Biased Agonism in Incretin-based Therapies

Around one-third of clinical drugs used today target G protein-coupled receptors (GPCRs). The action of hormones at GPCRs leads to downstream events predominantly mediated by cAMP through the activation of G proteins. The beta-arrestin (BA) pathway serves to recycle the receptor and desensitize the cell surface. Significant interest in manipulating GPCRs responsive to the incretins—glucagon-like polypeptide 1 (GLP1), gut insulinotropic polypeptide (GIP), and the glucose counter-regulatory hormone glucagon—has led to the development of agonists for these receptors. The development of molecules that act on more than one of these receptors has led to the field of unimolecular polypharmacy. The first of these agents to be commercially available for diabetes and obesity is tirzepatide (TZP). TZP is a full agonist at the GIP receptor and a partial agonist at the GLP1R. It is, however, able to elicit significant glucose reduction, increased insulin secretion, and weight loss; in addition, it improves insulin sensitivity independent of weight loss. The glucose reduction and weight loss are significantly greater than those achieved with semaglutide and are not fully explained by GIP action. Besides being an imbalanced agonist at the GIPR, TZP appears to be a biased agonist with reduced BA recruitment. This may in part explain the greater and prolonged action on the GLP1R of the molecule and its ability to reduce glucose. Other molecules in the pipeline appear to exploit this feature of biased agonism to overcome the limitations of dose escalation seen with traditional GLP1R agonists, aiming to reduce glucose and weight.