Medical Class of Sacubitril
Sacubitril is classified as a neprilysin inhibitor, and when combined with valsartan (as sacubitril/valsartan), it forms an angiotensin receptor-neprilysin inhibitor (ARNI). 1, 2
Mechanism of Action
- Sacubitril is a prodrug that is metabolized to LBQ657, which inhibits neprilysin (neutral endopeptidase; NEP), an enzyme that degrades several beneficial vasoactive peptides 2
- By inhibiting neprilysin, sacubitril increases levels of natriuretic peptides and other vasoactive peptides, leading to vasodilation, natriuresis, and diuresis 1
- When combined with valsartan (an angiotensin II type-1 receptor blocker), the dual mechanism provides simultaneous neprilysin inhibition and renin-angiotensin system blockade 2
- This combination results in decreased plasma aldosterone and endothelin-1 levels, contributing to its cardiovascular benefits 1
Pharmacological Classification Details
- Sacubitril/valsartan was the first-in-class ARNI approved for clinical use 3
- The European Society of Cardiology (ESC) guidelines specifically refer to sacubitril as a "neprilysin inhibitor" and the combination as an "angiotensin receptor neprilysin inhibitor" 4
- The FDA label confirms this classification, describing sacubitril/valsartan as "a combination of a neprilysin inhibitor and an angiotensin II receptor blocker" 2
Clinical Applications
- Sacubitril/valsartan is primarily indicated for heart failure with reduced ejection fraction (HFrEF) to reduce cardiovascular death and hospitalization 1, 5
- In the PARADIGM-HF trial, sacubitril/valsartan reduced the composite endpoint of cardiovascular death or heart failure hospitalization by 20% compared to enalapril 1
- The ESC guidelines recommend sacubitril/valsartan for patients with chronic coronary syndromes and heart failure with reduced ejection fraction 4
- Though initially developed for hypertension, its primary clinical use is in heart failure management 4, 6
Pharmacodynamic Properties
- Administration of sacubitril/valsartan results in increased levels of natriuretic peptides (which are neprilysin substrates) and decreased levels of NT-proBNP (not a neprilysin substrate) 2
- The cardiovascular benefits include vasodilation, reduced myocardial ischemia through decreased left ventricular wall stress, and improved coronary circulation 4
- Sacubitril/valsartan may also have antifibrotic and neurohumoral modulatory effects through various signaling pathways 7
Important Clinical Considerations
- When transitioning from an ACE inhibitor to sacubitril/valsartan, a 36-hour washout period is required to avoid angioedema risk 8
- The most common side effect is hypotension, not bradycardia, requiring careful monitoring of blood pressure 8
- Dose adjustments are recommended for patients with severe renal impairment or moderate hepatic impairment 2
Understanding sacubitril's classification as a neprilysin inhibitor and its role in the ARNI class is essential for appropriate clinical application in cardiovascular disease management.