Source of Timeline of incretin therapeutics

{{Infobox list | name = Timeline of incretin therapeutics | subtitle = Reference material | Span = 1900s to the present | Arrangement = Chronological }} This '''timeline''' sets out the development of incretin science and of the drugs derived from it, from the earliest observation that oral glucose provokes a larger insulin response than intravenous glucose, to the multi-receptor agonists in development.{{r|drucker2018}} Dates are given for the events most consistently reported in the literature. Where a discovery is attributable to a series of publications rather than one, the timeline names the period rather than a single year.{{r|holst2007}} Approval dates are jurisdiction-specific; those given are for the first approval in a major market and may differ elsewhere. See [[Regulatory status by jurisdiction]].{{r|ada2024}} == Physiology == | Period | Event | |---|---| | 1900s–1920s | Observation that oral glucose evokes a larger insulin response than intravenous | | 1960s | The term ''incretin'' revived; the enteroinsular axis proposed | | 1970s | GIP isolated and characterised | | 1980s | [[Glucagon-like peptide-1]] identified as a proglucagon product and shown to be insulinotropic | | 1986 | Reduced [[Incretin effect]] documented in type 2 diabetes | | 1990s | [[Dipeptidyl peptidase-4]] identified as the enzyme inactivating both incretins | The 1986 finding is the hinge of the field: it established that the incretin axis is defective in type 2 diabetes and therefore a therapeutic target rather than only a physiological curiosity.{{r|holst2007}} Identification of DPP-4 as the inactivating enzyme defined the engineering problem every subsequent agonist solves. See [[GLP-1 receptor agonist]].{{r|drucker2018}} == First-generation drugs == | Year | Event | |---|---| | 1990s | Exendin-4 identified in Gila monster venom | | 2005 | [[Exenatide]] approved — first GLP-1 receptor agonist | | 2006 | First DPP-4 inhibitor approved | | 2009 | [[Liraglutide]] approved for type 2 diabetes | | 2014 | Liraglutide approved for weight management | | 2014 | [[Dulaglutide]] approved | | 2016 | [[LEADER trial]] reports cardiovascular benefit | The 2016 result changed the framing of the class from glucose-lowering to outcome-modifying, and it did so in a period when cardiovascular outcome trials were being run principally to exclude harm.{{r|drucker2018}} == Second generation and beyond == | Year | Event | |---|---| | 2017 | [[Semaglutide]] approved for type 2 diabetes | | 2019 | [[Oral semaglutide]] approved | | 2021 | [[STEP trial programme]] first results published; semaglutide 2.4 mg approved for weight management | | 2022 | [[Tirzepatide]] approved for type 2 diabetes | | 2023 | [[SURMOUNT trial programme]] first results published; [[Retatrutide]] phase 2 published | | 2023 | [[SELECT trial]] reports cardiovascular benefit without diabetes | | 2024 | [[FLOW trial]] reports renal benefit | The 2021 and 2023 publications are the ones that moved the field from diabetes into obesity medicine at scale, and the 2023 and 2024 outcome trials are what distinguish these agents from weight-loss interventions without outcome evidence.{{r|ada2024}} Compounds beyond this point — [[Triple agonist|triple agonists]], [[CagriSema|combinations]], [[Orforglipron|oral small molecules]] — are investigational, and this timeline will require revision as their programmes report.{{r|drucker2018}} Material sold under those names outside licensed supply is unapproved.{{r|usp1503}} == References == {{reflist}} <ref name="drucker2018">Drucker DJ. "Mechanisms of action and therapeutic application of glucagon-like peptide-1." ''Cell Metabolism'' 27(4):740–756 (2018). PMID 29617641.</ref> <ref name="holst2007">Holst JJ. "The physiology of glucagon-like peptide 1." ''Physiological Reviews'' 87(4):1409–1439 (2007). PMID 17928588.</ref> <ref name="ada2024">American Diabetes Association. "Standards of Care in Diabetes." ''Diabetes Care'' 47(Suppl 1) (2024).</ref> <ref name="usp1503">United States Pharmacopeia, General Chapter <1503>, ''Quality Attributes of Synthetic Peptide Drug Substances''.</ref> == See also == * [[Incretin effect]] * [[GLP-1 receptor agonist]] * [[Semaglutide]] * [[Tirzepatide]] * [[SELECT trial]] * [[List of GLP-1 receptor agonists]] {{DEFAULTSORT:Timeline of incretin therapeutics}} [[Category:Timelines]] [[Category:Reference material]] [[Category:Clinical evidence]]