Sacubitril/valsartan (LCZ696) is used in HFrEF. Sacubitril inhibits neprilysin, which degrades natriuretic peptides. Why is valsartan (an ARB) combined with sacubitril in this formulation rather than using sacubitril alone?

• A Valsartan prevents the increase in renin that neprilysin inhibition causes
• B Valsartan provides additional diuretic action not available from sacubitril alone
• C Sacubitril competes with bradykinin for neprilysin binding sites, and valsartan prevents bradykinin accumulation
• D Neprilysin also degrades angiotensin II; its inhibition increases angiotensin II, necessitating ARB blockade of AT1 receptors ✓

Explanation

Neprilysin is an endopeptidase that degrades multiple vasoactive peptides including natriuretic peptides (beneficial) but also bradykinin, substance P, and importantly angiotensin I and II. Inhibiting neprilysin alone would increase not only beneficial natriuretic peptides but also angiotensin II, partially opposing therapeutic benefit. Combined ARB blockade prevents angiotensin II from acting on AT1 receptors. Additionally, ACEi cannot be combined with sacubitril (risk of severe angioedema from combined bradykinin accumulation), so an ARB is the logical partner. There is a mandatory 36-hour washout between ACEi and sacubitril/valsartan.

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

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