Multiple studies presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2025) reveal that semaglutide, a GLP-1 receptor agonist commonly used for diabetes and weight management, may offer unexpected benefits for people living with HIV, including slowing biological aging and improving cognitive function.
The findings suggest that semaglutide's therapeutic potential extends far beyond its established metabolic effects, potentially addressing age-related complications that increasingly affect the HIV population as they live longer with effective antiretroviral therapy.
Epigenetic Aging Benefits
A National Institutes of Health-funded study led by Dr. Grace McComsey of Case Western Reserve University examined semaglutide's effects in 108 HIV-positive adults with lipohypertrophy—abnormal abdominal fat accumulation that increases cardiovascular disease risk. Participants, with a median age of 52 and CD4 count around 800, were randomized to receive weekly semaglutide injections (1.0 mg) or placebo for 32 weeks.
Dr. Michael Corley of the University of California San Diego presented a secondary analysis focusing on epigenetic aging biomarkers in 84 participants. Using DNA methylation "epigenetic clock" algorithms to calculate biological age, researchers found that participants had increased epigenetic age and greater predicted mortality risk at baseline.
"Over 32 weeks of treatment, the pace of biological aging slowed by about 9% in the semaglutide group compared with the placebo group, and the annual rate of epigenetic aging mortality risk decreased by about three years," the researchers reported.
Corley emphasized that these effects appeared independent of inflammation or weight changes: "These findings suggest that semaglutide's favorable effects on epigenetic aging biomarkers may not be due simply to changes in inflammation or baseline adiposity measures, but potentially more fundamental impact on some of these hallmarks of aging."
Cognitive Function Improvements
In another analysis from the lipohypertrophy study, Dr. Ornina Atieh and colleagues investigated semaglutide's effects on neurocognitive function using Cognivue, an FDA-approved computer-based assessment tool that evaluates visual-spatial ability, attention, executive function, memory, and processing speed.
While overall cognitive scores were similar between groups, semaglutide recipients showed significantly better visual-spatial and delayed recall performance, with trends toward improved naming and language function. After adjusting for sex and CD4 count, visual-spatial improvements remained close to statistical significance.
Importantly, the cognitive benefits were not explained by weight loss or reduced visceral fat. Instead, improvements correlated with decreased levels of high-sensitivity C-reactive protein and sCD163, both inflammatory biomarkers.
"This effect appears to be mediated by the effect of the drug on attenuating inflammation and not on adiposity," the researchers concluded.
Liver Disease and Physical Fitness
The SLIM LIVER trial (ACTG A5371) enrolled 51 HIV-positive adults with metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease. Participants received weekly semaglutide injections for 24 weeks, achieving approximately one-third reduction in liver fat content.
Dr. Alina Pang of Weill Cornell Medicine presented new findings using an epigenetic clock incorporating physical fitness measures. Despite a mean chronological age of 52 years, participants' estimated epigenetic age was about 10 years older. Notably, participants with weaker baseline grip strength or greater grip strength improvement during treatment experienced larger reductions in liver fat, suggesting epigenetic biomarkers may predict semaglutide response.
Gut Microbiome and Alcohol Use
Additional analyses revealed broader health benefits. Dr. Stephanie Dillon of the University of Colorado found that semaglutide increased diversity and abundance of beneficial gut microbes, though certain pre-existing microbiome features were associated with smaller liver fat reductions.
Dr. Heidi Crane of the University of Washington Seattle analyzed alcohol consumption patterns among 443 HIV patients receiving semaglutide in routine clinical care. The study found lower alcohol use levels among semaglutide users compared to non-users, particularly among those with higher-risk consumption patterns.
"Additional evaluation of the role of GLP-1 receptor agonists as medications for alcohol use and other substance use disorders is needed," the researchers noted.
Access Disparities
Despite promising results, access to semaglutide remains limited. The medication costs approximately $1,000 monthly, and many insurers don't cover it for weight management. Dr. Andrew Hahn's analysis of 11,617 eligible HIV patients found only 7% received semaglutide prescriptions, with significant racial disparities—Black patients were 20% less likely than white patients to receive the medication despite higher qualification rates and more severe diabetes indicators.
Clinical Implications
These findings suggest GLP-1 receptor agonists may address multiple age-related complications in HIV patients beyond traditional metabolic benefits. As Corley noted, "Longitudinal studies looking at the long-term impact are going to be the most critical studies moving forward."
The research underscores the need for expanded access to these medications and inclusion of HIV patients in ongoing studies examining GLP-1 agonists for substance use disorders and other conditions. With HIV patients facing accelerated aging and increased comorbidity risks, these multi-faceted benefits could significantly impact long-term health outcomes.
