Background
Lipohypertrophy (central adipose tissue (AT) accumulation) and AT abnormalities are common in people with HIV (PWH) and are key drivers of cardiometabolic co-morbidities. In a recent randomized, double-blind, placebo-controlled phase 2b clinical trial, we observed significant effects of the glucagon-like peptide-1 receptor agonist (GLP-1 RA), semaglutide, over 32 weeks on key outcome measures, including reductions in weight, total body fat, and visceral adiposity in people with HIV-associated lipohypertrophy. The current analysis investigates the durability of semaglutide effects 24 weeks after drug discontinuation.
Methods
Virologically-suppressed PWH without known diabetes on stable antiretroviral therapy with body mass index ≥25 kg/m2 and increased waist circumference/waist-to-hip ratio were included. Participants were randomized 1:1 to 32 weeks semaglutide (8-week titration + 24 weeks 1.0 mg weekly nurse-administered subcutaneous injection) or matching placebo (intervention phase). Drug discontinuation occurred at week 32; outcome measures were reassessed at week 56 (post-interventional phase). Analyses were performed with intention-to-treat principles using sex-adjusted multiplicative regression modeling.
Results
108 participants (N=54 semaglutide) were enrolled (median age: 53 years; 60% male); 16 and 12 participants withdrew before week 32 and 56, respectively. Some residual semaglutide effects remained but were no longer statistically significant at week 56 (24 weeks after discontinuation) in key outcome measures (Figure 1). Semaglutide effects for weight, total body fat, abdominal visceral AT, and abdominal subcutaneous AT showed decreases from baseline of -5%, -12%, -16%, and -3% at week 56 (all p>0.05) vs. -10%, -20%, -32%, and -12% at week 32 (all p≤0.01), respectively. Improvements in glucose metabolism observed at 32 weeks were no longer evident at week 56 (0% and -1% at week 56 vs. baseline for hgbA1c and fasting glucose, respectively). Among 24 of 39 (62%) participants in the semaglutide group who lost ≥5% body weight during the intervention phase and completed week 56, 12 (50%) regained half to all the weight.
Conclusions
Much of the positive semaglutide effects achieved over 32 weeks was reversed after 24 weeks off drug. Apparent lack of durability with GLP-1 RA treatment in PWH raises concern for prolonged treatment requirements. Larger trials, particularly those assessing safety with higher doses and longer GLP-1 RA use, are needed in HIV.