Exenatide
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Exenatide (also Exendin-4, marketed as Byetta) is the first of a new class of medications approved for the treatment of type 2 diabetes. It is manufactured and marketed by Amylin Pharmaceuticals, Inc. and Eli Lilly and Company.
It is an incretin mimetic, which has glucoregulatory effects. While it is useful alone, it can also be combined with other medications such as pioglitazone, metformin, sulfonylureas, and/or insulin to improve glucose control. The medication is injected twice per day using a specially designed pen. Typical human responses to exenatide plus eating include improvements in the initial rapid release of internal insulin, suppression of glucagon release by the pancreas, and reduced appetite; all behaviors more typical of individuals without blood sugar control problems. The response to exenatide is further augmented when the blood sugar is more elevated yet there are negligible problems with glucose levels going too low, as with the sulfonylureas or insulins.
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[edit] Development history
The incretins hormones GLP-1 (glucagon-like peptide-1) and 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 GIP is ineffective. 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 thus was tested for it ability to stimulate insulin secretion and lower blood glucose in mammals and was found to be effective in the diabetic state. It has a longer half-life in vivo. 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. This discovery lead to source from which to test the protein as a GLP-1 alternative. 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 very desirable glucagon and appetite suppressant effects.
It received US Patent 5,424,286 which was filed May 24, 1993.
It received FDA approval in the US in April 2005 and is currently marketed as Byetta. Exenatide is approved "as adjunctive therapy to improve glycemic control in patients with type 2 diabetes mellitus who are taking metformin, a sulfonylurea, or a combination of metformin and a sulfonylurea but have not achieved adequate glycemic control". It has not been approved for use with thiazolidinediones such as pioglitazone.
Patent extension per 35 USC 156 requested on June 25, 2005 by Amylin Pharmaceuticals on behalf of John Eng.
Trademark - August 30, 2005.
[edit] Mode of action
Exenatide works to help improve glucose control in at least four ways:
- Exenatide augments pancreas response to release a higher, more appropriate amount of insulin in response to eating meals; this helps lower the rise in blood sugar rise from eating to more normal, flatter response levels. If blood sugar levels get closer to normal, the pancreas response to produce insulin is reduced. Other drugs (like injectable insulin itself) 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.
- 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).
- Exenatide helps slow down gastric emptying (the rate at which sugar enters the bloodstream) which also helps avoid hyperglycemia.
- Exenatide has a subtle yet prolonged effect to reduce appetite, overeating and weight gain. Most people using Exenatide slowly lose weight. Clinical trials have demonstated 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. Generally, the greatest weight loss is achived by people who are the most overweight at the beginning of exenatide therapy.
- 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 and more recently in man.
In an open-label 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 Byetta have stated that much of what is reported as nausea is actually a feeling of fullness. Byetta makes most patients need to eat less and until an adjustment is made to smaller portions, the result is the fullness feeling.
While other treatment options share one or more of the first three characteristics, many diabetics specialists view exenatide as a significant improvement over other available diabetic medications. In addition to its strong safety profile, the improved weight control is important for diabetes treatment; except for metformin, all other available drugs for improving glucose control have been associated with weight gain. In addition to gastrointestinal adverse reactions, a relative disadvantage of exenatide is that it is administered by injection.
[edit] Long-acting-release formulation
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 injectible form, with a similar safety, lower nausea rates and greater weight loss profile.
[edit] References
- ↑ Heine RJ, Van Gaal LF, Johns D, Mihm MJ, Widel MH, Brodows RG; GWAA Study Group. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med. 2005 Oct 18;143(8):559-69. PMID: 16230722
