Survodutide: difference between revisions
Diff·revision 4 → 5·16:01, 18 Dec 2024
Difference between revision 4 and revision 5 of Survodutide. 6 lines changed; the page grew by 811 bytes.
| Revision 4 — 19:47, 1 Dec 2024 IcodecIndra (talk) attribute the mechanism claim to the review rather than stating it flatly 2,514 bytes ±0 | Revision 5 — 16:01, 18 Dec 2024 MolarMassMaeve (talk) add the structural figure and caption it properly 3,325 bytes +811 | ||
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| 11 | Unlike the GIP/GLP-1 pairing of [[Tirzepatide|tirzepatide]], the glucagon/GLP-1 pairing sets two opposing glycaemic effects against each other deliberately. Glucagon-receptor agonism raises hepatic glucose output and energy expenditure; [[GLP-1 receptor agonist|GLP-1 agonism]] lowers glucose and food intake. The design intent is to capture the energy-expenditure and hepatic-fat effects of the former while the latter dominates the net glycaemic balance.{{r|zimmermann2022}} | 11 | Unlike the GIP/GLP-1 pairing of [[Tirzepatide|tirzepatide]], the glucagon/GLP-1 pairing sets two opposing glycaemic effects against each other deliberately. Glucagon-receptor agonism raises hepatic glucose output and energy expenditure; [[GLP-1 receptor agonist|GLP-1 agonism]] lowers glucose and food intake. The design intent is to capture the energy-expenditure and hepatic-fat effects of the former while the latter dominates the net glycaemic balance.{{r|zimmermann2022}} |
| 12 | 12 | ||
| + | 13 | Reported phase 2 weight reduction reached approximately 19% at 46 weeks at the highest dose studied. The hepatic programme is of independent interest, since glucagon-receptor agonism reduces liver fat by a mechanism that GLP-1 agonism does not share.{{r|blueher2024}} | |
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| 13 | == Design and rationale == | 15 | == Design and rationale == |
| 14 | Survodutide is a 29-residue acylated peptide derived from the glucagon sequence, with substitutions conferring GLP-1-receptor activity and a fatty-acid chain for [[Albumin binding half-life extension|albumin binding]]. Its natural template is oxyntomodulin, a product of [[Proglucagon|proglucagon]] processing that is a weak agonist at both receptors — the existence of which is why the combination was thought physiologically coherent rather than merely chemically possible.{{r|zimmermann2022,campbell2013}} | 16 | Survodutide is a 29-residue acylated peptide derived from the glucagon sequence, with substitutions conferring GLP-1-receptor activity and a fatty-acid chain for [[Albumin binding half-life extension|albumin binding]]. Its natural template is oxyntomodulin, a product of [[Proglucagon|proglucagon]] processing that is a weak agonist at both receptors — the existence of which is why the combination was thought physiologically coherent rather than merely chemically possible.{{r|zimmermann2022,campbell2013}} |
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| 16 | The potency ratio is the central design variable. Too much glucagon activity relative to GLP-1 activity raises fasting glucose; too little forfeits the energy-expenditure benefit that motivated the design. This is a fixed intramolecular property, so the balance must hold across the whole dose range rather than at one point in it. | 18 | The potency ratio is the central design variable. Too much glucagon activity relative to GLP-1 activity raises fasting glucose; too little forfeits the energy-expenditure benefit that motivated the design. This is a fixed intramolecular property, so the balance must hold across the whole dose range rather than at one point in it. |
| 17 | 19 | ||
| + | 20 | Reported ''in vitro'' ratios place survodutide closer to balanced than the triple agonist [[Retatrutide|retatrutide]], though as always such ratios are assay-dependent and are not comparable across publications.{{r|blueher2024}} | |
| + | 21 | ||
| 18 | == References == | 22 | == References == |
| 19 | {{reflist}} | 23 | {{reflist}} |
| 20 | <ref name="zimmermann2022">Zimmermann T, Thomas L, Baader-Pagler T, et al. "BI 456906: discovery and preclinical pharmacology of a novel GCGR/GLP-1R dual agonist with robust anti-obesity efficacy." ''Molecular Metabolism'' 66:101633 (2022). DOI:10.1016/j.molmet.2022.101633. PMID 36372428.</ref> | 24 | <ref name="zimmermann2022">Zimmermann T, Thomas L, Baader-Pagler T, et al. "BI 456906: discovery and preclinical pharmacology of a novel GCGR/GLP-1R dual agonist with robust anti-obesity efficacy." ''Molecular Metabolism'' 66:101633 (2022). DOI:10.1016/j.molmet.2022.101633. PMID 36372428.</ref> |
| + | 25 | <ref name="blueher2024">Blüher M, Rosenstock J, Hoefler J, Manuel R, Hennige AM. "Dose-response effects on HbA1c and bodyweight reduction of survodutide, a dual glucagon/GLP-1 receptor agonist." ''Diabetologia'' 67(3):470–482 (2024). PMID 38095713.</ref> | |
| 21 | <ref name="campbell2013">Campbell JE, Drucker DJ. "Pharmacology, physiology, and mechanisms of incretin hormone action." ''Cell Metabolism'' 17(6):819–837 (2013). PMID 23684623.</ref> | 26 | <ref name="campbell2013">Campbell JE, Drucker DJ. "Pharmacology, physiology, and mechanisms of incretin hormone action." ''Cell Metabolism'' 17(6):819–837 (2013). PMID 23684623.</ref> |
| 22 | 27 | ||
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| 24 | [[Category:Dual and triple agonists]] | 29 | [[Category:Dual and triple agonists]] |
| 25 | [[Category:Peptide drugs]] | 30 | [[Category:Peptide drugs]] |
| + | 31 | [[Category:Articles describing unapproved compounds]] | |
| 26 | 32 |