Exenatide

Names
Pronunciation	/ɛɡzˈɛnətaɪd/ (listen)
Trade names	Byetta, Bydureon, Bydureon BCise, others
Clinical data
Pregnancy category	AU: C US: C (Risk not ruled out)
Routes of use	Subcutaneous injection
Defined daily dose	15 ug (short acting)[1] 0.286 (long acting)[1]
External links
AHFS/Drugs.com	Monograph
MedlinePlus	a605034
Legal
License data	EU EMA: by INN US DailyMed: Exenatide
Legal status	AU: S4 (Prescription only) US: ℞-only In general: ℞ (Prescription only)
Pharmacokinetics
Bioavailability	N/A
Metabolism	proteolysis
Eliminationhalf-life	2.4 h
Excretion	Kidney/proteolysis
Chemical and physical data
Formula	C184H282N50O60S
Molar mass	4186.63 g·mol−1
3D model (JSmol)	Interactive image
SMILES [H]/N=C(\N)/NCCC[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](Cc2c[nH]c3c2cccc3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(=O)N)C(=O)NCC(=O)NCC(=O)N4CCC[C@H]4C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N5CCC[C@H]5C(=O)N6CCC[C@H]6C(=O)N7CCC[C@H]7C(=O)N[C@@H](CO)C(=O)N)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](Cc8ccccc8)NC(=O)[C@H]([C@@H](C)O)NC(=O)CNC(=O)[C@H](CCC(=O)O)NC(=O)CNC(=O)[C@H](Cc9cnc[nH]9)N
InChI InChI=1S/C184H282N50O60S/c1-16-94(10)147(178(289)213-114(52-58-144(257)258)163(274)218-121(73-101-77-195-105-39-24-23-38-103(101)105)168(279)215-116(68-90(2)3)165(276)205-107(41-26-28-61-186)158(269)219-122(75-134(189)243)154(265)198-79-135(244)196-83-139(248)231-63-30-43-129(231)175(286)225-127(87-238)174(285)223-125(85-236)155(266)200-80-136(245)202-96(12)181(292)233-65-32-45-131(233)183(294)234-66-33-46-132(234)182(293)232-64-31-44-130(232)176(287)222-124(84-235)150(190)261)229-170(281)119(71-99-34-19-17-20-35-99)217-166(277)117(69-91(4)5)214-159(270)108(42-29-62-194-184(191)192)212-177(288)146(93(8)9)228-151(262)95(11)203-156(267)111(49-55-141(251)252)208-161(272)112(50-56-142(253)254)209-162(273)113(51-57-143(255)256)210-164(275)115(59-67-295-15)211-160(271)110(47-53-133(188)242)207-157(268)106(40-25-27-60-185)206-172(283)126(86-237)224-167(278)118(70-92(6)7)216-169(280)123(76-145(259)260)220-173(284)128(88-239)226-180(291)149(98(14)241)230-171(282)120(72-100-36-21-18-22-37-100)221-179(290)148(97(13)240)227-138(247)82-199-153(264)109(48-54-140(249)250)204-137(246)81-197-152(263)104(187)74-102-78-193-89-201-102/h17-24,34-39,77-78,89-98,104,106-132,146-149,195,235-241H,16,25-33,40-76,79-88,185-187H2,1-15H3,(H2,188,242)(H2,189,243)(H2,190,261)(H,193,201)(H,196,244)(H,197,263)(H,198,265)(H,199,264)(H,200,266)(H,202,245)(H,203,267)(H,204,246)(H,205,276)(H,206,283)(H,207,268)(H,208,272)(H,209,273)(H,210,275)(H,211,271)(H,212,288)(H,213,289)(H,214,270)(H,215,279)(H,216,280)(H,217,277)(H,218,274)(H,219,269)(H,220,284)(H,221,290)(H,222,287)(H,223,285)(H,224,278)(H,225,286)(H,226,291)(H,227,247)(H,228,262)(H,229,281)(H,230,282)(H,249,250)(H,251,252)(H,253,254)(H,255,256)(H,257,258)(H,259,260)(H4,191,192,194)/t94-,95-,96-,97+,98+,104-,106-,107-,108-,109-,110-,111-,112-,113-,114-,115-,116-,117-,118-,119-,120-,121-,122-,123-,124-,125-,126-,127-,128-,129-,130-,131-,132-,146-,147-,148-,149-/m0/s1 N Key:HTQBXNHDCUEHJF-XWLPCZSASA-N N

