Sacubitril/valsartan (LCZ696) is approved for heart failure with reduced ejection fraction (HFrEF). The pharmacological advantage of neprilysin inhibition (sacubitril) in combination with ARB (valsartan) over ACE inhibitor alone is:

• A The combination provides additive blockade of both ACE and neprilysin, maximally reducing angiotensin II levels
• B Sacubitril directly inhibits aldosterone synthase, reducing aldosterone-mediated sodium retention
• C Sacubitril prevents neprilysin-mediated degradation of BNP and ANP, amplifying natriuresis and vasodilation, while valsartan prevents angiotensin II-mediated vasoconstriction; ACEi alone raises bradykinin but does not increase natriuretic peptides ✓
• D Neprilysin inhibition reduces endothelin-1 degradation, improving coronary vasodilation

Explanation

Neprilysin is the primary enzyme degrading natriuretic peptides (BNP, ANP, CNP). Sacubitril, as a prodrug converted to LBQ657 (active neprilysin inhibitor), prevents natriuretic peptide degradation, amplifying their vasodilatory, natriuretic, and anti-fibrotic effects. Valsartan blocks AT1 receptors to prevent angiotensin II's adverse cardiac remodeling. Critically, sacubitril must not be combined with ACEi (risk of life-threatening angioedema) because both raise bradykinin (neprilysin also degrades bradykinin, and ACEi blocks its breakdown). The PARADIGM-HF trial showed superiority over enalapril in reducing mortality in HFrEF.

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

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