From the Guidelines
Neprilysin (NEP) inhibitors are a class of medications that block the enzyme neprilysin, which breaks down natriuretic peptides, bradykinin, adrenomedullin, and other vasoactive peptides, and the most clinically important NEP inhibitor is sacubitril, combined with valsartan in the medication Entresto, primarily used to treat heart failure with reduced ejection fraction (HFrEF) as shown in the 2022 AHA/ACC/HFSA guideline 1. The mechanism of action of NEP inhibitors involves increasing levels of natriuretic peptides, which promote vasodilation, natriuresis, and diuresis, while reducing sympathetic tone and inhibiting cardiac remodeling. Key points to consider when using NEP inhibitors include:
- The typical starting dose of sacubitril-valsartan is 24/26 mg twice daily, which can be titrated up to 97/103 mg twice daily as tolerated 1.
- Patients should be monitored for hypotension, hyperkalemia, and renal dysfunction.
- NEP inhibitors should not be used concurrently with ACE inhibitors due to increased risk of angioedema, and a 36-hour washout period is required when switching from an ACE inhibitor. The use of NEP inhibitors, such as sacubitril-valsartan, has been shown to significantly reduce hospitalizations and mortality in heart failure patients compared to ACE inhibitors alone, as demonstrated in the PARADIGM-HF trial 1. Overall, NEP inhibitors, particularly sacubitril-valsartan, are a valuable treatment option for patients with HFrEF, offering improved outcomes and simplified management, as supported by the 2022 AHA/ACC/HFSA guideline 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
A Neprilysin (NEP) inhibitor is a type of drug that inhibits the action of neprilysin, also known as neutral endopeptidase.
- Key points:
- Neprilysin is an enzyme involved in the breakdown of certain peptides, such as natriuretic peptides.
- Inhibition of neprilysin increases the levels of these peptides, which can have beneficial effects on the cardiovascular system.
- Sacubitril is an example of a neprilysin inhibitor, which is used in combination with valsartan to treat heart failure 2.
From the Research
Definition of Neprilysin (NEP) Inhibitor
- A Neprilysin (NEP) inhibitor is a type of drug that inhibits the action of neprilysin, an endopeptidase that metabolizes different vasoactive peptides, including natriuretic peptides, bradykinin, and angiotensin II 3.
- NEP inhibitors, such as sacubitril, work by increasing the levels of these peptides, which can help to promote diuresis, natriuresis, and vasodilatation 3.
Mechanism of Action
- The inhibition of NEP increases the levels of natriuretic peptides, which can help to counteract the effects of the renin-angiotensin-aldosterone system (RAAS) 4.
- The increased levels of natriuretic peptides can also help to improve cardiac remodeling and reduce mortality in patients with heart failure with reduced ejection fraction (HFrEF) 4.
Examples of NEP Inhibitors
- Sacubitril/valsartan is a first-in-class angiotensin receptor-neprilysin inhibitor (ARNI) that has been shown to be effective in reducing morbidity and mortality in patients with HFrEF 5, 6.
- Sacubitril/valsartan has been recommended in clinical practice guidelines as a replacement for angiotensin-converting-enzyme inhibitors (ACE-I) in patients with HFrEF who remain symptomatic despite optimal medical therapy 7.