Exenatide

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Exenatide
Exenatide PDB=7MLL.png
Single conformer of the solution NMR structure of exenatide. PDB: 7MLL ​
Clinical data
Pronunciation /ɛɡzˈɛnətaɪd/ ⓘ
Trade names Byetta, Bydureon, Bydureon BCise, others
AHFS/Drugs.com Monograph
MedlinePlus a605034
License data
Pregnancy
category
  • AU:C
Routes of
administration 		Subcutaneous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability N/A
Metabolism proteolysis
Elimination half-life 2.4 h
Excretion Kidney
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
ECHA InfoCard 100.212.123 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C184H282N50O60S
Molar mass 4186.63 g·mol−1
3D model (JSmol)
  • [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=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 X mark.svgN
  • Key:HTQBXNHDCUEHJF-XWLPCZSASA-N X mark.svgN
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Exenatide, sold under the brand name Byetta among others, is a medication used to treat type 2 diabetes. [7] It is used together with diet, exercise, and potentially other antidiabetic medication. [7] It is a treatment option after metformin and sulfonylureas. [8] It is given by injection under the skin. [7]

Contents

Common side effects include low blood sugar, nausea, dizziness, abdominal pain, and pain at the site of injection. [7] Other serious side effects may include medullary thyroid cancer, angioedema, pancreatitis, and kidney injury. [7] Use in pregnancy and breastfeeding is of unclear safety. [9] Exenatide is a glucagon-like peptide-1 receptor agonist (GLP-1 receptor agonist) also known as incretin mimetics. [7] It works by increasing insulin release from the pancreas and decreases excessive glucagon 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]

Medical use

Exenatide is used to treat type 2 diabetes as an add-on to metformin, a biguanide, or a combination of metformin and a sulfonylurea, or thiazolidinediones such as pioglitazone. [1] [2]

A 2011 Cochrane review showed a HbA1c reduction of 0.20% more with Exenatide 2 mg compared to insulin glargine, exenatide 10 μg twice daily, sitagliptin and pioglitazone. [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]

Side effects

The main side 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 of lovastatin, paracetamol (acetaminophen), and digoxin, although this has not been proven to alter the effectiveness of these other medications.

In response to postmarketing reports of acute pancreatitis in patients using exenatide, the US Food and Drug Administration (FDA) added a boxed warning to the labeling of Byetta in 2007. [13] [14] In August 2008, four additional deaths from pancreatitis 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-induced hypoglycemia. [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 increase thyroid 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 additional rodent 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]

Mechanism of action

Exenatide binds to the intact human Glucagon-like peptide-1 receptor (GLP-1R) in a similar way to the human peptide glucagon-like peptide-1 (GLP-1); exenatide bears a 50% amino acid homology to GLP-1 and it has a longer half-life in vivo. [22]

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

  1. Exenatide augments pancreas response [23] (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 hypoglycemia.
  2. Exenatide also suppresses pancreatic release of glucagon in response to eating, which helps stop the liver from overproducing sugar when it is unneeded, which prevents hyperglycemia (high blood sugar levels).
  3. Exenatide helps slow down gastric 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, promote satiety via hypothalamic receptors (different receptors than for amylin). 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, [24] rat [25] and more recently in man. [26]

Chemistry

Exenatide is a 39-amino-acid peptide; it is a synthetic version of exendin-4, a peptide found in the venom of the Gila monster. [27]

History

During the early 1980s, Jean-Pierre Raufman worked as a postdoctoral researcher at the National 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 the Gila 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 the Veterans Administration Medical Center in New York City. [28] [29] Eng had trained under Rosalyn Sussman Yalow, who shared the 1977 Nobel Prize in Physiology or Medicine for development of the radioimmunoassay 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, the U.S. Department of Veterans Affairs, turned out to have no interest in obtaining a drug patent on exendin-4, so Eng filed the patent application himself in 1993. [28] He then spent three years on fruitless efforts to persuade the pharmaceutical 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 to present 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 1996 American Diabetes Association conference in San Francisco, Eng finally caught the attention of scientist Andrew Young of Amylin 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 an Eli 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 other oral 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 drug tirzepatide had transformed Lilly into the most valuable drug company in the world. [37]

