Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist
Francis S. Willard, … , Jonathan E. Campbell, Kyle W. Sloop
Francis S. Willard, … , Jonathan E. Campbell, Kyle W. Sloop
Published July 30, 2020
Citation Information: JCI Insight. 2020;5(17):e140532. https://doi.org/10.1172/jci.insight.140532.
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Research Article Therapeutics

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

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.

Authors

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

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Figure 1

Tirzepatide (TZP) is an imbalanced agonist of the GIP and GLP-1 receptors and shows biased pharmacology at the GLP-1 receptor.

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Tirzepatide (TZP) is an imbalanced agonist of the GIP and GLP-1 receptor...
(A–F) Intracellular cAMP accumulation was measured in low-density human GIPR- and GLP-1R–expressing HEK293 cells. (A) The intrinsic potency of TZP (n = 23) in the presence of casein (CAS) is equivalent to GIP(1-42) (n = 49). In the presence of human serum albumin (HSA), the potency of TZP right shifts 26-fold (n = 5), while GIP(1-42) is unaltered (n = 15). (B) The intrinsic potency of TZP (n = 22) is approximately 18-fold lower than GLP-1(7-36) (n = 57). In the presence of HSA, TZP right-shifts 81-fold (n = 5), while the potency of GLP-1(7-36) is unaltered (n = 24). (C–F) Agonist induced generation of cAMP was measured kinetically using a luminescence biosensor. Data are representative of 3 experiments. At the GIPR, GIP(1-42) (C), and TZP (E) have identical kinetic profiles. On the GLP-1R, native GLP-1(7-36) (D) has a complex profile with a bi-phasic kinetic response at high ligand concentrations, while TZP (F) is monophasic even at the highest tested concentrations. (G and H) Agonist-stimulated GTPγS binding of Gαs in GIPR and GLP-1R in HEK293 cell membranes are presented as the mean ± SEM of 3 independent experiments. (G) On the GIPR, TZP is fully efficacious with an EC50 (SEM, n) of 0.379 nM (0.070, 3) versus GIP(1-42) of 1.43 nM (0.18, 27). (H) On the GLP-1R, TZP is a partial agonist 51% stimulation (5.2, 3) with an EC50 of 0.617 nM (0.190, 3) versus GLP-1(7-36) of 1.63 nM (0.21, 26). (I and J) The recruitment of ARRB2 to GIPR and GLP-1R in CHO-K1 cells. Representative data are presented. (I) The potency of TZP to recruit ARRB2 to GIPR is 2.34 nM (0.60, 7) and is comparable with GIP(1-42) of 1.58 nM (0.52, 6). (J) The potency of TZP to recruit ARRB2 to GLP-1R is difficult to determine due to low efficacy (n = 5), while GLP-1(7-36) is a full agonist with an EC50 of 3.26 nM (0.71, 14).