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GLP-1 receptor agonist: difference between revisions

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Revision 6 — 01:32, 24 Jul 2024
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10Native 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, [[Albumin binding half-life extension|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.{{r|knudsen2019}}10Native 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, [[Albumin binding half-life extension|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.{{r|knudsen2019}}
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+12Efficacy 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|semaglutide]] at 2.4 mg, and glycaemic effect broadly tracks it.{{r|wilding2021}} 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]].
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12== Mechanism ==14== Mechanism ==
13The 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|arcuate nucleus]] of the hypothalamus and the area postrema. Agonist binding couples principally to G<sub>s</sub>, raising intracellular cAMP.{{r|drucker2018}}15The 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|arcuate nucleus]] of the hypothalamus and the area postrema. Agonist binding couples principally to G<sub>s</sub>, raising intracellular cAMP.{{r|drucker2018}}
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15At the beta cell, the rise in cAMP amplifies glucose-stimulated [[Insulin secretion|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|hypoglycaemia]] — a property that distinguishes the class sharply from sulfonylureas.{{r|nauck2016}}17At the beta cell, the rise in cAMP amplifies glucose-stimulated [[Insulin secretion|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|hypoglycaemia]] — a property that distinguishes the class sharply from sulfonylureas.{{r|nauck2016}}
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+19== Molecular strategies for half-life extension ==
+20Native 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.
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+22| Strategy | Example | Half-life | Mechanism |
+23|---|---|---|---|
+24| Exendin scaffold | [[Exenatide]] | 2.4 h | Gly at position 2 resists DPP-4 |
+25| Fatty-acid acylation | [[Liraglutide]] | 13 h | Reversible albumin binding |
+26| Acylation plus Aib | [[Semaglutide]] | 165 h | Albumin binding, DPP-4-resistant Aib8 |
+27| Fc fusion | [[Dulaglutide]] | 90 h | Reduced renal clearance, FcRn recycling |
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17== References ==29== References ==
18{{reflist}}30{{reflist}}
19<ref name="drucker2018">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.</ref>31<ref name="drucker2018">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.</ref>
20<ref name="knudsen2019">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.</ref>32<ref name="knudsen2019">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.</ref>
+33<ref name="wilding2021">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.</ref>
21<ref name="nauck2016">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.</ref>34<ref name="nauck2016">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.</ref>
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