What is the mechanism of action of Neprilysin (Neutral Endopeptidase)?

From the Guidelines

Neprilysin's mode of action involves degrading vasoactive peptides, including natriuretic peptides, bradykinin, and adrenomedullin, and its inhibition leads to increased levels of these beneficial peptides, resulting in improved cardiovascular outcomes. The mechanism of neprilysin inhibition is crucial in the management of heart failure with reduced ejection fraction (HFrEF) [ 1 ]. Neprilysin is a zinc-dependent metalloprotease enzyme that breaks down various peptides, including natriuretic peptides like ANP, BNP, and CNP, which normally promote vasodilation, natriuresis, and diuresis [ 1 ]. By inhibiting neprilysin with medications such as sacubitril (often combined with valsartan in the drug Entresto), the beneficial effects of natriuretic peptides are prolonged, leading to increased sodium and water excretion, vasodilation, reduced sympathetic activity, and decreased cardiac remodeling [ 1 ].

The combination of neprilysin inhibition with angiotensin receptor blockade provides a dual approach to heart failure treatment by simultaneously enhancing the protective natriuretic peptide system while blocking the harmful effects of the renin-angiotensin-aldosterone system [ 1 ]. This mechanism explains why neprilysin inhibitors have become important in managing HFrEF, as they help reduce cardiac workload and improve cardiovascular outcomes [ 1 ]. It is essential to note that neprilysin inhibitors should not be used in combination with ACE inhibitors due to the increased risk of angioedema [ 1 ].

Key points about neprilysin's mode of action include:

• Neprilysin degrades vasoactive peptides, including natriuretic peptides, bradykinin, and adrenomedullin [ 1 ]
• Inhibition of neprilysin leads to increased levels of beneficial peptides, resulting in improved cardiovascular outcomes [ 1 ]
• The combination of neprilysin inhibition with angiotensin receptor blockade provides a dual approach to heart failure treatment [ 1 ]
• Neprilysin inhibitors should not be used in combination with ACE inhibitors due to the increased risk of angioedema [ 1 ]

From the FDA Drug Label

Sacubitril and valsartan contains a neprilysin inhibitor, sacubitril, and an angiotensin receptor blocker, valsartan. Sacubitril and valsartan inhibits neprilysin (neutral endopeptidase; NEP) via LBQ657, the active metabolite of the prodrug sacubitril, and blocks the angiotensin II type-1 (AT1) receptor via valsartan The cardiovascular and renal effects of sacubitril and valsartan in heart failure patients are attributed to the increased levels of peptides that are degraded by neprilysin, such as natriuretic peptides, by LBQ657, and the simultaneous inhibition of the effects of angiotensin II by valsartan

The mode of action of sacubitril (a neprilysin inhibitor) is to inhibit neprilysin (neutral endopeptidase; NEP) via its active metabolite LBQ657. This leads to an increase in the levels of peptides that are degraded by neprilysin, such as natriuretic peptides. Sacubitril and valsartan also blocks the angiotensin II type-1 (AT1) receptor via valsartan, which inhibits the effects of angiotensin II and also inhibits angiotensin II-dependent aldosterone release 2.

• Key points:
  • Inhibition of neprilysin (NEP) by sacubitril
  • Increase in natriuretic peptides
  • Blockade of angiotensin II type-1 (AT1) receptor by valsartan
  • Inhibition of angiotensin II-dependent aldosterone release The mechanism of action of sacubitril and valsartan is a combination of neprilysin inhibition and angiotensin receptor blockade, which contributes to its cardiovascular and renal effects in heart failure patients 2.

From the Research

Mechanism of Action of Neprilysin Inhibitors

• Neprilysin is an enzyme that degrades biologically active natriuretic peptides, and inhibiting it increases levels of circulating natriuretic peptides, resulting in natriuretic, diuretic, and vasodilatory effects 3, 4, 5, 6.
• The combined angiotensin receptor and neprilysin inhibitor (ARNi) has been developed to increase vasodilatory natriuretic peptides and prevent counterregulatory activation of the angiotensin system 5.
• Neprilysin inhibitors, such as sacubitril/valsartan, have been shown to be effective in reducing the risks of death and hospitalization for heart failure in patients with heart failure and New York Heart Association functional class II to III symptoms 3, 4, 7.

Clinical Studies and Evidence

• The PARADIGM-HF trial demonstrated that sacubitril/valsartan significantly reduced the primary endpoint of cardiovascular mortality and heart failure hospitalization, compared with enalapril 3, 4, 6.
• The Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF) showed that sacubitril/valsartan reduced the occurrence of the primary end point (cardiovascular death or hospitalisation for HF) by 20% with a 16% reduction in all-cause mortality 4.
• Studies have suggested the cost-effectiveness of sacubitril/valsartan, but its high cost may be a factor in determining its widespread use 3, 7.

Potential Benefits and Limitations

• Neprilysin inhibition may not be an effective solution in advanced heart failure patients when there is downstream blunting of the response to natriuretic peptides, or among post-myocardial infarction patients in the absence of heart failure when there may not be a need for increased natriuretic peptide availability 5.
• There is a need for additional studies to determine the long-term effects of ARNi on albuminuria, obesity, glycemic control and lipid profile, blood pressure, and cognitive function in patients with heart failure 5.