Sacubitril/valsartan (LCZ696) is superior to enalapril in HFrEF. The mechanism by which sacubitril contributes to its benefit is:
- A Inhibits neprilysin, which degrades natriuretic peptides (BNP, ANP), augmenting their vasodilatory and natriuretic effects ✓
- B Directly blocks aldosterone receptors, reducing sodium retention
- C Acts as an ARB with higher affinity for AT1 receptors than valsartan alone
- D Inhibits neutral endopeptidase to prevent angiotensin II conversion
Explanation
Sacubitril is a prodrug converted to LBQ657, an active neprilysin inhibitor. Neprilysin is an endopeptidase that degrades natriuretic peptides (ANP, BNP), bradykinin, and angiotensin II. By inhibiting neprilysin, sacubitril raises levels of natriuretic peptides, promoting natriuresis, vasodilation, and anti-fibrotic effects. Because neprilysin inhibition alone would raise angiotensin II (which it would otherwise degrade), the combination with valsartan (ARB) is required to block this adverse effect. The PARADIGM-HF trial showed superiority of sacubitril/valsartan over enalapril in reducing cardiovascular death and HF hospitalization.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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