Exenatide

Exenatide is a relatively new drug for treating type 2 diabetes. It is made and marketed by Amylin Pharmaceuticals and Eli Lilly and Company as Byetta. Exenatide is the first in a class of medicines that exploits the physiology of the incretin hormones, which are normally released from the intestines after a meal. More specifically, exenatide behaves like a long-acting version of the incretin hormone glucagon-like peptide 1 (GLP-1)—that is, it acts as a long-acting GLP-1 agonist. Byetta is used to improve blood sugar control in conjunction with metformin (Glucophage), a sulfonylurea, or a thiazolidinedione. The Food and Drug Administration (FDA) approved exenatide on April 29, 2005. The structure of exenatide is related to a substance found in Gila monster venom (exendin-4). Weight loss is a notable side effect of the drug.

Gila monster Heloderma suspectum photo courtesy of US Fish and Wildlife Service

Uses

Exenatide is used to improve blood sugar levels in type 2 diabetic patients. Unlike sulfonylureas and meglitinides, exenatide increases insulin synthesis and secretion in the presence of glucose only, lessening the risk of hypoglycemia. Exenatide is also being used by some physicians to treat insulin resistance. Sustained weight loss has been noted in clinical trials, but this is not an approved indication for the drug.

How Exenatide Is Taken

Exenatide is injected subcutaneously (under the skin) twice a day using a pre-filled pen device. Each pen has 60 doses to provide 30 days of injections. Injections can be made in the upper leg, stomach area, or upper arm any time within one hour of morning and evening meals.

How Exenatide Works

Understanding the mechanism of exenatide requires a brief discussion of the incretin hormones, the multiple actions of GLP-1, and the differences between exenatide and GLP-1.

The incretin effect

If glucose is injected into a vein, blood glucose immediately rises, and the pancreas responds by releasing insulin. If the same amount of glucose is swallowed, however, the pancreas releases more insulin, and the blood glucose rises to a lesser extent. The increased insulin seen in response to oral carbohydrates is known as the incretin effect, and the hormones responsible are known as the incretin hormones. Glucose dependent insulinotropic polypeptide (GIP) was identified as an incretin hormone in 1970, and GLP-1 and its truncated form GLP-1(7-36) were recognized as incretins in 1985. Multiple antidiabetic qualities of GLP-1(7-36) and its analogues and mimetics have been demonstrated, and there is continuing interest in pharmacologically manipulating the incretin effect for therapeutic benefit^[1].

The many roles of GLP-1

Like other hormones, GLP-1 has effects on several organ systems. In general, the effects of this hormone tend to favor efficient use of ingested nutrients and tend to lower blood glucose levels.

• increased insulin secretion in response to glucose
• reduction in glucagon release by the pancreas
• increased beta-cell mass
• inhibition (delay) of gastric emptying
• inhibition of postprandial (after meals) acid secretion
• increased small intestine transit time
• improved fat insulin sensitivity and glucose uptake
• decreased feeding behavior; reduced appetite

Exenatide Compared to GLP-1

GLP-1 is metabolized extremely rapidly by the ubiquitous enzyme DPP IV, which cuts GLP-1 near one of its ends. The two resulting fragments are inactive. The amino acid sequence near the cleavage site of GLP-1 is different in exenatide, making exenatide much more resistant to cleavage by DPP IV.

How the Body Affects Exenatide

Exenatide is largely excreted from the body in the urine. Its half-life, the time needed for the concentration in the blood to be reduced by half, is approximately 2.4 hours. Exenatide is not metabolized to a significant extent in the liver.

In specific populations

Severe kidney impairment reduces excretion of exenatide by over 80% of that seen in healthy people. But, because exenatide is not metabolized in the liver, liver impairment is not expected to have an impact on the elimination of the drug. Race, weight, age, and gender do not affect either the absorption or elimination of exenatide.

Side Effects

The most common side effect associated with exenatide treatment is nausea, which is usually mild to moderate, and affects approximately half of patients. The severity usually decreases with time. Other side effects include the following:

• vomiting
• diarrhea
• headaches
• agitation
• an acidic stomach

Risks and Precautions

• Some people produce antibodies to exenatide and develop hypersensitivity and allergic reactions.

• Exenatide is not used in people with severe kidney impairment or severe gastrointestinal disease

• Pancreatitis has been reported in some patients taking exenatide. The principal symptom of pancreatitis is severe abdominal pain sometimes accompanied by vomiting.

Drug Interactions

When used with a sulfonylurea, exenatide can worsen episodes of low blood sugar (hypoglycemia); the dose of the sulfonylurea-containing medicine may need to be reduced while using exenatide.

