GLP-1 agonists could be a global game-changer, but need to be accessible and affordable

Popular GLP-1 weight-loss medications generally work well for people living with HIV, and they may improve liver, gut and cardiovascular health and reduce smoking, along with their well-known benefits for obesity and diabetes, according to studies presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2026). However, much remains to be learned about their long-term use.

“With the exception of antiretroviral therapy, I can’t think of another class of medications where there has been so much buzz,” Dr Todd Brown of Johns Hopkins Medicine said during his plenary talk entitled ‘GLP-1 Agonists: Are They a Cure for Everything?’ He concluded that the enthusiasm is warranted, but there are unanswered questions for people with HIV and “global access will be a major challenge.”

Weight gain and metabolic abnormalities are a growing concern for people with HIV as they age. Glucagon-like peptide-1 (GLP-1) receptor agonists, including semaglutide (Ozempic or Wegovy), mimic a natural hormone that suppresses appetite, regulates insulin and blood sugar and slows emptying of the stomach. Tirzepatide (Mounjaro or Zepbound) targets both GLP-1 and another gut hormone, glucose-dependent insulinotropic polypeptide (GIP). 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, improve sleep apnoea and arthritis pain, and they are being studied for fatty liver disease, addiction and other conditions.

Evidence from the real world

Three studies looked at real-world use of GLP-1 agonist among people living with HIV.

Dr Lauren O’Connor from George Washington University and colleagues assessed outcomes among 362 people with HIV who took GLP-1 medications for at least six months. Most had diabetes (82%) and/or obesity (78%). The most commonly used GLP-1 was semaglutide (50%), and the average time on the drugs was 3.2 years.

Nearly one in five (19%) lost 5% to 10% of their baseline body weight, and 11% lost 10% or more, but that left more than two thirds below the 5% weight-loss threshold. Black people appeared to lose less weight than White people, but the difference was not statistically significant after adjusting for other factors. People with diabetes were less likely to experience at least 10% weight loss than those with obesity/overweight alone, which is also the case in for HIV-negative people. Weight loss did not differ based on age or CD4 cell count.

Dr Daniel Lee of the University of California San Diego and colleagues looked specifically at use of tirzepatide, which leads to greater weight loss than semaglutide in the general population. In this analysis of 61 people with HIV, the overall mean weight loss was about 14% of baseline body weight at 12 months – slightly less than the 17% loss seen in the population at large. Here, too, people with diabetes lost less weight than those without (10 vs 17 kg, respectively). Participants also saw significant reductions in haemoglobin A1C (a measure of blood sugar) and blood pressure, improved HDL ‘good’ cholesterol levels and lower 10-year cardiovascular disease risk scores. However, more than a quarter (26%) stopped taking tirzepatide before completing one year, mostly due to either side effects or insurance issues.

Dr Heidi Crane of the University of Washington in Seattle and colleagues compared use of semaglutide versus tirzepatide among participants in the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort, which follows HIV-positive adults receiving care at academic clinics across the United States. Three quarters were men and the median age was 52 years. About 80% had obesity and half had diabetes. A total of 2187 started semaglutide between April 2018 and July 2025, but only 497 started tirzepatide, which was not approved until 2022. Although percentage weight loss was less in this study compared with the previous two, people who used tirzepatide lost more weight and saw more improvement in A1C levels compared with semaglutide recipients.

More than a weight-loss drug

Crane’s team also looked at changes in cigarette smoking among people who started semaglutide in the CNICS cohort. In this analysis, 204 people with HIV reported smoking at the time they initiated semaglutide for diabetes or weight management, with an average of 10.5 cigarettes a day. After starting the drug, smoking fell by 2.7 cigarettes a day,  a 26% decrease. “Semaglutide may result in additional benefit to overall health in people with HIV,” the researchers concluded.

In another CNICS analysis, Dr Lara Haidar from the University of Manitoba and colleagues assessed the impact of semaglutide on depression in people with HIV. Although some early reports suggested GLP-1 agonists might be associated with increased risk of suicide, extensive investigations by the European Medicines Association and the US Food and Drug Administration found no such link – and in fact some studies saw a reduced risk. Reassuringly, Haidar’s study, which included 354 HIV-positive people starting semaglutide, found that the drug was not associated with overall worsening of depressive symptoms among those with absent, mild, moderate or severe depression at baseline.

Looking again at the CNICS cohort, Dr Jimmy Ma of the University of Washington and colleagues assessed the association between semaglutide use and liver fibrosis. Metabolic dysfunction-associated steatotic liver disease (MASLD) and its more severe form, metabolic dysfunction-associated steatohepatitis (MASH), are a growing concern for people with HIV. Over time, the build-up of fat in the liver can lead to fibrosis (liver scarring), cirrhosis and liver cancer. Based on a study of HIV-negative people, the US Food and Drug Administration approved Wegovy for the treatment of MASH in people with moderate to advanced fibrosis last year.

