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

Aug 8, 2023Diabetes, obesity & metabolism

How activating the glucose-dependent insulinotropic polypeptide receptor may influence tirzepatide’s effects

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Abstract

Tirzepatide is a newly approved treatment for type 2 diabetes that shows significant improvements in glycaemic control and body weight.

Tirzepatide acts as a co-agonist at GLP-1 and GIP receptors.
The specific contributions of GIP receptor activation to the effects of tirzepatide are currently uncertain.
In vitro studies indicate a biased activation of the GLP-1 receptor and downregulation of the GIP receptor.
Tirzepatide does not appear to function through a classical co-activating mechanism in humans.
Three hypotheses regarding the mode of action of tirzepatide are proposed for future clinical trials.

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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.

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

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