Semaglutide may slow ageing, improve cognition and curb alcohol use

Semaglutide and related weight-loss medications, known as GLP-1 agonists, may slow biological ageing, reduce inflammation, improve cognitive function and gut health, and reduce alcohol use in people living with HIV, according to studies presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2025).

“While we know some of the types of benefits [related to] metabolic health, this new data points to potential ageing benefits,” said Dr Michael Corley of the University of California San Diego, the lead investigator for one of the studies. “It suggests that GLP-1 agonists may be helpful in stabilising biological ageing in a subset of people living with HIV.”

Weight gain and metabolic abnormalities are a growing concern for people with HIV as they get older. Glucagon-like peptide-1 (GLP-1) receptor agonists, including semaglutide (sold as Ozempic or Wegovy), mimic a natural hormone that suppresses appetite, regulates insulin and blood sugar, and slows emptying of the stomach. Originally developed to treat type 2 diabetes, these drugs are now widely used to manage obesity. They have been shown to reduce the risk of heart and kidney disease and some types of cancer, and they are being studied for fatty liver disease, Alzheimer’s disease and other conditions.

Epigenetic ageing

Professor Grace McComsey of Case Western Reserve University in Ohio and colleagues assessed the effects of semaglutide among HIV-positive people with lipohypertrophy, or abnormal fat accumulation. Visceral fat, or adipose tissue, within the abdomen is more strongly associated with health problems than subcutaneous fat under the skin.

The study included 108 adults classified as overweight or obese and a large waist circumference or waist-to-hip ratio. About 60% were men and the median age was 52. They were on suppressive antiretroviral therapy (mostly integrase inhibitors) and the median CD4 cell count was around 800. They were randomly assigned to receive semaglutide or a placebo injection once a week for 32 weeks.

As previously reported at IDWeek 2023 and in The Lancet Diabetes & Endocrinology, people taking semaglutide experienced notable declines in weight, total body fat and visceral abdominal fat, while those in the placebo group saw little change or slight gains. What’s more, semaglutide recipients showed favourable changes in biomarkers of inflammation. Semaglutide was generally well tolerated, with side effects similar to those seen in the general population (mainly gastrointestinal).

At CROI, Corley presented results from a secondary analysis looking at the effects of semaglutide on epigenetic markers of ageing. Epigenetics refers to changes in gene expression that are not attributable to modification of the DNA sequence itself. For example, DNA methylation involves addition of methyl group molecules to DNA, which can either silence or activate genes. The researchers used various DNA methylation ‘epigenetic clock’ algorithms to calculate epigenetic or biological age, which may be more predictive of health outcomes than chronological age. This analysis included a subgroup of 84 people.

At baseline, the participants had an increased epigenetic age, greater predicted mortality risk and a steady pace of ageing. But over 32 weeks of treatment, semaglutide appeared to stabilise epigenetic ageing. The pace of biological ageing slowed by about 9% in the semaglutide group compared with the placebo group, and the annual rate of epigenetic ageing mortality risk decreased by about three years.

“These findings suggest that semaglutide’s favourable effects on epigenetic ageing 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 ageing,” Corley said. “Longitudinal studies looking at the long-term impact are going to be the most critical studies moving forward.” 

In a related analysis, Dr Alina Pang of Weill Cornell Medicine and colleagues looked at epigenetic indicators of health, ageing and physical fitness among people with HIV and metabolic dysfunction-associated steatotic liver disease (MASLD) in the SLIM LIVER trial.

MASLD, formerly known as non-alcoholic fatty liver disease, is responsible for a growing proportion of advanced liver disease worldwide, and it is more common among people living with HIV. As the new name suggests, it is associated with obesity, type 2 diabetes and other metabolic abnormalities. Over time, the build-up of fat in the liver can lead to inflammation, cirrhosis and liver cancer. While one medication has been approved in the US, management of fatty liver disease still largely relies on lifestyle changes such as weight loss and exercise, but GLP-1 agonists show promise. 

