Mechanism of action of LCZ696. LCZ696 is a dual-acting neprilysin inhibitor and angiotensin receptor blocker as it comprises the molecular moieties of both sacubitril (AHU337) and valsartan. AHU377 is converted to the active neprilysin inhibitor LBQ657, which inhibits the neprilysin enzyme, responsible for the breakdown of the biologically active natriuretic peptides, including BNP, ANP, bradykinin, substance P, adrenomedullin, and angiotensin II. BNP contributes to natriuresis, diuresis, and vasodilation. The biologically inert NT-proBNP is not a substrate of this enzyme and is therefore unaffected by its inhibition. The valsartan component blocks the angiotensin II receptor type 1 (AT1) receptor, thus negating the effects of angiotensin II. The net combined effect is inhibition of neprilysin and the renin-angiotensin system. ANP, atrial natriuretic peptide; BNP, B-type natriuretic peptide. Reproduced with permission from Vardeny et al.⁸