JCI Insight (Sep 2020)

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

  • Francis S. Willard,
  • Jonathan D. Douros,
  • Maria B.N. Gabe,
  • Aaron D. Showalter,
  • David B. Wainscott,
  • Todd M. Suter,
  • Megan E. Capozzi,
  • Wijnand J.C. van der Velden,
  • Cynthia Stutsman,
  • Guemalli R. Cardona,
  • Shweta Urva,
  • Paul J. Emmerson,
  • Jens J. Holst,
  • David A. D’Alessio,
  • Matthew P. Coghlan,
  • Mette M. Rosenkilde,
  • Jonathan E. Campbell,
  • Kyle W. Sloop

Journal volume & issue
Vol. 5, no. 17

Abstract

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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.

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