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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.

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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.

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.

OBJECTIVE -In patients with type 2 diabetes, exenatide reduces A1C, postprandial and fasting glucose, and weight. In this study we investigated the effects of continuous exenatide administration from a long-acting release (LAR) formulation.RESEARCH DESIGN AND METHODS -In this randomized, placebo-controlled phase 2 study, exenatide LAR (0.8 or 2.0 mg) was administered subcutaneously once weekly for 15 weeks to subjects with type 2 diabetes (n ϭ 45) suboptimally controlled with metformin (60%) and/or diet and exercise (40%): 40% female, A1C (mean Ϯ SD) 8.5 Ϯ 1.2%, fasting plasma glucose 9.9 Ϯ 2.3 mmol/l, weight 106 Ϯ 20 kg, and diabetes duration 5 Ϯ 4 years.RESULTS -From baseline to week 15, exenatide LAR reduced mean Ϯ SE A1C by Ϫ1.4 Ϯ 0.3% (0.8 mg) and Ϫ1.7 Ϯ 0.3% (2.0 mg), compared with ϩ0.4 Ϯ 0.3% with placebo LAR (P Ͻ 0.0001 for both). A1C of Յ7% was achieved by 36 and 86% of subjects receiving 0.8 and 2.0 mg exenatide LAR, respectively, compared with 0% of subjects receiving placebo LAR. Fasting plasma glucose was reduced by Ϫ2.4 Ϯ 0.9 mmol/l (0.8 mg) and Ϫ2.2 Ϯ 0.5 mmol/l (2.0 mg) compared with ϩ1.0 Ϯ 0.7 mmol/l with placebo LAR (P Ͻ 0.001 for both). Exenatide LAR reduced self-monitored postprandial hyperglycemia. Subjects receiving 2.0 mg exenatide LAR had body weight reductions (Ϫ3.8 Ϯ 1.4 kg) (P Ͻ 0.05), whereas body weight was unchanged with both placebo LAR and the 0.8-mg dose. Mild nausea was the most frequent adverse event.No subjects treated with exenatide LAR withdrew from the study.CONCLUSIONS -Exenatide LAR offers the potential of 24-h glycemic control and weight reduction with a novel once-weekly treatment for type 2 diabetes.

OBJECTIVEIn 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 METHODSIn 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.RESULTSPatients 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 ≤6.5%, respectively. In both treatment arms, FPG was reduced by >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.CONCLUSIONExenatide 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.

OBJECTIVE—AC2993 (synthetic exendin-4; exenatide) is a peptide that enhances glucose-dependent insulin secretion, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying. AC2993 also promotes β-cell proliferation and neogenesis in vitro and in animal models. This study examines the activity and safety of subcutaneously injected AC2993 in patients with type 2 diabetes currently treated with diet and/or oral antidiabetic agents (OAAs). RESEARCH DESIGN AND METHODS—A total of 109 patients treated with diet and a sulfonylurea and/or metformin were enrolled in a blinded study. Patients were randomly assigned to one of three subcutaneously (SC) injected regimens of AC2993 (0.08 μg/kg) or placebo for 28 days. RESULTS—All three AC2993 regimens led to significant reductions in serum fructosamine relative to placebo (P ≤ 0.004). Mean reductions ranged from 39 to 46 μmol/l. All AC2993 groups had reductions in HbA1c ranging from 0.7 to 1.1% (P ≤ 0.006). An end-of-study HbA1c &lt;7% was achieved by 15% of AC2993 patients versus 4% of placebo patients, confirming AC2993 effects on fasting and postprandial glycemia. On days 14 and 28, the β-cell index (homeostasis model assessment) for patients treated with AC2993 was 50–100% higher than baseline, contrasting with unchanged levels for placebo. The most common adverse event was transient mild-to-moderate nausea. CONCLUSIONS—AC2993 is a promising therapeutic for patients with type 2 diabetes. In this study, it had significant effects on HbA1c levels in patients not currently achieving optimal glucose control with diet and/or OAAs.