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{{Short description|Medication}}
{{Cleanup|date=August 2007}}
{{Use dmy dates|date=March 2024}}
{{drugbox
{{cs1 config|name-list-style=vanc|display-authors=6}}
| Verifiedfields = changed
{{Infobox drug
| verifiedrevid = 417169504
| Verifiedfields = changed
| image = Exenatide sequence.svg
| CAS_number = 141732-76-5 | Watchedfields = changed
| verifiedrevid = 443485715
| UNII_Ref = {{fdacite|changed|FDA}}
| image = File:Exenatide PDB=7MLL.png
| UNII = 9P1872D4OL
| ATC_prefix = A10 | alt =
| caption = Single ] of the ] of exenatide. {{PDB|7MLL}}
| ATC_suffix = BX04

| PubChem =
<!-- Clinical data -->
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| pronounce = {{IPAc-en|audio=En-us-Exenatide.ogg|ɛ|g|z|'|ɛ|n|ə|t|aɪ|d}}
| DrugBank = DB01276
| tradename = Byetta, Bydureon, Bydureon BCise, others
| C=184|H=282|N=50|O=60|S=1
| Drugs.com = {{drugs.com|monograph|exenatide}}
| molecular_weight = 4186.6
| MedlinePlus = a605034
| bioavailability = N/A
| protein_bound = | DailyMedID = Exenatide
| metabolism = proteolysis | pregnancy_AU = C
| pregnancy_AU_comment =
| pregnancy_category =
| routes_of_administration = ]
| class =
| ATC_prefix = A10
| ATC_suffix = BJ01
| ATC_supplemental =
| biosimilars =

<!-- Legal status -->
| legal_AU = S4
| legal_AU_comment =
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->
| legal_BR_comment =
| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_CA_comment =
| legal_DE = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment =
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment =
| legal_UK = POM
| legal_UK_comment = <ref name=UKByettalabel /><ref name=UKBydureonlabel />
| legal_US = Rx-only
| legal_US_comment = <ref>{{cite web | title=Bydureon- exenatide injection, suspension, extended release Bydureon- exenatide kit | website=DailyMed | date=28 February 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=71fe88be-b4e6-4c2d-9cc3-8b1864467776 | access-date=2 December 2020}}</ref><ref>{{cite web | title=Bydureon BCise- exenatide injection, suspension, extended release | website=DailyMed | date=28 February 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2d18cfc4-e0de-4814-a712-c1b7c504bff5 | access-date=2 December 2020}}</ref><ref>{{cite web | title=Byetta- exenatide injection | website=DailyMed | date=28 February 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=53d03c03-ebf7-418d-88a8-533eabd2ee4f | access-date=2 December 2020}}</ref>
| legal_EU = Rx-only
| legal_EU_comment =
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment =
| legal_status = Rx-only

<!-- Pharmacokinetic data -->
| bioavailability = N/A
| protein_bound =
| metabolism = proteolysis
| elimination_half-life = 2.4 h | elimination_half-life = 2.4 h
| excretion = renal/proteolysis | excretion = ]

| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
<!-- Identifiers -->
| pregnancy_US = <!-- A / B / C / D / X -->
| CAS_number_Ref = {{cascite|correct|??}}
| pregnancy_category= C
| CAS_number = 141758-74-9
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
| PubChem = 16157882
| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII -->
| IUPHAR_ligand = 1135
| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C -->
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
| legal_status = Rx-only | DrugBank = DB01276
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| routes_of_administration = subcutaneous injection
| ChemSpiderID = 17314184
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 9P1872D4OL
| KEGG_Ref = {{keggcite|changed|kegg}}
| KEGG = D04121
| NIAID_ChemDB =
| PDB_ligand =
| synonyms =

<!-- Chemical data -->
| C = 184
| H = 282
| N = 50
| O = 60
| S = 1
| SMILES = /N=C(\N)/NCCC(C(=O)N(CC(C)C)C(=O)N(Cc1ccccc1)C(=O)N((C)CC)C(=O)N(CCC(=O)O)C(=O)N(Cc2cc3c2cccc3)C(=O)N(CC(C)C)C(=O)N(CCCCN)C(=O)N(CC(=O)N)C(=O)NCC(=O)NCC(=O)N4CCC4C(=O)N(CO)C(=O)N(CO)C(=O)NCC(=O)N(C)C(=O)N5CCC5C(=O)N6CCC6C(=O)N7CCC7C(=O)N(CO)C(=O)N)NC(=O)(C(C)C)NC(=O)(C)NC(=O)(CCC(=O)O)NC(=O)(CCC(=O)O)NC(=O)(CCC(=O)O)NC(=O)(CCSC)NC(=O)(CCC(=O)N)NC(=O)(CCCCN)NC(=O)(CO)NC(=O)(CC(C)C)NC(=O)(CC(=O)O)NC(=O)(CO)NC(=O)((C)O)NC(=O)(Cc8ccccc8)NC(=O)((C)O)NC(=O)CNC(=O)(CCC(=O)O)NC(=O)CNC(=O)(Cc9cnc9)N
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
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<!-- Definition and medical uses -->
'''Exenatide''' (]) (marketed as '''Byetta''') is a medication (] ]) approved (Apr 2005) for the treatment of ]. It is manufactured by ] and ].


