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
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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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 3

Deletion of β-arrestin1 in pancreatic β-cells increases GLP-1 receptor–activated insulin secretion.

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Deletion of β-arrestin1 in pancreatic β-cells increases GLP-1 receptor–a...
Islets from littermate controls and Arrb1βcell–/– mice (male) were perifused ex vivo, and insulin secretion was measured in response to glucose (A), GLP-1 (B), GIP (C), or tirzepatide (TZP; D). Islets from Arrb1βcell–/– mice secreted more insulin compared with control islets in response to 16 mM glucose (A) and 300 pM GLP-1 (B). By contrast, insulin secretion was not different between the sets of islets in response to either 3 nM GIP (C) or 1 nM tirzepatide (D). Exendin-4(9–39) (Ex9; 1 μM) was used prior to GIP stimulation to normalize the elevated glucose stimulated insulin secretion. The integrated AUC (iAUC) was determined during the stimulation period: 6–19 minutes for 16 mM glucose (A), 20–29 minutes for GLP-1 (B), 40–58 minutes for GIP (C), and 24–39 minutes for tirzepatide (D). Each panel depicts results of a representative experiment from at least 2 independent experiments. *P<0.05, values are mean ± SEM. Statistical differences in iAUC values were determined by a 2-tailed student’s t test.