What is the mechanism of action of Entresto (sacubitril/valsartan)?

Mechanism of Action of Entresto (Sacubitril/Valsartan)

Entresto works through a dual mechanism of action combining neprilysin inhibition via sacubitril and angiotensin II receptor blockade via valsartan, which together enhance beneficial cardiovascular peptides while blocking harmful effects of angiotensin II to reduce mortality and hospitalization in heart failure patients. The cardiovascular and renal effects of sacubitril/valsartan in heart failure patients are attributed to the increased levels of peptides that are degraded by neprilysin, such as natriuretic peptides, bradykinin, adrenomedullin, and other vasoactive peptides by LBQ657 (the active metabolite of sacubitril), and the simultaneous inhibition of the effects of angiotensin II by valsartan. 1

Dual Component Mechanism

Sacubitril Component

• Sacubitril is a prodrug that is metabolized to its active form LBQ657, which inhibits neprilysin (neutral endopeptidase; NEP) 1
• Neprilysin is an endopeptidase that normally degrades several beneficial vasoactive peptides including:
  • Natriuretic peptides (ANP, BNP)
  • Bradykinin
  • Adrenomedullin
  • Other vasoactive peptides 2
• By inhibiting neprilysin, sacubitril increases the levels of these beneficial peptides, leading to:
  • Increased natriuresis and diuresis
  • Vasodilation
  • Reduced cardiac fibrosis
  • Decreased sympathetic tone 1, 2

Valsartan Component

• Valsartan is an angiotensin receptor blocker (ARB) that selectively blocks the angiotensin II type-1 (AT1) receptor 1
• This blockade prevents the harmful effects of angiotensin II, including:
  • Vasoconstriction
  • Sodium and water retention
  • Cardiac and vascular remodeling
  • Sympathetic activation 2, 1
• Valsartan also inhibits angiotensin II-dependent aldosterone release 1

Pharmacodynamic Effects

• In heart failure patients, sacubitril/valsartan administration results in:

  • Increased urinary natriuresis
  • Increased urinary cGMP (cyclic guanosine monophosphate)
  • Decreased plasma NT-proBNP (not a neprilysin substrate)
  • Increased plasma BNP (a neprilysin substrate)
  • Decreased plasma aldosterone and endothelin-1 1, 2

• The PARADIGM-HF trial demonstrated that sacubitril/valsartan reduced the composite endpoint of cardiovascular death or heart failure hospitalization by 20% compared to enalapril (an ACE inhibitor) 2, 3

Clinical Significance

• Sacubitril/valsartan represents a significant advancement in heart failure therapy as the first angiotensin receptor neprilysin inhibitor (ARNI) 4
• It is indicated for reducing the risk of cardiovascular death and hospitalization in patients with heart failure with reduced ejection fraction (HFrEF) 2
• The drug is typically used in combination with other heart failure therapies in place of an ACE inhibitor or ARB 2
• Recent evidence suggests benefits even in patients with advanced chronic kidney disease and end-stage renal disease 5

Potential Side Effects and Interactions

• Common side effects include hypotension, renal insufficiency, and hyperkalemia 2
• Sacubitril/valsartan may lead to angioedema, though at a lower rate than ACE inhibitors 2, 3
• In vitro data indicate that sacubitril inhibits OATP1B1, OATP1B3, OAT1, and OAT3 transporters, which may affect statin metabolism 2
• Hyponatremia has been reported as a potential adverse effect 6
• Neprilysin is involved in amyloid-β clearance from the brain, though the clinical relevance of this finding is unknown 1

In summary, Entresto's innovative dual mechanism of action represents a significant advancement in heart failure therapy by simultaneously enhancing beneficial cardiovascular peptides through neprilysin inhibition while blocking the harmful effects of angiotensin II, resulting in improved outcomes for patients with heart failure with reduced ejection fraction.