Sacubitril/valsartan (LCZ696) reduces mortality in HFrEF beyond valsartan alone. The additional benefit of sacubitril is mediated by:
- A Inhibiting neprilysin, preventing degradation of natriuretic peptides (BNP, ANP) and bradykinin ✓
- B Directly activating natriuretic peptide receptors GC-A independent of ligand concentration
- C Blocking ACE thereby preventing angiotensin II formation synergistically with valsartan
- D Inhibiting aldosterone synthase (CYP11B2) reducing aldosterone-mediated myocardial fibrosis
Explanation
Sacubitril is a prodrug converted to sacubitrilat, which inhibits neprilysin (neutral endopeptidase 24.11). Neprilysin degrades vasoprotective peptides including ANP, BNP, CNP, bradykinin, and substance P. Neprilysin inhibition raises levels of these peptides, promoting natriuresis, vasodilation, and anti-fibrotic effects. Valsartan blocks AT1 receptors, preventing angiotensin II effects. The combination cannot include an ACE inhibitor as triple blockade causes excess bradykinin-mediated angioedema. This PARADIGM-HF-proven combination is now a cornerstone of HFrEF therapy.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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