. Kansas City Cardiomyopathy Questionnaire score is associated with incident heart failure hospitalization in patients with chronic kidney disease without previously diagnosed heart failure: Chronic Renal Insufficiency Cohort Study. Circ. Heart Fail. 2015;8:702–708. doi: 10.1161/CIRCHEARTFAILURE.115.002097. PubMed DOI PMC

Savarese G, Stolfo D, Sinagra G, Lund LH. Heart failure with mid-range or mildly reduced ejection fraction. Nat. Rev. Cardiol. 2022;19:100–116. doi: 10.1038/s41569-021-00605-5. PubMed DOI PMC

Massie BM, et al. Irbesartan in patients with heart failure and preserved ejection fraction. N. Engl. J. Med. 2008;359:2456–2467. doi: 10.1056/NEJMoa0805450. PubMed DOI

Lin DY, Wei LJ, Yang I, Ying Z. Semiparametric regression for the mean and rate functions of recurrent events. J. R. Stat. Soc. Ser. B Stat. Methodol. 2000;62:711–730. doi: 10.1111/1467-9868.00259. DOI