'''Exenatide''', sold under the brand name '''Byetta''' among others, is a ] used to treat ].<ref name=AHFS2019>{{cite web |title=Exenatide Monograph for Professionals |url=https://www.drugs.com/monograph/exenatide.html |website=Drugs.com |publisher=American Society of Health-System Pharmacists |access-date=22 March 2019 }}</ref> It is used together with diet, exercise, and potentially other ].<ref name=AHFS2019/> It is a treatment option after ] and ]s.<ref name=BNF76>{{cite book|title=British national formulary : BNF 76|date=2018|publisher=Pharmaceutical Press|isbn=978-0-85711-338-2|pages=684–685|edition=76}}</ref> It is given by ].<ref name=AHFS2019/>
Exenatide is administered as a ] (under the skin) of the abdomen, thigh, or arm, any time within the 60 minutes before the first and last meal of the day.<ref name="package insert"> . </ref>


<!-- Side effects and mechanisms -->
== Chemistry and Pharmacology ==
Common side effects include ], nausea, dizziness, abdominal pain, and pain at the site of injection.<ref name=AHFS2019/> Other serious side effects may include ], ], ], and ].<ref name=AHFS2019/> Use in ] and ] is of unclear safety.<ref name=Preg2019>{{cite web |title=Exenatide Pregnancy and Breastfeeding Warnings|url=https://www.drugs.com/pregnancy/exenatide.html |website=Drugs.com |access-date=3 March 2019 }}</ref> Exenatide is a ] (GLP-1 receptor agonist) also known as ] ].<ref name=AHFS2019/> It works by increasing insulin release from the ] and decreases excessive ] release.<ref name=AHFS2019/>
Exenatide is a synthetic version of exendin-4, a ] found in the saliva of the ] that was first isolated by ] in 1992 while working at the Veterans Administration Medical Center in the Bronx, New York. It displays biological properties similar to human ] (GLP-1), a regulator of ] metabolism and ] secretion. According to the package insert, exenatide enhances glucose-dependent insulin secretion by the pancreatic beta-cell, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying, although the mechanism of action is still under study.


<!-- History and culture -->
Exenatide is a 39-] ], an insulin ], with glucoregulatory effects. Exenatide was approved by the ] on April 28, 2005 for patients whose diabetes was not well-controlled on other ].<ref name="fda-approval">, from the ]. Accessed August 28, 2008.</ref> The medication is injected subcutaneously twice per day using a filled pen device. The abdomen is a common injection site, after the area is cleaned with an alcohol pad. A new pen must first be tested to see if the medicine is flowing.
Exenatide was approved for medical use in the United States in 2005.<ref name=AHFS2019/> In 2019, it was the 312th most commonly prescribed medication in the United States, with more than 1{{nbsp}}million prescriptions.<ref>{{cite web | title = Exenatide - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Exenatide | access-date = 7 October 2022}}</ref>


== Medical use ==
The incretin hormones GLP-1 and ] (GIP) are produced by the L and K endocrine cells of the intestine following ingestion of food. GLP-1 and GIP stimulate insulin secretion from the beta cells of the islets of Langerhans in the ]. Only GLP-1 causes insulin secretion in the diabetic state; however, GLP-1 itself is ineffective as a clinical treatment for diabetes as it has a very short half-life ''in vivo''. Exenatide bears a 50% amino acid homology to GLP-1 and it has a longer half-life ''in vivo''. Thus, it was tested for its ability to stimulate insulin secretion and lower blood glucose in mammals, and was found to be effective in the diabetic state. In studies on rodents, it has also been shown to increase the number of beta cells in the pancreas.
Exenatide is used to treat type 2 diabetes as an add-on to ], a ], or a combination of metformin and a ], or ] such as ].<ref name=UKByettalabel>{{cite web|title=Byetta 10 micrograms solution for injection, prefilled pen - Summary of Product Characteristics|url=https://www.medicines.org.uk/emc/product/8617/smpc|publisher=Electronic Medicines Compendium|access-date=21 April 2018|date=30 March 2017}}</ref><ref name=UKBydureonlabel>{{cite web|title=Bydureon 2 mg powder and solvent for prolonged-release suspension for injection in pre-filled pen - Summary of Product Characteristics|url=https://www.medicines.org.uk/emc/product/3650/smpc|publisher=Electronic Medicines Compendium|access-date=21 April 2018|date=10 November 2017|archive-date=20 August 2020|archive-url=https://web.archive.org/web/20200820053220/https://www.medicines.org.uk/emc/product/3650/smpc|url-status=dead}}</ref>


