Evaluation of glucagon-like peptide-1 receptor agonist on pathophysiology of inflammation and atherosclerosis in persons living with HIV: a multicenter randomized placebo-controlled TRI

The National Heart, Lung, and Blood Institute awarded the University of California, Los Angeles $1,282,827 on July 10, 2026, under the Cardiovascular Diseases Research program (CFDA 93.837) to conduct a multicenter randomized placebo-controlled trial evaluating glucagon-like peptide-1 receptor agonist therapy on inflammation and atherosclerosis in persons living with HIV.

The study will enroll 125 treatment-suppressed participants aged 40 and older with known cardiovascular disease or at least one cardiovascular risk factor. Researchers will administer oral semaglutide at 7 milligrams once daily and assess arterial inflammation using FDG-PET/CT imaging, along with biomarkers of inflammatory and immune activation, non-calcified plaque burden, and coronary artery inflammation. The trial addresses the elevated myocardial infarction and cardiovascular disease burden in people living with HIV, which prior research indicates involves heightened arterial inflammation distinct from atherosclerosis in the general population. Preliminary evidence from the research team demonstrates that semaglutide is safely tolerated and improves cardiometabolic indices and liver disease in this population, but its mechanistic impact on HIV-associated atherosclerosis remains unexplored.

Work is performed in Los Angeles, California. The period of performance runs through March 31, 2031. The award is classified as a Project Grant under the assistance type structure.

Abstract

People living with HIV (PWH) have a higher risk of myocardial infarction and are twice as likely to develop cardiovascular disease accounting for a significant global burden of disease. While the mechanism underlying this excess risk is multifactorial, studies demonstrate that atherosclerosis in the setting of HIV is distinct and characterized by heightened arterial inflammation. Glucagon-like peptide-1 receptor agonist (GLP1-RA) using semaglutide is associated with reductions in major adverse cardiovascular events along with improvements in blood pressure, weight, and inflammatory markers in the general population with or without diabetes. While the precise mechanism by which GLP1-RA improves cardiovascular events remains unknown, GLP1-RA lowers production of inflammatory cytokines including IL-6, IL-1B, TNF-alpha and CRP as well as reduces macrophage infiltration in blood vessels and tissues. Among PWH, our team showed that semaglutide was safely tolerated and improved cardiometabolic indices and liver disease; however, the impact of this approach on atherosclerosis in HIV has not been evaluated. Given the key role of monocytes/ macrophages and inflammation in HIV- associated cardiovascular disease (CVD), the purpose of this proof- of-concept mechanistic trial is to evaluate the impact of GLP1-RA using semaglutide on the biology of HIV- associated atherosclerosis. We will perform a randomized placebo-controlled study of 125 treated and suppressed PWH aged 40 years and older with either known CVD or 1 risk factor for CVD to study the effect of GLP1-RA using oral semaglutide at 7MG once daily on arterial inflammation (assessed by FDG-pet/CT), biomarkers of inflammatory/immune activation, non-calcified plaque, and coronary inflammation in the coronary arteries (assessed by coronary computed tomography angiography, ccta). This multicenter trial will include PWH enrolled at ucla, uthealth houston, and mass general brigham (MGB) which are all sites with extensive experience in performing trials among PWH. Long time collaborators at MGB will serve as the core facility for the imaging endpoints. We have 3 specific aims for the evaluation of glucagon-like peptide-1 receptor agonist on pathophysiology of inflammation and atherosclerosis in persons living with HIV: a multicenter randomized placebo-controlled trial (olympic- HIV trial): aim 1: to determine whether GLP1-RA using semaglutide can reduce arterial inflammation as assessed by FDG-pet/CT. We will also assess the impact of GLP1-RA on hematopoietic tissues; aim 2: to determine the effect of GLP1-RA using semaglutide on markers of inflammation/immune activation and cardiometabolic indices (weight, adipose tissue measurements, lipids and homa-IR); aim 3: to explore the impact of GLP1-RA on non-calcified coronary plaque (NCP) volume as measured by ccta and coronary inflammation using pericoronary adipose tissue density(PCAT). These results will provide much needed data for the purpose of informing a larger clinical outcomes study in PWH.