Society and culture

53 consolidated lawsuits against manufacturers of "GLP-1/DPP-4 products" were dismissed in 2015. [38]

Research

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 of Parkinson's disease. [39] A phase 3 clinical trial, started in January 2020 has an Estimated Study Completion Date of 30 June 2024 (NCT04232969). [40]

Related Research Articles

Drugs used in diabetes treat diabetes mellitus by decreasing glucose levels in the blood. With the exception of insulin, most GLP-1 receptor agonists, and pramlintide, all diabetes medications are administered orally and are thus called oral hypoglycemic agents or oral antihyperglycemic agents. There are different classes of hypoglycemic drugs, and selection of the appropriate agent depends on the nature of diabetes, age, and situation of the person, as well as other patient factors.

<span class="mw-page-title-main">Anti-obesity medication</span> Class of pharmacological agents

Anti-obesity medication or weight loss medications are pharmacological agents that reduce or control excess body fat. These medications alter one of the fundamental processes of the human body, weight regulation, by: reducing appetite and consequently energy intake, increasing energy expenditure, redirecting nutrients from adipose to lean tissue, or interfering with the absorption of calories.

<span class="mw-page-title-main">Incretin</span> Group of gastrointestinal hormones

Incretins are a group of metabolic hormones that stimulate a decrease in blood glucose levels. Incretins are released after eating and augment the secretion of insulin released from pancreatic beta cells of the islets of Langerhans by a blood-glucose–dependent mechanism.

<span class="mw-page-title-main">Pramlintide</span> Diabetes medication

Pramlintide is an injectable amylin analogue drug for diabetes, developed by Amylin Pharmaceuticals. Pramlintide is sold as an acetate salt.

<span class="mw-page-title-main">Vildagliptin</span> Chemical compound

Vildagliptin, sold under the brand name Galvus and others, is an oral anti-hyperglycemic agent of the dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs. Vildagliptin inhibits the inactivation of GLP-1 and GIP by DPP-4, allowing GLP-1 and GIP to potentiate the secretion of insulin in the beta cells and suppress glucagon release by the alpha cells of the islets of Langerhans in the pancreas.

<span class="mw-page-title-main">Dipeptidyl peptidase-4 inhibitor</span> Enzyme blocker and diabetes treatment drug

Inhibitors of dipeptidyl peptidase 4 are a class of oral hypoglycemics that block the enzyme dipeptidyl peptidase-4 (DPP-4). They can be used to treat diabetes mellitus type 2.

<span class="mw-page-title-main">Glucagon-like peptide-1</span> Gastrointestinal peptide hormone involved in glucose homeostasis

Glucagon-like peptide-1 (GLP-1) is a 30- or 31-amino-acid-long peptide hormone deriving from the tissue-specific posttranslational processing of the proglucagon peptide. It is produced and secreted by intestinal enteroendocrine L-cells and certain neurons within the nucleus of the solitary tract in the brainstem upon food consumption. The initial product GLP-1 (1–37) is susceptible to amidation and proteolytic cleavage, which gives rise to the two truncated and equipotent biologically active forms, GLP-1 (7–36) amide and GLP-1 (7–37). Active GLP-1 protein secondary structure includes two α-helices from amino acid position 13–20 and 24–35 separated by a linker region.

<span class="mw-page-title-main">Saxagliptin</span> Chemical compound

Saxagliptin, sold under the brand name Onglyza, is an oral hypoglycemic of the dipeptidyl peptidase-4 (DPP-4) inhibitor class. Early development was solely by Bristol-Myers Squibb; in 2007 AstraZeneca joined with Bristol-Myers Squibb to co-develop the final compound and collaborate on the marketing of the drug.

<span class="mw-page-title-main">Glucagon-like peptide-1 receptor</span> Receptor activated by peptide hormone GLP-1

The glucagon-like peptide-1 receptor (GLP1R) is a G protein-coupled receptor (GPCR) found on beta cells of the pancreas and on neurons of the brain. It is involved in the control of blood sugar level by enhancing insulin secretion. In humans it is synthesised by the gene GLP1R, which is present on chromosome 6. It is a member of the glucagon receptor family of GPCRs. GLP1R is composed of two domains, one extracellular (ECD) that binds the C-terminal helix of GLP-1, and one transmembrane (TMD) domain that binds the N-terminal region of GLP-1. In the TMD domain there is a fulcrum of polar residues that regulates the biased signaling of the receptor while the transmembrane helical boundaries and extracellular surface are a trigger for biased agonism.

