Sacubitril/valsartan (LCZ696) is superior to enalapril in HFrEF (PARADIGM-HF). The pharmacodynamic rationale for adding neprilysin inhibition to RAAS blockade is:

• A Neprilysin inhibition blocks ACE, providing additive RAAS suppression with valsartan
• B Neprilysin inhibition increases natriuretic peptides (ANP, BNP) and bradykinin, promoting natriuresis, vasodilation, and anti-fibrotic effects, while valsartan blocks the compensatory AT1-mediated vasoconstriction that neprilysin inhibition alone would unmask ✓
• C Sacubitril directly activates guanylyl cyclase C receptors on cardiomyocytes, increasing cGMP
• D Neprilysin inhibition specifically degrades aldosterone, reducing cardiac fibrosis independent of RAAS blockade

Explanation

Neprilysin (neutral endopeptidase 24.11) degrades natriuretic peptides (ANP, BNP, CNP), bradykinin, substance P, and angiotensin II. Sacubitril (the prodrug, converted to LBQ657) inhibits neprilysin, thereby increasing beneficial natriuretic peptide levels. However, neprilysin also degrades angiotensin II, and its inhibition raises angiotensin II — which would be counterproductive without simultaneous AT1 blockade (valsartan). Elevated BNP/ANP increase cGMP via particulate guanylyl cyclase (GC-A receptor), promoting natriuresis, vasodilation, and anti-hypertrophy/anti-fibrotic effects. Sacubitril must not be combined with ACEIs (risk of severe angioedema from bradykinin accumulation).

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

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Written and medically reviewed by the StethoPrep medical team.