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

Abstract

OBJECTIVE -This study evaluated the ability of the incretin mimetic exenatide (exendin-4) to improve glycemic control in patients with type 2 diabetes failing maximally effective doses of a sulfonylurea as monotherapy. RESEARCH DESIGN AND METHODS-This was a triple-blind, placebo-controlled, 30-week study conducted at 101 sites in the U.S. After a 4-week, single-blind, placebo lead-in period, 377 subjects were randomized (60% men, age 55 Ϯ 11 years, BMI 33 Ϯ 6 kg/m 2 , HbA 1c 8.6 Ϯ 1.2% [ϮSD]) and began 4 weeks at 5 g subcutaneous exenatide twice daily (before breakfast and dinner; arms A and B) or placebo. Subsequently, subjects in arm B were escalated to 10 g b.i.d. exenatide. All subjects continued sulfonylurea therapy.RESULTS -At week 30, HbA 1c changes from baseline were Ϫ0.86 Ϯ 0.11, Ϫ0.46 Ϯ 0.12, and 0.12 Ϯ 0.09% (ϮSE) in the 10-g, 5-g, and placebo arms, respectively (adjusted P Ͻ 0.001). Of evaluable subjects with baseline HbA 1c Ͼ 7% (n ϭ 237), 41% (10 g), 33% (5 g), and 9% (placebo) achieved HbA 1c Յ 7% (P Ͻ 0.001). Fasting plasma glucose concentrations decreased in the 10-g arm compared with placebo (P Ͻ 0.05). Subjects in the exenatide arms had dose-dependent progressive weight loss, with an end-of-study loss in the 10-g exenatide arm of Ϫ1.6 Ϯ 0.3 kg from baseline (P Ͻ 0.05 vs. placebo). The most frequent adverse events were generally mild or moderate and gastrointestinal in nature. No severe hypoglycemia was observed.CONCLUSIONS -Exenatide significantly reduced HbA 1c in patients with type 2 diabetes failing maximally effective doses of a sulfonylurea. Exenatide was generally well tolerated and was associated with weight loss.

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

“…In the clinic, a small percentage of exenatide-treated patients (placebo-corrected) experience emesis (9%), consistent with our current findings in the kaolin model in rats, whereas a greater proportion report nausea (38%). 10 Both events are mild to moderate in nature, and decrease with continued treatment. The finding that weight loss in exenatide-treated patients (10 mg, twice daily) continues for at least 82 weeks in the absence of continued nausea 42 points to a satiety-related mechanism of exenatide contributing to reduction of body Exenatide reduces body weight in high-fat-fed rats CM Mack et al weight, and not through pathways mediating aversive states.…”

“…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.…”

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.…”

The therapeutic actions of DPP-IV inhibition are not mediated by glucagon-like peptide-1

“…In clinical studies, incretin mimetics such as exenatide [20] and liraglutide [21] invariably cause nausea and vomiting in a proportion of patients. This adverse effect is less marked with GLP-1 [1], but the absence of such side effects in studies with DPP-IV inhibitors can be interpreted as evidence against the presence of high ('therapeutic') levels of endogenously secreted intact GLP-1.…”