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Context: We wanted to understand the effects of once-weekly vs. twice-daily glucagon-like peptide-1 receptor agonism for treatment of patients with type 2 diabetes., Objective: The objective of the study was to compare effects of exenatide once weekly (ExQW) and exenatide twice daily (ExBID) on glycemic control, body weight, and safety., Design: This was a 24-wk, randomized, open-label, comparator-controlled study., Setting: The study was conducted at 43 sites in the United States., Patients: The study population was 252 intent-to-treat patients with type 2 diabetes [baseline (mean ± SD): glycosylated hemoglobin (HbA1c) 8.4 ± 1.2%, fasting plasma glucose 171 ± 47 mg/dl, weight 96 ± 20 kg] that were drug naïve (19%) or previously treated with one (47%) or multiple (35%) oral antidiabetic medications., Interventions: Interventions included ExQW 2 mg for 24 wk or ExBID 5 μg for 4 wk followed by ExBID 10 μg for 20 wk., Main Outcome Measure: The change in HbA1c from baseline to wk 24 was measured., Results: At 24 wk, ExQW produced significantly greater changes from baseline (least squares mean ± SE) vs. ExBID in HbA1c (-1.6 ± 0.1% vs. -0.9 ± 0.1%; P < 0.0001) and fasting plasma glucose (-35 ± 5 mg/dl vs. -12 ± 5 mg/dl; P = 0.0008). Similar reductions in mean body weight from baseline to wk 24 were observed in both groups (-2.3 ± 0.4 kg and -1.4 ± 0.4 kg). Both treatments were generally well tolerated. Transient and predominantly mild to moderate nausea, the most frequent adverse event, was less common with ExQW (14%) than with ExBID (35%). Injection-site reactions were infrequent, but more common with ExQW. No major hypoglycemia occurred., Conclusions: Continuous glucagon-like peptide-1 receptor agonism with ExQW resulted in superior glycemic control, with less nausea, compared with ExBID in patients with type 2 diabetes. Both groups lost weight.

Objective: In the Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once Weekly (DURATION-1) study, the safety and efficacy of 30 weeks of treatment with the glucagon-like peptide-1 receptor agonist exenatide once weekly (exenatide QW; 2 mg) was compared with exenatide BID in 295 patients with type 2 diabetes. We now report the safety and efficacy of exenatide QW in 1) patients who continued treatment for an additional 22 weeks (52 weeks total) and 2) patients who switched from exenatide BID to exenatide QW after 30 weeks., Research Design and Methods: In this randomized, multicenter, comparator-controlled, open-label trial, 258 patients entered the 22-week open-ended assessment phase (n = 128 QW-only; n = 130 BID-->QW). A1C, fasting plasma glucose (FPG), body weight, blood pressure, fasting lipids, safety, and tolerability were assessed., Results: Patients continuing exenatide QW maintained A1C improvements through 52 weeks (least squares mean -2.0% [95% CI -2.1 to -1.8%]). Patients switching from exenatide BID to exenatide QW achieved further A1C improvements; both groups exhibited the same A1C reduction and mean A1C (6.6%) at week 52. At week 52, 71 and 54% of all patients achieved A1C <7.0% and 40 mg/dl, and body weight was reduced by >4 kg after 52 weeks. Nausea occurred less frequently in this assessment period and was predominantly mild. No major hypoglycemia was observed., Conclusion: Exenatide QW elicited sustained improvements in glycemic control and body weight through 52 weeks of treatment. Patients switching to exenatide QW experienced further improvements in A1C and FPG, with sustained weight loss.

Background: Exenatide is the first of a new class of agents known as incretin mimetics that are in development for the treatment of type 2 diabetes. Exenatide has been shown to reduce fasting and postprandial glucose in patients with type 2 diabetes, as well as provide sustained reductions in hemoglobin A 1c (HbA 1c). This study was designed to assess the dose dependencies of the glucoregulatory effects and tolerability of exenatide when added to diet and exercise or metformin monotherapy in patients with type 2 diabetes., Methods: In this randomized, triple-blinded, placebo-controlled Phase 2 clinical trial, 156 patients were randomized to placebo or exenatide at 2.5, 5.0, 7.5, or 10.0 microg administered b.i.d. for 28 days., Results: After 28 days of therapy, exenatide was associated with significant (P < 0.0001, linear contrast testing), dose-dependent reductions in HbA 1c (0.1 +/- 0.1%, -0.3 +/- 0.1%, -0.4 +/- 0.1%, +/-0.5 +/- 0.0%, and -0.5 +/- 0.1% for placebo and 2.5, 5.0, 7.5, and 10.0 microg b.i.d. exenatide, respectively) and significant (P = 0.0006, linear contrast testing) reductions in fasting plasma glucose (+6.8 +/- 4.1, -20.1 +/- 5.2, -21.2 +/- 3.9, -17.7 +/- 4.8, and -17.3 +/- 4.4 mg/dL for placebo and 2.5, 5.0, 7.5, and 10.0 microg b.i.d. exenatide, respectively) by Day 28. These reductions were similar for patients treated with diet/exercise and those treated with metformin. In addition, patients receiving exenatide exhibited dose-dependent reductions in body weight (0.0 +/- 0.3, -0.7 +/- 0.3, -0.7 +/- 0.2, -1.4 +/- 0.3, and -1.8 +/- 0.3 kg for placebo and 2.5, 5.0, 7.5, and 10.0 microg b.i.d. exenatide, respectively; P < 0.01 for 7.5 and 10.0 microg b.i.d. exenatide doses compared with placebo) at Day 28. The most common adverse event was mild-to-moderate nausea that was dose-dependent (seven of 123 patients randomized to exenatide withdrew from the study because of gastrointestinal effects)., Conclusions: Exenatide dose-dependently improved glycemic control and reduced body weight over 28 days in patients with type 2 diabetes treated with diet/exercise or metformin.

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. kg(-1). min(-1)) or placebo during a 270-min stepwise hyperinsulinemic-hypoglycemic clamp (insulin infusion 0.8 mU. kg(-1). 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 approximately 3.2 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 approximately 3.5-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 (

Despite the advent of new treatments, glucose control in the type 2 diabetes population is unsatisfactory. AC2993 (synthetic exendin-4; exenatide), a novel glucose-dependent insulinotropic agent, exhibited notable antidiabetic potential in two clinical studies in patients with type 2 diabetes. In study A, 24 subjects received sc injections of study medication (0.1 micro g/kg AC2993 or placebo) twice daily with meals for 5 d. Statistically significant reductions in mean postprandial circulating concentrations of glucose, insulin, and glucagon occurred following treatment with AC2993. In study B, 13 subjects receiving a single dose of study medication (0.05, 0.1, or 0.2 micro g/kg AC2993 or placebo) following an overnight fast had reduced fasting plasma glucose concentrations during the subsequent 8-h period. The relative glucose and insulin concentration profiles were consistent with glucose-dependent insulinotropism. AC2993 was well tolerated. Mild transient headache, nausea, and vomiting were the main adverse events. In conclusion, AC2993 acutely and markedly reduces fasting and postprandial glucose concentrations in patients with type 2 diabetes. During fasting, glucose-dependent enhancement of insulin secretion and suppression of glucagon secretion are the predominant mechanisms, and postprandially, slowing of gastric emptying is additionally operative. This robust antidiabetic effect warrants further evaluation of AC2993.