SLIM LIVER enrolled 51 adults on suppressive antiretroviral therapy with a large waist circumference, insulin resistance or pre-diabetes, and MASLD. They received semaglutide injections once weekly for 24 weeks. As reported at last year’s CROI, semaglutide reduced liver fat by about a third, and over half of participants saw at least a 30% reduction in intrahepatic fat content. This was accompanied by significant weight loss, reduced waist circumference and improvements in fasting glucose and triglyceride levels.

In the new analysis presented at this year’s meeting, Pang’s team used an epigenetic clock that incorporates maximum oxygen uptake, walking speed and grip strength to estimate biological age in 41 people with available data. Although the mean chronological age was 52 years, the average estimated epigenetic age was about 10 years older. Participants with weaker grip strength at baseline or greater improvement in grip strength after 24 weeks on semaglutide saw a larger decrease in liver fat after controlling for sex and chronological age. These findings suggest that epigenetic biomarkers may help predict clinical response to semaglutide in people with HIV, according to the researchers.

Cognitive function and gut health

Another analysis from McComsey’s lipohypertrophy study assessed the effect of semaglutide on neurocognitive function, asking whether changes in fat or inflammatory markers could explain the drug’s benefits.

Dr Ornina Atieh of Case Western Reserve University and colleagues used an approved computer-based test called Cognivue to evaluate cognitive function at baseline and after 32 weeks on semaglutide. This comprehensive tool assesses several cognitive components including visual-spatial ability, attention and executive function, naming and language, memory, and abstraction, as well as reaction time and processing speed. 

The overall Cognivue scores were similar in the semaglutide and placebo groups, but people taking semaglutide had significantly better visual-spatial and delayed recall scores, and there was a trend toward better naming and language performance. After adjusting for sex and CD4 count, however, only visual-spatial scores remained close to statistical significance.

Neither weight nor visceral adipose tissue could explain semaglutide’s effect on visual-spatial performance after adjusting for other factors, Atieh reported. In contrast, levels of high-sensitivity C-reactive protein (a biomarker of inflammation) and sCD163 (a marker of macrophage activation) were correlated with better scores.

“Semaglutide has shown a potential beneficial impact on cognitive function, specifically the visuospatial cognitive subdomain in people living with HIV,” the researchers concluded. “This effect appears to be mediated by the effect of the drug on attenuating inflammation and not on adiposity.”

Another analysis from the SLIM LIVER team looked at the effects of semaglutide on the gut microbiome, the ecosystem of bacteria and other microorganisms that live in the intestines. Prior studies have shown that imbalances in the microbiome can weaken the gut lining and trigger chronic inflammation.

Dr Stephanie Dillon of the University of Colorado and colleagues reported that participants who used semaglutide showed an overall increase in the diversity and abundance of microbes associated with good gut health. But people with certain pre-existing microbiome features had a smaller reduction in liver fat while taking semaglutide, suggesting that microbiome-targeted therapies might be used along with GLP-1 agonists to enhance clinical outcomes in people with MASLD.

Alcohol consumption

Finally, Dr Heidi Crane of the University of Washington in Seattle and colleagues looked at changes in alcohol use among people with HIV in routine clinical care who were receiving semaglutide for diabetes or weight management.

In addition to their effects on metabolism, there’s growing evidence that GLP-1 agonists act on the brain to reduce not only appetite for food but also cravings for alcohol, tobacco and recreational drugs. Some semaglutide users have even reported that it reduced their urge to gamble.

This analysis included 443 people who received care at eight sites across the US after April 2018. More than three quarters were men, the median age was 54 and the cohort was racially diverse. People who did not drink alcohol at baseline were not included.

The researchers found that people who were prescribed semaglutide had lower levels of alcohol use compared with those not taking the drug. This was particularly the case for people considered to have higher-risk alcohol consumption.

“Additional evaluation of the role of GLP-1 receptor agonists as medications for alcohol use and other substance use disorders is needed,” the study authors concluded. 

Studies of semaglutide and related drugs for management of alcohol use and drug addiction are already underway for the general population. These findings underscore the need to include people with HIV in such research.