Abstract
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.
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All data supporting the findings of this study are available from the corresponding author upon reasonable request.
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Acknowledgements
We thank central research institute of Kawasaki Medical School for technical supports of experiments.
Funding
This study was partially supported by a Research Project Grant from the Japan Arteriosclerosis Prevention Fund (Grant No. 2024-1-014) and by a grant from Kawasaki Medical School (Grant No. R05G004).
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J.S, T.K. and H.K. designed this experiment. K.D., J.S., Y.N. and Y.S. performed the experiments. J.S. and T.K. supervised the experimental procedures. K.D., J.S., and T.K. wrote the manuscript. Y.I., T.S., H.I., Y.F., M.S., S.N. and K.K. participated in discussion. H.K. participated in discussion and reviewed the manuscript. All authors approved the submission of the final version of this manuscript.
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T.K. has received honoraria for lectures from Novo Nordisk Pharma and Sumitomo Pharma. S. N. has received honoraria for lectures from Novo Nordisk Pharma and Daiichi Sankyo. K.K. has served as an advisor to, received honoraria for lectures from and received scholarship grants from Novo Nordisk Pharma, Sanwa Kagaku, Taisho Pharma, Kowa, Sumitomo Pharma, Mitsubishi Tanabe Pharma, Astellas and Boehringer Ingelheim. H.K. has received honoraria for lectures, scholarship grants and research grants from Novo Nordisk Pharma, Sanofi, Eli Lilly, Boehringer Ingelheim, Taisho Pharma, Sumitomo Pharma, Takeda Pharma, Ono Pharma, Daiichi Sankyo, Mitsubishi Tanabe Pharma, Kissei Pharma, MSD, AstraZeneca, Astellas, Novartis, Kowa and Abbott. All other authors have no conflict of interest.
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Dan, K., Sanada, J., Kimura, T. et al. Early intervention with tirzepatide or semaglutide influences anti-atherosclerotic effects in ApoE knockout mice. Sci Rep (2026). https://doi.org/10.1038/s41598-026-42437-8
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DOI: https://doi.org/10.1038/s41598-026-42437-8
