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

Clinical Snapshot

Key Findings

• P Value: P = .05 for adjusted visuospatial score

• Effect Size: Visuospatial score improvement maintained statistical significance after adjustment

• Primary Outcome: Significant improvement in visuospatial cognitive function with semaglutide vs placebo

• Nnt Or Sensitivity: Not calculable from available data

• Confidence Interval: Not reported

Clinical Application

Semaglutide available in Australia but not PBS-subsidised for cognitive indications; requires specialist HIV physician consideration Relevant to Australian HIV clinics; would require TGA approval for cognitive indication and PBS consideration for cost-effectiveness People with HIV on stable antiretroviral therapy experiencing cognitive concerns, particularly visuospatial deficits

Abstract

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.

References

1. 1.Atieh, O., Daher, J., Abboud, M., Wu, Q., Sattar, A., Baissary, J., Koberssy, Z., Labbato, D., Eckard, A. R., & McComsey, G. A. (2026). Effects of Semaglutide on Cognitive Function in People With HIV: A Randomized, Controlled Trial. Clinical Infectious Diseases. https://doi.org/10.1093/cid/ciaf577