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CROI 2024 GLP1 RAs for comorbidities
GLP-1 RAs to Treat Comorbidities in People Living With HIV: CROI 2024 Update

Released: March 27, 2024

Expiration: March 26, 2025

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Key Takeaways
  • Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as semaglutide, are approved to treat people with type 2 diabetes and obesity.
  • As presented at CROI 2024, semaglutide shows promise in reducing weight, addressing metabolic–associated steatotic liver disease, and decreasing cardiovascular disease risk in people living with HIV.
  • Larger studies are needed to better understand the full risks and benefits of GLP-1 RA therapy, including decreased muscle mass, in this population.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as semaglutide, are FDA-approved to treat both type 2 diabetes and obesity; however, there are limited data on the use of these agents in people living with HIV. The recent 2024 Conference on Retroviruses and Opportunistic Infections (CROI 2024) included several key abstracts that now provide insight into the use of GLP-1 RAs for weight loss and other comorbidities in people living with HIV.

Real-World Evidence
In an observational study from the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort 1 (n = 222), 77% of participants were diagnosed with diabetes and 97% were on antiretroviral therapy (ART), with 89% of those being virally suppressed. The results showed that, after 1 year of treatment with subcutaneous semaglutide 0.25 to 2.4 mg weekly, participants lost 6.5 kg and reduced their body weight by 5.7% on average.

Individuals with higher baseline BMI (obesity class 3; P <.001) saw significantly more weight loss than did those with a normal BMI, overweight, or obesity class 1 or 2. Interestingly, no significant differences between diabetes status or treatment dose were observed. These findings are consistent with prior studies looking at GLP-1 RA therapy among people living with HIV.

HIV-Associated MASLD or Lipohypertrophy
The GLP-1 RA semaglutide was also examined in the SLIM LIVER study (or ACTG A5371), which is an open-label, single-arm phase IIb study of 49 people with well-controlled HIV (on ART) and metabolic–associated steatotic liver disease (MASLD)—defined as having ≥5% intrahepatic triglyceride (IHTG) content on baseline MRI. Participants initiated weekly semaglutide that was titrated up to the 1 mg target at Week 4.

At CROI 2024, Lake and colleagues presented the primary outcome from this study (change in IHTG content by MRI after 24 weeks), showing that 58% of participants saw a ≥30% relative reduction in their IHTG and 29% saw complete resolution of their MASLD. Not surprisingly, the degree of weight loss among participants was significantly associated with the degree of IHTG improvement (P <.0001).

These results are very encouraging, given that MASLD is prevalent in people living with HIV, and its treatment options (beyond weight loss through diet and exercise) are extremely limited.

In another CROI 2024 abstract, Eckard and colleagues evaluated the impact of semaglutide on immune activation and inflammation in people with HIV-associated lipohypertrophy. In this population, lipohypertophy is an undesirable outcome of ART that is associated with elevated markers of inflammation and increased cardiovascular risk. The double-blind, placebo-controlled phase IIb trial enrolled 108 participants with well-controlled HIV who met predefined criteria for lipohypertrophy. They were randomized 1:1 to receive 1 mg of semaglutide or placebo for 32 weeks. Individuals with diabetes were excluded.

The results showed that those who received semaglutide saw significant reductions in several biomarker levels—IL-6, high-sensitivity C-reactive protein, and soluble CD163—that are associated with cardiovascular disease risk compared with placebo. These data provide a better understanding of the mechanism by which semaglutide leads to weight loss and improvements in cardiovascular outcomes among people living with HIV.   

Other Considerations
One concern about GLP-1 RAs is that, even though these agents induce significant weight loss and improvement in metabolic health, their use is also associated with a loss of muscle mass. Ditzenberger and colleagues presented an additional analysis at CROI 2024 of the SLIM LIVER study that evaluated the impact of semaglutide on psoas muscle quality, quantity (volume measured via MRI), and function (measured by chair-rise and gait speed) in people living with HIV being treated for MASLD.

Investigators found that 24 weeks of low-dose semaglutide significantly decreased psoas muscle volume compared with baseline. Further, this decrease was greatest among those aged 60 years or older. Despite these data, chair-rise and gait speed changes were not significant when compared to baseline results, suggesting that muscle function was not impacted.

GLP-1 RAs hold tremendous promise for people in the United States living with HIV, especially those with elevated BMI, MASLD, and increased cardiovascular disease risk. More data from larger, controlled studies are needed to better understand the full benefits of GLP-1 RA therapy in this population. We also need to continue to evaluate the potential negative effects of these agents, such as muscle mass loss, and identify strategies that could potentially mitigate these downsides.

Your Thoughts
How do you manage obesity, MASLD, and cardiovascular risk in people living with HIV? You can get involved with the conversation by posting a comment below.