Exenatide

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Exenatide
Systematic (IUPAC) name
?
Identifiers
CAS number	141732-76-5
ATC code	A10BX04
PubChem	?
DrugBank	DB01276
Chemical data
Formula	C184H282N50O60S
Mol. mass	4186.6
Pharmacokinetic data
Bioavailability	N/A
Metabolism	proteolysis
Half life	2.4 h
Excretion	renal/proteolysis
Therapeutic considerations
Pregnancy cat.	C
Legal status	℞ Prescription only
Routes	subcutaneous injection

Exenatide (INN, marketed as Byetta) is one of a new class of medications (incretin mimetics) approved (Apr 2005) for the treatment of diabetes mellitus type 2. (It is not approved for use in diabetes mellitus type 1.) It is manufactured by Eli Lilly and Company.

Exenatide is administered as a subcutaneous injection (under the skin) of the abdomen, thigh, or arm, 30 to 60 minutes before the first and last meal of the day.^[1]

Chemistry and Pharmacology

Exenatide is manufactured and marketed by Amylin Pharmaceuticals and Eli Lilly and Company. Exenatide is a synthetic version of exendin-4, a hormone found in the saliva of the Gila monster. It displays biological properties similar to human glucagon-like peptide-1 (GLP-1), a regulator of glucose metabolism and insulin 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.

Exenatide is a 39-amino-acid peptide an insulin secretagogue with glucoregulatory effects. Exenatide was approved by the FDA on April 28, 2005 for patients whose diabetes was not well-controlled on other oral medication.^[2] The medication is injected subcutaneously twice per day using a pre-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

The incretin hormones GLP-1 and Glucose-dependent insulinotropic peptide (GIP) are produced by the 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 pancreas. 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.

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 lead to the discovery of the also desirable glucagon and appetite-suppressant effects.

Exenatide is approved "as adjunctive therapy to improve glycemic control in patients with type 2 diabetes mellitus who are taking metformin, a biguanide, or a combination of metformin and a sulfonylurea but have not achieved adequate glycemic control". It has now been approved for use with thiazolidinediones such as pioglitazone or rosiglitazone.

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 6–8 hours.^[1] The medicine is available in two doses: 5 mcg and 10 mcg. Treatment often begins with the 5 mcg dosage, which is increased if adverse effects are not significant.^[3]

According to the manufacturer, the exenatide (Byetta) autoinjector must be stored in a refrigerator between 36 °F (2 °C) and 46 °F (8 °C) before first use, and then at a temperature between 36 °F (2 °C) and 77 °F (25 °C). In hot weather, therefore, they should be refrigerated.^[4] Exenatide (Byetta) pens contain sixty doses designed to be used twice a day for 30 days.

Exenatide received US Patent 5,424,286 which was filed May 24, 1993.

Mode of action

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

1. Exenatide augments pancreas response (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 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 that 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 non-alcoholic 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^[5] and more recently in man.^[6]

In an open-label randomized controlled trial of 551 patients,^[7] exenatide treatment for 26 weeks was associated with 2.3 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 that much of what is reported as nausea is actually a feeling of fullness. It is speculated that exenatide makes most patients need to eat less and until an adjustment is made to smaller portions, the result is the fullness feeling.

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 metformin and acarbose, 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 side effects section below.

Indications

• Adjunctive therapy to improve glycemic control in patients with type 2 diabetes who are taking metformin, 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
• Use with insulin, meglitinides, and alpha-glucosidase inhibitors has not been studied
• Some physicians are using exenatide as primary monotherapy, although this is not currently an FDA approved usage.

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 Type 1 diabetes.

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; exenatide is therefore not meant for people with severe gastrointestinal disease. Other side effects include dizziness, headache, and feeling jittery.^[3] 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 post-marketing reports of acute pancreatitis in patients using exenatide, the FDA added a warning to the labeling of Byetta in 2007.^[8][9] 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.^[10]

• May increase risk of sulfonylurea-induced hypoglycemia.

Future research

Eli Lilly & Co., Amylin Pharmaceuticals and Alkermes, Inc. are currently developing a long-acting-release (LAR) formula of the drug, which would be injected once per week. The initial trials for the medication have shown the LAR formulation to be approximately twice as effective as the original twice-daily injectable form, with a similar safety, lower nausea rates and greater weight loss profile. A Phase III study showed that 50% of patients treated with exenatide LAR had an Hb_A1c of 6.5% or better, and 75% reached 7.0%.^[11] A study published in 2008 also showed that the long-acting formulation resulted in a greater Hb_A1c decline and more patients reaching Hb_A1c targets.^[12]

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. A research group led by Hee-Sook Jun published a paper in Diabetes indicating that the delivery of GLP-1 through an Adenoviral vector had a significant long term effect on diabetes.

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 that "the label change in 2007 was not adequate".^[13]

References

External links

• Instructions
• Byetta website
• Byetta prescribing information (with clinical studies references)
• NY Times Article on Byetta
• MeSH exenatide
• Conference, inc graphs of results with exenatide

See also

• GLP-1 analogs, eg. liraglutide