By Michael H. Crawford, MD

Professor of Medicine, Lucy Stern Chair in Cardiology, University of California, San Francisco

SYNOPSIS: A prespecified subgroup analysis of heart failure patients with reduced ejection fraction who were on neprilysin inhibitors before empagliflozin was administered (vs. those not on neprilysin inhibitors) showed the reduction in mortality and hospital admissions for heart failure was not attenuated by concurrent neprilysin use.

SOURCE: Packer M, Anker SD, Butler J, et al. 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. Eur Heart J 2021;42:671-680.

There are little data on the effect of combining a neprilysin inhibitor with a sodium-glucose cotransporter-2 (SGLT2) inhibitor in patients with systolic heart failure. In the EMPEROR-Reduced trial of the SGLT2 empagliflozin vs. placebo in patients with heart failure and reduced ejection fraction, 20% of 3,730 randomized patients were on concomitant sacubitril/valsartan at baseline.1 Packer et al conducted a prespecified subgroup analysis of this 20% (727 patients). These patients were New York Heart Association (NYHA) class II-IV heart failure with ejection fraction less than 40% and were on appropriate treatment for heart failure, including devices. They were randomized to empagliflozin 10 mg/day vs. placebo. The primary endpoint was the composite of adjudicated cardiovascular death or hospitalization for heart failure. The authors also assessed several secondary endpoints involving renal function, symptoms, and blood metabolic parameters.

Among baseline clinical characteristics, those treated with neprilysin inhibition recorded lower blood pressure readings, heart rate, and BNP levels, and were more likely to have a cardiac device and be from North America. Compared to placebo, empagliflozin reduced the primary endpoint by 23% in those not on neprilysin inhibition and by 36% in those on neprilysin inhibition (HR, 0.77; 95% CI, 0.66-0.90; P = 0.0008 and HR, 0.64; 95% CI, 0.45-0.88; P = 0.009, respectively). The heart failure hospitalization component of the primary endpoint also declined by 29% in subjects who were not on a neprilysin inhibitor and by 35% in those on a neprilysin inhibitor (HR, 0.71; 95% CI, 0.58-0.88; P = 0.002 and HR, 0.65; 95% CI, 0.42-1.00; P = 0.052, respectively). Also, empagliflozin slowed the rate of decline in estimated glomerular filtration rate (eGFR) by 1.7 mL/min/1.7 m2/year in those not on a neprilysin inhibitor (P < 0.0001) and by 1.92 mL/min/1.7 m2/year in those on a neprilysin inhibitor (P = 0.016). There were no significant differences in adverse events between those on or off neprilysin inhibition treated with empagliflozin.

The authors concluded the beneficial effects of empagliflozin in patients with symptomatic heart failure with reduced ejection fraction are not attenuated by concomitant neprilysin inhibition treatment, and such therapy is well tolerated.


The most recent heart failure guideline update now recommends NYHA class II-IV patients with heart failure caused by systolic dysfunction to start an angiotensin receptor/neprilysin inhibitor (ARNI) and a beta-blocker soon after stabilization of volume status and relief of congestion. Then, in those with an eGFR > 30 mL/min and a potassium < 5 mEq/L, start a mineralocorticoid antagonist and a SGLT2 inhibitor.2 This recommendation was given on the strength of studies such as DAPA-HF, which showed robust reductions in mortality and hospitalizations when SGLT2 inhibitors were administered on top of ACEI or ARB, beta-blocker, and mineralocorticoid inhibition.3 However, in DAPA-HF, only 11% of patients also were on an ARNI, so the efficacy and safety of this subgroup was underpowered for firm conclusions.

Since EMPEROR-Reduced included about twice as many patients on an ARNI at baseline, it made sense to evaluate the benefit of adding an SGLT2 inhibitor in this subgroup. Not only were the beneficial effects statistically similar in this subgroup, numerically, the effects were larger. This is somewhat surprising, since the ARNI group was exceptionally well treated at baseline: 95% on beta-blockers, 70% on mineralocorticoid antagonists, 27% with an implanted cardiac defibrillator, and 10% with a cardiac resynchronization device. In addition, this combination was well tolerated. There was minimal additional blood pressure-lowering and volume depletion in the ARNI group, and other adverse effects were unusual in both groups.

What was disturbing was the aggregate of all serious adverse effects occurred in about 50% of subjects in both groups with the addition of empagliflozin. Hence, it is difficult to rationalize how the authors could state that empagliflozin was “well tolerated.” This observation raises the difficult issue of patient tolerance of the ever-growing list of must-have drugs to treat heart failure, especially since clinicians are supposed to titrate the drugs to the maximum doses used in trials. Of course, trial participants are not exactly equivalent to the patients seen in practice, such that most heart failure patients are not on the optimal doses of all these drugs because of intolerance, usually caused by low blood pressure or heart rate, or metabolic derangements, such as hyperkalemia. Once again, clinicians are challenged to bring patients on board with all these lifesaving drugs.

There were limitations to this study. For this type of trial, the number of patients was relatively small. The authors did not address the reverse issue of adding an ARNI to someone already on an SGLT2 inhibitor, such as a diabetic patient. Also, the authors did not explore the timing of initiation of the recommended drugs for systolic heart failure. The sequence and timing of the administration and titration of the recommended drugs in new heart failure patients are not well studied, but perhaps the SGLT2 inhibitors should be introduced before mineralocorticoid antagonists. 


  1. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020;383:1413-1424.
  2. Maddox TM, Januzzi JL Jr, Allen LA, et al. 2021 update to the 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment: Answers to 10 pivotal issues about heart failure with reduced ejection fraction: A report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 2021;77:772-810.
  3. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995-2008.