Effect of Sacubitril/Valsartan on Neurocognitive Function: Current Status and Future Directions
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CURRENT OPINION
Effect of Sacubitril/Valsartan on Neurocognitive Function: Current Status and Future Directions Jason Galo1 · Diego Celli1 · Rosario Colombo2 Accepted: 1 October 2020 © Springer Nature Switzerland AG 2020
Abstract Sacubitril/valsartan is a new medication approved for the treatment of heart failure with reduced ejection fraction. While the drug failed to meet the primary endpoint in patients with heart failure with preserved ejection fraction in the PARAGON-HF trial, improvements were noted in several secondary endpoints. Valsartan is an angiotensin receptor blocker and sacubitril is a neprilysin inhibitor. Neprilysin is postulated to have a role in the degradation of beta-amyloid in the brain; therefore, sacubitril could theoretically increase beta-amyloid plaque deposition in the brain and potentially increase the risk of Alzheimer’s disease. Although pre-clinical and clinical studies have shown promising safety results, those studies have been heavily criticized for short monitoring time and targeted populations. In accordance with the requirements of the US Food and drug Administration (FDA), the ongoing Prospective Evaluation of Cognitive Function in Heart Failure: Efficacy and Safety of Entresto compared to Valsartan on Cognitive Function in Patients with Chronic Heart Failure and Preserved Ejection Fraction (PERSPECTIVE; NCT02884206) multicenter, randomized, double-blinded trial is assessing the long-term neurocognitive effects and safety of sacubitril/valsartan, and results are expected in early 2022.
1 Neprilysin and Alzheimer’s Disease Sacubitril, a component of Entresto, is a neprilysin inhibitor that is used in combination with valsartan in the treatment of heart failure with reduced ejection fraction (HFrEF). Neprilysin is postulated to have a role in the degradation of beta-amyloid in the brain, and the accumulation of beta-amyloid plaques is pathognomonic of Alzheimer’s disease [1, 2]. Several studies have shown that polymorphisms in the genes encoding for the neprilysin enzyme are associated with Alzheimer’s disease. By inhibiting neprilysin, sacubitril may theoretically lead to increased levels of beta-amyloid, raising the concern that physicians may need to carefully monitor their patients on Entresto for potential neurocognitive side effects.
* Jason Galo [email protected] 1
Division of Internal Medicine, Department of Medicine, University of Miami/Jackson Memorial Hospital, 1611 NW 12th Ave, Central Building 600D, Miami, FL 33136, USA
Division of Cardiovascular Disease, Jackson Memorial Hospital, 1801 NW 9th Ave, Suite #209, Miami, FL 33136, USA
2
Key Points Sacubitril/valsartan is a new medication for the treatment of heart failure with reduced ejection fraction; it has been hypothesized that the long-term use of sacubitril, a neprilysin inhibitor, might be associated with increased risk for Alzheimer’s disease. Pre-clinical and clinical studies have shown promising safety results, but have been criticized due to the short period of follow-up and inclusion
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