Source of Dual incretin agonist

{{Infobox concept | name = Dual incretin agonist | subtitle = Drug class | image = receptor.svg | caption = One peptide, two class B receptors, one fixed intramolecular potency ratio. | Also called = Unimolecular dual agonist, twincretin | Usual receptor pair = GIP receptor and [[GLP-1 receptor]] | Marketed example = [[Tirzepatide]] (2022) }} {{hatnote|For the marketed example, see [[Tirzepatide]]. For three-receptor molecules, see [[Triple agonist]].}} A '''dual incretin agonist''' is a single engineered peptide that activates two receptors of the glucagon-secretin family — most often the receptor for [[Glucose-dependent insulinotropic polypeptide]] and the [[GLP-1 receptor]] — in a ratio fixed by its chemistry rather than by a prescriber's choice of two drugs.{{r|finan2013}} 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}} [[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}} == Design problem == 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}} The design proceeds by choosing a backbone, then substituting residues that confer activity at the second receptor while retaining activity at the first. In practice a GIP backbone has proved more tolerant of the substitutions needed for GLP-1 activity than the reverse, which is why tirzepatide is built from GIP rather than from GLP-1.{{r|coskun2018}} Reported potency ratios are assay-dependent — cell line, readout, incubation time and receptor expression level all move them — and cross-publication comparison of ratios is unreliable. A ratio quoted without its assay system is not a meaningful number. == Why dual agonism might work == Three explanations circulate, and they are not mutually exclusive. # ''Adipose GIP action''. GIP receptors are expressed on adipocytes, where GIP promotes triglyceride storage. Whether the clinical benefit arises from agonism or from functional antagonism through receptor desensitisation is genuinely disputed, and — awkwardly for the field — GIP-receptor antagonists have also produced weight loss in early studies. # ''Improved tolerability''. If GIP-receptor agonism in the area postrema reduces nausea, a dual agonist can be escalated to a total exposure that a GLP-1 agonist alone could not reach. On this account the benefit is not a new mechanism but a higher tolerable dose. # ''Restored beta-cell responsiveness''. Beta-cell responsiveness to GIP is impaired in type 2 diabetes but is partly restored when glycaemia improves, so a dual agonist may create the conditions for its own GIP component to work. None of the three has been isolated experimentally in humans. The trials were designed to establish efficacy, not to partition it.{{r|frias2021}} == Beyond GIP and GLP-1 == Other pairings exist. Glucagon/GLP-1 dual agonists — [[Survodutide|survodutide]], efinopegdutide — pair the energy-expenditure and hepatic-fat effects of glucagon-receptor agonism with the appetite and glycaemic effects of GLP-1 agonism, with the GLP-1 component dosed to dominate the glycaemic balance. See [[Glucagon]]. Amylin/GLP-1 pairing is achieved differently: [[CagriSema|CagriSema]] is a co-formulation of two separate peptides rather than one molecule, which reintroduces the possibility of differential pharmacokinetics but allows the ratio to be chosen at formulation. Adding a third receptor gives the [[Triple agonist|triple agonists]], of which [[Retatrutide|retatrutide]] is the most advanced. Each additional receptor multiplies the design constraints, and the tolerability window narrows as more pathways are engaged simultaneously.{{r|finan2013,campbell2013}} == References == {{reflist}} <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> <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> <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> <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> == See also == * [[Tirzepatide]] * [[Retatrutide]] * [[Triple agonist]] * [[Glucose-dependent insulinotropic polypeptide]] * [[CagriSema]] * [[Survodutide]] {{DEFAULTSORT:Dual incretin agonist}} [[Category:Dual and triple agonists]] [[Category:Receptor pharmacology]] [[Category:Compounds and pharmacology]]