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

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] .

Automated summary

The combination treatment of sacubitril/valsartan and empagliflozin in heart failure patients has been shown to reduce cardiovascular death or hospitalization risk, maintain stable glomerular filtration rate, and the effects are not diminished by intensive treatment.