<span class="mw-page-title-main">Amylin Pharmaceuticals</span> Biopharmaceutical company

Amylin Pharmaceuticals, Inc. is a biopharmaceutical founded in 1987 that was based in San Diego, California. The company was engaged in the discovery, development, and commercialization of drug candidates for the treatment of diabetes, obesity, and other diseases. Amylin produced three drugs: Symlin, Byetta (exenatide) and Bydureon.

<span class="mw-page-title-main">Liraglutide</span> Anti-diabetic medication

Liraglutide, sold under the brand name Victoza among others, is an anti-diabetic medication used to treat type 2 diabetes, and chronic obesity. It is a second-line therapy for diabetes following first-line therapy with metformin. Its effects on long-term health outcomes like heart disease and life expectancy are unclear. It is given by injection under the skin.

Albiglutide is a glucagon-like peptide-1 agonist drug marketed by GlaxoSmithKline (GSK) for treatment of type 2 diabetes. As of 2017 it is unclear if it affects a person's risk of death. In 2017 GSK announced Albiglutide's withdrawal from the worldwide market for economic reasons, and remaining stocks in the supply chain were effectively depleted by 2018.

Glucagon-like peptide-1 (GLP-1) receptor agonists, also known as GLP-1 analogs, GLP-1DAs or incretin mimetics, are a class of anorectic drugs that reduce blood sugar and energy intake by activating the GLP-1 receptor. They mimic the actions of the endogenous incretin hormone GLP-1 that is released by the gut after eating.

Taspoglutide is a former experimental drug, a glucagon-like peptide-1 agonist, that was under investigation for treatment of type 2 diabetes and being codeveloped by Ipsen and Roche.

Lixisenatide is a once-daily injectable GLP-1 receptor agonist for the treatment of type 2 diabetes.

<span class="mw-page-title-main">Dulaglutide</span> Diabetes medication

Dulaglutide, sold under the brand name Trulicity among others, is a medication used for the treatment of type 2 diabetes in combination with diet and exercise. It is also approved in the United States for the reduction of major adverse cardiovascular events in adults with type 2 diabetes who have established cardiovascular disease or multiple cardiovascular risk factors.

<span class="mw-page-title-main">Daniel J. Drucker</span> Canadian endocrinologist (born 1956)

Daniel Joshua Drucker is a Canadian endocrinologist. A Fellow of the Royal Society, he is a professor of medicine at the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto. He is known for his research into intestinal hormones and their use in the treatment of diabetes, obesity, and other metabolic diseases, as well as intestinal failure.

<span class="mw-page-title-main">Semaglutide</span> Anti-diabetic and anti-obesity medication

Semaglutide is an antidiabetic medication used for the treatment of type 2 diabetes and an anti-obesity medication used for long-term weight management. It is a peptide similar to the hormone glucagon-like peptide-1 (GLP-1), modified with a side chain. It can be administered by subcutaneous injection or taken orally. It is sold under the brand names Ozempic and Rybelsus for diabetes, and under the brand name Wegovy for weight loss.

Glucagon receptor agonists are a class of drugs under development for the treatment of obesity, non-alcoholic fatty liver disease, and congenital hyperinsulinism.

GLP1 poly-agonist peptides are a class of drugs that activate multiple peptide hormone receptors including the glucagon-like peptide-1 (GLP-1) receptor. These drugs are developed for the same indications as GLP-1 receptor agonists—especially obesity, type 2 diabetes, and non-alcoholic fatty liver disease. They are expected to provide superior efficacy with fewer adverse effects compared to GLP-1 mono-agonists, which are dose-limited by gastrointestinal disturbances. The effectiveness of multi-receptor agonists could possibly equal or exceed that of bariatric surgery. The first such drug to receive approval is tirzepatide, a dual agonist of GLP-1 and GIP receptors.

