5.1 Pharmacodynamic properties

 Pharmacotherapeutic group: Drugs used in diabetes, other blood glucose lowering drugs, excl. Insulins. ATC code: A10BX04.

Mechanism of action

Exenatide is a glucagon-like peptide-1 (GLP-1) receptor agonist 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 GLP1 receptor in vitro, its mechanism of action mediated by cyclic AMP and/or other intracellular signalling pathways.

Exenatide increases, on a glucosedependent basis, the secretion of insulin from pancreatic beta cells. As blood glucose concentrations decrease, insulin secretion subsides. When exenatide was used in combination with metformin and/or a thiazolidinedione, no increase in the incidence of hypoglycaemia was observed over that of placebo in combination with metformin and/or a thiazolidinedione which may be due to this glucose-dependent insulinotropic mechanism (see section 4.4).

Exenatide suppresses glucagon secretion which is known to be inappropriately elevated in patients with 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 mealderived glucose appears in the circulation.

Administration of exenatide has been shown to reduce food intake, due to decreased appetite and increased satiety.

Pharmacodynamic effects

Exenatide improves glycaemic control through the sustained effects of lowering both postprandial and fasting glucose concentrations in patients with type 2 diabetes. Unlike native GLP-1, BYDUREON has a pharmacokinetic and pharmacodynamic profile in humans suitable for once weekly administration.

A pharmacodynamic study with exenatide demonstrated in patients with type 2 diabetes (n=13) a restoration of first phase insulin secretion and improved second phase insulin secretion in response to an intravenous bolus of glucose.

Clinical efficacy

The results of long term clinical studies of BYDUREON are presented below, these studies comprised 1628 subjects (804 treated with BYDUREON), 54 % men and 46 % women, 281 subjects (141 treated with BYDUREON) were  65 years of age.

Glycaemic control

In two studies BYDUREON 2 mg once weekly has been compared to exenatide twice daily 5 µg for 4 weeks followed by exenatide twice daily 10 µg. One study was of 24 weeks in duration (n= 252) and the other of 30 weeks (n= 295) followed by an open labelled extension where all patients were treated with BYDUREON 2 mg once weekly for a further 22 weeks (n= 243). In both studies, decreases in HbA1c were evident in both treatment groups as early as the first posttreatment HbA1c measurement (weeks 4 or 6).

BYDUREON resulted in a statistically significant reduction in HbA1c compared to patients receiving exenatide twice daily (Table 3).

A clinically relevant effect of BYDUREON and exenatide twice daily-treated subjects was observed on HbA1c, regardless of the background anti-diabetic therapy in both studies.

Clinically and statistically significantly more subjects on BYDUREON compared to exenatide twice daily patients achieved an HbA1c reduction of&nb