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

M. Packer*, S.D. Anker, J. Butler, G. Filippatos, J.P. Ferreira, S.J. Pocock, H.P. Brunner-La Rocca, S. Janssens, H. Tsutsui, J. Zhang, M. Brueckmann, W. Jamal, D. Cotton, T. Iwata, J. Schnee, F. Zannad, EMPEROR‐Reduced Trial Committees and Investigators

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Aims 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.Methods and results 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< 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 m(2)/year in patients taking a neprilysin inhibitor (P= 0.016) and by 1.71 +/- 0.35 mL/min/1.73 m(2)/year in patients not taking a neprilysin inhibitor (P < 0.0001), interaction P= 0.81. Combined inhibition of SGLT2 and neprilysin was well-tolerated.Conclusion 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.[GRAPHICS].
Original languageEnglish
Pages (from-to)671-680
Number of pages10
JournalEuropean Heart Journal
Issue number6
Publication statusPublished - 7 Feb 2021


  • Empagliflozin
  • Heart failure
  • Sacubitril/valsartan

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