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

  • Milton Packer
    Baylor Heart and Vascular Institute, Baylor University Medical Center , 621 N. Hall Street, Dallas, TX, USA
  • Stefan D Anker
    Department of Cardiology (CVK), and Berlin Institute of Health Center for Regenerative Therapies, German Centre for Cardiovascular Research Partner Site Berlin, Charité Universitätsmedizin , Berlin, Germany
  • Javed Butler
    Department of Medicine, University of Mississippi School of Medicine , Jackson, MS, USA
  • Gerasimos Filippatos
    National and Kapodistrian, University of Athens School of Medicine, Athens University Hospital Attikon , Athens, Greece
  • Joao Pedro Ferreira
    Université de Lorraine, Inserm INI-CRCT, CHRU , Nancy, France
  • Stuart J Pocock
    Department of Medical Statistics, London School of Hygiene and Tropical Medicine , London, UK
  • Hans-Peter Brunner-La Rocca
    Department of Cardiology, Maastricht University Medical Center , Maastricht, The Netherlands
  • Stefan Janssens
    Department of Cardiology, University Hospital Gasthuisberg of Leuven , Leuven, Belgium
  • Hiroyuki Tsutsui
    Department of Cardiovascular Medicine, Kyushu University , Higashi-ku, Fukuoka, Japan
  • Jian Zhang
    Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing, People’s Republic of China
  • Martina Brueckmann
    Boehringer Ingelheim International GmbH and Faculty of Medicine Mannheim, University of Heidelberg , Mannheim, Germany
  • Waheed Jamal
    Boehringer Ingelheim International GmbH , Ingelheim, Germany
  • Daniel Cotton
    Boehringer Ingelheim Pharmaceuticals, Inc , Ridgefield, CT, USA
  • Tomoko Iwata
    Boehringer Ingelheim Pharma GmbH & Co. KG , Biberach, Germany
  • Janet Schnee
    Boehringer Ingelheim Pharmaceuticals, Inc , Ridgefield, CT, USA
  • Faiez Zannad
    Université de Lorraine, Inserm INI-CRCT, CHRU , Nancy, France

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<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Aims</jats:title> <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> </jats:sec> <jats:sec> <jats:title>Methods and results</jats:title> <jats:p>The EMPEROR-Reduced trial randomized 3730 patients with heart failure and an ejection fraction ≤40% to placebo or empagliflozin (10 mg/day), in addition to recommended treatment for heart failure, for a median of 16 months. 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 &lt; 0.001) 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 0.45–0.89), P = 0.009 and hazard ratio 0.77 (95% CI 0.66–0.90), P = 0.0008, respectively, interaction P = 0.31]. Empagliflozin slowed the rate of decline in estimated glomerular filtration rate by 1.92 ± 0.80 mL/min/1.73 m2/year in patients taking a neprilysin inhibitor (P = 0.016) and by 1.71 ± 0.35 mL/min/1.73 m2/year in patients not taking a neprilysin inhibitor (P &lt; 0.0001), interaction P = 0.81. Combined inhibition of SGLT2 and neprilysin was well-tolerated.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion</jats:title> <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> </jats:sec>

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