ArticlesOnce weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes (DURATION-3): an open-label randomised trial
Introduction
Management of diabetes has developed from a symptomatic glucocentric approach to include strategies targeting pathophysiological principles and, in addition to durable blood-glucose lowering, reduce bodyweight.1 Treatments are needed that are convenient, address both fasting and postprandial glucose control, reduce risk of hypoglycaemia, and avoid counterproductive side-effects (eg, weight gain).2 A class of agents introduced within the past 5 years, the glucagon-like peptide-1 (GLP-1) receptor agonists, has the potential to address fasting and postprandial glucose control with weight loss and a low risk of hypoglycaemia.1, 3 Exenatide twice a day, the first approved GLP-1 receptor agonist, has several glucoregulatory actions, including stimulation of glucose-dependent insulin secretion, reduction of glucagon secretion, decrease of food intake, and slowing of gastric emptying.4 In clinical trials, exenatide twice a day lowered fasting and postprandial glucose concentrations and was associated with improved glycaemic control and reduced bodyweight in a substantial percentage of patients.5, 6, 7, 8
A once weekly formulation of exenatide has been developed, with the goal of sustained glycaemic control alongside increased convenience of standard once-a-week dosing. This formulation has been associated with haemoglobin A1c (HbA1c) reduction, weight loss, and low hypoglycaemic risk in randomised clinical trials.9 We aimed to test the hypothesis that improvement in HbA1c concentration achieved with once-weekly exenatide is better than that achieved with the existing standard second-line treatment for patients not responding to oral blood-glucose-lowering agents, insulin glargine titrated to glucose targets.
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Patients
This phase 3, open-label, randomised, parallel study was undertaken during 26 weeks between May 13, 2008, and May 19, 2009, at 72 sites across the USA (and Puerto Rico), the European Union, Russia, Australia, Korea, Taiwan, and Mexico. Patients were identified, under direction from the site principal investigators, from patient populations at all trial sites. Potential participants were subsequently recruited according to standard local practices. Written informed consent and patient screening
Results
Table 1 shows baseline characteristics. 456 patients received one or more doses of study drug and were included in the primary efficacy analysis (233 exenatide, 223 insulin glargine; figure 1). The number of patients who discontinued participation did not differ between treatment groups (p=0·130). Mean doses of insulin glargine increased from a baseline 10 IU per day to 31 IU per day at endpoint (last measurement brought forward). Mean doses of metformin were roughly 2000 mg throughout the
Discussion
Exenatide once weekly resulted in greater HbA1c reduction after 26 weeks of treatment than did insulin glargine titrated to target, and was associated with progressive bodyweight reduction. However, the clinical importance of this improvement in glycaemic control is uncertain. Insulin glargine produced significantly greater reductions in fasting glucose than did exenatide; however, significantly greater reductions in postprandial glucose excursions were recorded for exenatide than for insulin
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