Sacubitril-valsartan (LCZ696) differs from plain valsartan in its mechanism. Which enzyme does sacubitril's active metabolite LBQ657 inhibit, and what is the principal benefit?
- A ACE, preventing angiotensin II formation and potentiating bradykinin accumulation
- B Neprilysin (NEP), preventing degradation of natriuretic peptides, thereby enhancing ventricular unloading and remodelling prevention ✓
- C DPP-4, increasing GLP-1 levels that exert cardioprotective effects
- D Aldosterone synthase (CYP11B2), reducing mineralocorticoid-mediated cardiac fibrosis
Explanation
Sacubitril is a prodrug converted by esterases to the active metabolite LBQ657, which inhibits neprilysin (neutral endopeptidase, NEP). Neprilysin normally degrades natriuretic peptides (ANP, BNP, CNP), bradykinin, adrenomedullin, and substance P. Neprilysin inhibition elevates levels of these vasoactive and natriuretic peptides, promoting vasodilation, natriuresis, diuresis, and — importantly — anti-fibrotic and anti-hypertrophic effects on the myocardium. Combined with valsartan's AT1-receptor blockade, this dual neurohormonal antagonism reduced cardiovascular death and HF hospitalization by 20% compared to enalapril in the PARADIGM-HF trial. ACE inhibitors are not co-administered due to risk of angioedema from additive bradykinin accumulation.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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