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Background <p>The Glucagon-like peptide-1 receptor (GLP-1R) and the glucose-dependent insulinotropic polypeptide receptor (GIPR) are well-established drug targets for the treatment of diabetes and obesity. Studies have linked GLP-1R agonist to cardiometabolic diseases (CMDs), while the therapeutic potential of the GIPR agonist remains a topic of debate.</p> Methods <p>Using genetic variants as instrumental variables, we performed a two-sample Mendelian randomization (MR) analysis to investigate causal relationships between genetically proxied GIPR agonist and 23 CMD outcomes, and a two-step mediation analysis to identify mediating inflammatory biomarkers. The inverse variance weighted (IVW) method served as the primary analytical approach, supplemented by sensitivity analyses to validate robustness.</p> Results <p>The genetic mimicry of GIPR enhancement showed significant protective associations with 14 CMDs.&#xa0;Mediation analysis revealed that Fms-related tyrosine kinase 3 ligand (Flt3L) partially mediated the effects of GIPR agonist on angina (OR 0.997 [0.995–0.999], <i>P</i> = 0.0048) and myocardial infarction(MI) (OR 0.998 [0.996–0.999], <i>P</i> = 0.0077), accounting for 15.49% and 16.71% of the total risk reduction, respectively.</p> Conclusion <p>Our study revealed that GIPR agonist lowers the risk of 14 CMDs. Flt3L is pinpointed as a key mediating factor in reducing angina and MI risk, suggesting a new therapeutic avenue.</p>

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Decoding the impact of glucose-dependent insulinotropic polypeptide receptor (GIPR) agonist on cardiometabolic health: inflammatory mediators at the focus

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月28日

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  • Fang Cheng,
  • Xinyu Niu,
  • Yaoling Wang,
  • Fan Yang,
  • Kang Yang,
  • Wei Li

摘要

Background

The Glucagon-like peptide-1 receptor (GLP-1R) and the glucose-dependent insulinotropic polypeptide receptor (GIPR) are well-established drug targets for the treatment of diabetes and obesity. Studies have linked GLP-1R agonist to cardiometabolic diseases (CMDs), while the therapeutic potential of the GIPR agonist remains a topic of debate.

Methods

Using genetic variants as instrumental variables, we performed a two-sample Mendelian randomization (MR) analysis to investigate causal relationships between genetically proxied GIPR agonist and 23 CMD outcomes, and a two-step mediation analysis to identify mediating inflammatory biomarkers. The inverse variance weighted (IVW) method served as the primary analytical approach, supplemented by sensitivity analyses to validate robustness.

Results

The genetic mimicry of GIPR enhancement showed significant protective associations with 14 CMDs. Mediation analysis revealed that Fms-related tyrosine kinase 3 ligand (Flt3L) partially mediated the effects of GIPR agonist on angina (OR 0.997 [0.995–0.999], P = 0.0048) and myocardial infarction(MI) (OR 0.998 [0.996–0.999], P = 0.0077), accounting for 15.49% and 16.71% of the total risk reduction, respectively.

Conclusion

Our study revealed that GIPR agonist lowers the risk of 14 CMDs. Flt3L is pinpointed as a key mediating factor in reducing angina and MI risk, suggesting a new therapeutic avenue.