Wondering how Entresto works? This plain-English guide explains how Sacubitril and Valsartan work together to treat heart failure and protect your heart.
Entresto (Sacubitril/Valsartan) helps treat heart failure by combining two medications that work together — one relaxes your blood vessels and reduces fluid buildup, while the other boosts your body's natural heart-protecting signals. Think of it as easing the workload on your heart from two different directions at the same time.
If you've been prescribed Entresto and want to understand what it's actually doing inside your body — without needing a medical degree — this guide is for you.
To understand how Entresto works, it helps to know what's going wrong in heart failure. When your heart can't pump blood efficiently, your body activates emergency systems to compensate. These systems raise blood pressure, retain fluid, and make your heart work even harder — which actually makes things worse over time. It's like your body is flooring the gas pedal when the engine is already overheating.
Entresto contains two active ingredients, and each one tackles a different part of this problem:
Your body naturally produces substances called natriuretic peptides — think of them as your heart's built-in repair crew. They relax blood vessels, help your kidneys flush out extra salt and water, and slow down the harmful remodeling that makes heart failure progress.
The problem? An enzyme called neprilysin breaks down these helpful peptides too quickly. In heart failure, your body is making these protective signals, but they're getting destroyed before they can do their job.
Sacubitril blocks neprilysin — so your natriuretic peptides stick around longer and work harder. It's like calling off the cleanup crew so the repair crew can actually finish the job.
Valsartan is an angiotensin II receptor blocker (ARB). Angiotensin II is a hormone that tells your blood vessels to constrict (tighten), signals your body to retain salt and water, and triggers the release of aldosterone — another hormone that increases fluid retention.
In heart failure, the renin-angiotensin system is in overdrive, pumping out too much angiotensin II. Valsartan blocks the receptor where angiotensin II docks, so those stress signals don't get through. The result: your blood vessels relax, your blood pressure drops, and your heart doesn't have to push as hard.
Here's what makes Entresto special. ACE inhibitors (like Enalapril or Lisinopril) and ARBs (like Valsartan alone) have been used for heart failure for decades. They work — but they only address one side of the problem (blocking the harmful stress signals).
By adding Sacubitril, Entresto also boosts the beneficial signals. It's a two-pronged approach: reduce the bad and amplify the good. This combination is why Entresto outperformed Enalapril in the major PARADIGM-HF clinical trial, reducing cardiovascular death by 20% and heart failure hospitalizations by 21%.
Entresto starts lowering blood pressure within a few hours of your first dose. However, the full benefits for heart failure develop over weeks to months of consistent use.
During the first few weeks, your doctor will gradually increase your dose (a process called titration) to reach the target maintenance dose of 97/103 mg twice daily. This gradual approach helps minimize side effects — especially low blood pressure and dizziness.
Entresto's two components have slightly different durations:
This is why Entresto is taken twice daily — to maintain consistent levels throughout the day and night. If you miss a dose, the medication levels drop, and your heart loses that protection. Consistency is key.
If you're wondering how Entresto compares to other heart failure medications, here's a quick breakdown:
ACE inhibitors block the production of angiotensin II by inhibiting the angiotensin-converting enzyme. They've been a mainstay of heart failure treatment for decades. But Entresto was directly compared to Enalapril in the PARADIGM-HF trial and came out ahead — reducing death and hospitalization significantly more. ACE inhibitors also tend to cause more cough. The major caveat: you cannot take Entresto and an ACE inhibitor at the same time, and you must wait 36 hours between stopping one and starting the other.
Valsartan — one of Entresto's own ingredients — is also available as a standalone ARB. ARBs are typically used when patients can't tolerate ACE inhibitors (usually due to cough). While ARBs help with heart failure, they lack the Sacubitril component that boosts natriuretic peptides. Entresto adds that second mechanism, which is why it's more effective.
SGLT2 inhibitors like Farxiga (Dapagliflozin) and Jardiance (Empagliflozin) are newer additions to heart failure treatment. They work through a completely different mechanism — reducing blood sugar reabsorption in the kidneys, which also reduces fluid overload. These are typically used alongside Entresto, not instead of it. Current guidelines recommend both as part of comprehensive heart failure therapy.
Beta blockers slow the heart rate and reduce the heart's workload by blocking adrenaline signals. Like SGLT2 inhibitors, beta blockers are used alongside Entresto as part of guideline-directed medical therapy — not as a replacement. Most heart failure patients take both.
For a complete look at alternatives, see our guide on alternatives to Entresto.
Entresto works by attacking heart failure from two angles: Sacubitril amplifies your body's natural heart-protecting signals, while Valsartan blocks the stress hormones that make heart failure worse. This dual mechanism is what makes it more effective than older heart failure medications and why it's become a first-line treatment recommended by major cardiology guidelines.
Understanding how your medication works can help you appreciate why consistency matters — every dose keeps those protective systems running and those harmful signals blocked. Take it twice daily, keep your follow-up appointments, and talk to your doctor if you have questions or experience side effects.
Need help finding Entresto at an affordable price? Medfinder can help you locate a pharmacy with stock near you.
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