By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Asst. Clinical Professor of Medicine, University of California, San Francisco; Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Chan and Elliott report no financial relationships to this field of study.
The first of a new class of antidiabetic drugs has been approved for the treatment of type 2 diabetes mellitus. Exenatide is a polypeptide amide that mimics the action of the incretin hormone glucagon-like peptide (GLP)-1. It is manufactured by Amylin Pharmaceuticals, Inc and co-marketed by Amylin and Eli Lilly and Company as “Byetta™”.
Indications
Exenatide is indicated as adjunctive therapy in type 2 diabetics who have not achieved adequate glycemic control while taking metformin, a sulfonylurea, or a combination of the two.1
Dosage
The initial recommended dose is 5 mg administered subcutaneously twice daily at any time within 60 minutes before the morning or evening meal. If the response is not adequate after one month of therapy, the dose may be increased to 10 mg twice daily. The recommended sites of injection are thigh, abdomen, or upper arm. If exenatide is added to a sulfonylurea, dose reduction should be considered to reduce the risk of hypoglycemia. Metformin dose reduction is not generally required.1
Exenatide is available as 5 mg and 10 mg per dose prefilled pens.
Potential Advantages
Exenatide provides a drug with a different mechanism of action than existing drugs. It provides improved glycemic control in type 2 diabetics being treated with metformin, sulfonylurea, or a metformin-sulfonylurea combination.1-4 Exenatide also produces weight loss.
Potential Disadvantages
The most common adverse events associated with exenatide were gastrointestinal. Nausea is the most frequent, and is generally mild or moderate in severity, occurring during the initial weeks of therapy, and is dose dependent.2,3 Exenatide must be administered by injection. It is currently not recommended for use in type 1 diabetes and is not a substitute for insulin in type 2 diabetes requiring insulin.1
Comments
GLP-1 is a naturally occurring incretin hormone released in the gastrointestinal tract in response to nutrient stimulus. It is rapidly inactivated by dipeptidyl peptidase-4 in the plasma.5 Exenatide effectively binds to the GLP-1 receptor but is resistant to degradation by dipeptidyl peptidase-4. It was first isolated from the salivary secretion of the Gila monster. The current preparation is synthetic 39-amino acid peptide with a 53% amino acid sequence overlap with mammalian pancreatic GLP-1. The drug’s action includes glucose-dependent stimulation of insulin secretion, suppression of glucagon secretion, enhancement of beta cell mass, slowing of gastric emptying, and inhibition of food intake.6,7 Results from 30-week studies showed a 0.4% to 0.6% reduction in HbA1c and 0.8% to 0.9% reduction in HbA1c when exenatide 5 mg twice daily and 10 mg twice daily, respectively, were added to patients on sulfonylurea, metformin or the combination of the 2 compared to a 0.1% to 0.2% increase with placebo.1-3 The baseline HbA1c of these patients ranged from 8.2% to 8.7%. Patients with higher baseline HbA1c had greater reductions. Reduction of 0.58% and 1.22% were reported in patients with a baseline HbA1c 9%. Weight loss up to 2.8 kg in body weight has also been reported and larger loss tended to be associated with patients with a greater baseline BMI (> 30).1,2 Exenatide appears to be generally well tolerated. The most common side effect is nausea (44% vs 18% for placebo), vomiting (13% vs 4%), diarrhea (13% vs 6%), feeling jittery (9% vs 4%), and dyspepsia 6% vs 3%).1 Adverse event related withdrawal from clinical studies were 7% for exenatide vs 3% for placebo.
Antiexenatide antibodies have been reported with a frequency of 43%. However the titers tend to be low and the clinical significance not clear.2 The wholesale cost of exenatide is $147 for a 30-day supply of 5 mg twice daily and $172.50 for 10 mg twice daily.
Clinical Implications
Exanetide provides a new therapeutic agent with the ability to stimulate insulin secretion in response to rising blood glucose. In addition, it slows gastric emptying thus slowing the absorption of glucose. The major disadvantage is that the drug must be given by injection. Its effectiveness has been demonstrated only in type 2 diabetics on a sulfonylurea, metformin, or the combination. GLP-1 agonist analogs are being studied in combination with insulin in type 1 diabetics.8 Amylin is currently working on a longer-acting preparation.9
References
1. Byetta Product Information. Amylin Pharmaceuticals, Inc. April 2005.
2. Kendall DM, et al. Effects of exenatide on glycemic control in patients with DM2 treated with metformin and a sulfonylurea. Diabetes Care. 2005;28:1083-1091.
3. Buse JB et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care. 2004;27:2628-2635.
4. Fineman MS, et al. Effect on glycemic control of exenatide (synthetic exendin-4) additive to existing metformin and/or sulfonylurea treatment in patients with type 2 diabetes. Diabetes Care. 2003;26:2370-2377.
5. Kieffer TJ, et al. Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV. Endocrinology. 1995;136:3585-3596.
6. Nielsen LL et al. Pharmacology of exenatide. Regul Pept. 2004;117:77-88.
7. Chen YE, Drucker DJ. Tissue-specific expression of unique mRNAs that encode proglucagon-derived peptides. J Biol Chem. 1997;272:4108-4115.
8. Dupre J. Glycaemic effects of incretins in Type 1 diabetes mellitus. Regul Pept. 2005;128:149-157.
9. Anonymous. Exenatide. Drugs R D. 2004;5(1):35-40.
The first of a new class of antidiabetic drugs has been approved for the treatment of type 2 diabetes mellitus.
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