Semaglutide May Help Improve Cognition in Adults With HIV

Injections of semaglutide were associated with significant improvement in cognitive function in people living with HIV (PWH), based on data from 108 individuals. 

Previous research has shown an increased risk for visceral adiposity and greater inflammation, as well as reduced neurocognitive function, in PWH compared with individuals without HIV, said Ornina Atieh, MD, a postdoctoral fellow at Case Western Reserve University, Cleveland, Ohio, in a presentation at the Conference on Retroviruses and Opportunistic Infections 2025 Annual Meeting. 

However, recent studies with semaglutide in PWH showed decreases in weight and visceral adipose tissue, as well as in high sensitivity C-reactive protein levels (hs-CRP). 

The study is the first and currently the only randomized placebo-controlled study of glucagon-like peptide 1 receptor agonist (GLP-1 RA) in patients with HIV, said senior author Grace A. McComsey, MD, director of the Clinical and Translational Science Institute at Case Western University, in an interview. 

Addressing issues of increased visceral adiposity accumulation, including in the liver and muscle, in people living with HIV is imperative because they are associated with increased diabetes and cardiovascular disease, McComsey said. “Cognitive dysfunction is also very prevalent in HIV, and data had previously shown an association between cognitive dysfunction and increased visceral adiposity and inflammation in HIV; therefore, adding cognitive assessment to this trial was an important endpoint,” she said.

In the current study, Atieh and colleagues examined the impact of semaglutide on neurocognitive function and any mediation from improved adiposity and inflammatory markers. The study population included 108 adults with controlled HIV on antiretroviral therapy, randomized to subcutaneous semaglutide or placebo once a week for 32 weeks. Cognitive function was assessed at baseline and 32 weeks using Cognivue, an US Food and Drug Administration–approved computer-based test. The median age of the participants was 53 years, 40% were women, and 62% were non-White individuals. 

At 32 weeks, the semaglutide group showed significant increases in visuospatial, naming/language, and delayed recall scores compared to the placebo group (P = .01, P = .05, and P = .04, respectively). However, only the visuospatial score retained significance after adjusting for sex and CD4 count (P = .05). 

The researchers then considered weight, visceral adipose tissue, hs-CRP, and other inflammatory markers as potential mediators of visuospatial improvement. The total natural direct effect of semaglutide had a significant effect on the visuospatial score while accounting for potential changes in hs-CRP levels (P = .04), but no mediating effect was noted for changes in total or central adiposity.

The researchers predicted that cognitive dysfunction would improve on GLP-1 RA and that this effect would be mediated by the attenuation of inflammation and in visceral adiposity, McComsey told Medscape Medical News. “The latter did not pan out in our analysis; decreases in weight and visceral adiposity on GLP-1 RA did not mediate the effect of GLP-1 RA on cognition,” she said.

“We continue to learn about consequences and management of increased visceral adiposity in HIV, but so far treatment options are very limited,” McComsey said. “Similarly, we have very limited treatment options for cognitive dysfunction in HIV, but by using GLP-1 RA, we may be able to tackle several problems at once, and are able to improve visceral adiposity, inflammation and cognitive impairment,” she said. 

Although the study design was a solid randomized, controlled trial, the findings were limited by the relatively small sample size and the duration of only 32 weeks, McComsey noted. “Larger and longer studies are needed to better understand the full effect of GLP-1 RA on cognitive impairment,” she said. “Although we used Cognivue to objectively assess cognitive function, it would be important to repeat the study with another method of assessing cognition to ensure reproducibility,” she added.

The study received no outside funding. McComsey disclosed serving as an investigator on a long COVID study funded by Cognivue; the grant was paid to her institution.