Source of Triple agonist

{{Infobox concept | name = Triple agonist | subtitle = Drug class | Usual receptors = GIP, [[GLP-1 receptor|GLP-1]] and [[Glucagon|glucagon]] | Leading example = [[Retatrutide]] | Design constraint = A fixed three-way potency ratio }} A '''triple agonist''' is a single engineered peptide that activates three receptors of the glucagon-secretin family — conventionally the receptors for GIP, [[Glucagon-like peptide-1|GLP-1]] and [[Glucagon|glucagon]]. [[Retatrutide|Retatrutide]] is the most advanced example and is investigational.{{r|coskun2022}} The design extends the logic of the [[Dual incretin agonist|dual agonists]] by one receptor, and multiplies the constraints accordingly: the sequence must retain activity at three targets in a ratio fixed by chemistry, and that ratio must remain appropriate across the whole dose range.{{r|coskun2022}} Adding glucagon-receptor agonism introduces an effect that opposes the others glycaemically, in exchange for increased energy expenditure and reduced hepatic fat. The balance is the central difficulty. See [[Glucagon]].{{r|jastreboff2023}} == Why three receptors == Each added receptor is intended to contribute a mechanism the others do not. GLP-1 agonism supplies appetite suppression and glucose-dependent insulin secretion; GIP agonism appears to improve tolerability and contributes adipose-tissue effects; glucagon agonism raises energy expenditure and mobilises hepatic fat.{{r|coskun2022}} Because the receptors share a common architecture and their ligands a common precursor family, a peptide can be engineered to engage all three — see [[Proglucagon]] — but the sequence space in which all three activities coexist at usable ratios is narrow.{{r|jastreboff2023}} Reported potency ratios are assay-dependent and are not comparable between publications, a caution that applies with more force here because three numbers are being compared rather than two.{{r|coskun2022}} == Consequences of the glucagon arm == Two observations in the phase 2 data are attributable to glucagon-receptor agonism: a dose-dependent heart-rate increase larger than that seen with GLP-1 monotherapy, and transient rises in fasting glucose at low doses in participants with diabetes.{{r|jastreboff2023}} The second is the design's predicted failure mode. At low total dose the glucagon component is not yet offset by sufficient GLP-1 agonism, so glycaemia worsens before it improves — which is why escalation schedules for these compounds are long.{{r|coskun2022}} Long-term consequences of sustained heart-rate elevation are the question phase 3 exists to answer, and no answer is available yet. See [[TRIUMPH trial programme]].{{r|jastreboff2023}} == Status == No triple agonist is approved anywhere. [[Retatrutide|Retatrutide]] is in phase 3; others are earlier.{{r|coskun2022}} Material sold under these names by research-chemical suppliers is unapproved and, having no marketed reference product, has no generally available [[Reference standard|reference standard]] for identity confirmation. See [[Research use only]].{{r|usp1503}} This wiki does not represent investigational compounds as suitable for human administration, and nothing here is medical advice.{{r|reports}} == References == {{reflist}} <ref name="coskun2022">Coskun T, Urva S, Roell WC, et al. "LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist." ''Cell Metabolism'' 34(9):1234–1247 (2022). PMID 35985340.</ref> <ref name="jastreboff2023">Jastreboff AM, Kaplan LM, Frías JP, et al. "Triple-hormone-receptor agonist retatrutide for obesity — a phase 2 trial." ''New England Journal of Medicine'' 389(6):514–526 (2023). PMID 37366315.</ref> <ref name="usp1503">United States Pharmacopeia, General Chapter <1503>, ''Quality Attributes of Synthetic Peptide Drug Substances''.</ref> <ref name="reports">PeptidePedia Wiki community test-report tally, 2024–2026 (self-reported; see [[Project:Sourcing_guidelines]]).</ref> == See also == * [[Retatrutide]] * [[Dual incretin agonist]] * [[Glucagon]] * [[Survodutide]] * [[TRIUMPH trial programme]] {{DEFAULTSORT:Triple agonist}} [[Category:Dual and triple agonists]] [[Category:Receptor pharmacology]] [[Category:Articles describing unapproved compounds]]