Beyond Glycemic Control: Glucagon-Like Peptide-1 Receptor Agonists as Potential Modifiers of Aortic Disease

This review summarizes mechanistic, preclinical, and emerging clinical evidence on whether glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) may modify aortic disorders. In addition to metabolic effects, GLP-1 RAs have anti-inflammatory, antioxidant, and antiatherogenic properties and reduce major cardiovascular events in large trials. Since inflammation and extracellular matrix remodeling contribute to aortic valve calcification, root dilation, aneurysm growth, and aorto-occlusive disease, GLP-1 RAs may offer a unified therapeutic approach. A narrative review was performed using animal studies, population data, and cardiovascular outcome trials published up to May 2025, focusing on mechanisms, disease outcomes, and translational gaps. In vitro and rodent studies show that GLP-1 RAs inhibit IL-1β, TNF-α, and matrix metalloproteinases, preserve elastin structure, and promote M2 macrophage activity, slowing both thoracic and abdominal aneurysm growth. Similar antiosteogenic signaling may reduce valve calcification, though clinical validation is lacking. Observational data and post hoc analyses report fewer adverse limb events and improved walking distance in peripheral artery disease, suggesting benefit in aorto-occlusive syndromes. However, evidence for aortic regurgitation is currently absent. Overall, mechanistic and early clinical findings support GLP-1 RAs as potential disease-modifying agents along the aortic tree. Further imaging-based studies in calcific valve disease and aneurysms and trials focused on peripheral artery disease are now warranted. If confirmed, these agents could extend their benefits beyond metabolic disease to patients at risk of serious aortic complications.