How does a Neprilysin (neutral endopeptidase) inhibitor work?

From the Guidelines

Neprilysin inhibitors work by blocking the enzyme neprilysin, which normally breaks down beneficial peptides like natriuretic peptides, bradykinin, and adrenomedullin in the body, as demonstrated in the 2022 AHA/ACC/HFSA guideline for the management of heart failure 1. The mechanism of action of neprilysin inhibitors involves inhibiting the enzyme neprilysin, leading to the accumulation of beneficial peptides in the circulation. This results in increased diuresis, natriuresis, vasodilation, and reduced sympathetic tone, which is particularly useful in heart failure treatment. Key points about neprilysin inhibitors include:

• They increase the levels of beneficial peptides like natriuretic peptides, bradykinin, and adrenomedullin
• They are often combined with angiotensin receptor blockers (ARBs) to provide dual benefits in heart failure treatment
• The most common neprilysin inhibitor in clinical use is sacubitril, which is typically combined with valsartan in the medication Entresto
• This combination therapy has been shown to reduce mortality and hospitalization in heart failure patients with reduced ejection fraction, as seen in the PARADIGM-HF trial 1
• Patients should be monitored for hypotension, hyperkalemia, and renal dysfunction when starting this medication, and it should not be combined with ACE inhibitors due to increased risk of angioedema. The use of neprilysin inhibitors, such as sacubitril-valsartan, has been approved for patients with symptomatic heart failure, and they may be initiated de novo in patients hospitalized with acute heart failure with reduced ejection fraction (HFrEF) before discharge, or in patients with chronic symptomatic HFrEF to simplify management 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

A Neprilysin inhibitor works by inhibiting the enzyme neprilysin, which is responsible for breaking down certain peptides, such as natriuretic peptides. By inhibiting neprilysin, the levels of these peptides increase, leading to cardiovascular and renal effects. The neprilysin inhibitor, sacubitril, inhibits neprilysin via its active metabolite, LBQ657. This mechanism of action is supported by studies, including PARADIGM-HF and PANORAMA-HF, which showed increases in plasma BNP and urine cGMP, and decreases in plasma NT-proBNP 2.

• The main peptides affected by neprilysin inhibition are natriuretic peptides, which play a role in cardiovascular and renal function.
• The inhibition of neprilysin leads to increased levels of these peptides, resulting in cardiovascular and renal effects.
• The simultaneous inhibition of the angiotensin II type-1 (AT1) receptor by valsartan also contributes to the overall effect of sacubitril and valsartan.

From the Research

Mechanism of Action

• A Neprilysin (neutral endopeptidase) inhibitor works by blocking the enzyme neprilysin, which is responsible for degrading biologically active natriuretic peptides 3, 4.
• By inhibiting neprilysin, the levels of circulating natriuretic peptides increase, resulting in natriuretic, diuretic, and vasodilatory effects 4.
• Neprilysin also cleaves other vasoactive peptides, including angiotensin I and II, endothelin-1, bradykinin, and adrenomedullin, which have various effects on the cardiovascular system 5, 6.

Effects on the Cardiovascular System

• The combination of a neprilysin inhibitor with an angiotensin receptor blocker (ARB) has been shown to be effective in reducing morbidity and mortality in heart failure patients 3, 4.
• The simultaneous blockage of neprilysin and angiotensin II receptors reduces the degradation of natriuretic peptides and other counterregulatory peptide systems, while avoiding the deleterious effects of angiotensin II receptor activation 3.
• Neprilysin inhibitors have been found to increase the levels of various hormones, including bradykinin, substance P, and adrenomedullin, which may contribute to their efficacy in heart failure 7.

Clinical Implications

• The use of neprilysin inhibitors, such as sacubitril/valsartan, has been associated with improved outcomes in patients with heart failure with reduced ejection fraction 4, 6.
• However, the benefits of neprilysin inhibitors in advanced heart failure patients or in patients with left ventricular dysfunction but without heart failure are still unclear and require further study 6.
• Additionally, the long-term effects of neprilysin inhibitors on various physiological parameters, such as albuminuria, obesity, glycemic control, and lipid profile, need to be investigated further 6.