Dual incretin agonist: difference between revisions
Diff·revision 5 → 6·21:01, 31 Aug 2024
Difference between revision 5 and revision 6 of Dual incretin agonist. 3 lines changed; the page grew by 635 bytes.
| Revision 5 — 05:18, 21 Aug 2024 MolarMassMaeve (talk) expand §Beyond GIP and GLP-1 2,556 bytes ±0 | Revision 6 — 21:01, 31 Aug 2024 StubSorterBot (talk) bot: add drug-class category 3,191 bytes +635 | ||
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| 10 | The approach differs fundamentally from co-administration of two agents. A single molecule delivers both activities to the same tissues with identical pharmacokinetics, so the ratio at the receptor does not drift with differential clearance. The price is that the ratio cannot be adjusted: it is a property of the molecule, and changing it means changing the drug.{{r|coskun2018}} | 10 | The approach differs fundamentally from co-administration of two agents. A single molecule delivers both activities to the same tissues with identical pharmacokinetics, so the ratio at the receptor does not drift with differential clearance. The price is that the ratio cannot be adjusted: it is a property of the molecule, and changing it means changing the drug.{{r|coskun2018}} |
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| + | 12 | [[Tirzepatide|Tirzepatide]] is the only member marketed to date. Why dual agonism outperforms [[GLP-1 receptor agonist|GLP-1 monotherapy]] is not settled, and the leading explanations — adipose-tissue GIP action, central GIP effects that improve tolerability, and restoration of beta-cell GIP responsiveness under ambient GLP-1 signalling — have not been separated by any published trial.{{r|frias2021}} | |
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| 12 | == Design problem == | 14 | == Design problem == |
| 13 | The receptors of this family share a common architecture — a large extracellular domain capturing the C-terminal helix of the ligand, and a transmembrane bundle engaged by the ligand N-terminus — and roughly 40–50% sequence identity in the transmembrane region. That relatedness is what makes a single ligand for two of them possible.{{r|finan2013}} | 15 | The receptors of this family share a common architecture — a large extracellular domain capturing the C-terminal helix of the ligand, and a transmembrane bundle engaged by the ligand N-terminus — and roughly 40–50% sequence identity in the transmembrane region. That relatedness is what makes a single ligand for two of them possible.{{r|finan2013}} |
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| 21 | <ref name="finan2013">Finan B, Ma T, Ottaway N, et al. "Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans." ''Science Translational Medicine'' 5(209):209ra151 (2013). DOI:10.1126/scitranslmed.3007218. PMID 24174327.</ref> | 23 | <ref name="finan2013">Finan B, Ma T, Ottaway N, et al. "Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans." ''Science Translational Medicine'' 5(209):209ra151 (2013). DOI:10.1126/scitranslmed.3007218. PMID 24174327.</ref> |
| 22 | <ref name="coskun2018">Coskun T, Sloop KW, Loghin C, et al. "LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus." ''Molecular Metabolism'' 18:3–14 (2018). PMID 30473097.</ref> | 24 | <ref name="coskun2018">Coskun T, Sloop KW, Loghin C, et al. "LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus." ''Molecular Metabolism'' 18:3–14 (2018). PMID 30473097.</ref> |
| + | 25 | <ref name="frias2021">Frías JP, Davies MJ, Rosenstock J, et al. "Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes." ''New England Journal of Medicine'' 385(6):503–515 (2021). PMID 34170647.</ref> | |
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| 24 | {{DEFAULTSORT:Dual incretin agonist}} | 27 | {{DEFAULTSORT:Dual incretin agonist}} |