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

Mechanism of Action of Entresto (Sacubitril/Valsartan)

Entresto (sacubitril/valsartan) works through a dual mechanism of action: it simultaneously inhibits neprilysin via sacubitril and blocks the angiotensin II type-1 receptor via valsartan, providing complementary cardiovascular benefits in heart failure patients. 1

Detailed Mechanism

Entresto contains two active components that work together:

1. Sacubitril Component:

   • Functions as a prodrug that is metabolized to the active form LBQ657
   • LBQ657 inhibits neprilysin (neutral endopeptidase; NEP)
   • This inhibition prevents the breakdown of beneficial peptides such as natriuretic peptides
   • Results in increased levels of these peptides, which promote vasodilation, natriuresis, and diuresis 1

2. Valsartan Component:

   • Selectively blocks the angiotensin II type-1 (AT1) receptor
   • Inhibits angiotensin II-dependent aldosterone release
   • Provides renin-angiotensin-aldosterone system (RAAS) blockade 1

Pharmacodynamic Effects

The combination of these mechanisms produces several beneficial physiological effects:

• Increases natriuresis (sodium excretion)
• Elevates urine cGMP levels
• Decreases plasma NT-proBNP levels (a marker of heart failure severity)
• Reduces plasma aldosterone and endothelin-1 levels
• Increases plasma BNP (a neprilysin substrate) 1

Clinical Significance

The American College of Cardiology recommends sacubitril/valsartan for reducing cardiovascular death and hospitalization in patients with heart failure with reduced ejection fraction (HFrEF) with NYHA class II-IV symptoms. This recommendation is based on the PARADIGM-HF trial, which demonstrated a 20% reduction in cardiovascular death or heart failure hospitalization compared to enalapril. 2

Important Considerations

• Drug Interactions: Sacubitril may inhibit certain transporters (OATP1B1, OATP1B3, OAT1, and OAT3), potentially affecting the pharmacokinetics of statins and other medications 2
• Amyloid-β Effects: Neprilysin is involved in the clearance of amyloid-β from the brain and CSF. Administration of sacubitril/valsartan has been associated with increased CSF Aβ1-38, though the clinical relevance remains unknown 1
• Blood Pressure Effects: The combination can produce additional blood pressure reduction when used with other vasodilators 1

Potential Antiarrhythmic Effects

Emerging evidence suggests that sacubitril/valsartan may also play a role in reducing arrhythmogenesis and sudden cardiac death through its effects on cardiac remodeling and neurohormonal modulation 3.

This dual mechanism of action represents a significant advancement in heart failure therapy by simultaneously enhancing beneficial peptide systems while blocking harmful neurohormonal activation.