Exenatide, sold under the brand nameByetta andBydureon among others, is a medication used to treatdiabetes mellitus type 2.^[2] It is used together with diet, exercise, and potentially otherantidiabetic medication.^[2] It is a less preferred treatment option aftermetformin andsulfonylureas.^[3] It is given byinjection under the skin within an hour before the first and last meal of the day.^[2] A once-weekly injection version is also available.^[2]

Common side effects includelow blood sugar, nausea, dizziness, abdominal pain, and pain at the site of injection.^[2] Other serious side effects may includemedullary thyroid cancer,angioedema,pancreatitis, andkidney injury.^[2] Use inpregnancy andbreastfeeding is of unclear safety.^[4] Exenatide is aglucagon-like peptide-1 receptor agonist (GLP-1 receptor agonist) also known asincretinmimetics.^[2] It works by increasing insulin release from thepancreas and decreases excessiveglucagon release.^[2]

Exenatide was approved for medical use in the United States in 2005.^[2] A month supply in the United Kingdom costs theNHS about £82 for the daily injectable and £73 for the weekly injectable version as of 2019.^[3] In the United States the wholesale cost of this amount is aboutUS$700 andUS$789 respectively.^[5] In 2017, it was the 260th most commonly prescribed medication in the United States, with more than one million prescriptions.^[6][7]

Medical use

Exenatide is used to treat type 2 diabetes mellitus as an add-on tometformin, abiguanide, or a combination of metformin and asulfonylurea, orthiazolidinediones such aspioglitazone.^[8][9] It is also being evaluated for use in the treatment ofParkinson's disease.^[10]

The medication is injected subcutaneously twice per day using a filled pen-like device (Byetta), or on a weekly basis with either a pen-like device or conventional syringe (Bydureon). The abdomen is a common injection site.^[8][9]

Dosage

Thedefined daily dose is 15 micrograms for the short acting formulation by injection and 0.286 mg for the long acting formulation by injection into a muscle.^[1]

Side effects

The mainside effects of exenatide use are gastrointestinal in nature, including acid or sour stomach, belching, diarrhea, 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.^[11] 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, theFDA added a warning to the labeling of Byetta in 2007.^[12][13] 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.^[14] 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.^[15][16]

It also may increase risk of mild sulfonylurea-inducedhypoglycemia.^[17]

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.^[18]

In March 2013, the FDA issued a Drug Safety Communication announcing investigations into incretin mimetics due to findings by academic researchers.^[19] A few weeks later, the European Medicines Agency launched a similar investigation into GLP-1 agonists and DPP-4 inhibitors.^[20]

Mechanism of action

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.^[21]

Exenatide is believed to facilitate glucose control in at least five ways:

1. Exenatide augments pancreas response^[22] (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 becometoo low, resulting in the dangerous condition ofhypoglycemia.
2. Exenatide also suppresses pancreatic release ofglucagon in response to eating, which helps stop the liver from overproducing sugar when it is unneeded, which preventshyperglycemia (high blood sugar levels).
3. Exenatide helps slow downgastric emptying and thus decreases the rate at which meal-derived glucose appears in the bloodstream.
4. Exenatide has a subtle yet prolonged effect to reduce appetite, promotesatiety viahypothalamic receptors (different receptors than foramylin). 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.
5. 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,^[23] rat^[24] and more recently in man.^[25]

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.^[24]

Chemistry

Exenatide is a 39-amino-acidpeptide; it is a synthetic version ofExendin-4, ahormone found in the saliva of theGila monster.^[26]

History

Exenatide was first isolated by John Eng in 1992 while working at the Veterans Administration Medical Center in the Bronx, New York.^[26] It is made byAmylin Pharmaceuticals and commercialized byAstraZeneca.

Exenatide was approved by theFDA on April 28, 2005 for people whose diabetes was not well-controlled on otheroral medication.^[27]

Society and culture

53 consolidated lawsuits against manufacturers of "GLP-1/DPP-4 products" were dismissed in 2015.^[28]

Cost

A month supply in the United Kingdom costs theNHS about £82 for the daily injectable and £73 for the weekly injectable version as of 2019.^[3] In the United States the wholesale cost of this amount is aboutUS$700 andUS$789 respectively.^[5] In 2017, it was the 260th most commonly prescribed medication in the United States, with more than one million prescriptions.^[6][7]

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  Exenatide costs (US)

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  Exenatide prescriptions (US)

References

External links

• exenatide at the US National Library of MedicineMedical Subject Headings (MeSH)

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