Weight-loss drug effective in people with HIV, but may worsen muscle loss and lipoatrophy

The Glucagon-like peptide (GLP-1) receptor agonist semaglutide could help people living with HIV (PLWH) lose weight gained after starting antiretroviral treatment (ART)—but it may also exacerbate muscle loss or lipoatrophy, according to research presented at IDWeek 2023 in Boston, Massachusetts.

Participant Characteristics and Study Construction

This randomized, double-blind, single-site trial conducted in Cleveland, Ohio, investigated the effect of the GLP-1 receptor agonist semaglutide in 108 adult PLWH. Participants were on stable ART and were not diabetic, but had experienced lipohypertrophy (in the form of increased abdominal girth) since starting ART. All participants had a body mass index of 25 kg/m2 or higher; had a waist circumference greater than 94 centimeters for women or 95 centimeters for men; and had a waist-to-hip ratio over 0.88 for women and over 0.94 for men.

After a lead-in phase of lifestyle counseling, participants were randomized 1:1 to weekly subcutaneous semaglutide or placebo injections. The drug dose was ramped up gradually over eight weeks, followed by 24 weeks of full-dose injections, and another 24 weeks of observation.

Demographic characteristics were similar between the two arms, except for sex: 70% of participants in the treatment arm were men compared to 50% of participants in the control arm. Overall the median age was around 52 years and 63% of participants were Black, and 8% and 9% were Latinx in the treatment arm and control arm, respectively.

All participants had maintained a viral load below 400 copies/mL on ART for at least six months, with most participants on integrase strand transfer inhibitors (83% in the treatment arm, 80% in the placebo arm) and a minority on protease inhibitors (19% in the treatment arm, 15% in the placebo arm). Body composition parameters were similar across arms, with a median weight of 98 kg and a median body mass index of about 33 kg/m².

Study Methods and Results

The study’s primary endpoint was visceral adipose tissue. “It’s not just weight that counts, it’s where the weight is,” presenter Grace A. McComsey, M.D., noted.

Participants in the treatment arm lost an average of 8.3% of their weight, with 65% of participants losing ≥ 5% of their body weight. In the control arm, participants gained an average of 0.2% of their weight and 4% of participants lost ≥ 5% of their body weight.

Lean mass was lost in both groups: an average 5.4% of muscle mass in the treatment arm, compared to an average 0.6% of muscle mass in the control arm. “There is a concern that [semaglutide] decreases lean mass in a population that gets sarcopenia frequently,” McComsey said.

Visceral adipose tissue and limb fat each dropped by 13% in the treatment arm, while visceral fat increased by 5% and limb fat did not change in the control arm. Decreasing limb fat could worsen pre-existing lipoatrophy, a common complication experienced by long-term HIV survivors with significant HIV treatment experience, McComsey noted.

Neither pericardial nor liver fat changed in either arm. “That was disappointing for us,” McComsey said.

More encouraging was the high level of study adherence among participants. “People were so in tune with the study; they wanted to come, they wanted to lose weight, they felt they needed it,” McComsey commented. “We did the study during COVID time and the shutdown, and they still came into the clinic.”

Over 90% in either arm experienced at least one adverse event. The number of possibly/probably study-related adverse events was similar between the arms. Treatment arm side effects were similar to those reported in general population studies of the drug, mainly gastrointestinal issues and an increase in triglycerides.

Sixteen participants dropped out, three of them for study-related reasons: one for abdominal pain/nausea, another for memory loss that the patient attributed to the study drug (though the issue did not resolve after discontinuation), and one for sustained grade 4 lipase elevation – “the patient was asymptomatic, but honestly we got scared,” recounted McComsey. The participant’s lipase levels returned to normal six weeks after discontinuing the study drug.

Next Steps

The study team is still analyzing data on cardiovascular disease, immune activation, and other endpoints. Another avenue for investigation is the impact of a mixed intervention that includes exercise on fat loss and muscle mass preservation in PLWH.

Study Information

Abstract 1984, “Effects of Semaglutide on Adipose Tissue in HIV-Associated Lipohypertrophy,” was presented on Oct. 13, 2023, by Grace A. McComsey, M.D., at IDWeek 2023 in Boston, Massachusetts.

By Barbara Jungwirth