Mechanism of Action of Sacubitril
Sacubitril is a prodrug that is metabolized to LBQ657, which inhibits the enzyme neprilysin (neutral endopeptidase), thereby preventing the degradation of beneficial vasoactive peptides including natriuretic peptides, bradykinin, adrenomedullin, and substance P. 1
Dual Mechanism in Combination Therapy
Sacubitril is always administered in combination with valsartan (an angiotensin receptor blocker) because:
Neprilysin inhibition alone would paradoxically worsen heart failure by raising angiotensin II levels, since neprilysin also degrades angiotensin II; concurrent AT1-receptor blockade with valsartan prevents this harmful effect. 2
The combination cannot use an ACE inhibitor instead of an ARB because both ACE inhibitors and neprilysin inhibitors increase bradykinin concentrations, creating a markedly elevated risk of life-threatening angioedema—making this combination absolutely contraindicated. 2
Valsartan provides safe AT1-receptor blockade without affecting bradykinin metabolism, allowing safe co-administration with sacubitril. 2
Specific Pharmacologic Effects
The neprilysin inhibition by sacubitril's active metabolite LBQ657 produces:
Increased levels of natriuretic peptides (atrial natriuretic peptide, B-type natriuretic peptide, C-type natriuretic peptide) that promote vasodilation, natriuresis, and diuresis. 1
Elevated bradykinin, substance P, and adrenomedullin which contribute to vasodilation and counterregulatory effects against maladaptive neurohormonal activation. 2, 3
Reduced left ventricular wall stress and improved coronary circulation, potentially decreasing myocardial ischemia. 4
Decreased plasma aldosterone and endothelin-1 levels, further mitigating heart failure pathophysiology. 2, 1
Clinical Pharmacodynamics
In heart failure patients, sacubitril/valsartan administration results in:
Increased urine cyclic GMP and atrial natriuretic peptide, reflecting enhanced natriuretic peptide activity. 1
Decreased plasma NT-proBNP (not a neprilysin substrate) while increased plasma BNP (a neprilysin substrate), demonstrating dual pathway modulation. 1
Increased plasma renin activity and renin concentrations, confirming AT1-receptor blockade by the valsartan component. 1
Important Pharmacologic Considerations
Sacubitril inhibits hepatic and renal drug transporters OATP1B1, OATP1B3, OAT1, and OAT3, potentially altering the pharmacokinetics of co-administered drugs such as statins. 2
Neprilysin is involved in amyloid-β clearance from the brain and cerebrospinal fluid; administration of sacubitril/valsartan increases CSF Aβ1-38, though the clinical relevance remains unknown. 1
The cardiovascular and renal benefits in heart failure are attributed to the combined effect of increased beneficial peptides (via neprilysin inhibition) and simultaneous blockade of angiotensin II effects (via AT1-receptor antagonism). 1