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

• Published in: European heart journal Vol. 42; no. 6; pp. 671 - 680
• Main Authors: Packer, Milton, Anker, Stefan D, Butler, Javed, Filippatos, Gerasimos, Ferreira, Joao Pedro, Pocock, Stuart J, Rocca, Hans-Peter Brunner-La, Janssens, Stefan, Tsutsui, Hiroyuki, Zhang, Jian, Brueckmann, Martina, Jamal, Waheed, Cotton, Daniel, Iwata, Tomoko, Schnee, Janet, Zannad, Faiez
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 11.02.2021; Oxford University Press (OUP)
• Subjects: Aminobutyrates - therapeutic use; Angiotensin Receptor Antagonists - therapeutic use; Benzhydryl Compounds; Cardiology and cardiovascular system; Drug Combinations; Fast Track Clinical Research; Glucosides; Heart Failure - drug therapy; Human health and pathology; Humans; Life Sciences; Neprilysin; Stroke Volume; Tetrazoles - therapeutic use; Heart failure; Empagliflozin; Sacubitril/valsartan
• ISSN: 0195-668X; 1522-9645; 1522-9645
• DOI: 10.1093/eurheartj/ehaa968

Abstract 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 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 < 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. Graphical Abstract