A 2011 ] ] showed a ] reduction of 0.20% more with Exenatide 2&nbsp;mg compared to ], exenatide 10&nbsp;μg twice daily, ] and ].<ref name=":0">{{cite journal | vauthors = Shyangdan DS, Royle P, Clar C, Sharma P, Waugh N, Snaith A | title = Glucagon-like peptide analogues for type 2 diabetes mellitus | journal = The Cochrane Database of Systematic Reviews | issue = 10 | pages = CD006423 | date = October 2011 | volume = 2011 | pmid = 21975753 | pmc = 6486297 | doi = 10.1002/14651858.cd006423.pub2 }}</ref> Exenatide, lead to greater weight loss than glucagon-like peptide analogues.<ref name=":0" /> Due to shorter duration of studies, this review did not allow for long-term positive or negative effects to be assessed.<ref name=":0" />
Commercially, exenatide is produced by direct chemical synthesis. Historically, exenatide was discovered as a protein naturally secreted in the saliva and concentrated in the tail of the Gila monster. While the exenatide protein was structurally analogous to GLP-1, it had a much longer half-life after injection; this enabled consideration and development of exenatide as a diabetes mellitus treatment strategy. Given this history, exenatide is sometimes referred to as "lizard spit". Subsequent clinical testing led to the discovery of the also desirable glucagon and appetite-suppressant effects.


== Side effects ==
Exenatide is approved "as adjunctive therapy to improve glycemic control in patients with type 2 diabetes mellitus who are taking ], a ], or a combination of metformin and a ], but have not achieved adequate glycemic control". It has now been approved for use with ] such as ] or ].
The main ]s of exenatide use are gastrointestinal in nature, including acid or sour stomach, belching, diarrhea, heartburn, indigestion, nausea, and vomiting.<ref name=":0" /> These tend to subside with time;<ref name=":0" /> exenatide is therefore not meant for people with severe gastrointestinal disease. Other side effects include dizziness, headache, and feeling jittery.<ref name="drugs.com">.</ref> Drug interactions listed on the package insert include delayed or reduced concentrations of ], ] (acetaminophen), and ], although this has not been proven to alter the effectiveness of these other medications.
In response to ] of ] in patients using exenatide, the US ] (FDA) added a ] to the labeling of Byetta in 2007.<ref name="fda-1">, from the ]. Accessed 28 August 2008.</ref><ref name="FDA">{{cite web |url=https://www.fda.gov/Medwatch/SAFETY/2007/safety07.htm#Byetta |title=Byetta (exenatide) FDA warning |website=] |access-date=18 October 2007 }}</ref> In August 2008, four additional deaths from ] 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.<ref name="nyt-2008">. '']''. 26 August 2008; accessed 28 August 2008.</ref> 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.<ref name=pmid21577242>{{cite journal | vauthors = Lai SW, Muo CH, Liao KF, Sung FC, Chen PC | title = Risk of acute pancreatitis in type 2 diabetes and risk reduction on anti-diabetic drugs: a population-based cohort study in Taiwan | journal = The American Journal of Gastroenterology | volume = 106 | issue = 9 | pages = 1697–1704 | date = September 2011 | pmid = 21577242 | doi = 10.1038/ajg.2011.155 | s2cid = 25665019 }}</ref><ref name=pmid20833867>{{cite journal | vauthors = Gonzalez-Perez A, Schlienger RG, Rodríguez LA | title = Acute pancreatitis in association with type 2 diabetes and antidiabetic drugs: a population-based cohort study | journal = Diabetes Care | volume = 33 | issue = 12 | pages = 2580–2585 | date = December 2010 | pmid = 20833867 | pmc = 2992194 | doi = 10.2337/dc10-0842 }}</ref>


It also may increase risk of mild sulfonylurea-induced ].<ref name=pmid15504997>{{cite journal | vauthors = Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD | title = Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes | journal = Diabetes Care | volume = 27 | issue = 11 | pages = 2628–2635 | date = November 2004 | pmid = 15504997 | doi = 10.2337/diacare.27.11.2628 | doi-access = free }}</ref>
Exenatide raises insulin levels quickly (within about ten minutes of administration) with the insulin levels subsiding substantially over the next hour or two. A dose taken after meals has a much smaller effect on blood sugar than one taken beforehand. The effects on blood sugar diminish after six to eight hours.<ref name="package insert"/> The medicine is available in two doses: 5&nbsp;mcg and 10&nbsp;mcg. Treatment often begins with the 5&nbsp;mcg dosage, which is increased if adverse effects are not significant.<ref name="drugs.com"/>


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 increase ] 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 (]) 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 additional ] to better identify the thyroid issue. The approved form of the once weekly exenatide 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.<ref>{{cite web | vauthors = Silverman E | url = http://www.pharmalot.com/2010/04/lillys-once-weekly-byetta-may-have-cancer-risk | archive-url = https://web.archive.org/web/20100606210411/http://pharmalot.com/2010/04/lillys-once-weekly-byetta-may-have-cancer-risk | archive-date = 6 June 2010 | url-status = dead | title = Lilly's Once-Weekly Byetta May Have Cancer Risk | work = Pharmalot | date = 12 April 2010 }}</ref>
According to the manufacturer, the exenatide (Byetta) autoinjector must be stored in a refrigerator between 2°C (36°F) and 8°C (46°F) before first use, and then at a temperature between 2°C (36°F) and 25°C (77°F). In hot weather, therefore, they should be refrigerated.<ref name="Diabetes Monitor"> . </ref> Exenatide (Byetta) pens contain sixty doses designed to be used twice a day for 30 days.


