The PARADIGM-HF trial demonstrated superiority of sacubitril/valsartan over enalapril in HFrEF. The mechanism of sacubitril (a neprilysin inhibitor) involves:

• A Inhibition of ACE, reducing angiotensin II formation and bradykinin degradation
• B Aldosterone receptor antagonism reducing myocardial fibrosis
• C Inhibition of neprilysin (neutral endopeptidase), preventing degradation of natriuretic peptides (ANP, BNP, CNP) and bradykinin ✓
• D Beta-1 receptor blockade reducing sympathetic activation

Explanation

Sacubitril (AHU377) is a prodrug converted to LBQ657, which inhibits neprilysin — the enzyme responsible for degradation of natriuretic peptides (ANP, BNP, CNP), bradykinin, angiotensin II, and substance P. Neprilysin inhibition increases endogenous natriuretic peptide levels, promoting natriuresis, vasodilation, and anti-fibrotic/anti-hypertrophic effects. Valsartan blocks AT1R concurrently to prevent angiotensin II accumulation. This dual mechanism (ARNI = angiotensin receptor-neprilysin inhibitor) reduces mortality and HF hospitalisations significantly.

Reference: Harrison's Principles of Internal Medicine, 21st ed.

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