TY - JOUR

T1 - The importance of glucose-dependent insulinotropic polypeptide receptor activation for the effects of tirzepatide

AU - Gasbjerg, Lærke S.

AU - Rosenkilde, Mette M.

AU - Meier, Juris J.

AU - Holst, Jens J.

AU - Knop, Filip K.

N1 - Publisher Copyright: © 2023 John Wiley & Sons Ltd.

PY - 2023

Y1 - 2023

N2 - Tirzepatide is a unimolecular co-agonist of the glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors recently approved for the treatment of type 2 diabetes by the US Food and Drug Administration and the European Medicine Agency. Tirzepatide treatment results in an unprecedented improvement of glycaemic control and lowering of body weight, but the contribution of the GIP receptor-activating component of tirzepatide to these effects is uncertain. In this review, we present the current knowledge about the physiological roles of the incretin hormones GLP-1 and GIP, their receptors, and previous results of co-targeting the two incretin hormone receptors in humans. We also analyse the molecular pharmacological, preclinical and clinical effects of tirzepatide to discuss the role of GIP receptor activation for the clinical effects of tirzepatide. Based on the available literature on the combination of GLP-1 and GIP receptor activation, tirzepatide does not seem to have a classical co-activating mode of action in humans. Rather, in vitro studies of the human GLP-1 and GIP receptors reveal a biased GLP-1 receptor activation profile and GIP receptor downregulation. Therefore, we propose three hypotheses for the mode of action of tirzepatide, which can be addressed in future, elaborate clinical trials.

AB - Tirzepatide is a unimolecular co-agonist of the glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors recently approved for the treatment of type 2 diabetes by the US Food and Drug Administration and the European Medicine Agency. Tirzepatide treatment results in an unprecedented improvement of glycaemic control and lowering of body weight, but the contribution of the GIP receptor-activating component of tirzepatide to these effects is uncertain. In this review, we present the current knowledge about the physiological roles of the incretin hormones GLP-1 and GIP, their receptors, and previous results of co-targeting the two incretin hormone receptors in humans. We also analyse the molecular pharmacological, preclinical and clinical effects of tirzepatide to discuss the role of GIP receptor activation for the clinical effects of tirzepatide. Based on the available literature on the combination of GLP-1 and GIP receptor activation, tirzepatide does not seem to have a classical co-activating mode of action in humans. Rather, in vitro studies of the human GLP-1 and GIP receptors reveal a biased GLP-1 receptor activation profile and GIP receptor downregulation. Therefore, we propose three hypotheses for the mode of action of tirzepatide, which can be addressed in future, elaborate clinical trials.

KW - antidiabetic drug

KW - antiobesity drug

KW - GIP

KW - GLP-1

KW - insulin secretion

KW - pharmacodynamics

U2 - 10.1111/dom.15216

DO - 10.1111/dom.15216

M3 - Review

C2 - 37551549

AN - SCOPUS:85166976064

VL - 25

SP - 3079

EP - 3092

JO - Diabetes, Obesity and Metabolism

JF - Diabetes, Obesity and Metabolism

SN - 1462-8902

IS - 11

ER -