OBJECTIVE -This study evaluates the ability of the incretin mimetic exenatide (exendin-4) to improve glycemic control in patients with type 2 diabetes failing to achieve glycemic control with maximally effective metformin doses. RESEARCH DESIGN AND METHODS-A triple-blind, placebo-controlled, 30-week study at 82 U.S. sites was performed with 336 randomized patients. In all, 272 patients completed the study. The intent-to-treat population baseline was 53 Ϯ 10 years with BMI of 34.2 Ϯ 5.9 kg/m 2 and HbA 1c of 8.2 Ϯ 1.1%. After 4 weeks of placebo, subjects self-administered 5 g exenatide or placebo subcutaneously twice daily for 4 weeks followed by 5 or 10 g exenatide, or placebo subcutaneously twice daily for 26 weeks. All subjects continued metformin therapy.RESULTS -At week 30, HbA 1c changes from baseline Ϯ SE for each group were Ϫ0.78 Ϯ 0.10% (10 g), Ϫ0.40 Ϯ 0.11% (5 g), and ϩ0.08 Ϯ 0.10% (placebo; intent to treat; adjusted P Ͻ 0.002). Of evaluable subjects, 46% (10 g), 32% (5 g), and 13% (placebo) achieved HbA 1c Յ7% (P Ͻ 0.01 vs. placebo). Exenatide-treated subjects displayed progressive dose-dependent weight loss (Ϫ2.8 Ϯ 0.5 kg [10 g], Ϫ1.6 Ϯ 0.4 kg [5 g]; P Ͻ 0.001 vs. placebo). The most frequent adverse events were gastrointestinal in nature and generally mild to moderate. Incidence of mild to moderate hypoglycemia was low and similar across treatment arms, with no severe hypoglycemia.CONCLUSIONS -Exenatide was generally well tolerated and reduced HbA 1c with no weight gain and no increased incidence of hypoglycemia in patients with type 2 diabetes failing to achieve glycemic control with metformin.

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.

Aim: Exenatide, an incretin mimetic for the adjunct treatment of type 2 diabetes (DM2), reduced A1C and weight in 30-week placebo-controlled trials. This analysis examined the effects of exenatide on glycaemic control and weight over an 82-week period in patients with DM2 unable to achieve adequate glycaemic control with sulphonylurea (SU) and/or metformin (MET). [À0.9 AE 0.1% (mean AE SE)] was sustained to week 82 (À1.1 AE 0.1%), with 48% of patients achieving A1C 7% at week 82. At week 30, exenatide reduced body weight (a secondary endpoint) from baseline (À2.1 AE 0.2 kg), with progressive reduction at week 82 (À4.4 AE 0.3 kg). Similar results were observed for the intent-to-treat population (n ¼ 551), with reductions in A1C and weight at week 82 of À0.8 AE 0.1% and À3.5 AE 0.2 kg respectively. The 82-week completer cohort showed statistically significant improvement in some cardiovascular risk factors. The most frequent adverse events were generally mild-to-moderate nausea and hypoglycaemia. Conclusion: In summary, 82 weeks of adjunctive exenatide treatment in patients with DM2 treated with SU and/or MET resulted in sustained reduction in A1C and progressive reduction in weight, as well as improvement in some cardiovascular risk factors.

All of the incretin-based therapies in the present meta-analysis were associated with significant reductions from baseline in HbA(1c) and FPG. Further direct comparative studies between the GLP-1RAs and the DPP-4 inhibitors and within the GLP-1RA class are justified.

This study assessed whether glucose-dependent insulin secretion and overall counterregulatory response are preserved during hypoglycemia in the presence of exenatide. Twelve healthy fasted volunteers were randomized in a triple-blind crossover study to receive either intravenous exenatide (0.066 pmol ⅐ kg ؊1 ⅐ min ؊1 ) or placebo during a 270-min stepwise hyperinsulinemichypoglycemic clamp (insulin infusion 0.8 mU ⅐ kg ؊1 ⅐ min ؊1 ). Plasma glucose was clamped sequentially at 5.0 (0 -120 min), 4.0 (120 -180 min), 3.2 (180 -240 min), and 2.7 mmol/l (240 -270 min). At 270 min, insulin infusion was terminated and plasma glucose increased to ϳ3.2 mmol/l. The time to achieve plasma glucose >4 mmol/l thereafter was recorded. Insulin secretory rates (ISRs) and counterregulatory hormones were measured throughout. Glucose profiles were superimposable between the exenatide and placebo arms. In the presence of euglycemic hyperinsulinemia, ISRs in the exenatide arm were ϳ3.5-fold higher than in the placebo arm (353 ؎ 29 vs. 100 ؎ 29 pmol/min [least-square means ؎ SE]). However, ISRs declined similarly and rapidly at all hypoglycemic steps (<4 mmol/l) in both groups. Glucagon was suppressed in the exenatide arm during euglycemia and higher than placebo during hypoglycemia. Plasma glucose recovery time was equivalent for both treatments. The areas under the concentration-time curve from 270 to 360 min for cortisol, epinephrine, norepinephrine, and growth hormone were similar between treatment arms. There were no differences in adverse events. In the presence of exenatide, there was a preserved, glucose-dependent insulin secretory response and counterregulatory response during hypoglycemia. Diabetes 53:2397-2403, 2004 T he pathogenesis of type 2 diabetes is characterized by peripheral insulin resistance and progressive failure of pancreatic ␤-cell function, ultimately resulting in deficient insulin secretion. Furthermore, an excessive glucagon secretion and an impaired incretin response to meals contribute to the metabolic derangement of the disease (1-4). Control of circulating glucose levels is rarely optimal, and many currently available therapies also have unfavorable side effects and restrictions, limiting the extent of their use (5-8). This emphasizes the need for novel antidiabetic agents.Glucagon-like peptide (GLP)-1 is an incretin hormone secreted from the intestinal mucosa in response to meal ingestion. Physiological GLP-1 exhibits several glucoregulatory functions, such as glucose-dependent enhancement of insulin secretion, suppression of glucagon secretion, delayed gastric emptying, and reduction of food intake. It may even promote ␤-cell preservation and improved neogenesis (9). GLP-1 has an extremely short half-life in plasma.Exenatide (synthetic exendin-4) is a 39 -amino acid peptide incretin mimetic that demonstrates the above glucoregulatory actions of GLP-1 (10,11), and it has been shown to be a potent agonist to the GLP-1 receptor in vitro (12). Clinical studies in humans have demonstrated markedly improved ...