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(10mg/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; Figure 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.