New weight-loss drugs appear safe and effective for people living with HIV

Weight-loss medications, including the popular glucagon-like peptide-1 (GLP-1) receptor agonists semaglutide (Wegovy) and tirzepatide (Mounjaro), look like a promising option for people with HIV, although data are limited and more studies are needed.

Weight gain is a growing concern for people living with HIV and their health care providers. Not only do many people find weight gain and body shape changes distressing, they also raise the risk for cardiovascular disease and other health problems. HIV-positive people are often urged to take steps to manage their weight, but this is easier said than done.

“Lifestyle changes, exercise and diet are incredibly important for your health, but to shift weight downwards in someone with established weight gain is next to impossible,” Professor Francois Venter of the University of Witwatersrand in South Africa said at the International AIDS Society Conference on HIV Science (IAS 2023) in July. “You really do need pharmaceutical or surgical help.”

As aidsmap has reported, research has yielded conflicting data about weight changes after starting or switching antiretrovirals, especially integrase inhibitors. Numerous studies have found that people who start a new regimen can gain weight, sometimes as much as 5-10kg. This appears to be more likely when people switch away from tenofovir disoproxil or efavirenz, which have a weight-suppressing effect. But in general, changing antiretrovirals in an effort to lose weight does not seem to have much effect. Weight gain among people with HIV may also be attributable to a return to health after starting treatment or normal changes that occur with age.

The use of weight-loss medications has skyrocketed in recent years. The European Medicines Agency (EMA) has authorised the use of Wegovy for people with obesity or overweight. (The same drug was previously approved for the treatment of type 2 diabetes under the brand name Ozempic.) On 9 November, the EMA’s Committee for Medicinal Products for Human Use recommended expanding the indication for tirzepatide, previously approved for diabetes, to include weight management. (In the United States, tirzepatide was recently approved for weight management under the brand name Zepbound.)

Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist that mimics a natural hormone that suppresses appetite, regulates insulin and blood sugar levels and slows emptying of the stomach. Tirzepatide mimics the action of both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). Other related drugs, including orforglipron and retatrutide (which mimics three hormones), are currently in the pipeline.

Semaglutide and tirzepatide are generally safe, but they can cause side effects including nausea, vomiting, diarrhoea, constipation, abdominal pain and bloating. More serious adverse events may include gastroparesis (stomach paralysis) and pancreatitis. They can lead to loss of lean muscle mass as well as fat, which may be a concern for older people. What’s more, the drugs are expensive and they may need to be used long term, as weight typically rebounds after they are discontinued.

In clinical trials of HIV-negative people, non-diabetic adults with obesity who used semaglutide reduced their weight by around 15% on average, while those who used higher doses of tirzepatide lost around 20%. Semaglutide may also improve fatty liver disease, and a recent study showed that it reduced the risk of heart attacks and strokes in non-diabetic people with obesity and cardiovascular disease.

Weight gain on antiretroviral therapy

To date, there has not been much specific research on weight loss medications for people with HIV, but data are starting to emerge.

As reported at the IAS conference, Marisa Brizzi of the University of Cincinnati and colleagues evaluated the effect of GLP-1 receptor agonists on metabolic outcomes in HIV-positive and HIV-negative people with type 2 diabetes. They hypothesised that GLP-1 might be depleted during HIV infection and that integrase inhibitors might disrupt fat cells, affect hormones that regulate glucose and lipid metabolism, stimulate appetite or reduce insulin sensitivity.

This retrospective cohort study included 15 adults with HIV matched with 30 HIV-negative people. Nearly 90% were men and the mean age was 57 years. Most of the HIV-positive people were on integrase inhibitors. Nearly three quarters used dulaglutide (Trulicity) and 13% used liraglutide (Victoza for diabetes or Saxenda for weight loss), two older and less effective drugs; only 13% used semaglutide and none used tirzepatide.

HIV-positive people with diabetes lost 10.4kg, on average, compared with 1.7kg for HIV-negative people, or 8.0% versus 1.5% of their baseline body weight. What’s more, 60% of people with HIV achieved at least 5% weight loss, compared with 33% of HIV-negative participants.

In this cohort, people with HIV and diabetes “had significantly greater weight loss” compared to people with diabetes alone, the researchers concluded. “The greater weight loss observed in people with HIV may be related to differences in the mechanistic pathways leading to weight gain.”

