Effect of empagliflozin on major heart failure outcomes and renal function in patients with heart failure with a reduced ejection fraction, with and without sacubitril/valsartan

In the EMPEROR-Reduced Trial, empagliflozin reduced cardiovascular death or HF hospitalization and slowed the progressive decline in kidney function in patients with HFrEF. We evaluated the influence of neprilysin inhibition with sacubitril/valsartan (ARNi) on the effects of SGLT2i with empagliflozin. The EMPEROR-Reduced trial randomized 3730patients with HF and an ejection fraction ≤ 40% to placebo or empagliflozin(10 mg/day), in addition to recommended treatment for HF, for a median of 16months. A total of 727patients (19.5%) received ARNi at baseline. Analysis of the effect of ARNi was 1 of 12 pre-specified subgroups. Patients receiving ARNi were particularly well-treated, as evidenced by lower systolic pressures, heart rates, NT-Pro-BNP, and greater use of cardiac devices (all P < 0.001) when compared with those not receiving ARNi. Nevertheless, when compared with placebo, empagliflozin reduced the risk of cardiovascular death or hospitalization for HF in patients receiving or not receiving ARNi [HR = 0.64 (95% CI 0.45–0.89), P = 0.009 and HR = 0.77(95% CI 0.66–0.90), P = 0.0008, respectively, interaction P = 0.31; Fig. 1]. Empagliflozin slowed the rate of decline in estimated glomerular filtration rate by 1.92 ± 0.80mL/min/1.73m2/year in patients taking ARNi (P = 0.016) and by 1.71 ± 0.35mL/min/1.73m2/year in patients not taking ARNi (P < 0.0001), interaction P = 0.81. Combined inhibition of SGLT2 and ARNi was well-tolerated. 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.