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| Pronunciation | /ɛɡzˈɛnətaɪd/ ⓘ |
| Trade names | Byetta, Bydureon, Bydureon BCise, others |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a605034 |
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| Routes of administration | Subcutaneous |
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| Pharmacokinetic data | |
| Bioavailability | N/A |
| Metabolism | proteolysis |
| Eliminationhalf-life | 2.4 h |
| Excretion | Kidney |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.212.123 |
| Chemical and physical data | |
| Formula | C184H282N50O60S |
| Molar mass | 4186.63 g·mol−1 |
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Exenatide, sold under the brand nameByetta among others, is amedication used to treattype 2 diabetes.[7] It is used together with diet, exercise, and potentially otherantidiabetic medication.[7] It is a treatment option aftermetformin andsulfonylureas.[8] It is given byinjection under the skin.[7]
Common side effects includelow blood sugar, nausea, dizziness, abdominal pain, and pain at the site of injection.[7] Other serious side effects may includemedullary thyroid cancer,angioedema,pancreatitis, andkidney injury.[7] Use inpregnancy andbreastfeeding is of unclear safety.[9] Exenatide is aglucagon-like peptide-1 receptor agonist (GLP-1 receptor agonist) also known asincretinmimetics.[7] It works by increasing insulin release from thepancreas and decreases excessiveglucagon release.[7]
Exenatide was approved for medical use in the United States in 2005.[7] In 2019, it was the 312th most commonly prescribed medication in the United States, with more than 1 million prescriptions.[10]
Exenatide is used to treat type 2 diabetes as an add-on tometformin, abiguanide, or a combination of metformin and asulfonylurea, orthiazolidinediones such aspioglitazone.[2][3]
A 2011Cochranereview showed aHbA1c reduction of 0.20% more with Exenatide 2 mg compared toinsulin glargine, exenatide 10 μg twice daily,sitagliptin andpioglitazone.[11] Exenatide, lead to greater weight loss than glucagon-like peptide analogues.[11] Due to shorter duration of studies, this review did not allow for long-term positive or negative effects to be assessed.[11]
The mainside effects of exenatide use are gastrointestinal in nature, including acid or sour stomach, belching, diarrhea, heartburn, indigestion, nausea, and vomiting.[11] These tend to subside with time;[11] exenatide is therefore not meant for people with severe gastrointestinal disease. Other side effects include dizziness, headache, and feeling jittery.[12] Drug interactions listed on the package insert include delayed or reduced concentrations oflovastatin,paracetamol (acetaminophen), anddigoxin, although this has not been proven to alter the effectiveness of these other medications.
In response topostmarketing reports ofacute pancreatitis in patients using exenatide, the USFood and Drug Administration (FDA) added aboxed warning to the labeling of Byetta in 2007.[13][14] In August 2008, four additional deaths frompancreatitis in users of exenatide were reported to the FDA; while no definite relationship had been established, the FDA was reportedly considering additional changes to the drug's labeling.[15] Examination of the medical records of the millions of patients part of the United Healthcare Insurance plans did not show any greater rate of pancreatitis among Byetta users than among diabetic patients on other medications. However, diabetics do have a slightly greater incidence of pancreatitis than do non-diabetics.[16][17]
It also may increase risk of mild sulfonylurea-inducedhypoglycemia.[18]
Additionally, the FDA has raised concerns over the lack of data to determine if the long-acting once-weekly version of exenatide (but not the twice-daily form of exenatide) may increasethyroid cancer risk. This concern comes out of observing a very small but nevertheless increased risk of thyroid cancer in rodents that was observed for another drug (liraglutide) that is in the same class as exenatide. The data available for exenatide showed less of a risk towards thyroid cancer than liraglutide, but to better quantify the risk the FDA has required Amylin to conduct additionalrodent studies to better identify the thyroid issue. The approved form of the once weekly exenatide [Bydureon] has a black box warning discussing the thyroid issue. Eli Lilly has reported they have not seen a link in humans, but that it cannot be ruled out. Eli Lilly has stated the drug causes an increase in thyroid problems in rats given high doses.[19]
In March 2013, the FDA issued a Drug Safety Communication announcing investigations into incretin mimetics due to findings by academic researchers.[20] A few weeks later, the European Medicines Agency launched a similar investigation into GLP-1 agonists and DPP-4 inhibitors.[21]
Exenatide binds to the intact human Glucagon-like peptide-1 receptor (GLP-1R) in a similar way to the human peptideglucagon-like peptide-1 (GLP-1); exenatide bears a 50% amino acid homology to GLP-1 and it has a longer half-lifein vivo.[22]
