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Pharmacological Classification: Antidiabetic Agents

CONTENTS: Exenatide

ACTIONS: Pharmacology: Mechanism of Action: Exenatide is an incretin mimetic that exhibits several antihyperglycaemic actions of glucagon-like peptide-1 (GLP-1). The amino acid sequence of exenatide partially overlaps that of human GLP-1. Exenatide has been shown to bind to and activate the known human GLP-1 receptor in vitro, its mechanism of action mediated by cyclic AMP and/or other intracellular signaling pathways. Exenatide increases, on a glucose-dependent basis, the secretion of insulin from pancreatic P-cells. As blood glucose concentrations decrease, insulin secretion subsides. When exenatide was used in combination with metformin alone, no increase in the incidence of hypoglycaemia was observed over that of placebo in combination with metformin which may be due to this glucose-dependent insulinotropic mechanism. Exenatide suppresses glucagon secretion which is known to be inappropriately elevated in type 2 diabetes. Lower glucagon concentrations lead to decreased hepatic glucose output. However, exenatide does not impair the normal glucagon response and other hormone responses to hypoglycaemia.

Exenatide slows gastric emptying thereby reducing the rate at which meal-derived glucose appears in the circulation.

Pharmacodynamic Effects: Byetta improves glycaemic control through the immediate and sustained effects of lowering both postprandial and fasting glucose concentrations in patients with type 2 diabetes.

Clinical Efficacy: The clinical studies comprised 3945 subjects (2997 treated with exenatide), 56% men and 44% women, 319 subjects (230 treated with exenatide) were ≥ 70 years of age and 34 subjects (27 treated with exenatide) were ≥ 75 years of age.

Byetta reduced HbA_1c and body weight in patients treated for 30 weeks in 3 placebo-controlled studies, whether the Byetta was added to metformin, a sulfonylurea or a combination of both. These reductions in HbA_1c were generally observed at 12 weeks after initiation of treatment. The reduction in HbA_1c was sustained and the weight loss continued for at least 82 weeks in the subset of 10 mcg twice daily patients completing both the placebo-controlled studies and the uncontrolled study extensions (n=137).

In a placebo-controlled study of 16 weeks duration, Byetta (n=121) or placebo (n=112) was added to existing thiazolidinedione treatment, with or without metformin. Byetta (5 mcg twice daily for 4 weeks, followed by 10 mcg twice daily) resulted in statistically significant reductions from baseline HbA_1c compared to placebo (-0.8% versus +0.1%) as well as significant reductions in body weight (-1.5 versus -0.2 kg).

When Byetta was used in combination with a thiazolidinedione, the incidence of hypoglycaemia was similar to that of placebo in combination with a thiazolidinedione. The experience in patients >65 years and in patients with impaired renal function is limited.

In insulin-comparator studies, Byetta (5 mcg twice daily for 4 weeks, followed by 10 mcg twice daily) in combination with metformin and sulfonylurea significantly (statistically and clinically) improved glycaemic control, as measured by decrease in HbA_1c. This treatment effect was comparable to that of insulin glargine in a 26-week study (mean insulin dose 24.9 iu/day, range 4-95 iu/day, at the end of study) and biphasic insulin aspart in a 52-week study (mean insulin dose 24.4 iu/day, range 3-78 iu/day, at the end of study). Byetta lowered HbA_1c from 8.21 (n=228) and 8.6% (n=222) by 1.13 and 1.01% while insulin glargine lowered from 8.24 (n=227) by 1.1 % and biphasic insulin aspart from 8.67 (n=224) by 0.86%. Weight loss of 2.3 kg (2.6%) was achieved with Byetta in the 26-week study and a loss of 2.5 kg (2.7%) in a 52-week study whereas treatment with insulin was associated with weight gain. Treatment differences (Byetta minus comparator) were -4.1 kg in the 26-week study and -5.4 kg in the 52-week study. Seven-point self-monitored blood glucose profiles (before and after meals and at 3 am) demonstrated significantly reduced glucose values compared to insulin in the postprandial periods after Byetta injection. Premeal blood glucose concentrations were generally lower in patients taking insulin compared to Byetta. Mean daily blood glucose values were similar between Byetta and insulin. In these studies, the incidence of hypoglycaemia was similar for Byetta and insulin treatment.

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