Mechanism of Action of Entresto (Sacubitril/Valsartan)
Entresto (sacubitril/valsartan) works through a dual mechanism of action, combining neprilysin inhibition with angiotensin receptor blockade to reduce cardiovascular mortality and hospitalization in heart failure patients with reduced ejection fraction. 1
Primary Mechanisms
1. Neprilysin Inhibition (Sacubitril)
- Sacubitril is a prodrug that is metabolized to its active form LBQ657
- LBQ657 inhibits neprilysin (neutral endopeptidase; NEP), an enzyme that degrades several vasoactive peptides 1
- This inhibition leads to increased levels of:
- Natriuretic peptides (ANP, BNP)
- Bradykinin
- Adrenomedullin
- Other vasoactive peptides
2. Angiotensin Receptor Blockade (Valsartan)
- Valsartan selectively blocks the angiotensin II type-1 (AT1) receptor 1
- This blockade:
- Prevents the vasoconstrictive effects of angiotensin II
- Inhibits angiotensin II-dependent aldosterone release
- Reduces sodium and water retention
Physiological Effects
The combination of these two mechanisms produces several beneficial physiological effects:
- Enhanced natriuresis and diuresis: Increased natriuretic peptide levels promote sodium and water excretion 1
- Vasodilation: Reduction in vascular resistance and blood pressure
- Decreased cardiac preload and afterload: Reduces cardiac workload
- Anti-remodeling effects: Inhibits cardiac hypertrophy and fibrosis
- Neurohormonal modulation: Counteracts the harmful effects of an overactivated renin-angiotensin-aldosterone system
Pharmacodynamic Evidence
Clinical studies have demonstrated these effects through various biomarkers:
- Increased urine cGMP (cyclic guanosine monophosphate) levels 1
- Decreased plasma NT-proBNP levels (not a neprilysin substrate) 1
- Increased plasma BNP levels (a neprilysin substrate) 1
- Decreased plasma aldosterone and endothelin-1 levels 1
- Increased plasma renin activity and plasma renin concentrations (evidence of AT1-receptor blockade) 1
Clinical Significance
This dual mechanism of action provides superior clinical outcomes compared to ACE inhibition alone:
- 20% reduction in cardiovascular death or heart failure hospitalization compared to enalapril in the PARADIGM-HF trial 2, 3
- Indicated for reducing cardiovascular death and hospitalization in patients with heart failure with reduced ejection fraction (NYHA class II-IV) 2
- Now recommended in guidelines as an alternative to ACE inhibitors or ARBs in HFrEF patients 2, 4
Important Considerations
- Unlike previous attempts at neprilysin inhibition (e.g., omapatrilat), sacubitril is highly selective for neprilysin, minimizing the risk of angioedema 3
- The combination with valsartan provides simultaneous RAAS blockade while avoiding the increased bradykinin levels associated with ACE inhibition 3
- Sacubitril may inhibit certain transporters (OATP1B1, OATP1B3, OAT1, and OAT3), potentially affecting the pharmacokinetics of statins and other drugs 2
This unique dual mechanism represents a significant advancement in heart failure pharmacotherapy, offering mortality and morbidity benefits beyond traditional RAAS blockade alone.