In March 2013, the FDA issued a Drug Safety Communication announcing investigations into incretin mimetics due to findings by academic researchers.<ref name='FDA, 2013'>{{cite web | url = https://www.fda.gov/Drugs/DrugSafety/ucm343187.htm | title = FDA investigating reports of possible increased risk of pancreatitis and pre-cancerous findings of the pancreas from incretin mimetic drugs for type 2 diabetes | access-date = 14 March 2013 | date = 3 March 2013 | work = FDA | publisher = U.S. Food and Drug Administration}}</ref> A few weeks later, the European Medicines Agency launched a similar investigation into GLP-1 agonists and DPP-4 inhibitors.<ref name='EMA, 2013'>{{cite web | url = http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/03/news_detail_001753.jsp&,mid=WC0b01ac058004d5c1 | title = European Medicines Agency investigates findings on pancreatic risks with GLP-1-based therapies for type-2 diabetes | access-date = 26 March 2013 | date = 26 March 2013 | work = EMA | publisher = European Medicines Agency Sciences Medicines Health | archive-date = 28 August 2021 | archive-url = https://web.archive.org/web/20210828082926/https://www.ema.europa.eu/en/news/european-medicines-agency-investigates-findings-pancreatic-risks-glp-1-based-therapies-type-2 | url-status = dead }}</ref>
Exenatide received US Patent which was filed May 24, 1993.

== Mechanism of action ==
Exenatide binds to the intact human Glucagon-like peptide-1 receptor (GLP-1R) in a similar way to the human peptide ] (GLP-1); exenatide bears a 50% amino acid homology to GLP-1 and it has a longer half-life ''in vivo''.<ref name="pmid28283573">{{cite journal | vauthors = Koole C, Reynolds CA, Mobarec JC, Hick C, Sexton PM, Sakmar TP | title = Genetically encoded photocross-linkers determine the biological binding site of exendin-4 peptide in the N-terminal domain of the intact human glucagon-like peptide-1 receptor (GLP-1R) | journal = The Journal of Biological Chemistry | volume = 292 | issue = 17 | pages = 7131–7144 | date = April 2017 | pmid = 28283573 | pmc = 5409479 | doi = 10.1074/jbc.M117.779496 | doi-access = free }}</ref>


