Sacubitril (combined with valsartan as sacubitril/valsartan) improves outcomes in heart failure with reduced ejection fraction by inhibiting:

• A Angiotensin-converting enzyme (ACE)
• B Aldosterone synthase in the adrenal gland
• C Phosphodiesterase-3 in cardiomyocytes
• D Neprilysin (neutral endopeptidase), increasing natriuretic peptide levels ✓

Explanation

Sacubitril is a prodrug converted to LBQ657, which inhibits neprilysin — a neutral endopeptidase that degrades natriuretic peptides (BNP, ANP), bradykinin, and angiotensin II; inhibition raises natriuretic peptide levels, promoting natriuresis, vasodilation, and anti-fibrotic effects. It is combined with valsartan (ARB) because neprilysin inhibition alone would increase angiotensin II (also a neprilysin substrate), causing vasoconstriction. Sacubitril/valsartan replaces ACE inhibitors in HFrEF, not combined with them.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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Written and medically reviewed by the StethoPrep medical team.