How does Entresto (sacubitril/valsartan) work?

How Entresto (Sacubitril/Valsartan) Works

Dual Mechanism of Action

Entresto combines two distinct pharmacologic actions: sacubitril inhibits the neprilysin enzyme while valsartan blocks the angiotensin II type-1 (AT1) receptor, creating simultaneous enhancement of protective peptides and suppression of harmful neurohormonal activation. 1, 2

Neprilysin Inhibition Component (Sacubitril)

• Neprilysin is a zinc-dependent metalloprotease that normally degrades beneficial vasoactive peptides including natriuretic peptides (ANP, BNP, CNP), adrenomedullin, bradykinin, and substance P. 1, 2

• By inhibiting neprilysin through its active metabolite LBQ657, sacubitril increases levels of these protective peptides, leading to vasodilation, natriuresis (sodium excretion), diuresis, reduced myocardial fibrosis, and decreased left ventricular wall stress. 1, 2, 3

• The increased natriuretic peptide activity enhances cyclic GMP production, which mediates many of the cardiovascular benefits including improved coronary circulation and reduced myocardial ischemia. 2, 4

Angiotensin Receptor Blockade Component (Valsartan)

• Valsartan selectively blocks the AT1 receptor, preventing the harmful effects of angiotensin II including vasoconstriction, sodium and water retention, sympathetic nervous system activation, and myocardial remodeling. 1, 2

• Valsartan also inhibits angiotensin II-dependent aldosterone release, further reducing fluid retention and potassium loss. 1, 2

Why the Combination Is Necessary

• Neprilysin also degrades angiotensin II; therefore, isolated neprilysin inhibition would paradoxically raise angiotensin II levels and worsen heart failure. 1, 3

• Concomitant AT1-receptor blockade with valsartan prevents this harmful effect, allowing the benefits of neprilysin inhibition to predominate. 1

Why an ARB Instead of an ACE Inhibitor

• ACE inhibitors and neprilysin inhibitors both increase bradykinin concentrations; their combination markedly raises the risk of life-threatening angioedema, making this combination absolutely contraindicated. 1, 5

• Valsartan (an ARB) provides AT1-receptor blockade without influencing bradykinin degradation, allowing safe co-administration with sacubitril. 1

• A mandatory 36-hour washout period from ACE inhibitors is required before initiating Entresto to prevent angioedema. 5

Measurable Pharmacodynamic Effects

• Administration of Entresto increases urine ANP and cyclic GMP, and plasma cyclic GMP levels. 2

• Entresto decreases plasma NT-proBNP (not a neprilysin substrate), aldosterone, and endothelin-1. 2, 6

• Entresto increases plasma BNP (a neprilysin substrate) because BNP is normally degraded by neprilysin. 2

• Entresto increases plasma renin activity and plasma renin concentrations, confirming effective AT1-receptor blockade. 2

Clinical Efficacy Evidence

• The PARADIGM-HF trial demonstrated that Entresto reduced the composite endpoint of cardiovascular death or heart failure hospitalization by 20% compared to enalapril in patients with heart failure with reduced ejection fraction (HFrEF). 1, 7, 8

• Higher doses of Entresto (97/103 mg twice daily) are associated with greater reduction in NT-proBNP levels (-667.24 pg/mL; 95% CI: -1312.69 to -21.8; p=0.04) compared to lower doses, indicating improved cardiac stress. 6

Additional Beneficial Effects Beyond Natriuretic Peptides

• Entresto augments other vasoactive substances including bradykinin, substance P, and adrenomedullin, which may contribute to its efficacy through additional vasodilation and anti-inflammatory effects. 4

• The concept of "autoinhibition" suggests that by pre-emptively inhibiting neprilysin, Entresto induces an earlier surge of protective peptides during decompensation, potentially explaining the superior outcomes observed in clinical trials. 4

Important Safety Considerations

• Common side effects include hypotension, renal insufficiency, and hyperkalemia (not hypokalemia), though hyperkalemia risk is actually lower compared to ACE inhibitors like enalapril. 1

• Entresto may lead to angioedema, though at a lower rate than ACE inhibitors. 1

• Entresto increases cerebrospinal fluid amyloid-β1-38 concentrations, though the clinical relevance regarding Alzheimer's disease or macular degeneration remains unknown. 2, 4

Drug Interactions Requiring Attention

• Sacubitril inhibits OATP1B1, OATP1B3, OAT1, and OAT3 transporters, which may affect statin metabolism. 9, 5

• Coadministration with atorvastatin increases atorvastatin Cmax up to 2-fold and AUC by 1.3-fold, though no significant adverse events were reported in clinical trials; lower statin doses may be considered. 9, 5

• Concomitant use with potassium-sparing diuretics, mineralocorticoid receptor antagonists, or NSAIDs requires close monitoring of serum potassium and renal function. 5