Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist

Tirzepatide (LY3298176) is a dual GIP and GLP-1 receptor agonist under development for the treatment of type 2 diabetes mellitus (T2DM), obesity, and nonalcoholic steatohepatitis. Early phase trials in T2DM indicate that tirzepatide improves clinical outcomes beyond those achieved by a selective GLP-1 receptor agonist. Therefore, we hypothesized that the integrated potency and signaling properties of tirzepatide provide a unique pharmacological profile tailored for improving broad metabolic control. Here, we establish methodology for calculating occupancy of each receptor for clinically efficacious doses of the drug. This analysis reveals a greater degree of engagement of tirzepatide for the GIP receptor than…

• AD
  American Diabetes Association
• EL
  Eli Lilly and Company
• NN
  Novo Nordisk
• NI
  National Institutes of Health
• NI
  National Institute of Diabetes and Digestive and Kidney Diseases
• NC
  NIH Clinical Center

  Award: F32 DK116542,1-18-JDF-017,R01 DK123075,R01 DK101991