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

From the Guidelines

Entresto (sacubitril/valsartan) works through a dual mechanism of action that targets two key pathways in heart failure, providing a comprehensive approach to managing the condition and ultimately reducing morbidity and mortality in patients with heart failure with reduced ejection fraction, as supported by the most recent guidelines and studies, including those published in 2021 1.

Mechanism of Action

The dual mechanism of action of Entresto involves:

• Sacubitril, which inhibits neprilysin, an enzyme that breaks down natriuretic peptides. These peptides are beneficial hormones that promote vasodilation, natriuresis, and diuresis while reducing cardiac fibrosis and hypertrophy.
• Valsartan, which blocks angiotensin II type 1 receptors, preventing the harmful effects of angiotensin II such as vasoconstriction, sodium retention, and cardiac remodeling.

Clinical Implications

This combination effectively counterbalances the neurohormonal imbalance present in heart failure by simultaneously enhancing the protective natriuretic peptide system while suppressing the harmful renin-angiotensin-aldosterone system. The result is improved cardiac function, reduced cardiac workload, decreased blood pressure, increased sodium excretion, and ultimately reduced morbidity and mortality in patients with heart failure with reduced ejection fraction, as noted in recent clinical guidelines 1.

Key Considerations

When using Entresto, it is crucial to consider the following:

• Contraindications, such as use within 36 hours of ACE inhibitor use, history of angioedema, pregnancy, lactation, severe hepatic impairment, concomitant aliskiren use in patients with diabetes, and known hypersensitivity to either ARBs or ARNIs.
• Cautions, including renal impairment, hepatic impairment, renal artery stenosis, systolic blood pressure <100 mm Hg, and volume depletion, as outlined in the 2021 update to the ACC expert consensus decision pathway for optimization of heart failure treatment 1.

Conclusion is not allowed, so the answer will be ended here, but the main point is that Entresto works through a dual mechanism of action and its use should be guided by the most recent clinical evidence and guidelines to optimize outcomes for patients with heart failure with reduced ejection fraction.

From the Research

Mechanism of Action of Entresto

The mechanism of action of Entresto (sacubitril/valsartan) involves the simultaneous blockage of two key pathways:

• Angiotensin II receptors: Valsartan blocks the action of angiotensin II, a potent vasoconstrictor, thereby reducing blood pressure and decreasing the heart's workload 2, 3, 4.
• Neprilysin: Sacubitril inhibits the enzyme neprilysin, which breaks down natriuretic peptides, leading to increased levels of these peptides and resulting in natriuretic, diuretic, and vasodilatory effects 2, 5, 4.

Effects on the Body

The combination of these two mechanisms has a beneficial impact on two important neurohormonal pathways activated in heart failure:

• Reduces the degradation of natriuretic peptides and other counterregulatory peptide systems 2.
• Avoids the deleterious effects of angiotensin II receptor activation 2. This leads to a reduction in morbidity and mortality in heart failure patients, while maintaining a safety profile comparable to established therapies 2, 5.

Clinical Benefits

The use of sacubitril/valsartan has been shown to:

• Reduce all-cause mortality and hospitalization due to heart failure in patients with systolic heart failure 5, 4.
• Provide a potentially superior alternative to ACE inhibitor therapy in the management of systolic heart failure 5.
• Be cost-effective in the treatment of heart failure 4.