References

  1. 1 2 "Byetta 10 micrograms solution for injection, prefilled pen - Summary of Product Characteristics". Electronic Medicines Compendium. 30 March 2017. Retrieved 21 April 2018.
  2. 1 2 "Bydureon 2 mg powder and solvent for prolonged-release suspension for injection in pre-filled pen - Summary of Product Characteristics". Electronic Medicines Compendium. 10 November 2017. Archived from the original on 20 August 2020. Retrieved 21 April 2018.
  3. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 October 2023.
  4. ↑ "Bydureon- exenatide injection, suspension, extended release Bydureon- exenatide kit". DailyMed. 28 February 2020. Retrieved 2 December 2020.
  5. ↑ "Bydureon BCise- exenatide injection, suspension, extended release". DailyMed. 28 February 2020. Retrieved 2 December 2020.
  6. ↑ "Byetta- exenatide injection". DailyMed. 28 February 2020. Retrieved 2 December 2020.
  7. 1 2 3 4 5 6 7 8 "Exenatide Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 22 March 2019.
  8. ↑ British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 684–685. ISBN   978-0-85711-338-2.
  9. ↑ "Exenatide Pregnancy and Breastfeeding Warnings". Drugs.com. Retrieved 3 March 2019.
  10. ↑ "Exenatide - Drug Usage Statistics". ClinCalc. Retrieved 7 October 2022.
  11. 1 2 3 4 5 Shyangdan DS, Royle P, Clar C, Sharma P, Waugh N, Snaith A (October 2011). "Glucagon-like peptide analogues for type 2 diabetes mellitus". The Cochrane Database of Systematic Reviews. 2011 (10): CD006423. doi:10.1002/14651858.cd006423.pub2. PMC   6486297 . PMID   21975753.
  12. ↑ Drugs.com Accessed September 6, 2008.
  13. ↑ 2007 Safety Alerts for Drugs, Biologics, Medical Devices, and Dietary Supplements, from the U.S. Food and Drug Administration. Accessed 28 August 2008.
  14. ↑ "Byetta (exenatide) FDA warning". Food and Drug Administration . Retrieved 18 October 2007.
  15. ↑ Diabetes Drug Tied to New Deaths. The New York Times . 26 August 2008; accessed 28 August 2008.
  16. ↑ Lai SW, Muo CH, Liao KF, Sung FC, Chen PC (September 2011). "Risk of acute pancreatitis in type 2 diabetes and risk reduction on anti-diabetic drugs: a population-based cohort study in Taiwan". The American Journal of Gastroenterology. 106 (9): 1697–1704. doi:10.1038/ajg.2011.155. PMID   21577242. S2CID   25665019.
  17. ↑ Gonzalez-Perez A, Schlienger RG, Rodríguez LA (December 2010). "Acute pancreatitis in association with type 2 diabetes and antidiabetic drugs: a population-based cohort study". Diabetes Care. 33 (12): 2580–2585. doi:10.2337/dc10-0842. PMC   2992194 . PMID   20833867.
  18. ↑ Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD (November 2004). "Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes". Diabetes Care. 27 (11): 2628–2635. doi: 10.2337/diacare.27.11.2628 . PMID   15504997.
  19. ↑ Silverman E (12 April 2010). "Lilly's Once-Weekly Byetta May Have Cancer Risk". Pharmalot. Archived from the original on 6 June 2010.
  20. ↑ "FDA investigating reports of possible increased risk of pancreatitis and pre-cancerous findings of the pancreas from incretin mimetic drugs for type 2 diabetes". FDA. U.S. Food and Drug Administration. 3 March 2013. Retrieved 14 March 2013.
  21. ↑ "European Medicines Agency investigates findings on pancreatic risks with GLP-1-based therapies for type-2 diabetes". EMA. European Medicines Agency Sciences Medicines Health. 26 March 2013. Archived from the original on 28 August 2021. Retrieved 26 March 2013.
  22. ↑ Koole C, Reynolds CA, Mobarec JC, Hick C, Sexton PM, Sakmar TP (April 2017). "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)". The Journal of Biological Chemistry. 292 (17): 7131–7144. doi: 10.1074/jbc.M117.779496 . PMC   5409479 . PMID   28283573.
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  24. ↑ Ding X, Saxena NK, Lin S, Gupta NA, Gupta N, Anania FA (January 2006). "Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice". Hepatology. 43 (1): 173–181. doi:10.1002/hep.21006. PMC   2925424 . PMID   16374859.
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