Sacubitril/valsartan, sold under the brand name Entresto among others, is a fixed-dose combination medication for use in heart failure. It consists of the neprilysin inhibitor sacubitril and the angiotensin receptor blocker valsartan. The combination is sometimes described as an "angiotensin receptor-neprilysin inhibitor" (ARNi). In 2016, the American College of Cardiology/American Heart Association Task Force recommended it as a replacement for an ACE inhibitor or an angiotensin receptor blocker in people with heart failure with reduced ejection fraction. Potential side effects include angioedema, nephrotoxicity, and low blood pressure. It was approved for medical use in the United States and in the European Union in 2015, and in Australia in 2016. In 2023, it was the 199th most commonly prescribed medication in the United States, with more than 2 million prescriptions. It is available as a generic medication.
Medical uses Sacubitril/valsartan can be used instead of an ACE inhibitor or an angiotensin receptor blocker in people with heart failure and a reduced left ventricular ejection fraction (LVEF), alongside other standard therapies (e.g., beta blockers) for heart failure. To investigate its use for heart failure in those with heart failure with preserved ejection fraction (HFpEF), Novartis funded the PARAGON-HF trial which was designed to investigate the use of sacubitril/valsartan in the treatment of HFpEF patients with a LVEF of 45% or more. Concluding in 2019, it failed to show significance for reducing hospitalisation related to heart failure or reducing death from cardiovascular causes, and therefore appearing to show limited benefit to those with HFpEF. There is moderate evidence to suggest that treating people with HFpEF using MRA and ARNI may reduce the rate of people being hospitalized due to heart failure, however, there is no evidence that this type of treatment improves the person's quality of life or rate of survival due to cardiovascular disease. Evidence is lacking to support the use of ACE Inhibitors, ARBs or ARNIs in people with HFpEF at this time, and that the mainstay pharmacological therapy for HFpEF still remains the treatment of co-morbidities such as hypertension or other triggers for decompensation. Patients who exhibit symptoms of NYHA Class II or III heart failure and are still symptomatic despite maximally tolerated dose of an ACE inhibitor or ARB alone, may be considered for sacubitril/valsartan dual therapy to decrease the risk of cardiovascular-related and all-cause mortality. Mortality benefits have only been observed to date in those with LVEF less than 35%.
Adverse effects Common adverse effects (>1%) include hyperkalemia (high potassium levels in the blood, a known side effect of valsartan), hypotension (low blood pressure, common in vasodilators and extracellular fluid volume reducers), a persistent dry cough, and renal impairment (reduced kidney function). Angioedema, a rare but more serious reaction, can occur in some patients (<1%) and involves swelling of the face and lips. Angioedema is more common in black (African American) patients. Sacubitril/Valsartan should not be taken within 36 hours of an angiotensin-converting enzyme inhibitor to reduce the risk of developing angioedema. The side effect profile in trials of sacubitril/valsartan compared to valsartan alone or enalapril (an angiotensin-converting enzyme inhibitor) is very similar, with the incidence of hypotension slightly higher in sacubitril/valsartan, the risk for angioedema comparable, and the chance of hyperkalaemia, renal impairment and cough slightly lower. Sacubitril/valsartan is contraindicated in pregnancy because it contains valsartan, a known risk for birth defects.
Pharmacology Valsartan blocks the angiotensin II receptor type 1 (AT1). This receptor is found on both vascular smooth muscle cells, and on the zona glomerulosa cells of the adrenal gland which are responsible for aldosterone secretion. In the absence of AT1 blockade, angiotensin causes both direct vasoconstriction and adrenal aldosterone secretion, the aldosterone then acting on the distal tubular cells of the kidney to promote sodium reabsorption which expands extracellular fluid (ECF) volume. Blockade of (AT1) thus causes blood vessel dilation and reduction of ECF volume. Sacubitril is a prodrug that is activated to sacubitrilat (LBQ657) by de-ethylation via esterases. Sacubitrilat inhibits the enzyme neprilysin, a neutral endopeptidase that degrades vasoactive peptides, including natriuretic peptides, bradykinin, and adrenomedullin. Thus, sacubitril increases the levels of these peptides, causing blood vessel dilation and reduction of ECF volume via sodium excretion. Despite these actions, neprilysin inhibitors have been found to have limited efficacy in the treatment of hypertension and heart failure when taken on their own. This is attributed to a reduction in enzymatic breakdown of angiotensin II by the reduction of neprilysin activity, which results in an increase in systemic angiotensin II levels and the negation of the positive effects of this drug family in cardiovascular disease treatment. Combined treatment with a neprilysin inhibitor and an angiotensin converting enzyme (ACE) inhibitor has been shown to be effective in reducing angiotensin II levels, and demonstrated superiority in lowering blood pressure compared to ACE inhibition alone. However, due to an increase in bradykinins from the inhibition of both ACE and neprilysin, there was a threefold increase in relative risk of angioedema compared with ACE inhibition alone following this combination treatment. The combination of a neprilysin inhibitor with an angiotensin receptor blocker instead of the ACE inhibitor has been shown to have a comparable risk of angioedema, whilst also demonstrating superiority in treating moderate-severe heart failure to ACE inhibitor treatment. Neprilysin also has a role in clearing the protein amyloid beta from the cerebrospinal fluid, and its inhibition by sacubitril has shown increased levels of AB1-38 in healthy subjects (Entresto 194/206 for two weeks). Amyloid beta is considered to contribute to the development of Alzheimer's disease, and there exist concerns that sacubitril may promote the development of Alzheimer's disease.
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