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Meta-Analysis
. 2025 Oct;42(10):907-920.
doi: 10.1007/s40266-025-01233-1. Epub 2025 Jul 29.

Sacubitril/Valsartan Reduces the Risk of All-Cause Dementia in Patients with Heart Failure: A Systematic Review and Meta-Analysis

Mohamed Mohsen Helal  1 , Nereen A Almosilhy #  2   3 , Nada G Hamam #  4 , Mohamed Ahmed Adel Abdelbaset  5 , Ali Nagy Shelbaya  2   6 , Halima Abdirashid Y Musse  2   7 , Aishwarya Prasad  8
Affiliations
Meta-Analysis

Sacubitril/Valsartan Reduces the Risk of All-Cause Dementia in Patients with Heart Failure: A Systematic Review and Meta-Analysis

Mohamed Mohsen Helal et al. Drugs Aging. 2025 Oct.

Abstract

Background: Sacubitril/valsartan, an angiotensin receptor neprilysin inhibitor (ARNI), has become a cornerstone therapy for heart failure (HF) since its approval over a decade ago. However, concerns have emerged about potential cognitive risks, as neprilysin inhibition may contribute to the accumulation of amyloid-beta (Aβ) in the brain-a hallmark of Alzheimer's disease, the most common form of dementia.

Objective: Given the already elevated risk of dementia in patients with HF and the widespread use of sacubitril/valsartan, this meta-analysis aimed to evaluate whether its use is associated with an increased risk of all-cause dementia in HF populations.

Methods: A systematic literature search was conducted on 23 March 2025, to identify eligible studies comparing the risk of dementia in patients receiving sacubitril/valsartan versus those receiving placebo, no treatment, or other HF medications. Risk ratios (RRs) and 95% confidence intervals (CIs) were pooled using a random-effects model.

Results: Six studies, comprising 101,074 participants and published between 2017 and 2024, were included in the meta-analysis. Treatment with sacubitril/valsartan was associated with a significant 15% reduction in the risk of all-cause dementia (RR = 0.85; 95% CI: 0.74-0.98; p = 0.02). Leave-one-out sensitivity and subgroup analyses confirmed the robustness of the findings.

Conclusions: This meta-analysis suggests that sacubitril/valsartan is associated with a reduced risk of dementia in patients with HF, helping to alleviate previous concerns about potential cognitive adverse effects. These findings support the continued use of sacubitril/valsartan as a foundational therapy in this high-risk population.

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Conflict of interest statement

Declarations. Ethics Approval and Consent to Participate: Not applicable. Consent for Publication: Not applicable. Availability of Data and Materials: Not applicable. Competing Interests: Mohamed Mohsen Helal, Nereen A. Almosilhy, Nada G. Hamam, Mohamed Ahmed Adel Abdelbaset, Ali Nagy Shelbaya, Halima Abdirashid Y. Musse, and Aishwarya Prasad declare that they have no potential conflicts of interest that might be relevant to the contents of this manuscript. Funding: No funding was received to assist with the preparation of this manuscript. Authors’ Contributions: M.M.H. conceived the study idea, developed the overall design and direction, conducted the analysis, contributed to writing, and provided supervision. N.A.A. supervised the screening process and contributed to writing. N.G.H. oversaw the screening, data extraction quality assessment processes, and contributed to writing. M.A. and A.N.S. contributed to screening, data extraction, quality assessment, and writing. H.M. and A.P. contributed to writing.

Comment in

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