Exenatide
Encyclopedia
Exenatide is a medication approved in April 2005 for the treatment of diabetes mellitus type 2
Diabetes mellitus type 2
Diabetes mellitus type 2formerly non-insulin-dependent diabetes mellitus or adult-onset diabetesis a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Diabetes is often initially managed by increasing exercise and...

. It belongs to the group of incretin
Incretin
Incretins are a group of gastrointestinal hormones that cause an increase in the amount of insulin released from the beta cells of the islets of Langerhans after eating, even before blood glucose levels become elevated. They also slow the rate of absorption of nutrients into the blood stream by...

 mimetics and is manufactured by Amylin Pharmaceuticals
Amylin Pharmaceuticals
Amylin Pharmaceuticals is a biopharmaceutical company based in San Diego, CA, that was founded in 1987. The company is engaged in the discovery, development and commercialization of drug candidates for the treatment of diabetes, obesity and other diseases. Currently, Amylin produces two drugs,...

 and Eli Lilly and Company
Eli Lilly and Company
Eli Lilly and Company is a global pharmaceutical company. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States...

.

Exenatide is administered as a subcutaneous injection
Subcutaneous injection
A subcutaneous injection is administered as a bolus into the subcutis, the layer of skin directly below the dermis and epidermis, collectively referred to as the...

 (under the skin) of the abdomen, thigh, or arm, any time within the 60 minutes before the first and last meal of the day.

Chemistry and pharmacology

Exenatide is a synthetic version of exendin-4, a hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...

 found in the saliva of the Gila monster
Gila monster
The Gila monster is a species of venomous lizard native to the southwestern United States and northwestern Mexican state of Sonora...

 that was first isolated by Dr. John Eng in 1992 while working at the Veterans Administration Medical Center in the Bronx, New York. It displays biological properties similar to human glucagon-like peptide-1
Glucagon-like peptide-1
Glucagon-like peptide-1 is derived from the transcription product of the proglucagon gene. The major source of GLP-1 in the body is the intestinal L cell that secretes GLP-1 as a gut hormone. The biologically active forms of GLP-1 are: GLP-1- and GLP-1-NH2...

 (GLP-1), a regulator of glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...

 metabolism and insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....

 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
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...

, an insulin secretagogue
Secretagogue
A secretagogue is a substance that causes another substance to be secreted. One example is gastrin,, which stimulates the H/K ATPase in the parietal cells...

, 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. 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.

The incretin hormones GLP-1 and glucose-dependent insulinotropic peptide
Glucose-dependent insulinotropic peptide
Gastric inhibitory polypeptide , also known as the glucose-dependent insulinotropic peptide is a member of the secretin family of hormones....

 (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 pancreas
Pancreas
The pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...

. 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 led 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
Metformin
Metformin is an oral antidiabetic drug in the biguanide class. It is the first-line drug of choice for the treatment of type 2 diabetes, in particular, in overweight and obese people and those with normal kidney function. Its use in gestational diabetes has been limited by safety concerns...

, a biguanide
Biguanide
Biguanide can refer to a molecule, or to a class of drugs based upon this molecule. Biguanides can function as oral antihyperglycemic drugs used for diabetes mellitus or prediabetes treatment...

, or a combination of metformin and a sulfonylurea
Sulfonylurea
Sulfonylurea derivatives are a class of antidiabetic drugs that are used in the management of diabetes mellitus type 2. They act by increasing insulin release from the beta cells in the pancreas.-First generation:* Carbutamide...

, but have not achieved adequate glycemic control". It has now been approved for use with thiazolidinediones such as pioglitazone
Pioglitazone
Pioglitazone is a prescription drug of the class thiazolidinedione with hypoglycemic action.Pioglitazone is marketed as trademarks Actos in the USA, Canada, the UK and Germany, Glustin in Europe,"Glizone" and "Pioz" in India by Zydus CND and USV respectively and Zactos in Mexico by Takeda...

 or rosiglitazone
Rosiglitazone
Rosiglitazone is an antidiabetic drug in the thiazolidinedione class of drugs. It works as an insulin sensitizer, by binding to the PPAR receptors in fat cells and making the cells more responsive to insulin...

.

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. 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.

According to the manufacturer, the 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. 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
    Hypoglycemia
    Hypoglycemia or hypoglycæmia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood"...

    .
  2. Exenatide also suppresses pancreatic release of glucagon
    Glucagon
    Glucagon, a hormone secreted by the pancreas, raises blood glucose levels. Its effect is opposite that of insulin, which lowers blood glucose levels. The pancreas releases glucagon when blood sugar levels fall too low. Glucagon causes the liver to convert stored glycogen into glucose, which is...

     in response to eating, which helps stop the liver from overproducing sugar when it is unneeded, which prevents hyperglycemia
    Hyperglycemia
    Hyperglycemia or Hyperglycæmia, or high blood sugar, is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a glucose level higher than 13.5mmol/l , but symptoms may not start to become noticeable until even higher values such as 15-20 mmol/l...

     (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
    Hypothalamus
    The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...

     receptors (different receptors than for amylin
    Amylin
    Amylin, or Islet Amyloid Polypeptide , is a 37-residue peptide hormone secreted by pancreatic β-cells at the same time as insulin .-Clinical significance:...

    ). 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 and more recently in man.


In an open-label
Open-label trial
An open-label trial or open trial is a type of clinical trial in which both the researchers and participants know which treatment is being administered....

, randomized, controlled trial of 551 patients, 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 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.

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
Metformin
Metformin is an oral antidiabetic drug in the biguanide class. It is the first-line drug of choice for the treatment of type 2 diabetes, in particular, in overweight and obese people and those with normal kidney function. Its use in gestational diabetes has been limited by safety concerns...

 and acarbose
Acarbose
Acarbose is an anti-diabetic drug used to treat type 2 diabetes mellitus and, in some countries, prediabetes. It is a generic sold in Europe and China as Glucobay , in North America as Precose , and in Canada as Prandase...

