A patient with heart failure with reduced ejection fraction (HFrEF) is started on sacubitril-valsartan (Entresto). The addition of sacubitril provides benefit primarily by:

• A Inhibiting neprilysin to increase levels of natriuretic peptides, bradykinin, and adrenomedullin ✓
• B Blocking angiotensin receptor preventing vasoconstriction and aldosterone release
• C Directly activating guanylyl cyclase in cardiomyocytes increasing cGMP
• D Inhibiting ACE to prevent conversion of angiotensin I to angiotensin II

Explanation

Sacubitril is an inactive prodrug converted to LBQ657, which inhibits neprilysin — an endopeptidase that degrades natriuretic peptides (ANP, BNP), bradykinin, and adrenomedullin. By inhibiting neprilysin, sacubitril increases these cardioprotective peptides, promoting vasodilation, natriuresis, diuresis, and reduced cardiac fibrosis. Valsartan blocks the AT1 receptor; the combination is superior to ACE inhibitors alone in reducing HF mortality (PARADIGM-HF trial).

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

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Written and medically reviewed by the StethoPrep medical team.