Sacubitril/valsartan (S/V), a first-in-class angiotensin receptor–neprilysin inhibitor, has demonstrated significant clinical benefits in the treatment of heart failure (HF). However, concerns have emerged regarding its cognitive safety, as neprilysin also degrades amyloid-β peptides — a key pathological feature of Alzheimer’s disease. To date, evidence assessing the long-term cognitive outcomes associated with S/V remains limited.

We conducted a systematic review and meta-analysis in accordance with PRISMA guidelines. Databases including PubMed, Embase, Scopus, Cochrane Library, and Web of Science were searched for studies evaluating cognitive function in HF patients treated with S/V. Data extraction focused on changes in cognitive scores (MMSE), hazard ratios for dementia, and adverse event reports. Meta-analysis was performed using R (version 4.3.3), and heterogeneity was assessed using τ², I², and Q-tests.

14 studies encompassing over 5000 patients were included. MMSE showed no significant change from baseline. MMSE scores between S/V and control group revealed no significant difference. Three large-scale studies assessing overall dementia incidence reported a non-significant trend toward reduced risk with S/V (OR: 0.7099; 95% CI: 0.5018 to 1.0044; p = 0.0530; I² = 84.7%). For Alzheimer’s-type dementia, the odds ratio also favored S/V but was not significant (OR: 0.6035; 95% CI: 0.3230 to 1.1275; p = 0.1133; I² = 86.2%). In contrast, vascular dementia risk was significantly lower in the S/V group (OR: 0.6074; 95% CI: 0.4650 to 0.7935; p = 0.0003; I² = 0%). Analysis of SMQ adverse event reports found no significant link between S/V and cognitive disorders.