From the Guidelines
Neprilysin inhibition, particularly through the use of sacubitril-valsartan, is a recommended treatment for patients with symptomatic heart failure with reduced ejection fraction (HFrEF) to reduce morbidity and mortality, as evidenced by the 2022 AHA/ACC/HFSA guideline 1.
Mechanism and Benefits
Neprilysin is an enzyme that breaks down various peptides, including natriuretic peptides, bradykinin, and angiotensin II, playing a crucial role in cardiovascular health by regulating blood pressure and fluid balance. Inhibition of neprilysin has become an important therapeutic target in heart failure treatment. The combination of sacubitril (a neprilysin inhibitor) with valsartan (an angiotensin receptor blocker) in the medication Entresto increases levels of beneficial peptides while blocking the harmful effects of the renin-angiotensin-aldosterone system, promoting vasodilation, sodium excretion, and reduced cardiac remodeling.
Clinical Use and Safety
The standard starting dose of Entresto is typically 49/51 mg twice daily, which may be titrated to 97/103 mg twice daily as tolerated 1. Common side effects include hypotension, hyperkalemia, cough, and dizziness. It is essential to note that ARNI should not be administered concomitantly with ACE inhibitors or within 36 hours of the last dose of an ACE inhibitor, and it should not be administered to patients with a history of angioedema 1.
Key Considerations
- Initiation of ARNI: Should be considered for patients with symptomatic HFrEF to simplify management and reduce morbidity and mortality.
- Contraindications: History of angioedema, concomitant use with ACE inhibitors.
- Monitoring: Blood pressure, renal function, and potassium levels during initiation and titration.
Recent Guidelines
The 2022 AHA/ACC/HFSA guideline recommends the use of ARNI in patients with symptomatic HFrEF, highlighting its benefits in reducing the composite endpoint of cardiovascular death or HF hospitalization 1. The guideline also emphasizes the importance of careful patient selection, initiation, and monitoring to minimize potential side effects.
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 Neprilysin is one of multiple enzymes involved in the clearance of amyloid-β (Aβ) from the brain and cerebrospinal fluid (CSF)
Neprilysin Inhibition: Sacubitril and valsartan inhibits neprilysin (NEP) via its active metabolite LBQ657.
- The inhibition of neprilysin increases the levels of peptides that are degraded by neprilysin, such as natriuretic peptides.
- Neprilysin is also involved in the clearance of amyloid-β (Aβ) from the brain and cerebrospinal fluid (CSF) 2
From the Research
Neprilysin Inhibition in Heart Failure
- Neprilysin inhibition has been shown to be effective in reducing the risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and reduced ejection fraction 3, 4, 5.
- The angiotensin receptor-neprilysin inhibitor sacubitril-valsartan has been found to reduce the risk of hospitalization for heart failure or death from cardiovascular causes among patients with heart failure and reduced ejection fraction 3, 4, 5.
- Neprilysin inhibition has also been found to be effective in patients with advanced chronic kidney disease, with sacubitril/valsartan showing more favorable outcomes than standard heart failure care without ARNI 6.
Combination Therapy with Neprilysin Inhibition
- The combination of neprilysin inhibition with sodium-glucose cotransporter 2 (SGLT2) inhibition has been found to be well-tolerated and effective in reducing the risk of cardiovascular death or hospitalization for heart failure 7.
- The effects of empagliflozin, an SGLT2 inhibitor, were found to be not diminished in patients receiving sacubitril/valsartan, suggesting that combined treatment with both SGLT2 and neprilysin inhibitors can yield substantial additional benefits 7.
Clinical Use of Sacubitril/Valsartan
- Sacubitril/valsartan has been found to be effective in reducing morbidity and mortality in patients with heart failure and reduced ejection fraction, and should be considered as a replacement for ACE inhibitors or angiotensin receptor blockers in these patients 5.
- The use of sacubitril/valsartan in clinical practice requires careful consideration of patient characteristics, including renal function and blood pressure, as well as dose escalation to achieve optimal outcomes 6.