Timeline of incretin therapeutics (revision 20)
Old revision·22:37, 21 Aug 2025·OrforglipronOona
| Timeline of incretin therapeuticsReference material | |
|---|---|
| Span | 1900s to the present |
| Arrangement | Chronological |
| List infobox · conventions | |
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.[1]
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.[2]
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.[3]
Physiology
[edit]| 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.[2]
Identification of DPP-4 as the inactivating enzyme defined the engineering problem every subsequent agonist solves. See GLP-1 receptor agonist.[1]
First-generation drugs
[edit]| 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.[1]
Second generation and beyond
[edit]| 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.[3]
Compounds beyond this point — triple agonists, combinations, oral small molecules — are investigational, and this timeline will require revision as their programmes report.[1] Material sold under those names outside licensed supply is unapproved.[4]
See also
- Incretin effect
- GLP-1 receptor agonist
- Semaglutide
- Tirzepatide
- SELECT trial
- List of GLP-1 receptor agonists
References
- ^ a b c d Drucker DJ. "Mechanisms of action and therapeutic application of glucagon-like peptide-1." Cell Metabolism 27(4):740–756 (2018). PMID 29617641.
- ^ a b Holst JJ. "The physiology of glucagon-like peptide 1." Physiological Reviews 87(4):1409–1439 (2007). PMID 17928588.
- ^ a b American Diabetes Association. "Standards of Care in Diabetes." Diabetes Care 47(Suppl 1) (2024).
- ^ United States Pharmacopeia, General Chapter <1503>, Quality Attributes of Synthetic Peptide Drug Substances.