Updated: January 26, 2026

How Does Entresto (Sacubitril/Valsartan) Work? Mechanism of Action Explained in Plain English

Author

Peter Daggett

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The Problem: What Happens to the Heart in Heart Failure
The Two-Part Solution: How Entresto Works
Part 1: Sacubitril — The Neprilysin Inhibitor
Part 2: Valsartan — The ARB
Why Does Sacubitril Have to Be Paired with an ARB?
Why Can't Entresto Be Combined with ACE Inhibitors?
The Evidence: How Well Does It Work?
Learn More About Entresto

How does Entresto work? We explain the sacubitril/valsartan mechanism of action in plain English — no medical degree required.

Entresto works in a completely unique way that no other heart medication does. Understanding how it works can help you understand why it's prescribed, why it's so effective, and why certain drug combinations are forbidden. Here is the science of sacubitril/valsartan — explained in plain English.

The Problem: What Happens to the Heart in Heart Failure

In heart failure with reduced ejection fraction (HFrEF), the heart's left ventricle doesn't pump enough blood with each beat. The body senses this and activates emergency response systems — primarily the renin-angiotensin-aldosterone system (RAAS) — that raise blood pressure and increase fluid retention to compensate. Short-term, this helps. Long-term, it damages the heart further, causing it to enlarge, stiffen, and weaken in a vicious cycle.

At the same time, the heart and other organs produce beneficial signaling molecules called natriuretic peptides (ANP, BNP, and others). These peptides try to counteract the RAAS — they dilate blood vessels, promote sodium and water excretion, and reduce harmful cardiac remodeling. The problem? An enzyme called neprilysin rapidly breaks down these beneficial peptides, limiting their effect.

The Two-Part Solution: How Entresto Works

Entresto attacks the failing heart's problems on two fronts simultaneously — hence why it belongs to its own drug class, the ARNIs (angiotensin receptor-neprilysin inhibitors).

Part 1: Sacubitril — The Neprilysin Inhibitor

Sacubitril is a prodrug — when you swallow it, your body converts it to its active form, called LBQ657. LBQ657 blocks neprilysin, the enzyme that breaks down natriuretic peptides. By blocking neprilysin, sacubitril allows beneficial natriuretic peptides to stay active longer. The result:

Vasodilation: Blood vessels relax and widen, reducing the heart's workload

Natriuresis and diuresis: The kidneys excrete more sodium and water, reducing fluid buildup

Anti-fibrotic effects: Reduced harmful cardiac scarring and remodeling

Part 2: Valsartan — The ARB

Valsartan is an angiotensin II receptor blocker (ARB). Angiotensin II is a hormone produced by the overactivated RAAS that causes blood vessels to constrict and drives fluid and sodium retention. Valsartan blocks the angiotensin II receptor, so angiotensin II can't cause these harmful effects. The result:

Lower blood pressure: Reducing afterload (the resistance the heart must pump against)

Reduced aldosterone release: Less sodium retention and fluid buildup

Cardiac protection: Slowing harmful heart remodeling driven by the RAAS

Why Does Sacubitril Have to Be Paired with an ARB?

This is a critical scientific insight. Neprilysin also breaks down angiotensin II — so blocking neprilysin alone would actually increase angiotensin II levels and worsen RAAS activation. That's why sacubitril cannot be used as a standalone drug. Pairing it with valsartan blocks the angiotensin II receptor, preventing this "angiotensin II rebound" while still allowing natriuretic peptides to accumulate. The two components work synergistically.

Why Can't Entresto Be Combined with ACE Inhibitors?

ACE inhibitors also increase bradykinin levels by blocking its breakdown. Since sacubitril (by inhibiting neprilysin) also raises bradykinin, combining the two creates dangerously high bradykinin levels, dramatically increasing the risk of angioedema — potentially life-threatening swelling of the throat. This is why Entresto is absolutely contraindicated with ACE inhibitors, and why you must wait at least 36 hours after your last ACE inhibitor dose before starting Entresto.

The Evidence: How Well Does It Work?

The landmark PARADIGM-HF trial compared sacubitril/valsartan to enalapril (the previous gold standard) in over 8,000 patients with HFrEF. Entresto reduced the composite endpoint of cardiovascular death or heart failure hospitalization by 20% compared to enalapril. Cardiovascular mortality was reduced by 20%, and all-cause mortality was reduced by 16%. These were landmark results that established Entresto as the preferred ARNI in modern heart failure guidelines.

Learn More About Entresto

For a complete overview of Entresto, read What Is Entresto? and Entresto side effects guides to understand the full picture of this medication.

Frequently Asked Questions

ACE inhibitors (like lisinopril, enalapril) block angiotensin-converting enzyme, which reduces angiotensin II production. Entresto works differently: the sacubitril component blocks neprilysin to raise beneficial natriuretic peptides, while valsartan directly blocks the angiotensin II receptor. This dual mechanism provides complementary and additive benefits beyond what ACE inhibitors alone can achieve. Because both elevate bradykinin, they cannot be combined safely.

Sacubitril/valsartan is taken twice daily because the pharmacokinetics of both components — their absorption, distribution, and elimination — require dosing approximately every 12 hours to maintain consistent therapeutic blood levels and keep the beneficial natriuretic peptide system activated throughout the day. Once-daily dosing would leave gaps in coverage.

Studies have shown that long-term treatment with sacubitril/valsartan can lead to modest improvements in LVEF (left ventricular ejection fraction) in some patients with HFrEF, as well as reduction in left ventricular size and mass. The primary benefit driving its FDA approval, however, is the reduction in cardiovascular mortality and heart failure hospitalizations, as demonstrated in the PARADIGM-HF trial.

Combining Entresto with an ACE inhibitor creates dangerously high levels of bradykinin. Both sacubitril (by blocking neprilysin) and ACE inhibitors prevent bradykinin breakdown, and together they cause a dramatic bradykinin surge that greatly increases the risk of angioedema — a potentially fatal swelling of the throat. A mandatory 36-hour washout period is required when switching from an ACE inhibitor to Entresto.

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