Immunometabolic reprogramming via GLP-1 receptor agonists in people with HIV: A multidimensional systemic framework

Antiretroviral therapy (ART) has transformed HIV infection into a manageable chronic condition, but pathological weight gain, adipose dysfunction, and persistent inflammation are increasingly prevalent among aging people with HIV (PWH). Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual GIP/GLP-1 RAs have emerged as transformative therapies, although PWH were underrepresented in pivotal trials. This review integrates randomized trials, observational cohorts, pharmacogenomic studies, and emerging mechanistic evidence within a framework of GLP-1-mediated immunometabolic reprogramming. HIV-specific trials demonstrate reductions in visceral adiposity, body weight, inflammatory biomarkers, and liver fat. Exploratory or preliminary studies suggest possible effects on gut epithelial integrity, immune-cell trafficking, lymphoid pyroptosis, and DNA-methylation aging measures; however, several of these findings remain conference-level, preprint, or post hoc evidence and require prospective validation. We also examine lean-mass loss, weight regain after discontinuation, pharmacogenomic variation, drug access, and research priorities. Overall, GLP-1 RAs are promising components of cardiometabolic care for PWH, but immunologic, gerotherapeutic, and HIV-reservoir applications should currently be considered hypothesis-generating.