, 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

  • As an adjunctive therapy, exenatide is indicated to improve glycemic control in patients with type 2 diabetes who are taking metformin
    Metformin
    Metformin is an oral antidiabetic drug in the biguanide class. It is the first-line drug of choice for the treatment of type 2 diabetes, in particular, in overweight and obese people and those with normal kidney function. Its use in gestational diabetes has been limited by safety concerns...

    , 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, meglitinide
    Meglitinide
    Meglitinides, aka "Glinides", are a class of drugs used treat diabetes type 2.They bind to an ATP-dependent K+ channel on the cell membrane of pancreatic beta cells in a similar manner to sulfonylureas but at a separate binding site. This inhibits a tonic, hyperpolarizing outflux of potassium,...

    s, and alpha-glucosidase inhibitor
    Alpha-glucosidase inhibitor
    Alpha-glucosidase inhibitors are oral anti-diabetic drugs used for diabetes mellitus type 2 that work by preventing the digestion of carbohydrates . Carbohydrates are normally converted into simple sugars , which can be absorbed through the intestine...

    s has not been studied.
  • Some physicians are using exenatide as primary monotherapy, an indication approved by the FDA October 30, 2009 as announced by Eli Lilly and Co.


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 effect
Adverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...

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. Drug interactions listed on the package insert include delayed or reduced concentrations of lovastatin
Lovastatin
Lovastatin is a member of the drug class of statins, used for lowering cholesterol in those with hypercholesterolemia and so preventing cardiovascular disease...

, paracetamol
Paracetamol
Paracetamol INN , or acetaminophen USAN , is a widely used over-the-counter analgesic and antipyretic . It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies...

 (acetaminophen), and digoxin
Digoxin
Digoxin INN , also known as digitalis, is a purified cardiac glycoside and extracted from the foxglove plant, Digitalis lanata. Its corresponding aglycone is digoxigenin, and its acetyl derivative is acetyldigoxin...

, although this has not been proven to alter the effectiveness of these other medications.

In response to postmarketing reports of acute pancreatitis
Acute pancreatitis
Acute pancreatitis or acute pancreatic necrosis is a sudden inflammation of the pancreas. It can have severe complications and high mortality despite treatment...

 in patients using exenatide, the FDA added a warning to the labeling of Byetta in 2007. In August 2008, four additional deaths from pancreatitis
Pancreatitis
Pancreatitis is inflammation of the pancreas. It occurs when pancreatic enzymes that digest food are activated in the pancreas instead of the small intestine. It may be acute – beginning suddenly and lasting a few days, or chronic – occurring over many years...

 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.

It also may increase risk of sulfonylurea-induced hypoglycemia
Hypoglycemia
Hypoglycemia or hypoglycæmia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood"...

.

Additionally, the FDA has raised concerns over exenatide raising thyroid cancer
Thyroid cancer
Thyroid neoplasm is a neoplasm or tumor of the thyroid. It can be a benign tumor such as thyroid adenoma, or it can be a malignant neoplasm , such as papillary, follicular, medullary or anaplastic thyroid cancer. Most patients are 25 to 65 years of age when first diagnosed; women are more affected...

 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
Black box warning
In the United States, a black box warning is a type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects...

, the agency’s strictest caution on pharmaceuticals. 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.

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. His attorney stated "the label change in 2007 was not adequate".

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 trade name 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.

The phase III study DURATION-1 published in 2008 showed the once weekly formulation resulted in a greater HbA1c decline and more patients reaching HbA1c targets compared to twice-daily Byetta.

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).

In October 18, 2011 National Institute for Health and Clinical Excellence
National Institute for Health and Clinical Excellence
The National Institute for Health and Clinical Excellence is a special health authority of the English National Health Service , serving both English NHS and the Welsh NHS...

 (NHS) has published preliminary recommendations for using Bydureon injection weekly. The recommendations came in triple therapy regimens (in combination with metformin and a sulphonylurea, or metformin and a thiazolidinedione) and dual therapy regimens (in combination with metformin or a sulphonylurea).

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.

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

See also

  • Glucagon-like peptide-1 analog
    Glucagon-like peptide-1 analog
    Glucagon-like peptide-1 analogs are a new class of drug for treatment of type 2 diabetes.One of their advantages is that they have a lower risk of causing hypoglycemia.Licenced : exenatide , liraglutide...

    s
    • Liraglutide
      Liraglutide
      Liraglutide , marketed under the brand name Victoza, is a long-acting glucagon-like peptide-1 analog that has been developed by Novo Nordisk for the treatment of type 2 diabetes. The product was approved by the European Medicines Agency on July 3, 2009, and by the U.S...

       (Victoza)
    • Albiglutide
      Albiglutide
      Albiglutide is a GLP-1 analog drug under investigation by GlaxoSmithKline for treatment of type 2 diabetes.It is a dipeptidyl peptidase-4-resistant glucagon-like peptide-1 dimer fused to human albumin....

    • Taspoglutide
      Taspoglutide
      Taspoglutide is a pharmaceutical drug. It is a glucagon-like peptide-1 analog, under investigation for treatment of type 2 diabetes being codeveloped by Ipsen and Roche.Two phase II trials reported it was effective and well tolerated....

  • DPP4 inhibitors
  • Incretin
    Incretin
    Incretins are a group of gastrointestinal hormones that cause an increase in the amount of insulin released from the beta cells of the islets of Langerhans after eating, even before blood glucose levels become elevated. They also slow the rate of absorption of nutrients into the blood stream by...


External links

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