What is the mechanism of action of Entresto (sacubitril/valsartan) in patients with heart failure with reduced ejection fraction?

Mechanism of Action of Entresto (Sacubitril/Valsartan)

Entresto works through a dual mechanism: sacubitril inhibits neprilysin (an enzyme that breaks down beneficial natriuretic peptides), while valsartan blocks the angiotensin II type-1 receptor, together enhancing vasodilation and reducing harmful neurohormonal activation in heart failure. 1, 2

Neprilysin Inhibition Component (Sacubitril)

• Neprilysin is a zinc-dependent metalloprotease that normally degrades several beneficial vasoactive peptides including natriuretic peptides (ANP, BNP, CNP), adrenomedullin, bradykinin, and substance P—all of which play protective roles in heart failure pathophysiology 1, 2

• By inhibiting neprilysin, sacubitril increases circulating levels of these beneficial peptides, leading to:

  • Vasodilation (reduced afterload) 2
  • Natriuresis and diuresis (reduced preload and volume overload) 2
  • Anti-fibrotic effects on the myocardium 2
  • Reduced sympathetic activation 2

• Critical mechanistic caveat: Neprilysin also degrades angiotensin II, so neprilysin inhibition alone would paradoxically increase angiotensin II levels and worsen heart failure—this is why sacubitril must be combined with an angiotensin receptor blocker 1

Angiotensin Receptor Blockade Component (Valsartan)

• Valsartan blocks the angiotensin II type-1 (AT1) receptor, preventing the harmful effects of angiotensin II that would otherwise be elevated by neprilysin inhibition 1, 2

• This blockade prevents:

  • Vasoconstriction (reduces afterload) 2
  • Sodium and water retention (reduces preload) 2
  • Aldosterone release (reduces volume overload and myocardial fibrosis) 2
  • Sympathetic nervous system activation (reduces arrhythmia risk and myocardial oxygen demand) 2

Net Pharmacodynamic Effects

• The combination results in decreased plasma aldosterone and endothelin-1 levels, both of which are elevated and harmful in heart failure 2

• Clinical translation: In the PARADIGM-HF trial, this dual mechanism reduced the composite endpoint of cardiovascular death or heart failure hospitalization by 20% compared to enalapril (an ACE inhibitor), demonstrating superiority over traditional renin-angiotensin-aldosterone system inhibition alone 1, 2

Why Neprilysin Inhibitors Cannot Be Combined with ACE Inhibitors

• ACE inhibitors are absolutely contraindicated with sacubitril/valsartan because both drugs increase bradykinin levels (ACE inhibitors by blocking bradykinin degradation, neprilysin inhibitors by the same mechanism), leading to a markedly elevated risk of life-threatening angioedema 1, 3

• A mandatory 36-hour washout period is required when switching from an ACE inhibitor to sacubitril/valsartan 3

• This is why the combination uses an ARB (valsartan) rather than an ACE inhibitor—ARBs do not affect bradykinin metabolism 1

FDA-Approved Indications Based on This Mechanism

• Sacubitril/valsartan is FDA-approved to reduce the risk of cardiovascular death and hospitalization in adult patients with chronic heart failure and reduced ejection fraction 4

• It is also approved for symptomatic heart failure with systemic left ventricular systolic dysfunction in pediatric patients aged one year and older 4

• The drug reduces NT-proBNP levels (a biomarker of cardiac stress) and is expected to improve cardiovascular outcomes through its dual mechanism 4, 5