== Mode of action ==
Exenatide is believed to facilitate glucose control in at least five ways: Exenatide is believed to facilitate glucose control in at least five ways:
# Exenatide augments pancreas response<ref name="pmid19196887">{{cite journal| author=Bunck MC, Diamant M, Cornér A, Eliasson B, Malloy JL, Shaginian RM et al.| title=One-year treatment with exenatide improves beta-cell function, compared with insulin glargine, in metformin-treated type 2 diabetic patients: a randomized, controlled trial. | journal=Diabetes Care | year= 2009 | volume= 32 | issue= 5 | pages= 762–8 | pmid=19196887 | doi=10.2337/dc08-1797 | pmc=2671094 }} </ref> (i.e. increases insulin secretion) in response to eating meals; the result is the release of a higher, more appropriate amount of insulin that helps lower the rise in blood sugar from eating. Once blood sugar levels decrease closer to normal values, the pancreas response to produce insulin is reduced; however, other drugs (like injectable insulin) are effective at lowering blood sugar, but can "overshoot" their target and cause blood sugar to become ''too'' low, resulting in the dangerous condition of ]. # Exenatide augments pancreas response<ref name="pmid19196887">{{cite journal | vauthors = Bunck MC, Diamant M, Cornér A, Eliasson B, Malloy JL, Shaginian RM, Deng W, Kendall DM, Taskinen MR, Smith U, Yki-Järvinen H, Heine RJ | title = One-year treatment with exenatide improves beta-cell function, compared with insulin glargine, in metformin-treated type 2 diabetic patients: a randomized, controlled trial | journal = Diabetes Care | volume = 32 | issue = 5 | pages = 762–768 | date = May 2009 | pmid = 19196887 | pmc = 2671094 | doi = 10.2337/dc08-1797 }}</ref> (i.e. increases insulin secretion) in response to eating meals; the result is the release of a higher, more appropriate amount of insulin that helps lower the rise in blood sugar from eating. Once blood sugar levels decrease closer to normal values, the pancreas response to produce insulin is reduced; other drugs (like injectable insulin) are effective at lowering blood sugar, but can "overshoot" their target and cause blood sugar to become ''too'' low, resulting in the dangerous condition of ].
# Exenatide also suppresses pancreatic release of ] in response to eating, which helps stop the liver from overproducing sugar when it is unneeded, which prevents ] (high blood sugar levels). # Exenatide also suppresses pancreatic release of ] in response to eating, which helps stop the liver from overproducing sugar when it is unneeded, which prevents ] (high blood sugar levels).
# Exenatide helps slow down ] and thus decreases the rate at which meal-derived glucose appears in the bloodstream. # Exenatide helps slow down ] and thus decreases the rate at which meal-derived glucose appears in the bloodstream.
# Exenatide has a subtle yet prolonged effect to reduce appetite, promote ] via ] receptors (different receptors than for ]). Most people using exenatide slowly lose weight, and generally the greatest weight loss is achieved by people who are the most overweight at the beginning of exenatide therapy. Clinical trials have demonstrated the weight reducing effect continues at the same rate through 2.25 years of continued use. When separated into weight loss quartiles, the highest 25% experience substantial weight loss, and the lowest 25% experience no loss or small weight gain. # Exenatide has a subtle yet prolonged effect to reduce appetite, promote ] via ] receptors (different receptors than for ]). Most people using exenatide slowly lose weight, and generally the greatest weight loss is achieved by people who are the most overweight at the beginning of exenatide therapy. Clinical trials have demonstrated the weight reducing effect continues at the same rate through 2.25 years of continued use. When separated into weight loss quartiles, the highest 25% experience substantial weight loss, and the lowest 25% experience no loss or small weight gain.
# Exenatide reduces liver fat content. Fat accumulation in the liver or nonalcoholic fatty liver disease (NAFLD) is strongly related with several metabolic disorders, in particular low HDL cholesterol and high triglycerides, present in patients with type 2 diabetes. It became apparent that exenatide reduced liver fat in mice<ref name="pmid16374859">{{cite journal| author=Ding X, Saxena NK, Lin S, Gupta NA, Gupta N, Anania FA| title=Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice. | journal=Hepatology | year= 2006 | volume= 43 | issue= 1 | pages= 173–81 | pmid=16374859| pmc=2925424 | doi=10.1002/hep.21006 }} </ref> and more recently in man.<ref name="pmid16953843">{{cite journal| author=Tushuizen ME, Bunck MC, Pouwels PJ, van Waesberghe JH, Diamant M, Heine RJ| title=Incretin mimetics as a novel therapeutic option for hepatic steatosis. | journal=Liver Int | year= 2006 | volume= 26 | issue= 8 | pages= 1015–7 | pmid=16953843 | doi=10.1111/j.1478-3231.2006.01315.x }} </ref> # Exenatide reduces liver fat content. Fat accumulation in the liver or nonalcoholic fatty liver disease (NAFLD) is strongly related with several metabolic disorders, in particular low HDL cholesterol and high triglycerides, present in patients with type 2 diabetes. It became apparent that exenatide reduced liver fat in mice,<ref name="pmid16374859">{{cite journal | vauthors = Ding X, Saxena NK, Lin S, Gupta NA, Gupta N, Anania FA | title = Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice | journal = Hepatology | volume = 43 | issue = 1 | pages = 173–181 | date = January 2006 | pmid = 16374859 | pmc = 2925424 | doi = 10.1002/hep.21006 }}</ref> rat<ref name="Ali ES 2016">{{cite journal | vauthors = Ali ES, Hua J, Wilson CH, Tallis GA, Zhou FH, Rychkov GY, Barritt GJ | title = The glucagon-like peptide-1 analogue exendin-4 reverses impaired intracellular Ca(2+) signalling in steatotic hepatocytes | journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | volume = 1863 | issue = 9 | pages = 2135–2146 | date = September 2016 | pmid = 27178543 | doi = 10.1016/j.bbamcr.2016.05.006 | doi-access = free }}</ref> and more recently in man.<ref name="pmid16953843">{{cite journal | vauthors = Tushuizen ME, Bunck MC, Pouwels PJ, van Waesberghe JH, Diamant M, Heine RJ | title = Incretin mimetics as a novel therapeutic option for hepatic steatosis | journal = Liver International | volume = 26 | issue = 8 | pages = 1015–1017 | date = October 2006 | pmid = 16953843 | doi = 10.1111/j.1478-3231.2006.01315.x | s2cid = 32332119 | url = https://zenodo.org/record/896082 }}</ref>


==Chemistry==
In an ], randomized, controlled trial of 551 patients,<ref name="pmid16230722">{{cite journal| author=Heine RJ, Van Gaal LF, Johns D, Mihm MJ, Widel MH, Brodows RG et al.| title=Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. | journal=Ann Intern Med | year= 2005 | volume= 143 | issue= 8 | pages= 559–69 | pmid=16230722 }} </ref> exenatide treatment for 26 weeks was associated with 2.3&nbsp;kg weight loss; however, gastrointestinal symptoms were more common in the exenatide group, including nausea (57.1%), vomiting (17.4%) and diarrhea (8.5%). For most patients, the nausea is mild to moderate and goes away entirely after a few days or weeks. Medical professionals who work with exenatide have stated much of what is reported as nausea is actually a feeling of fullness. Exenatide is speculated to make most patients need to eat less, and until an adjustment is made to smaller portions, the result is the fullness feeling.
Exenatide is a 39-] ]; it is a synthetic version of exendin-4, a peptide found in the venom of the ].<ref name=Raufman1996>{{cite journal | vauthors = Raufman JP | title = Bioactive peptides from lizard venoms | journal = Regulatory Peptides | volume = 61 | issue = 1 | pages = 1–18 | date = January 1996 | pmid = 8701022 | doi = 10.1016/0167-0115(96)00135-8 | s2cid = 5293453 }}</ref>