Exenatide is believed to facilitate glucose control in at least five ways:
Exenatide is a 39-amino-acidpeptide; it is a synthetic version of exendin-4, a peptide found in the venom of theGila monster.[27]
During the early 1980s, Jean-Pierre Raufman worked as apostdoctoral researcher at theNational Institutes of Health for John Pisano, an "eccentric biochemist" who specialized in collecting venoms from various animals and looking for novel substances that could affect human physiology.[28] In the course of this work, Raufman focused on investigating theGila monster because he was curious about how it only eats once or twice per year.[29] He discovered molecules in the monster's saliva "that caused inflammation of the pancreas in test animals".[29] He later recalled: "We got a tremendous response from Gila monster venom".[30]
When Raufman gave a lecture about his findings,[30] his research piqued the curiosity of John Eng, an endocrinologist at theVeterans Administration Medical Center in New York City.[28][29] Eng had trained underRosalyn Sussman Yalow, who shared the 1977Nobel Prize in Physiology or Medicine for development of theradioimmunoassay technique.[28][29]
In 1992, Eng used that technique to isolate a novel substance from Gila monster venom which he called exendin-4.[28][29][30] He tested exendin-4 on diabetic mice and discovered that it was not only effective for reducing blood glucose but was effective for several hours.[28][30] This was an enormously significant clinical finding, because it was GLP-1's extremely short half-life which had defeated earlier attempts to turn that substance into a drug.[28][30] Attempts to bypass that issue by infusing patients in clinical tests with very high doses of GLP-1—in order to overcome its rapid metabolism in the bloodstream—had produced extremely severe nausea, followed by immediate vomiting.[28][30]
Eng's employer, theU.S. Department of Veterans Affairs, turned out to have no interest in obtaining adrug patent on exendin-4, so Eng filed thepatent application himself in 1993.[28] He then spent three years on fruitless efforts to persuade thepharmaceutical industry to develop exendin-4 into a drug.[28][30]Jens Juul Holst, a GLP-1 expert, later recalled seeing the skepticism which Eng encountered when he tried topresent his work on a poster at industry conferences: "He was extremely frustrated ... Nobody was interested in his work. None of the important people. It was too strange for people to accept".[30]
At a 1996American Diabetes Association conference in San Francisco, Eng finally caught the attention of scientist Andrew Young ofAmylin Pharmaceuticals, who immediately recognized exendin-4's potential and arranged for his company to license Eng's patent.[28][29][30][31] Young was excited to see Eng's poster at the conference summarizing his findings, but then noticed anEli Lilly and Company executive reading the same poster, and he became worried that Lilly might beat Amylin to a license.[30][31] When Eng arrived at Amylin's San Diego headquarters, he was astonished to discover how much information Amylin's scientists had already figured out about exendin-4 in the brief period of time after Young saw his poster, which convinced him that Amylin was the right company to partner with.[31] Amylin went on to create exenatide, a synthetic version of exendin-4, and later formed an alliance with Lilly in 2002 to bring the drug to market.[28][29][32]
Exenatide was approved by the FDA in April 2005, for people whose diabetes is not well controlled on otheroral medications.[33][34][35] This was a landmark event which proved that targeting the GLP-1 receptor was a viable strategy and inspired other pharmaceutical companies to focus their research and development on that receptor.[28][30]
In 2011, Lilly and Amylin dissolved their partnership, with Amylin keeping the rights to exenatide.[36] Meanwhile, Lilly had been awakened to the possibilities of this class of drugs and continued to develop newer drugs of the same class. By October 2024, the blockbuster drugtirzepatide had transformed Lilly into the most valuable drug company in the world.[37]
53 consolidated lawsuits against manufacturers of "GLP-1/DPP-4 products" were dismissed in 2015.[38]
In 2016, work published showing that it can reverse impaired calcium signalling in steatotic liver cells, which, in turn, might be associated with proper glucose control.[25]
It is being evaluated for use in the treatment ofParkinson's disease.[39] Aphase 3 clinical trial, started in January 2020 has an Estimated Study Completion Date of 30 June 2024 (NCT04232969).[40]
A 2025 study that randomly assignedParkinson’s patients to receive exenatide, a drug related toOzempic, found no evidence that it slowed disease progression or provided any benefit after 96 weeks.[41] The research, inThe Lancet, showed no improvements in patient symptoms, brain scans, or any specific subgroup—regardless of how the data was analyzed, the outcome remained unchanged.[42]
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