Tirzepatide Attenuates Wire Injury-Induced Arterial Remodeling in Non-Diabetic and Diabetic Mice: Comparison with Semaglutide

Background: Glucose-dependent insulinotropic polypeptide receptor (GIPR) and glucagon-like peptide-1 receptor (GLP-1R) activation exert anti-diabetic and anti-obesity effects. Tirzepatide, a dual GIPR/GLP-1R agonist, has demonstrated cardiovascular benefits in clinical studies. However, the direct vascular actions of tirzepatide and their potential advantages over selective GLP-1 receptor agonists (GLP-1RA) remain unclear. We investigated the vasoprotective effects of tirzepatide and compared them with those of GLP-1 receptor agonists in vivo and in vitro. Methods: Non-diabetic C57BL/6 and diabetic KK-Ay mice received tirzepatide, semaglutide, or vehicle. Arterial remodeling was induced by femoral artery wire injury. A subset of mice was co-treated with the nitric oxide synthase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME). After 4 weeks, biochemical, morphometric, and immunofluorescence analyses were performed. In vitro, human umbilical vein endothelial cells (HUVECs) were stimulated with tirzepatide or liraglutide to assess nitric oxide (NO) production. Results: In non-diabetic mice, tirzepatide suppressed intimal hyperplasia without affecting metabolic parameters, whereas semaglutide had no significant effect on intimal hyperplasia at the same molar dose. The protective effects of tirzepatide were abolished by L-NAME. In diabetic mice, tirzepatide and semaglutide similarly improved metabolic parameters and attenuated intimal hyperplasia. In HUVECs, tirzepatide increased NO production in a dose-dependent manner, and this effect was preserved under hyperglycemic conditions. Tirzepatide and liraglutide induced comparable NO production at equivalent molar concentrations. Conclusions: Tirzepatide exerted greater vasoprotective effects than selective GLP-1RA under non-diabetic conditions in an NO-dependent manner, whereas both agents exhibited comparable vasoprotective effects under diabetic conditions.