The use of GLP1 Receptor Agonists in People living with HIV

ABSTRACT Background People living with HIV (PLWH) on long-term antiretroviral therapy (ART) face a growing burden of metabolic complications, including obesity, dyslipidaemia, insulin resistance, and the metabolic syndrome, largely driven by adipose tissue dysfunction and amplified by the widespread use of integrase strand transfer inhibitors (INSTIs) and tenofovir alafenamide (TAF). Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), with proven efficacy on weight, glycaemic control, and cardiovascular protection in the general population, have emerged as a promising option in this setting. However, evidence in PLWH is limited to a few short-term trials, and their impact on bone turnover, body composition, and broader metabolic and cognitive outcomes remains largely unexplored, particularly in real-world settings. Methods This longitudinal observational study enrolled ART-experienced PLWH attending the Modena HIV Metabolic Clinic, Italy, between 2023 and 2026, aged ≥18 years with ≥2 evaluations. The exposed group received at least one GLP-1 RA prescription. The index date was the first prescription; baseline was the closest visit within a 12-month window (9 months before to 3 months after), with follow-up to the last visit on therapy. Users were matched 1:3 to GLP-1 PLWH on age, sex, and baseline cardiovascular-kidney-metabolic (CKM) stage, in the overall cohort and in a subcutaneous (SC) semaglutide subgroup. Visits included metabolic and lipid panels, DEXA body composition, hepatic elastography (CAP, liver stiffness), SCORE2/SCORE2-OP risk, and sarcopenia/frailty screening. The primary outcome was the longitudinal CKM trajectory, assessed as stage transitions and through a purpose-built continuous CKM Z-score. Results Of 523 PLWH meeting inclusion criteria, 37 were GLP-1 RA users, of whom 18 received SC semaglutide. At baseline, users had a more compromised profile than matched controls. Across the class, changes were directionally consistent with the literature, though not in magnitude, reflecting the small, heterogeneous sample. In the semaglutide subgroup the benefit was consistent: users lost significantly more weight and showed greater reductions in BMI, waist circumference, visceral adipose tissue, and hepatic fat, with improved glycaemic control. These gains spared the musculoskeletal system: appendicular muscle mass, strength, performance and bone density were preserved, the modest lean-mass loss confined to the trunk. For the primary outcome, semaglutide use was associated with a significantly more favourable change in the CKM Z-score than non-use, confirmed in the adjusted mixed-effects model for SC semaglutide. Conclusion In this matched cohort of PLWH, GLP-1 RA therapy, most consistently SC semaglutide, was associated with a more favourable CKM trajectory than non-use, with slowed stage progression and within-stage improvement on the continuous CKM Z-score, alongside reductions in adiposity, visceral and hepatic fat, and glycaemia, while muscle, function, and bone were preserved. Because users began from a more compromised, largely diabetic baseline, the true benefit may be underestimated. Furthermore this single-centre observational proof-of-concept is hypothesis-generating and supports adequately powered trials, to test whether GLP-1 RAs can modify cardiometabolic trajectory in HIV.