Angiotensin Receptor-Neprilysin Inhibitors (ARNIs)

Reviewed by: HU Medical Review Board | Last reviewed: June 2023

Angiotensin receptor-neprilysin inhibitors (ARNIs) combine the drugs sacubitril and valsartan to treat heart failure. Valsartan is an angiotensin II receptor blocker (ARB), and sacubitril is a neprilysin inhibitor.1,2

ARNIs are used to treat heart failure with a reduced injection fraction of 40 percent or less. ARNIs can also help treat heart failure with preserved ejection fraction. This is an ejection fraction of 50 percent or higher.1,2

Studies show that compared to ACE inhibitors or ARBs, ARNIs:2

  • Help people with heart failure live longer
  • Improve quality of life
  • Slow down the progression of heart failure
  • Reduce the amount of time spent in the hospital

How do ARNIs work?

Valsartan keeps your blood vessels from tightening, or constricting. This helps lower your blood pressure.1,2

Sacubitril blocks neprilysin in the body. Neprilysin is an enzyme that plays several important roles in how your body works, including your heart. By blocking neprilysin, sacubitril helps your body:1,2

  • Get rid of more sodium (salt)
  • Widen your blood vessels
  • Make you urinate

Together, sacubitril/valsartan lowers your blood pressure and makes it easier for your heart to work.1,2


Sacubitril/valsartan is currently the only ARNI approved by the US Food and Drug Administration (FDA). It is sold under the brand name Entresto®.1,2

What are the possible side effects?

The most common side effects of sacubitril/valsartan include:1,2

  • Low blood pressure, especially if you also take water pills (diuretics)
  • Kidney problems
  • High potassium levels in your blood

Sacubitril/valsartan may also cause serious allergic reactions, causing swelling of your face, lips, tongue, and throat. Allergic reactions while taking sacubitril/valsartan are more common in Black people. Get emergency medical care right away if you have signs of an allergic reaction or trouble breathing while taking sacubitril/valsartan.1,2

Sacubitril/valsartan has a boxed warning, the strictest warning from the FDA. It has this warning because this medicine can harm an unborn baby. Talk to your doctor about other ways to treat your heart failure if you plan to become pregnant. Tell your doctor right away if you get pregnant during treatment with Entresto.1

These are not all the possible side effects of sacubitril/valsartan. Talk to your doctor about what to expect when taking sacubitril/valsartan. You also should call your doctor if you have any changes that concern you when taking sacubitril/valsartan.

Other things to know

Before starting treatment with sacubitril/valsartan, tell your doctor if you:1

  • Have a history of allergic reactions.
  • Have kidney or liver problems.
  • Are pregnant or planning to become pregnant.
  • Are breastfeeding or plan to breastfeed. Doctors do not know if sacubitril/valsartan passes into breast milk. You and your doctor should decide if you will take Entresto or breastfeed since you should not do both.

Your doctor will do blood tests to check your potassium levels and kidney function while taking sacubitril/valsartan.1,2

Taking sacubitril/valsartan with some other medicines can cause serious side effects. Tell your doctor if you take:1

  • Potassium supplements
  • Nonsteroidal anti-inflammatory drugs (NSAIDs)
  • Lithium
  • Other medicines for high blood pressure or heart problems, like ACE inhibitors, ARBs, and aliskiren

Before beginning treatment for heart failure, tell your doctor about all your health conditions and any other drugs, vitamins, or supplements you are taking. This includes over-the-counter drugs.

For more information, read the full prescribing information of Entresto.

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