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

Journal Article (Journal Article)

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 the GLP-1 receptor, corroborating an imbalanced mechanism of action. Pharmacologically, signaling studies demonstrate that tirzepatide mimics the actions of native GIP at the GIP receptor but shows bias at the GLP-1 receptor to favor cAMP generation over β-arrestin recruitment, coincident with a weaker ability to drive GLP-1 receptor internalization compared with GLP-1. Experiments in primary islets reveal β-arrestin1 limits the insulin response to GLP-1, but not GIP or tirzepatide, suggesting that the biased agonism of tirzepatide enhances insulin secretion. Imbalance toward GIP receptor, combined with distinct signaling properties at the GLP-1 receptor, together may account for the promising efficacy of this investigational agent.

Full Text

Duke Authors

Cited Authors

  • Willard, FS; Douros, JD; Gabe, MB; Showalter, AD; Wainscott, DB; Suter, TM; Capozzi, ME; van der Velden, WJ; Stutsman, C; Cardona, GR; Urva, S; Emmerson, PJ; Holst, JJ; D'Alessio, DA; Coghlan, MP; Rosenkilde, MM; Campbell, JE; Sloop, KW

Published Date

  • September 3, 2020

Published In

Volume / Issue

  • 5 / 17

PubMed ID

  • 32730231

Pubmed Central ID

  • PMC7526454

Electronic International Standard Serial Number (EISSN)

  • 2379-3708

Digital Object Identifier (DOI)

  • 10.1172/jci.insight.140532


  • eng

Conference Location

  • United States