GLP-1 receptor agonist (revision 7)
Old revision·13:36, 31 Jul 2024·StubSorterBot
| GLP-1 receptor agonist | |
|---|---|
| Class | Incretin mimetic |
| Molecular target | GLP-1 receptor (GLP1R) |
| First approval | Exenatide, 2005 |
| Topic infobox · conventions | |
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]
Efficacy within the class is not uniform. Placebo-adjusted weight loss over 68 weeks ranges from roughly 4% for the earliest daily peptides to about 15% for weekly semaglutide at 2.4 mg, and glycaemic effect broadly tracks it.[3] Members of the class supplied through research-chemical channels are not approved for human use, and material obtained that way carries none of the identity, purity or fill assurances that accompany a licensed product; see Research use only.
Mechanism
[edit]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 Gs, 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.[4]
Molecular strategies for half-life extension
[edit]Native GLP-1 has a circulating half-life of one to two minutes. The agonists in clinical use extend that by between three and four orders of magnitude, and the strategies fall into four families.
| Strategy | Example | Half-life | Mechanism |
|---|---|---|---|
| Exendin scaffold | Exenatide | 2.4 h | Gly at position 2 resists DPP-4 |
| Fatty-acid acylation | Liraglutide | 13 h | Reversible albumin binding |
| Acylation plus Aib | Semaglutide | 165 h | Albumin binding, DPP-4-resistant Aib8 |
| Fc fusion | Dulaglutide | 90 h | Reduced renal clearance, FcRn recycling |
References
- ^ a b Drucker DJ. "Mechanisms of action and therapeutic application of glucagon-like peptide-1." Cell Metabolism 27(4):740–756 (2018). DOI:10.1016/j.cmet.2018.03.001. PMID 29617641.
- ^ Knudsen LB, Lau J. "The discovery and development of liraglutide and semaglutide." Frontiers in Endocrinology 10:155 (2019). DOI:10.3389/fendo.2019.00155. PMID 31031702.
- ^ Wilding JPH, Batterham RL, Calanna S, et al. "Once-weekly semaglutide in adults with overweight or obesity." New England Journal of Medicine 384(11):989–1002 (2021). DOI:10.1056/NEJMoa2032183. PMID 33567185.
- ^ Nauck MA, Meier JJ. "The incretin effect in healthy individuals and those with type 2 diabetes: physiology, pathophysiology, and response to therapeutic interventions." The Lancet Diabetes & Endocrinology 4(6):525–536 (2016). PMID 26876794.