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

Paper

Abstract

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.

Analysis

Paper intelligence

Summary

This study characterizes tirzepatide, a dual GIP and GLP-1 receptor agonist, revealing its imbalanced GIP receptor engagement and biased signaling at the GLP-1 receptor, which may contribute to its potent metabolic benefits.

Key findings

Tirzepatide has greater engagement with the GIP receptor than the GLP-1 receptor.
Tirzepatide mimics native GIP at the GIP receptor.
Tirzepatide is biased at the GLP-1 receptor, favoring cAMP over β-arrestin recruitment.
Tirzepatide's biased agonism enhances insulin secretion by overcoming β-arrestin1-mediated limitations.

Methods

Developed methodology for calculating receptor occupancy for clinically efficacious doses.
Conducted signaling studies to demonstrate tirzepatide's actions at GIP and GLP-1 receptors.
Investigated tirzepatide's effect on insulin secretion in primary islets.
Compared tirzepatide's signaling properties to native GIP and GLP-1.

Limitations

The study focuses on in vitro and ex vivo experiments, and in vivo validation may be needed.
The precise clinical implications of the observed signaling biases require further investigation.
The study does not directly compare tirzepatide to other dual agonists in all aspects.

Applications

Treatment of type 2 diabetes mellitus
Treatment of obesity
Treatment of nonalcoholic steatohepatitis

Confidence90%

Discovery

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Source record

Publication metadata

Authors: Francis S. Willard; Jonathan D. Douros; M 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
Published: Jul 30, 2020
Journal or venue: JCI Insight
DOI: 10.1172/jci.insight.140532
Paper type: journal article
Source: Openalex

DOI OpenAlex