Early intervention with tirzepatide or semaglutide influences anti-atherosclerotic effects in ApoE knockout mice.

This study aimed to investigate the anti-atherosclerotic properties of tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor agonist, in comparison with semaglutide, a selective GLP-1 receptor agonist. ApoE knockout mice were divided into early diabetes (dosed from 10 to 22 weeks of age), late diabetes (dosed from 18 to 30 weeks of age), and non-diabetic groups after streptozotocin treatment, and each group received semaglutide, tirzepatide, or saline for 12 weeks. In the early diabetes group, both agents significantly suppressed aortic plaque formation compared with control, while modestly improving glycemia and lipid levels. No significant vascular effects were observed in late diabetes or non-diabetic groups. Tirzepatide markedly reduced inflammatory mediators, including Mcp-1, Il-6, I-cam, and Cd68, whereas semaglutide showed partial overlap. Notably, these anti-inflammatory effects were also detected in non-diabetic mice, suggesting vascular protection may involve arterial actions independently of metabolic control. Taken together, our findings demonstrate that tirzepatide exerts anti-atherosclerotic effects comparable to semaglutide, supporting the concept that GIP and GLP-1 signaling can confer vascular benefits. These results highlight the potential clinical relevance of dual incretin receptor agonism for cardiovascular risk reduction, although further studies are required to clarify the specific role of GIP signaling.