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

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.

Rapid evidence‐based sequencing of foundational drugs for heart failure and a reduced ejection fraction

“… 27 , 28 , 29 Finally, in the two trials of SGLT2 inhibitors in heart failure with a reduced ejection fraction, background therapy with a neprilysin inhibitor did not minimize the benefits of treatment with dapagliflozin and empagliflozin. 33 , 60 Background therapy has influenced the effects of the study medication only when the treatments unequivocally interfered with the same pathophysiological pathway (i.e. angiotensin‐converting enzyme inhibitors, angiotensin receptor blockers and renin inhibitors).…”

Optimizing sodium-glucose co-transporter 2 inhibitor use in patients with heart failure with reduced ejection fraction: A collaborative clinical practice statement

“…[ 36 , 37 ] It is important to note that these cardio-renal benefits occurred despite high utilization rates of standard GDMT (~92% treated with ACEI/ARB/ARNI, ~95% with a β-blocker, and ~71% with a MRA), and were maintained regardless of background HFrEF GDMT (including ARNI use) or achieved GDMT target doses (≥50% or <50%). [38] , [39] , [40] , [41] , [42] Finally, reductions in adverse clinical outcomes were discernible within weeks of SGLT2i initiation, which is very relevant for clinical care as patients with HFrEF have a high risk for 30-day readmissions and short survival once diagnosed.…”

“…If the decision is made to circumvent MRA and/or ARNI for SGLT2i therapy, it is reassuring that the cardio-renal benefits from SGLT2i were achieved regardless of background HFrEF GDMT. [39] , [40] , [41] , [42] Additionally, both therapies have been shown to be cost-effective in patients with HFrEF and display comparable value to one another. [ 69 , 70 ]…”

ANMCO POSITION PAPER: on administration of type 2 sodium-glucose co-transporter inhibitors to prevent heart failure in diabetic patients and to treat heart failure patients with and without diabetes

“…Surprisingly, the association of dapagliflozin and empagliflozin with ARNI generated an additive benefit on cardiovascular mortality and hospitalizations for decompensation in patients with heart failure, with no statistically significant interaction between the two drug classes in the study with empagliflozin. 25 Moreover, the relative risk reduction for the combined outcome of cardiovascular death or hospitalization for heart failure in the two trials with SGLT2 inhibitors was not less than that generated by ARNI in the comparison with valsartan in the PARADIGM-HF trial 26 ( Table 2 ), amplifying the benefit of the drug combination. On the other hand, the most striking finding seems to be presented in the study with empagliflozin.…”