While these results appear to suggest that people with HIV might benefit more from weight-loss drugs, most participants used older medications and the amount of weight lost in the HIV-negative group was substantially lower than that seen in pivotal trials of semaglutide and tirzepatide for people without diabetes.

In a related study, presented at IDWeek in Boston in October, Quynh Nguyen of the University of California San Diego and colleagues looked at prescribing practices and clinical outcomes among people with HIV who used weight-loss drugs. This retrospective cohort study included 225 adults who were classified as overweight or obese and who were prescribed GLP-1 receptor agonists between February 2021 and February 2023. A majority were men and the average age was 54 years. Most were on integrase inhibitors, 90% had an undetectable viral load and CD4 counts were high.

In this study, 53% received injectable semaglutide, 31% used dulaglutide, 8% used an oral formulation of semaglutide, 6% used tirzepatide and 3% used liraglutide. Ninety-nine people (43%) received the drugs for weight management alone, while the rest also had type 2 diabetes.

People who received GLP-1 drugs lost 5.4kg, on average. Nearly a quarter achieved greater than 5% weight loss, body mass index (BMI) fell by 1.8 and 18% went from obesity to overweight classification; blood glucose (haemoglobin A1C) also decreased. Those without diabetes tended to lose more weight. People with a higher baseline BMI and longer duration of treatment were more likely to experience greater than 5% weight loss, while those who used dulaglutide were less likely to do so. Age, sex, race/ethnicity, HIV viral load, CD4 count and antiretroviral regimen were not predictive of weight change.

“Use of GLP-1 receptor agonists led to improvements in weight, BMI and haemoglobin A1C among people with HIV and offers an additional strategy to address weight gain and related metabolic complications,” the researchers concluded.

Lipohypertrophy

In another study presented at IDWeek, Professor Grace McComsey, of Case Western Reserve University in Ohio and colleagues assessed the effects of semaglutide on lipohypertrophy, or abnormal fat accumulation. McComsey noted that it’s not just weight that matters but also where fat is located. Visceral fat within the abdomen is more strongly associated with cardiovascular disease and other health problems than subcutaneous fat under the skin.

This trial enrolled 108 non-diabetic adults on stable antiretroviral therapy with viral suppression. A majority (60%) were men and the median age was 52 years. More than 80% were on integrase inhibitors and CD4 counts were high. They had a BMI of 25 or higher (indicating overweight or obesity), a large waist circumference or waist-to-hip ratio and reported that they developed increased abdominal girth after starting antiretrovirals. They were randomly assigned to receive semaglutide or a placebo once weekly for 32 weeks. CT and DEXA scans were done to measure total, visceral, subcutaneous, trunk and limb fat, lean body mass and body composition.

Body weight fell by 8.3% in the semaglutide group while rising by 0.2% in the placebo group. A majority (65%) of people taking semaglutide, but only 4% of those taking the placebo, achieved at least 5% weight loss. BMI also decreased significantly in the semaglutide group.

" HIV-positive people are often urged to take steps to manage their weight, but this is easier said than done."

Total fat fell by 15% in the semaglutide group but rose by 0.2% in the placebo group. Visceral and trunk fat fell by 13% and 17% in the semaglutide group but increased by 5% and 0.4%, respectively, in the placebo group. Subcutaneous and limb fat both fell by 13% in the semaglutide group; in the placebo group, subcutaneous fat rose by 1.5% and limb fat was unchanged. Lean body mass fell by 5.4% in the semaglutide group compared with just 0.6% in the placebo group. However, fat accumulation in the liver and around the heart did not change much in either group.

Semaglutide was safe and well tolerated, McComsey reported. Side effects were common, but severe or serious adverse events were rare. Adherence was good despite the COVID-19 pandemic and the need for weekly injection visits. (Outside of clinical trials, most people use self-injection pens.)

“Semaglutide significantly decreased central fat in people with HIV with lipohypertrophy, primarily driven by reductions in visceral adipose tissue,” the researchers concluded. “Semaglutide may offer an effective treatment to decrease visceral adiposity and reduce comorbidity risk.”

McComsey noted that the loss of lean body mass could be a problem for a population prone to losing muscle mass over time, and there is concern that lipoatrophy, or fat wasting in the face and limbs, could potentially worsen.

