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

From the Guidelines

Entresto, a combination of sacubitril and valsartan, works through a dual mechanism of action to improve heart function in patients with heart failure, by inhibiting neprilysin and blocking angiotensin II type 1 receptors, respectively. The mechanism of action of Entresto involves sacubitril, which inhibits neprilysin, an enzyme that breaks down natriuretic peptides, allowing these beneficial hormones to accumulate and exert their effects, including vasodilation, natriuresis, and diuresis, as noted in the 2017 ACC/AHA/HFSA guideline update 1. Simultaneously, valsartan blocks angiotensin II type 1 receptors, preventing the harmful effects of angiotensin II, such as vasoconstriction, sodium retention, and cardiac remodeling, as discussed in the 2017 AHA/ACC clinical performance and quality measures for adults with ST-elevation and non-ST-elevation myocardial infarction 1. This combination has been shown to reduce mortality and hospitalization rates in patients with heart failure with reduced ejection fraction compared to ACE inhibitor therapy alone, as demonstrated in the PARADIGM-HF trial 1. Some key considerations for the use of Entresto include contraindications such as use within 36 hours of ACEI, history of angioedema, pregnancy, lactation, and severe hepatic impairment, as outlined in the 2021 update to the 2017 ACC expert consensus decision pathway for optimization of heart failure treatment 1. Overall, the dual mechanism of action of Entresto provides a complementary approach to enhance beneficial neurohormonal pathways while blocking detrimental ones, resulting in improved cardiac output, reduced cardiac workload, and better overall heart function. Key benefits of Entresto include:

• Improved cardiac output
• Reduced cardiac workload
• Better overall heart function
• Reduced mortality and hospitalization rates in patients with heart failure with reduced ejection fraction. It is essential to carefully consider the contraindications and cautions when prescribing Entresto, as outlined in the 2021 update to the 2017 ACC expert consensus decision pathway for optimization of heart failure treatment 1.

From the FDA Drug Label

Sacubitril and valsartan contains a neprilysin inhibitor, sacubitril, and an angiotensin receptor blocker, valsartan. Sacubitril and valsartan inhibits neprilysin (neutral endopeptidase; NEP) via LBQ657, the active metabolite of the prodrug sacubitril, and blocks the angiotensin II type-1 (AT1) receptor via valsartan The cardiovascular and renal effects of sacubitril and valsartan in heart failure patients are attributed to the increased levels of peptides that are degraded by neprilysin, such as natriuretic peptides, by LBQ657, and the simultaneous inhibition of the effects of angiotensin II by valsartan Valsartan inhibits the effects of angiotensin II by selectively blocking the AT1 receptor, and also inhibits angiotensin II-dependent aldosterone release.

The mechanism of action of Entresto (sacubitril and valsartan) is through neprilysin inhibition and angiotensin receptor blockade.

• Neprilysin inhibition increases the levels of peptides such as natriuretic peptides.
• Angiotensin receptor blockade inhibits the effects of angiotensin II and also inhibits angiotensin II-dependent aldosterone release. 2

From the Research

Mechanism of Action of Entresto

The mechanism of action of Entresto (sacubitril and valsartan) is based on its unique properties as an angiotensin receptor neprilysin inhibitor (ARNI) 3, 4, 5, 6, 7.

• Neprilysin Inhibition: Sacubitril, a component of Entresto, inhibits neprilysin, an endopeptidase that breaks down several vasoactive peptides, including natriuretic peptides (NPs), bradykinin, endothelin, and angiotensin II (Ang-II) 3.
• Angiotensin II Receptor Antagonism: Valsartan, the other component of Entresto, is an angiotensin II receptor antagonist, which blocks the action of Ang-II, reducing vasoconstriction and aldosterone release 3, 4, 5.
• Combined Effect: The combined inhibition of neprilysin and angiotensin II receptor antagonism enhances the benefits of natriuretic peptides' effects in heart failure, such as natriuresis and diuresis, while reducing the harmful effects of Ang-II 3, 4, 5, 6, 7.

Clinical Significance

The unique mechanism of action of Entresto has been shown to reduce cardiovascular and all-cause mortality, as well as hospitalizations due to heart failure, in patients with heart failure with reduced ejection fraction (HFrEF) 3, 4, 5, 7.

• PARADIGM-HF Trial: The PARADIGM-HF trial, a large clinical trial with 8442 patients, demonstrated that Entresto significantly reduced cardiovascular and all-cause mortality, as well as hospitalizations due to heart failure, compared to enalapril 3, 4, 7.
• Clinical Use: Entresto is approved for the treatment of symptomatic chronic heart failure in adults with reduced ejection fraction and is considered a viable option for newly diagnosed New York Heart Association (NYHA) class II to III patients, as well as an alternative to patients currently being treated with maximum doses of current gold standard treatment 4, 6.