==History==
'''Advantages''': While other treatment options share one or more of the first three characteristics, some diabetics specialists view exenatide as a significant improvement over other available diabetic medications, although most doctors do not use it as primary therapy at this time. Except for ] and ], all other available drugs for improving glucose control have been associated with weight gain.
'''Disadvantages''': In addition to gastrointestinal adverse reactions, a relative disadvantage of exenatide is that it is administered by injection. See ] section below.


During the early 1980s, Jean-Pierre Raufman worked as a ] at the ] for John Pisano, an "eccentric biochemist" who specialized in collecting venoms from various animals and looking for novel substances that could affect human physiology.<ref name="Molteni">{{cite news | vauthors = Molteni M, Chen E |title=GLP-1 drugs are transforming diabetes, obesity and more. Could a Nobel be next? |url=https://www.statnews.com/2023/09/30/weight-loss-ozempic-nobel-prize-science/ |access-date=October 16, 2024 |work=STAT News |date=September 30, 2023}}</ref> In the course of this work, Raufman focused on investigating the ] because he was curious about how it only eats once or twice per year.<ref name="Schwarcz">{{cite news | vauthors = Schwarcz J |title=The Right Chemistry: How the Gila monster assisted weight-loss research |url=https://montrealgazette.com/opinion/columnists/the-right-chemistry-how-the-gila-monster-assisted-weight-loss-research |access-date=October 16, 2024 |work=The Montreal Gazette |date=May 26, 2023}}</ref> He discovered molecules in the monster's saliva "that caused inflammation of the pancreas in test animals".<ref name="Schwarcz" /> He later recalled: "We got a tremendous response from Gila monster venom".<ref name="Winkler">{{cite news | vauthors = Winkler R, Cohen B |title=Monster Diet Drugs Like Ozempic Started With Actual Monsters |url=https://www.wsj.com/articles/ozempic-mounjaro-gila-monster-anglerfish-8c9c1ff2 |access-date=October 16, 2024 |work=The Wall Street Journal |date=June 23, 2023 |url-access=subscription}}</ref>
== Indications ==
* As an adjunctive therapy, exenatide is indicated to improve glycemic control in patients with type 2 diabetes who are taking ], a sulfonylurea, thiazolidinediones, or a combination of metformin and sulfonylurea or thiazolidinediones, but who have not been able to achieve adequate control of blood glucose.
* Its use with insulin, ]s, and ]s has not been studied.
* Some physicians are using exenatide as primary monotherapy, an indication approved by the FDA October 30, 2009 .


When Raufman gave a lecture about his findings,<ref name="Winkler" /> his research piqued the curiosity of John Eng, an endocrinologist at the ] in New York City.<ref name="Molteni" /><ref name="Schwarcz" /> Eng had trained under ], who shared the 1977 ] for development of the ] technique.<ref name="Molteni" /><ref name="Schwarcz" />
Note: Since the major action of this drug is to enhance the release of endogenous insulin from the pancreas, exenatide is not for use in ].


In 1992, Eng used that technique to isolate a novel substance from Gila monster venom which he called exendin-4.<ref name="Molteni" /><ref name="Schwarcz" /><ref name="Winkler" /> 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.<ref name="Molteni" /><ref name="Winkler" /> 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.<ref name="Molteni" /><ref name="Winkler" /> 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.<ref name="Molteni" /><ref name="Winkler" />
== Side effects ==
The main ]s of exenatide use are gastrointestinal in nature, including acid or sour stomach, belching, diarrhoea, heartburn, indigestion, nausea, and vomiting; exenatide is therefore not meant for people with severe gastrointestinal disease. Other side effects include dizziness, headache, and feeling jittery.<ref name="drugs.com"> . </ref> Drug interactions listed on the package insert include delayed or reduced concentrations of ], ] (acetaminophen), and ], although this has not been proven to alter the effectiveness of these other medications.
In response to ] of ] in patients using exenatide, the ] added a warning to the labeling of Byetta in 2007.<ref name="fda-1">, from the ]. Accessed August 28, 2008.</ref><ref name="FDA">{{cite web |url=http://www.fda.gov/Medwatch/SAFETY/2007/safety07.htm#Byetta |title=Byetta (exenatide) FDA warning |accessdate=2007-10-18 |work= }}</ref> In August 2008, four additional deaths from ] 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.<ref name="nyt-2008">. '']''. August 26, 2008; accessed August 28, 2008.</ref>


Eng's employer, the ], turned out to have no interest in obtaining a ] on exendin-4, so Eng filed the ] himself in 1993.<ref name="Molteni" /> He then spent three years on fruitless efforts to persuade the ] to develop exendin-4 into a drug.<ref name="Molteni" /><ref name="Winkler" /> ], a GLP-1 expert, later recalled seeing the skepticism which Eng encountered when he tried to ] 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".<ref name="Winkler" />
It also may increase risk of sulfonylurea-induced ].


