ARNI therapy does not affect CV reduction by SGLT2i in HFrEF

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

Literature - Packer M, Anker SD, Butler J, et al., - Eur Heart J. 2021 Jan 11;ehaa968.

Introduction and methods

Inhibition of neprilysin or sodium glucose cotransporter 2 (SGLT2) in patients with HFrEF has been shown to reduce the risk of CV death and hospitalization for HF [1-3]. Modelling analysis has suggested that the two pharmacological agents combined would substantially alleviate major CV outcomes [4]. This analysis assumed that the effects of neprilysin and SGLT2 inhibition are additive. However, it is unclear whether the beneficial effects of neprilysin and SGLT2 inhibition are truly independent of each other. This information is important for the development of clinical practice guidelines.

This subanalysis of the EMPEROR-Reduced trial evaluated the influence of the ARNI sacubitril/valsartan on the efficacy and safety of empagliflozin in patients with HFrEF.

The EMPEROR-Reduced trial was a randomized, double-blind, parallel-group, placebo-controlled, event-driven trial that included patients with chronic HF (New York Heart Association [NYHA] functional class II-IV) with LVEF ≤40%. The cohort was enriched for patients with an LVEF ≤30% by requiring patients with an ejection fraction >30% to have been hospitalized for HF within 12 months, or to have increased levels of NT-proBNP (≥1000 pg/mL in those with LVEF 31-35% or ≥2500 pg/mL in those with LVEF 36-40%). These NT-proBNP inclusion levels were doubled in patients with atrial fibrillation. Patients (n=3730) were randomized (1:1) to empagliflozin 10 mg daily or placebo, in addition to their standard intensive therapy for HF. The primary endpoint was the composite of CV death or first HF hospitalization. The first secondary endpoint was total hospitalizations for HF (first and recurrent events). The second secondary endpoint was the slope of the change in eGFR during treatment, which was supported by an analysis of serious adverse renal outcomes. Additional analyses included the individual components of the primary endpoint, the intensity of treatment received during HF hospitalization, changes in the NYHA functional class and KCCQ at 52 weeks, and changes in vital signs and biomarkers. The cohort was stratified by medication prescription to assess outcomes in patients treated with empagliflozin while receiving sacubitril/valsartan.

Main results

  • 727 (19.5%) Patients received sacubitril/valsartan at baseline. These patients had a lower SBP, heart rate, and NT-proBNP levels and more often a cardiac device compared to those not receiving an ARNI (all P≤0.0001).
  • Empagliflozin treatment reduced the risk for the primary endpoint by 36% (HR 0.64, 95% CI: 0.45-0.89, P=0.009) in patients receiving sacubitril/valsartan and 23% (HR 0.77, 95% CI: 0.66-0.90, P=0.0008) in patients not treated with sacubitril/valsartan, compared to placebo (P interaction=0.31).
  • There was, compared to placebo, a reduction of 35% (HR 0.65, 95% CI:0.42-1.00, P=0.052) in total numbers of hospitalizations for HF with empagliflozin in patients taking sacubitril/valsartan and 29% (HR 0.71, 95% CI: 0.58-0.88, P=0.002) in patients without an ARNI (P interaction=0.72).
  • The rate of decline in eGFR was slowed by 1.92±0.80 mL/min/1.73 m² per year (P=0.016) by empagliflozin compared to placebo in patients with sacubitril/valsartan and 1.71 ±0.35 mL/min/1.73 m² per year (P<0.0001) in patients without sacubitril/valsartan (P interaction=0.81).
  • Empagliflozin reduced the risk of time to first HF hospitalization by 39% (HR 0.61, 95% CI: 0.42-0.90, P=0.013) in the group treated with sacubitril/valsartan and this reduction by empagliflozin, compared to placebo, was 29% (HR 0.71, 95% CI: 0.59-0.85, P=0.0002) in patients not taking an ARNI (P interaction=0.50).
  • Empagliflozin reduced the risk of time to first hospitalization for HF requiring intensive care to a similar degree in patients with or without sacubitril/valsartan (P interaction=0.95).
  • The effect of empagliflozin compared to placebo on time to first hospitalization for HF requiring IV inotropic or vasopressor drug, or mechanical or surgical intervention in patients treated with sacubitril/valsartan was reduced by 55% (HR 0.45, 95% CI: 0.25-0.80, P=0.007) and 16% (HR 0.84, 95% CI: 0.66-1.08, P=0.18) in those without sacubitril/valsartan (P interaction=0.049).
  • Empagliflozin reduced the estimated risk of the composite of serious adverse renal outcomes by 61% in patients treated with sacubitril/valsartan (HR 0.39, 95%CI: 0.11-1.45) and in patients without sacubitril/valsartan this risk was reduced by 49% (HR 0.51, 95%CI: 0.32-0.81).
  • The KCCQ score for the effect of empagliflozin was comparable in patient treated with or without sacubitril/valsartan.
  • Rates of adverse events, related to hyper- or hypokalemia, hypotension, or hypoglycemia were similar among the empagliflozin and placebo groups and independent of sacubitril/valsartan.


The treatment efficacy of empagliflozin in patients with HFrEF were not affected by the neprilysin inhibitor sacubitril/valsartan. The combination therapy was well-tolerated and the safety profile was consistent between the empagliflozin and placebo groups in the presence or absence of an ARNI. Furthermore, concurrent treatment with a neprilysin inhibitor is expected to have an incremental effect on HF risk reduction and renal outcomes in patients with HFrEF.

The authors emphasize that efforts should be made towards developing and implementing strategies that would encourage combination therapy of both classes of drugs in a broad range of patients diagnosed with HFrEF.


1. McMurray JJ, Packer M, Desai AS, et al.; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993–1004.

2. McMurray JJV, Solomon SD, Inzucchi SE, et al.; DAPA-HF Trial Committees and Investigators. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995–2008.

3. Packer M, Anker SD, Butler J, et al.; EMPEROR-Reduced Trial Investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020;383:1413–1424.

4. Vaduganathan M, Claggett BL, Jhund PS et al.. Estimating lifetime benefits of comprehensive disease-modifying pharmacological therapies in patients with heart failure with reduced ejection fraction: a comparative analysis of three randomised controlled trials. Lancet 2020;396:121–128.

Find this article online at Eur Heart J.

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