GLP-1 receptor agonist (revision 6)

A GLP-1 receptor agonist (GLP-1 RA) is a drug that activates the GLP-1 receptor, reproducing and prolonging the actions of the endogenous incretin hormone Glucagon-like peptide-1. The class was developed for type 2 diabetes and has since been approved, for several of its members, for the treatment of obesity and for reduction of cardiovascular risk.^[1]

Native GLP-1 is unusable as a medicine because Dipeptidyl peptidase-4 inactivates it within one to two minutes of secretion. Every clinically successful agonist therefore solves the same engineering problem in one of a small number of ways: substitution of the residue attacked by the protease, fatty-acid acylation that ties the molecule to serum albumin, fusion to an immunoglobulin fragment, or use of a naturally protease-resistant scaffold such as exendin-4.^[2]

The GLP-1 receptor is a class B G-protein-coupled receptor expressed on pancreatic beta cells, on gastric smooth muscle and enteric neurons, on cardiomyocytes, and at several sites in the central nervous system including the arcuate nucleus of the hypothalamus and the area postrema. Agonist binding couples principally to G_s, raising intracellular cAMP.^[1]

At the beta cell, the rise in cAMP amplifies glucose-stimulated insulin secretion without initiating it. Because the amplification requires a permissive glucose signal, agonism does not provoke insulin release at low glucose, and monotherapy carries a low intrinsic risk of hypoglycaemia — a property that distinguishes the class sharply from sulfonylureas.^[3]