Effects of Exenatide (Exendin-4) on Glycemic Control Over 30 Weeks in Patients With Type 2 Diabetes Treated With Metformin and a Sulfonylurea

Abstract

OBJECTIVE -This study evaluated the effects of exenatide, a novel incretin mimetic, in hyperglycemic patients with type 2 diabetes unable to achieve glycemic control with metforminsulfonylurea combination therapy. RESULTS -Week 30 A1C changes from baseline (ϮSE) were Ϫ0.8 Ϯ 0.1% (10 g), Ϫ0.6 Ϯ 0.1% (5 g), and ϩ0.2 Ϯ 0.1% (placebo; adjusted P Ͻ 0.0001 vs. placebo), yielding placeboadjusted reductions of Ϫ1.0% (10 g) and Ϫ0.8% (5 g). In the evaluable population, exenatide-treated subjects were more likely to achieve A1C Յ7% than placebo-treated subjects (34% [10 g], 27% [5 g], and 9% [placebo]; P Ͻ 0.0001). Both exenatide arms demonstrated significant weight loss (Ϫ1.6 Ϯ 0.2 kg from baseline each exenatide arm, Ϫ0.9 Ϯ 0.2 kg placebo; P Յ 0.01 vs. placebo). Mild or moderate nausea was the most frequent adverse event. The incidence of mild/moderate hypoglycemia was 28% (10 g), 19% (5 g), and 13% (placebo) and appeared lower with MIN than with MAX sulfonylurea treatment. RESEARCH DESIGN AND METHODSCONCLUSIONS -Exenatide significantly reduced A1C in patients with type 2 diabetes unable to achieve adequate glycemic control with maximally effective doses of combined metformin-sulfonylurea therapy. This improvement in glycemic control was associated with no weight gain and was generally well tolerated.

Medical management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy

“…Synthetic exendin-4 (exenatide) was approved for use in the USA in 2005 and is administered twice per day by subcutaneous injection. Although there are less published data on this new compound than the other blood glucose-lowering medications, exendin-4 appears to lower HbA 1c levels by 0.5-1 percentage points, mainly by lowering postprandial blood glucose levels [78][79][80][81]. Exenatide also suppresses glucagon secretion and slows gastric motility.…”

“…Exenatide also suppresses glucagon secretion and slows gastric motility. It is not associated with hypoglycaemia, but causes a relatively high frequency of gastrointestinal disturbances, with 30-45% of treated patients experiencing one or more episodes of nausea, vomiting or diarrhoea [78][79][80][81]. These side effects tend to abate over time.…”

Glucagon-like peptide-1: from extract to agent. The Claude Bernard Lecture, 2005

“…This apart, exenatide seems to share all of the effects of native GLP-1 [58]. The compound has been tested in several clinical trials, most recently in three controlled pivotal phase III studies involving 1,494 patients, in whom exenatide was given for 30 weeks as an add-on therapy to type 2 diabetic patients inadequately treated with sulfonylureas [68], metformin [69] or a combination of metformin and sulfonylureas [70]. After 30 weeks of treatment, fasting blood glucose concentrations fell, HbA 1 c levels were reduced by approximately 0.8% overall and to or below 7% in 41, 46 and 34% of the patients in the three groups.…”

Antiobesity action of peripheral exenatide (exendin-4) in rodents: effects on food intake, body weight, metabolic status and side-effect measures

“…6 Agents that activate the GLP-1 receptor possess high therapeutic potential for the treatment of diabetes; [7][8][9] exenatide is a currently marketed antidiabetic agent that is shown to improve glycemic control in patients with type 2 diabetes. [10][11][12] Glucose-lowering with exenatide, GLP-1 and GLP-1 analogs has been associated with several mechanisms of action, the first of which to be identified was an enhancement of glucose-dependent insulin secretion. 13,14 The principal result of this insulinotropic effect is an acceleration of glucose disappearance into peripheral tissues.…”

“…6,18,[26][27][28] Recent data from clinical trials have also revealed sustainable weight loss in exenatide-treated type 2 diabetic subjects. [10][11][12] In preclinical models, body weight reductions with systemic exenatide treatment have been demonstrated in leptinreceptor-deficient rodents under low-fat dietary conditions, 6,18,27,28 and most report single-dose effects. One can readily postulate that polygenic models of obesity that mimic human consumption patterns may return a more physiologic picture of potential clinical utility.…”