Several drug interactions have been reported with exenatide but none have had significant clinical consequences:

• digoxin (Lanoxin)– Exenatide has been shown to delay the absorption of digoxin but not affect digoxin concentrations in the blood. The interaction is unlikely to be significant.
• lovastatin (Mevacor, Altocor)– Exenatide can reduce the blood concentrations of lovastatin. However, exenatide did not influence the effectiveness (control of cholesterol) of other statins when the drugs were used in combination in clinical trials.
• lisinopril (Zestril, Prinivilc)– Exenatide has been shown to delay the absorption of Lisinopril in patients with mild to moderate high blood pressure, but the effectiveness of the latter drug was not changed in this interaction.
• warfarin– The effectiveness of warfarin, the ability of the drug to thin the blood, is not affected by exenatide in healthy people, even though exenatide does slow the absorption of warfarin.

Discovery

Exenatide is based on bioactive peptide hormones in the venom of the Gila monster Heloderma suspectum, a lizard found in the southwestern US and northern Mexico. The presence of bioactive components of the venom was known by indigenous people, who would (on special occasions) subject themselves to bites by the lizard and experience profound low blood pressure. Scientists studying the lizard suspected that something in the venom, possibly analogous to vasoactive intestinal peptide (VIP), would be found in the venom. As part of the search for VIP in the venom, scientists isolated exendin-4, which proved to share all of the activities of GLP-1 but have vastly increased stability.

Alternatives

Amylin and Eli Lilly, in collaboration with Alkermes, are actively developing a once-weekly formulation of Byetta, which may offer improved convenience to patients once it becomes available. In addition, there are other drugs on the horizon that exploit the beneficial effects of the incretin hormones by mimicking GLP-1 or by inhibiting the enzyme that degrades GLP-1, thus prolonging GLP-1's beneficial effects.

Liraglutide

Liraglutide is a once-daily GLP-1 analogue that will compete directly with exenatide. Novo Nordisk hopes to win FDA approval for this drug in 2009 based on clinical trials that showed a statistically significant benefit in lowering blood glucose levels. Liraglutide was also associated with weight loss.

Dipeptidyl Peptidase IV Inhibitors

GLP-1 is inactivated by the proteolytic enzyme dipeptidyl peptidase IV (DPP-IV). This observation prompted the search for small molecules that would inhibit the enzyme and prolong the activity (and beneficial effects) of native GLP-1. Vildagliptin (to be marketed as Galvus by Novartis Pharmaceuticals) and sitagliptin (marketed in the US as Januvia by Merck & Co.) are specific inhibitors of DPP-IV that are used in type 2 diabetes.

Clinical Trials

Clinical trials involving exenatide, are listed here

Cardiovascular

A study of patients taking exenatide for at least three years demonstrated improvements in blood pressure, triglycerides, total cholesterol, low-density lipoprotein (LDL)-C, and high-density lipoprotein (HDL)-C. The expected outcomes of improved blood glucose control (as evidenced by decreases in hemoglobin A1C) and weigh loss were also observed.^[2]

Weight Loss

The weight loss effects of the long-acting release form of exenatide were examined in a 15-week clinical trial. The drug was given subcutaneously once weekly to 45 patients with type 2 diabetes. Subjects receiving 2.0 mg exenatide had body weight reductions averaging 3.8 kg(8.4 lb) whereas body weight was unchanged with both placebo and the 0.8-mg dose.^[3]

Free Full-Text Articles

Bloomgarden ZT. Gut-derived incretin hormones and new therapeutic approaches. Diabetes Care. 2004 Oct;27(10):2554-9. Abstract | Full Text | PDF

Gleeson JM, Berenbeim DM, Gilkin RJ. Incretin mimetics: promising new therapeutic options in the treatment of type 2 diabetes. J Manag Care Pharm. 2005 Sep;11(7 Suppl):S2-13. Abstract |PDF

Holst JJ, Orskov C. The incretin approach for diabetes treatment: modulation of islet hormone release by GLP-1 agonism. Diabetes. 2004 Dec;53 Suppl 3:S197-204. Abstract |Full Text | PDF

MacDonald PE, El-Kholy W, Riedel MJ, Salapatek AM, Light PE, Wheeler MB. The multiple actions of GLP-1 on the process of glucose-stimulated insulin secretion. Diabetes. 2002 Dec;51 Suppl 3:S434-42. Abstract | Full Text | PDF

Schnabel CA, Wintle M, Kolterman O. Metabolic effects of the incretin mimetic exenatide in the treatment of type 2 diabetes. Vasc Health Risk Manag. 2006;2(1):69-77. Abstract | Full Text | PDF

Wajchenberg BL. beta-cell failure in diabetes and preservation by clinical treatment. Endocr Rev. 2007 Apr;28(2):187-218. Abstract |Full Text | PDF

References

1. ↑ Creutzfeldt W. The [pre-] history of the incretin concept. Regul Pept. 2005 Jun 15;128(2):87-91. Abstract
2. ↑ Klonoff DC et al., Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Curr Med Res Opin. 2008 Jan;24(1):275-86. Abstract
3. ↑ Kim D et al., Effects of once-weekly dosing of a long-acting release formulation of exenatide on glucose control and body weight in subjects with type 2 diabetes. Diabetes Care. 2007 Jun;30(6):1487-93. Abstract | Full Text | PDF