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.

The continual reassessment method as described by O'Quigley, Pepe, and Fisher (1990, Biometrics 46, 33-48) leans to a large extent upon a Bayesian methodology. Initial experimentation and sequential updating are carried out in a natural way within the context of a Bayesian framework. In this paper we argue that such a framework is easily changed to a more classic one leaning upon likelihood theory. The essential features of the continual reassessment method remain unchanged. In particular, large sample properties are the same unless the prior is degenerate. For small samples and as far as the final recommended dose level is concerned, simulations indicate that there is not much to choose between a likelihood approach and a Bayesian one. However, for in-trial allocation of dose levels to patients, there are some differences and these are discussed. In contrast to the Bayesian approach, a likelihood one requires some extra effort to get off the ground. This is because the likelihood equation has no solution until we observe a toxicity. Initially then we suggest working with either a standard Up-and-Down scheme or standard continual reassessment method until toxicity is observed and then switching to the new scheme.

OBJECTIVE -Mealtime amylin replacement with the human amylin analog pramlintide, as an adjunct to mealtime insulin replacement, reduces postprandial glucose excursions in patients with type 2 diabetes. The aim of the present study was to assess the long-term efficacy and safety of pramlintide in this patient population.RESEARCH DESIGN AND METHODS -In a 52-week, double-blind, placebocontrolled, parallel-group, multicenter study, 656 patients with type 2 diabetes (age 57 Ϯ 10 years, diabetes duration 12 Ϯ 7 years, BMI 34.0 Ϯ 7.0 kg/m 2 , HbA 1c 9.1 Ϯ 1.2%, mean Ϯ SD) treated with insulin (alone or in combination with sulfonylureas and/or metformin) were randomized to receive additional preprandial subcutaneous injections of either placebo or pramlintide (60 g TID, 90 g BID, or 120 g BID).RESULTS -Treatment with pramlintide 120 g BID led to a sustained reduction from baseline in HbA 1c (Ϫ0.68 and Ϫ0.62% at weeks 26 and 52, respectively), which was significantly greater than that seen with placebo (P Ͻ 0.05). The proportion of patients achieving an HbA 1c Ͻ8% was approximately twofold greater with pramlintide (120 g BID) than with placebo (46 vs. 28%, P Ͻ 0.05). The glycemic improvement with pramlintide 120 g BID was accompanied by a mean weight loss (Ϫ1.4 kg vs. ϩ0.7 kg with placebo at week 52, P Ͻ 0.05) and occurred without an overall increase in the severe hypoglycemia event rate. The most common adverse event associated with pramlintide use was transient, mild-to-moderate nausea.CONCLUSIONS -Mealtime amylin replacement with pramlintide 120 g BID, as an adjunct to insulin therapy, improves long-term glycemic and weight control in patients with type 2 diabetes. Diabetes Care 26:784 -790, 2003

These results show that mealtime amylin replacement with pramlintide, as an adjunct to insulin therapy, improves long-term glycaemic and weight control in patients with Type 1 diabetes.

OBJECTIVE -To assess the effect of mealtime amylin replacement with pramlintide on long-term glycemic and weight control in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS-In a 52-week, double-blind, placebocontrolled, multicenter study, 480 patients with type 1 diabetes were randomized to receive preprandial injections of placebo or 30 g pramlintide q.i.d., in addition to existing insulin regimens. At week 20, pramlintide-treated patients were re-randomized to 30 or 60 g pramlintide q.i.d. if decreases from baseline in HbA 1c were Ͻ1% at week 13. Of the 342 patients who completed the 52-week study, 236 individuals (ϳ70%) elected to participate in a 1-year openlabel extension in which all patients received 30 or 60 g pramlintide q.i.d..RESULTS -Treatment with pramlintide led to a mean reduction in HbA 1c of 0.67% from baseline to week 13 that was significantly (P Ͻ 0.0001) greater than the placebo reduction (0.16%), and a significant placebo-corrected treatment difference was sustained through week 52 (P ϭ 0.0071). The greater HbA 1c reduction was associated with an average weight loss, rather than weight gain, and was not accompanied by an increased overall event rate of severe hypoglycemia. In the open-label extension, mean HbA 1c levels decreased rapidly in patients receiving pramlintide for the first time and remained at reduced levels in patients who continued pramlintide treatment. The most common adverse events reported by the pramlintide group were mild nausea and anorexia, which both occurred during the initial weeks of treatment and dissipated over time.CONCLUSIONS -Mealtime pramlintide treatment as an adjunct to insulin improved longterm glycemic control without inducing weight gain or increasing the overall risk of severe hypoglycemia in patients with type 1 diabetes. Diabetes Care 25:724 -730, 2002

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.

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