TY - JOUR

T1 - Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist

AU - Willard, Francis S.

AU - Douros, Jonathan D.

AU - Gabe, Maria

AU - Showalter, Aaron D.

AU - Wainscott, David B.

AU - Suter, Todd M.

AU - Capozzi, Megan E.

AU - van der Velden, Wijnand J. C.

AU - Stutsman, Cynthia

AU - Cardona, Guemalli R.

AU - Urva, Shweta

AU - Emmerson, Paul J.

AU - Holst, Jens J.

AU - D'Alessio, David A.

AU - Coghlan, Matthew P.

AU - Rosenkilde, Mette M.

AU - Campbell, Jonathan E.

AU - Sloop, Kyle W.

PY - 2020

Y1 - 2020

N2 - 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 beta-arrestin recruitment, coincident with a weaker ability to drive GLP-1 receptor internalization compared with GLP-1. Experiments in primary islets reveal beta-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.

AB - 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 beta-arrestin recruitment, coincident with a weaker ability to drive GLP-1 receptor internalization compared with GLP-1. Experiments in primary islets reveal beta-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.

KW - GLUCAGON-LIKE PEPTIDE-1

KW - DEPENDENT INSULINOTROPIC POLYPEPTIDE

KW - SERUM-PROTEIN BINDING

KW - IN-VITRO

KW - DULAGLUTIDE

KW - AFFINITY

KW - PHARMACOLOGY

KW - SEMAGLUTIDE

KW - ACTIVATION

KW - INHIBITORS

U2 - 10.1172/jci.insight.140532

DO - 10.1172/jci.insight.140532

M3 - Journal article

C2 - 32730231

VL - 5

JO - JCI Insight

JF - JCI Insight

SN - 2379-3708

IS - 17

M1 - 140532

ER -