At a 1996 ] conference in San Francisco, Eng finally caught the attention of scientist Andrew Young of ], who immediately recognized exendin-4's potential and arranged for his company to license Eng's patent.<ref name="Molteni" /><ref name="Schwarcz" /><ref name="Winkler" /><ref name="Dunaief">{{cite news | vauthors = Dunaief D |title=Setauket scientist Andrew Young’s work paves way for drugs like Ozempic |url=https://tbrnewsmedia.com/setauket-scientist-andrew-youngs-work-paves-way-for-drugs-like-ozempic/ |access-date=October 16, 2024 |work=TBR News Media |date=August 31, 2023}}</ref> Young was excited to see Eng's poster at the conference summarizing his findings, but then noticed an ] executive reading the same poster, and he became worried that Lilly might beat Amylin to a license.<ref name="Winkler" /><ref name="Dunaief" /> 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.<ref name="Dunaief" /> 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.<ref name="Molteni" /><ref name="Schwarcz" /><ref name="Pollack">{{cite news | vauthors = Pollack A |title=Eli Lilly in Deal For the Rights To a New Drug For Diabetes |url=https://www.nytimes.com/2002/09/21/business/eli-lilly-in-deal-for-the-rights-to-a-new-drug-for-diabetes.html |work=The New York Times |date=September 21, 2002 |page=C1}}</ref>
Additionally, the FDA has raised concerns over exenatide raising ] risk. The FDA delayed the decision on May 15, 2010, asking for more information from Amylin and Eli Lilly. The drug likely will be given a black box warning, the agency’s strictest caution on pharmaceuticals.<ref>. Businessweek. Retrieved on 2011-04-16.</ref> Eli Lilly has reported they have not seen a link in humans, but that it cannot be ruled out. Eli Lilly has admitted the drug causes an increase in thyroid problems in rats given high doses.<ref>. Pharmalot.com (2010-04-12). Retrieved on 2011-04-16.</ref>


Exenatide was approved by the FDA in April 2005, for people whose diabetes is not well controlled on other ]s.<ref name="Pollack2">{{cite news |last1=Pollack |first1=Andrew |title=Lizard-Derived Diabetes Drug Is Approved by the F.D.A. |url=https://www.nytimes.com/2005/04/30/business/lizardderived-diabetes-drug-is-approved-by-the-fda.html |access-date=November 2, 2024 |work=The New York Times |date=April 30, 2005 |url-access=subscription}}</ref><ref name="fda-approval">{{cite web | title=CDER Drug and Biologic Approvals for Calendar Year 2005 | website=U.S. ] (FDA) | date=4 September 2006 | url=https://www.fda.gov/cder/rdmt/InternetNDA05.htm | archive-url=https://web.archive.org/web/20060904041024/https://www.fda.gov/cder/rdmt/InternetNDA05.htm | archive-date=4 September 2006 | url-status=dead | access-date=8 March 2024}}</ref><ref>{{cite web | title=Drug Approval Package: Byetta (Exenatide) NDA #021773 | website=U.S. ] (FDA) | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021773_ByettaTOC.cfm | access-date=8 March 2024}}</ref> 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.<ref name="Molteni" /><ref name="Winkler" />
=== Lawsuit ===
On August 19, 2008 a Virginia man filed what is believed to be the first personal injury lawsuit stemming from injuries associated with the use of exenatide (Byetta). His attorney stated "the label change in 2007 was not adequate".
<ref>. Business Wire (2008-08-20). Retrieved on 2011-04-16.</ref>


In 2011, Lilly and Amylin dissolved their partnership, with Amylin keeping the rights to exenatide.<ref name="Staton">{{cite news |last1=Staton |first1=Tracy |title=Amylin gets Byetta custody in split with Lilly |url=https://www.fiercepharma.com/sponsored/evolving-expanding-integrated-platform-partnerships-drive-access-affordability-outcomes |access-date=November 2, 2024 |work=Fierce Pharma |date=November 8, 2011}}</ref> 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 drug ] had transformed Lilly into the most valuable drug company in the world.<ref name="Barnes">{{cite news | vauthors = Barnes O |title=Can Eli Lilly become the first $1tn drugmaker? |url=https://www.ft.com/content/ed81ca79-1fd6-48ea-8e50-246d0849c3f5 |work=Financial Times |date=October 2, 2024 |url-access=subscription}}</ref>
== Future research==
===Long acting release===
Eli Lilly & Co., Amylin Pharmaceuticals and Alkermes, Inc. are currently developing a long-acting release (LAR) formula of the drug, which can be injected once per week. If approved, this LAR will be marketed under the tradename Bydureon. Bydureon is tested in a Phase III clinical study program called DURATION. A cardiovascular outcomes trial (EXSCEL) has also been initiated, and will include more than 9000 patients with an estimated completion in 2017. Initial trials have shown once-weekly Bydureon provides better glycemic control than the original twice-daily injectable form, with a similar weight loss profile and lower rates of nausea.


