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

• Published in: JCI insight Vol. 5; no. 17
• Main Authors: Willard, Francis S., Douros, Jonathan D., Gabe, Maria B.N., Showalter, Aaron D., Wainscott, David B., Suter, Todd M., Capozzi, Megan E., van der Velden, Wijnand J.C., Stutsman, Cynthia, Cardona, Guemalli R., Urva, Shweta, Emmerson, Paul J., Holst, Jens J., D’Alessio, David A., Coghlan, Matthew P., Rosenkilde, Mette M., Campbell, Jonathan E., Sloop, Kyle W.
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 03.09.2020; American Society for Clinical investigation
• Subjects: Animals; beta-Arrestin 1 - physiology; Blood Glucose - metabolism; Gastric Inhibitory Polypeptide - pharmacology; Glucagon-Like Peptide-1 Receptor - agonists; Hypoglycemic Agents - pharmacology; Insulin - metabolism; Islets of Langerhans - drug effects; Islets of Langerhans - metabolism; Islets of Langerhans - pathology; Male; Mice; Mice, Knockout; Receptors, Gastrointestinal Hormone - agonists; Therapeutics; Therapeutics; Diabetes
• DOI: 10.1172/jci.insight.140532
• ISSN: 2379-3708

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.