Ma’s analysis included 1850 people with HIV who started semaglutide for diabetes or weight loss and had available data to calculate FIB-4 liver fibrosis scores (age, platelet count and ALT and AST liver enzyme levels). About three quarters were men, the median age was 52 years, most had an undetectable viral load and the mean CD4 count was approximately 800. Based on FIB-4 scores, 74% had absent to mild fibrosis, 23% had moderate fibrosis and 3% had advanced fibrosis.

Semaglutide was associated with reduced FIB-4 fibrosis scores in participants with moderate to advanced liver stiffness, with the greatest improvement seen in those with the worst fibrosis. “Our findings, together with earlier studies, suggest semaglutide could play a role in managing MASLD and liver fibrosis in people with HIV, especially as they age and experience the longer-term impacts of cardiometabolic disease,” the researchers concluded.

While the studies above were observational, Dr Allison Ross Eckard from the Medical University of South Carolina and colleagues reported new findings from a randomised controlled trial of semaglutide versus a placebo in people with HIV, focusing on subclinical cardiovascular health. This trial enrolled 108 non-diabetic people on stable antiretroviral therapy with viral suppression who had lipohypertrophy, or central fat accumulation. About 60% were men and the median age was 53 years.

The researchers previously reported that participants assigned to semaglutide showed improvements in weight, total body fat, visceral fat, blood pressure, glucose metabolism and lipid levels compared with placebo recipients at 32 weeks.

In the current analysis, they saw “no discernible effects” on markers of subclinical vascular disease, including endothelial function and arterial stiffness, or on calcified atherosclerotic plaque. However, they did observe “improvements in overall cardiometabolic health and cardiovascular disease risk,” including a significant decline in C-reactive protein (an inflammation biomarker), a significant decrease in 10-year cardiovascular disease risk scores and trend toward improved oxygen consumption.

Finally, Dr Miguel Marin of the Africa Health Research Institute in Durban and colleagues looked at changes in gut health in five people taking liraglutide in South Africa. HIV is known to disrupt gut homeostasis and the integrity of the intestinal epithelial lining, contributing to chronic immune activation and inflammation despite viral suppression on antiretroviral therapy. Liraglutide (Victoza or Saxenda) is an older GLP-1 agonist injected once daily (semaglutide and tirzepatide are once-weekly injections).

The researchers collected blood samples and biopsies of colon and duodenal tissue from participants at four timepoints. As expected, liraglutide led to weight loss and reduced A1C levels. Biopsy samples showed favourable changes in gut T cells and epithelial cells after starting liraglutide, while blood samples showed decreases in various inflammation biomarkers. Based on these findings, the researchers suggested that GLP-1 receptor agonists might be “a potential strategy to mitigate gut pathology in people with HIV.”

Big promise, big obstacles

These studies represent just the tip of the iceberg when it comes to research on GLP-1 medications for people living with HIV. At last year’s CROI, researchers reported data showing that semaglutide may slow biological ageing, improve cognitive function and gut health, and reduce alcohol use in people living with HIV.

Reviewing the body of evidence to date, Brown noted that these drugs appear to significantly improve inflammation even before people lose much weight, possibly due to a direct effect on T cells. Their well-known ability to reduced ‘food noise’ could carry over to other cravings and addictions. They are even being explored as longevity drugs.

But outstanding questions remain. People on GLP-1 agonists lose lean body mass in addition to fat, but it’s not yet clear whether this leads to functional decline due to muscle loss or fractures due to bone loss. Weight loss tends to reverse when the drugs are stopped, and little is known about maintenance strategies such as lower doses or less frequent dosing. Pivotal clinical trials included few participants over 75, so more research is needed on outcomes as people age. Are the risks and benefits any different in people with and without HIV? Can the drugs attenuate chronic inflammation and immune activation in people with HIV, and if so, how will that impact common comorbid conditions?

Brown noted that it’s been estimated that 27% of the global population is eligible for GLP-1 drugs, and that with universal access, we could reduce global obesity by 20% and save 28 million lives over a five-year period. The World Health Organisation recently issued guidelines saying that GLP-1 therapies may be used as long-term treatment for obesity.

“Of course, the challenge is getting these drugs to the people who need them the most,” Brown said. “Here we get to the real Achilles heel of these therapies. I hope that the changing landscape will decrease cost, increase production and improve access to these medications.”

Patents for semaglutide are now expiring in several countries, paving the way for cheaper generics. Dr Andrew Hill of the University of Liverpool – known for his analyses of how much the cost of HIV and hepatitis C drugs could be brought down – has estimated that injectable semaglutide could be produced for as little as $3 per month. Brown predicted that the Wegovy pill recently approved in the US and other forthcoming oral medications, which are easier to produce and distribute, will be a game-changer. More than 60 experimental GLP-1 agonists and related drugs are in development for various indications, which has the potential to increase competition and lower prices.

“Is our exuberance regarding GLP-1 receptor agonists rational or irrational?” Brown asked. “I’d say it’s rational. This class of medications has really transformed how the way that we treat multiple diseases, and we really are just at the beginning of this transformation.”

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