Effects of semaglutide on subclinical cardiovascular health in people with HIV

Design and objective: Lipohypertrophy, characterized by central adipose tissue accumulation, is common in people with HIV (PWH) and contributes to cardiometabolic risk. In a recent randomized, double-blind, placebo-controlled phase 2b trial, semaglutide significantly improved weight, total fat, visceral adiposity, blood pressure, glucose metabolism, and lipids over 32 weeks in PWH with lipohypertrophy. This prespecified secondary analysis evaluated semaglutide's effects on subclinical cardiovascular health. Methods: Virologically suppressed adults with HIV without known diabetes, receiving stable antiretroviral therapy, with body mass index >25 kg/m 2 and increased waist circumference/waist-to-hip ratio were enrolled. Participants were randomized 1 : 1 to semaglutide or placebo for 32 weeks. Pulse wave velocity (PWV) and endothelial peripheral arterial tonometry (endoPAT) assessed arterial stiffness and endothelial function, and coronary artery calcium (CAC) score assessed calcified coronary atherosclerosis. Indirect calorimetry measured resting energy expenditure (REE) and oxygen consumption (VO 2 ). 10-year atherosclerotic cardiovascular disease (ASCVD) risk scores were calculated. Analyses followed intention-to-treat principles using sex-adjusted multiplicative regression. Results: One hundred eight participants ( n = 54 semaglutide) were enrolled (median age 53 years; 60% male; 65% non-White; 35% smokers). Semaglutide had no significant effect on PWV, CAC score, reactive hyperemia index, augmentation index, or REE. VO 2 showed a downward trend ( β −43 ml/min; P = 0.087). At week 32, significant reductions were observed in 10-year ASCVD risk (−32.6%; P = 0.026) and hsCRP (−23.4%; P = 0.02) in the semaglutide group relative to placebo. Conclusion: Semaglutide did not improve subclinical vascular markers over 32 weeks but significantly improved overall cardiometabolic health and cardiovascular disease risk. Longer and larger studies of GLP-1 RAs are indicated in HIV to further assess their effects on long-term cardiovascular disease outcomes. Trial registration: NCT04019197.