Sacubitril-Valsartan Mechanism — EECC MCQ
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Correct answer: B — Neprilysin — an enzyme that degrades natriuretic peptides (ANP, BNP, CNP), bradykinin, and adrenomedullin; inhibition increases their levels, promoting vasodilation, natriuresis, and anti-fibrotic effects
Sacubitril is a prodrug that is converted to LBQ657, which inhibits neprilysin (neutral endopeptidase). Neprilysin degrades several vasoactive peptides including ANP, BNP, CNP, bradykinin, adrenomedullin, and substance P. By inhibiting neprilysin, sacubitril increases levels of these protective peptides, promoting vasodilation, natriuresis, diuresis, and anti-hypertrophic/anti-fibrotic effects. Importantly, neprilysin also degrades angiotensin II — so neprilysin inhibition alone would increase angiotensin II levels. This is why sacubitril is combined with valsartan (ARB) to block the detrimental RAAS activation. Sacubitril must NOT be combined with ACEi (risk of angioedema from excessive bradykinin accumulation — mandating a 36-hour washout when switching from ACEi).
Reference: ESC (2023): HF Guidelines; PARADIGM-HF Trial