Decoding the impact of glucose-dependent insulinotropic polypeptide receptor (GIPR) agonist on cardiometabolic health: inflammatory mediators at the focus
Diabetology & Metabolic Syndrome, 2025
Cheng F., Niu X., Wang Y., Yang F., Yang K., Li W.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Metabolic Diseases CVD | Pathophysiology | Plasma |  Olink Target 96 |
Abstract
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.