Byetta (exenatide), derived from a compound found in the saliva of the Gila monster, a large lizard native to the southwestern US, is a functional analog of Glucagon-Like Peptide-1 (GLP-1), a naturally occuring peptide which enhances insulin secretion in response to elevated plasma glucose levels. By mimicking the function of GLP-1, the drug helps more strongly activate this pathway to improve glycemic control.

Byetta is specifically indicated as adjunctive therapy to improve glycemic control in patients with Type 2 diabetes mellitus who are taking metformin, a sulfonylurea, or a combination of both, but have not achieved adequate glycemic control.

Byetta is supplied as as a sterile solution for subcutaneous injection. The recommended initial dose is 5 mcg twice daily, anytime within the 60 minute period prior to the monring and evening meal. This dose may be escalated to 10 mcg twice daily after 1 month, based on response

FDA Approval
Approval of Byetta was based on 3 double-blind, placebo-controlled safety and efficacy clinical trials, which enrolled a combined 1446 subjects with type 2 diabetes. Each trial combined the two now-approved doses of Byetta or placebo with existing therapy: with metformin in one trial (336 total subjects), with sulfonylurea in the second trial (377 total subjects), and with both drugs in the third (733 total subjects). The primary endpoint in all 3 trials was change from baseline in HbA1c levels at 30 weeks, a measure of long term glycemic control. Secondary efficacy endpoints were the proportion of subjects achiving HbA1c levels at or below 7% (a level considered "normal") at week 30, and mean change in body weight at week 30. The addition of Byetta was seen to reduce mean HbA1c levels in combination with metformin (+0.1% for placebo vs. -0.4% at 5 mcg, p<0.05; -0.8% at 10 mcg, p<0.0001), sulfonylurea (+0.1% vs. -0.5%, p<0.05; -0.9%, p<0.0001), and both drugs (+0.2%, vs. -0.6%, p<0.0001; -0.8%, p<0.0001). The mean proportion of subjects achiving HbA1c levels at or below 7% was significant for all Byetta groups in all 3 trials, and subjects receiving Byetta achieved significantly greater weight loss in all trial groups except the 5 mcg dose group in combination with sulfonylurea, which trended towards improvement. These results indicated that Byetta in combination metformin, sulfonylurea or both produced superior recudtions in fasting and post-prandial plasma glucose levels, brought a greater portion of subjects into normal glucose ranges, and produced greater reductions in mean body weight than either or both drugs alone.

Ongoing Study Commitments

• Deferred pediatric study under PREA for the treatment of type 2 diabetes in adolescents ages 12 through 16 years, who have not achieved adequate glycemic control on metformin, a sulfonylurea, or a combination of metformin and a sulfonylurea, to evaluate the pharmacokinetics and relevant pharmacodynamic effects of different subcutaneous doses of the drug.
  Protocol submission due: July 29, 2005
  Study start: January 31, 2006
  Final report submission due: December 31, 2007
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• Human in vivo drug interaction study between exenatide and a combination oral contraceptive (e.g., ethinyl estradiol plus norethindrone) to define the effect of timing of the exenatide injection relative to the administration of the oral contraceptive on the bioavailability of the components of the oral contraceptive.
  Protocol submission due: July 29, 2005
  Study start: January 31, 2006
  Final report submission due: January 31, 2007

Adverse events associated with the use of Byetta may include, but are not limited to, the following:

• Nausea
• Vomiting
• Diarrhea
• Jittery sensation
• Dizziness
• Headache
• Dyspepsia

In addition, instances of hypoglycemia occurred in all 3 pivotal trials. These events occurred roughly as often as with placebo in combination with metformin, but occurred more often than placebo when Byetta was co-administered with either sulfonylurea alone or the metformin/sulfonylurea combination. Most episodes of hypoglycemia were mild-to-moderate, and resolvable with carbohydrate supplementation.

Byetta is a functional analog of the human incretin Glucagon-Like Peptide-1 (GLP-1) . Incretins enhance glucose-dependent insulin secretion and exhibit other antihyperglycemic actions following their release into the circulation from the gut. The GLP-1 system increases insulin secretion only in the presence of elevated plasma glucose levels, avoiding inappropriately high insulin levels during fasting. The drug also moderates peak serum glucagon levels during hyperglycemic periods following meals, but does not interfere with glucagon release in response to hypoglycemia. Secondary effects of drug administration reduces the rate of gastric emptying and decreases food intake, mitigating the potential severity of hyperglycemic events after meals.

Defronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 2005 May;28(5):1092-100.

Calara F, Taylor K, Han J, Zabala E, Carr EM, Wintle M, Fineman M. A randomized, open-label, crossover study examining the effect of injection site on bioavailability of exenatide (synthetic exendin-4). Clinical Therapeutics 2005 Feb;27(2):210-5.

Nauck MA, Meier JJ. Glucagon-like peptide 1 and its derivatives in the treatment of diabetes. Regulatory Peptides 2005 Jun 15;128(2):135-48.

Gedulin BR, Nikoulina SE, Smith PA, Gedulin G, Nielsen LL, Baron AD, Parkes DG, Young AA. Exenatide (exendin-4) improves insulin sensitivity and {beta}-cell mass in insulin-resistant obese fa/fa Zucker rats independent of glycemia and body weight. Endocrinology 2005 Apr;146(4):2069-76.

For additional information regarding Byetta or Type 2 diabetes mellitus, please visit the Byetta web page.