Empagliflozin in heart failure patients with reduced ejection fraction: a randomized clinical trial (Empire HF)

Jesper Jensen, Massar Omar, Caroline Kistorp, Mikael Kjær Poulsen, Christian Tuxen, Ida Gustafsson, Lars Køber, Finn Gustafsson, Emil Fosbøl, Niels Eske Bruun, Lars Videbæk, Peter Hartmund Frederiksen, Jacob Eifer Møller, Morten Schou, Jesper Jensen, Massar Omar, Caroline Kistorp, Mikael Kjær Poulsen, Christian Tuxen, Ida Gustafsson, Lars Køber, Finn Gustafsson, Emil Fosbøl, Niels Eske Bruun, Lars Videbæk, Peter Hartmund Frederiksen, Jacob Eifer Møller, Morten Schou

Abstract

Background: Data from recent cardiovascular outcome trials in patients with type 2 diabetes (T2D) suggest that sodium-glucose cotransporter 2 (SGLT2) inhibitors can prevent development of heart failure (HF) and prolong life in patients without HF. Ongoing event-driven trials are investigating whether the same effect is present in patients with well-defined HF. The mechanism behind the effect of SGLT2 inhibitors in patients with T2D and the potential effect in patients with overt HF is presently unknown.

Methods: This is a randomized, double-blinded, placebo-controlled, parallel group, clinical trial including HF patients with reduced left ventricular ejection fraction (HFrEF) with an ejection fraction ≤ 40% on optimal therapy recruited from specialized HF clinics in Denmark. The primary aim is to investigate the effect of the SGLT2 inhibitor empagliflozin on N-terminal pro-brain natriuretic peptide (NT-proBNP). Secondary endpoints include cardiac biomarkers, function and hemodynamics, metabolic and renal parameters, daily activity level, and quality of life. Patients are assigned 1:1 to 90 days treatment with empagliflozin 10 mg daily or placebo. Patients with T2D are required to be on recommended doses of anti-glycemic therapy with a hemoglobin A1c (HbA1c) of 6.5-10.0% (48-86 mmol/mol). To show a between-group difference in the change of NT-proBNP of 30%, a total of 189 patients will be included.

Discussion: The Empire HF trial will elucidate the effects and modes of action of empagliflozin in HFrEF patients with and without T2D and provide important mechanistic data which will complement ongoing event-driven trials.

Trial registration: Clinicaltrialsregister.eu, EudraCT Number 2017-001341-27 . Registered on 29 May 2017. ClinicalTrials.gov, NCT03198585 . Registered on 26 June 2017.

Keywords: Cardiac function; Daily activity level; Heart failure; Mechanism; Metabolic endpoints; Mode of action; NT-proBNP; Quality of life; Renal endpoints; SGLT2 inhibitors.

Conflict of interest statement

JJ, MO, CK, MKP, CT, IG, LK, EF, NEB, LV, PHF, and JEM declare no conflicts of interest. FG reports lecture fee from Boehringer Ingelheim. MS reports lecture fee from Novo Nordisk and Boehringer Ingelheim.

Figures

Fig. 1
Fig. 1
Empire HF hypotheses. SGLT2 sodium-glucose cotransporter 2, GFR glomerular filtration rate, eECV estimated extracellular volume, ePV estimated plasma volume, UACR urine albumin to creatinine ratio, NT-proBNP N-terminal pro-brain natriuretic peptide, MR-proADM mid-region pro-peptide of adrenomedullin, hs-cTNI high-sensitivity cardiac troponin I, LV left ventricular, KCCQ Kansas City cardiomyopathy questionnaire, EQ-5D-5 L EuroQol 5-dimension 5-level
Fig. 2
Fig. 2
Schedule of enrolment, interventions, and assessments in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT). #Only performed in the patients enrolled at Herlev-Gentofte Hospital. *Only performed in a sub-group of the patients enrolled at Odense University Hospital. ECG electrocardiogram, OGTT oral glucose tolerance test, DXA dual-energy X-ray absorptiometry, 51Cr-EDTA chromium-51 labeled ethylenediamine tetra-acetic acid. AE adverse event, SAE severe adverse event, IP investigational product

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