==Society and culture==
The phase III study DURATION-1 published in 2008 showed the once weekly formulation resulted in a greater Hb<sub>A1c</sub> decline and more patients reaching Hb<sub>A1c</sub> targets compared to twice-daily Byetta.<ref name="pmid18782641">{{cite journal |author=Drucker DJ, Buse JB, Taylor K, ''et al.'' |title=Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study |journal=Lancet |volume= 372|issue= 9645|pages= 1240–50|year=2008 |pmid=18782641 |doi=10.1016/S0140-6736(08)61206-4 }}</ref>
53 consolidated lawsuits against manufacturers of "GLP-1/DPP-4 products" were dismissed in 2015.<ref>{{cite news | vauthors = Moylan T |title=Preemption Summary Judgment Granted In Incretin-Mimetic Multidistrict Litigation |url= https://www.lexisnexis.com/legalnewsroom/litigation/b/litigation-blog/archive/2015/11/11/preemption-summary-judgment-granted-in-incretin-mimetic-multidistrict-litigation.aspx |work=Lexisnexis |date=11 November 2015}}</ref>


== Research ==
DURATION-2 and DURATION-3, published in 2010, showed once weekly Bydureon provided superior glycemic control and superior weight loss compared to pioglitazone (Actos), the DPP-4 inhibitor sitagliptin (Januvia) and the basal insulin glargine (Lantus).<ref>{{cite journal |doi=10.1016/S0140-6736(10)60406-0 |title=Once weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes (DURATION-3): an open-label randomised trial |year=2010 |last1=Diamant |first1=Michaela |last2=Van Gaal |first2=Luc |last3=Stranks |first3=Stephen |last4=Northrup |first4=Justin |last5=Cao |first5=Dachuang |last6=Taylor |first6=Kristin |last7=Trautmann |first7=Michael |journal=The Lancet |volume=375 |issue=9733 |pages=2234–2243}}</ref><ref>{{cite journal|doi=10.1016/S0140-6736(10)60590-9|title=Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial|year=2010|last1=Bergenstal|first1=Richard M|last2=Wysham|first2=Carol|last3=MacConell|first3=Leigh|last4=Malloy|first4=Jaret|last5=Walsh|first5=Brandon|last6=Yan|first6=Ping|last7=Wilhelm|first7=Ken|last8=Malone|first8=Jim|last9=Porter|first9=Lisa E|journal=The Lancet|volume=376|issue=9739|pages=431–439}}</ref>
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.<ref name="Ali ES 2016"/>


It is being evaluated for use in the treatment of ].<ref>{{cite journal | vauthors = Kim DS, Choi HI, Wang Y, Luo Y, Hoffer BJ, Greig NH | title = A New Treatment Strategy for Parkinson's Disease through the Gut-Brain Axis: The Glucagon-Like Peptide-1 Receptor Pathway | journal = Cell Transplantation | volume = 26 | issue = 9 | pages = 1560–1571 | date = September 2017 | pmid = 29113464 | pmc = 5680957 | doi = 10.1177/0963689717721234 }}</ref> A ], started in January 2020 has an Estimated Study Completion Date of 30 June 2024 (NCT04232969).<ref>{{Cite web | vauthors = Bailey S |date=30 November 2021 |title=The Bydureon (exenatide) phase 3 trial |url=https://cureparkinsons.org.uk/2021/11/the-exenatide-trial/ |access-date=11 September 2022 |website=Cure Parkinson's |language=en-GB}}</ref>
===Gene therapies===
Scientists at the National Institutes of Health in Bethesda MD and other academic institutions are developing gene therapy based administration of ''Exendin-4'' without the need for expensive daily injections.<ref name=Baggio2006>{{cite journal|doi=10.2337/db05-1502|title=Lymphocytic Infiltration and Immune Activation in Metallothionein Promoter–Exendin-4 (MT-Exendin) Transgenic Mice |year=2006|last1=Baggio|first1=L. L.|journal=Diabetes|volume=55|issue=6|pages=1562–1570|pmid=16731818|last2=Holland|first2=D|last3=Wither|first3=J|last4=Drucker|first4=DJ}}</ref>


== References ==
A research group led by Hee-Sook Jun published a paper in ''Diabetes'' indicating the delivery of ] through an adenoviral vector had a significant long term effect on diabetes.<ref name=Lee2007>{{cite journal|doi=10.2337/db06-1182|title=Glucagon-Like Peptide-1 Gene Therapy in Obese Diabetic Mice Results in Long-Term Cure of Diabetes by Improving Insulin Sensitivity and Reducing Hepatic Gluconeogenesis |year=2007 |author=Young-Sun Lee et al.|journal=Diabetes|volume=56|issue=6|pages=1671–1679|pmid=17369525 }}</ref>
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== External links ==
==References==
{{reflist|30em}} * {{MeshName|Exenatide}}

==External links==
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==See also==
* ]s:
: ] (Victoza)
: ]
: ]
* ]
* ]


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