A study presented at the recent European AIDS Conference (EACS 2023) in Warsaw raised another potential concern. Dr Sebastian Noe of MVZ München am Goetheplatz and colleagues assessed the effect of GLP-1 receptor agonists on circulating CD4 cells in people living with HIV with sustained viral suppression. Based on previous studies of related drugs, they hypothesised that these medications might lead to a decrease in CD4 counts.

This retrospective analysis included 76 people with HIV treated with semaglutide or dulaglutide for type 2 diabetes or obesity at two HIV clinics in Germany. Most were white men in their fifties and about half had diabetes. The median current CD4 count was high, above 800, but the median nadir (lowest-ever) count was just under 300. The data suggested that GLP-1 receptor agonist use “might be associated with a non-time-dependent decrease in CD4 cells,” with a median decrease of 64 cells, but not everyone was equally affected. “Further research is needed to confirm our findings and to identify people living with HIV at risk of a relevant decrease in CD4 cells,” the researchers concluded. “The clinical relevance of these findings merits further investigation.”

Finally, another study at IDWeek evaluated the effect of tesamorelin (Egrifta) on visceral fat in people taking integrase inhibitors. Tesamorelin, a synthetic growth hormone-releasing factor analogue, works differently from GLP-1 receptor agonists, acting on the pituitary gland in the brain to stimulate growth hormone production. It is approved in the United States, but its EMA application was withdrawn.

 A previous study showed that tesamorelin reduced visceral adipose tissue by about 15% in HIV-positive people with lipohypertrophy, but the research was done before integrase inhibitors were the preferred treatment for HIV. Therefore, Dr Taryn McLaughlin of Theratechnologies and colleagues asked whether it would have a similar effect for people taking newer regimens. The researchers drew on data from a previous trial that enrolled 61 HIV-positive participants with fatty liver disease. Of these, 39 (64%) were on integrase inhibitors, most commonly dolutegravir. They were randomly assigned to take tesamorelin or a placebo for 52 weeks.

At baseline, demographics, HIV-related variables and body composition measurements were similar for integrase inhibitor recipients and those taking other antiretrovirals. Over a year of treatment, BMI did not change significantly in either the tesamorelin or placebo groups. Integrase inhibitor recipients assigned to receive tesamorelin saw an 8.3% reduction in visceral adipose tissue, while placebo recipients had a 10.8% increase. Furthermore, the tesamorelin group experienced a 5% decline in liver fat from baseline while the placebo group saw no change. People taking integrase inhibitors in the placebo group experienced a gain in visceral fat despite no change in BMI, while tesamorelin reduced both visceral and liver fat, the researchers concluded.

Advocacy needed for access

Taken together, these studies indicate that weight-loss medications hold promise for people with HIV who struggle to lose weight or reduce abdominal fat. But the medications are not without drawbacks, including side effects and cost.

“GLP-1 agonists are revolutionizing the treatment of obesity in the general population, and I have no doubt they will do the same in people with HIV,” Dr Rajesh Gandhi of Harvard Medical School, commented in a New England Journal of Medicine IDWeek conference update.

“Because some people with HIV have fat maldistribution, with disproportionate central adipose tissue hypertrophy, the finding that semaglutide reduces visceral adipose tissue is particularly welcome,” he continued. “We have known for years that excessive visceral fat is associated with an increased risk for cardiac disease, so the impact of GLP-1 agonists on cardiometabolic health in people with HIV could be substantial.”

Venter, however, took a more cautious tone, noting that advocacy will be needed to get the greatest benefits from weight-loss medications for people living with HIV.

“In the last few weeks alone, there’s been an explosion of new agents, but they are eye-wateringly expensive in rich countries and completely unavailable in low- and middle-income countries,” he said at the IAS conference. “The levels of cost of these agents and the levels of overweight that we’re seeing in these communities are going to require some focussed activism in terms of access to these drugs, because there’s no way we’re going to be able to deal with this…We need to start testing these agents in the HIV-positive population so that we can get access to these drugs for our patients as quickly as possible.”

One such study, the SWIFT trial (NCT04174755), is currently underway in Ireland. It compares semaglutide plus a lifestyle intervention against lifestyle changes alone; results are expected in 2025.