Durability of semaglutide effects after treatment discontinuation in HIV-associated lipohypertrophy: a randomized, double-blind, placebo-controlled phase IIb clinical trial

Abstract Background HIV-associated lipohypertrophy is characterized by excess central and visceral adiposity and is associated with increased cardiometabolic risk among people with HIV (PWH). In a previously reported randomized trial, semaglutide significantly reduced body weight, regional adiposity, and insulin resistance over 32 weeks of active treatment. However, the durability of these benefits after treatment discontinuation is unknown. Methods We conducted a randomized, placebo-controlled trial in PWH with HIV-associated lipohypertrophy. Participants were randomized to semaglutide or placebo for 32 weeks, followed by discontinuation of study drug and observational follow-up through week 56. The current analysis investigated effects of semaglutide at week 56, as compared to baseline and week 32. Outcomes included adipose tissue quantity by body compartment. Analyses were performed using intention-to-treat principles. This trial was registered ClinicalTrials.gov (NCT04019197) and is complete. Results Of 108 participants initially randomized, 92 completed the 32-week intervention and 80 participants (39 semaglutide, 41 placebo) completed the post-treatment phase. Participants previously assigned to semaglutide experienced increases in body weight, BMI, waist circumference, total body fat, and visceral adipose tissue between weeks 32 and 56, accompanied by worsening glycemic indices and insulin resistance. Despite this rebound, net reductions in body weight, BMI, and waist circumference were retained at week 56 compared with baseline. Placebo-treated participants demonstrated relative stability across outcomes. Conclusions Discontinuation of semaglutide in PWH with lipohypertrophy resulted in partial loss of improvements in weight, adiposity, and metabolic parameters. These findings support that sustained pharmacologic exposure is likely needed to achieve long-term benefit.