Effects of Semaglutide on Cognitive Function in People With HIV: A Randomized, Controlled Trial

BACKGROUND: People with human immunodeficiency virus (HIV, PWH) are at higher risk for visceral adiposity, enhanced inflammation, and cognitive decline than controls who do not have HIV. We previously demonstrated that PWH with lipohypertrophy had a decrease in weight, visceral adipose tissue, and several inflammatory markers after receiving semaglutide, a glucagon-like peptide-1 receptor agonist. Our aim was to investigate the effect of semaglutide on cognitive function in PWH and the possible mediation of this effect by changes in adiposity or inflammation. METHODS: In this randomized, double-blind, placebo-controlled phase 2b clinical trial, PWH on antiretroviral therapy were randomized 1:1 to receive 32 weeks of subcutaneous semaglutide or placebo. The primary outcome was the change in cognitive function at 32 weeks. Secondary measures included changes in body composition and inflammatory markers. Causal mediation analysis assessed semaglutide's direct and indirect effects on Cognivue scores through changes in adiposity and inflammation. RESULTS: 108 participants were included (54 per arm); 65% were non-White, 40% were female, and median age was 53 years. Compared with placebo, PWH on semaglutide significantly increased visuospatial, naming/language, and delayed recall scores at 32 weeks (P = .01, .05, and .04, respectively). After adjusting for sex and absolute CD4 count, only visuospatial score remained statistically significant (P = .05). Semaglutide's total natural direct effect maintained a positive effect on the visuospatial score while accounting for potential changes in high-sensitivity C-reactive protein and soluble CD163 levels (P = .04). CONCLUSIONS: Semaglutide may have a beneficial impact on visuospatial cognitive function in PWH through its effect on inflammation. Clinical Trials Registration . NCT04019197.