Incretin receptor agonists

Small-molecule GLP-1 receptor agonism with a short half-life requiring twice-daily administration. The Institute includes this monograph specifically because a discontinued programme is evidence, and because the reasons for…

Receptor pharmacology is that of the selective GLP-1 class, delivered from a large fusion protein. Because the molecule is above the renal filtration threshold, clearance is not renal, and the pharmacokinetics are governed by…

Selective GLP-1 receptor agonism with a reported bias towards Gαs-coupled cyclic-AMP signalling. Whether signalling bias translates into a clinically distinguishable profile in humans is unresolved, and the Institute regards this…

Exenatide is a naturally DPP-4-resistant GLP-1 receptor agonist. The immediate-release presentation gives short, high peaks that produce a pronounced effect on gastric emptying and postprandial glucose but a modest effect on…

Receptor pharmacology is that of the selective GLP-1 class. The pharmacokinetic engineering differs: self-association into heptamers at the subcutaneous depot slows absorption, and albumin binding through the palmitoyl chain…

A short-acting prandial GLP-1 receptor agonist. Its dominant pharmacodynamic effect is marked slowing of gastric emptying, which produces substantial postprandial glucose reduction with comparatively modest effects on fasting…

GLP-1 receptor agonism supplies appetite suppression; GIP receptor antagonism is proposed to act on adipose tissue and central pathways in a manner that also reduces adiposity. The antibody scaffold gives a very long half-life…

Mazdutide reproduces the natural dual activity of oxyntomodulin with a pharmacokinetic profile suitable for weekly dosing. The glucagon arm contributes energy expenditure and hepatic lipid mobilisation; the GLP-1 arm supplies…

Orforglipron activates the GLP-1 receptor from a non-peptide scaffold, producing the insulinotropic, glucagonostatic and central appetite effects of the class from an orally bioavailable molecule that does not require an…

Retatrutide adds glucagon receptor agonism to the dual incretin mechanism. Glucagon receptor activation increases hepatic fatty-acid oxidation and resting energy expenditure and reduces hepatic steatosis, and in the reported…

Semaglutide is a full agonist at the glucagon-like peptide-1 receptor, a class B G protein-coupled receptor signalling principally through Gαs and adenylyl cyclase. In pancreatic beta cells the resulting rise in cyclic AMP…

Receptor pharmacology is identical to subcutaneous semaglutide. The distinguishing pharmacology is absorption: SNAC buffers the gastric microenvironment, inhibits local pepsin activity and transiently increases permeability…

Glucagon receptor agonism increases hepatic fatty-acid oxidation, resting energy expenditure and hepatic lipid clearance; GLP-1 receptor agonism supplies appetite suppression and offsets the glycaemic consequences of glucagon…

GLP-2 receptor agonism promotes intestinal mucosal growth, increases villus height and crypt depth, slows gastric emptying and reduces intestinal secretion. The therapeutic consequence in short-bowel syndrome is improved fluid…

Tirzepatide engages both incretin receptors from a single molecule. GLP-1 receptor agonism reproduces the insulinotropic, glucagonostatic, gastric and central appetite effects of the selective class. Concurrent GIP receptor…