Elsevier

The Lancet

Volume 375, Issue 9733, 26 June–2 July 2010, Pages 2234-2243
The Lancet

Articles
Once weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes (DURATION-3): an open-label randomised trial

https://doi.org/10.1016/S0140-6736(10)60406-0Get rights and content

Summary

Background

Diabetes treatments are needed that are convenient, provide effective glycaemic control, and do not cause weight gain. We aimed to test the hypothesis that improvement in haemoglobin A1c (HbA1c) achieved with once weekly exenatide was superior to that achieved with insulin glargine titrated to glucose targets.

Methods

In this 26-week, open-label, randomised, parallel study, we compared exenatide with insulin glargine in adults with type 2 diabetes who had suboptimum glycaemic control despite use of maximum tolerated doses of blood-glucose-lowering drugs for 3 months or longer. Patients were randomly assigned to add exenatide (2 mg, once-a-week injection) or insulin glargine (once-daily injection, starting dose 10 IU, target glucose range 4·0–5·5 mmol/L) to their blood-glucose-lowering regimens. Randomisation was with a one-to-one allocation and block size four, stratified according to country and concomitant treatment (70% metformin only; 30% metformin plus sulphonylurea). Participants and clinical investigators were not masked to assignment, but investigators analysing data were. The primary endpoint was change in HbA1c from baseline, and analysis of this outcome was by modified intention to treat for all patients who received at least one dose of study drug. This trial is registered at ClinicalTrials.gov, number NCT00641056.

Findings

456 patients were randomly allocated to treatment and were included in the modified intention-to-treat analysis (233 exenatide, 223 insulin glargine). Participants who received at least one dose of study drug and for whom baseline and at least one postbaseline measurement of HbA1c were available were included in the primary efficacy analysis. Change in HbA1c at 26 weeks was greater in patients taking exenatide (n=228; −1·5%, SE 0·05) than in those taking insulin glargine (n=220; −1·3%, 0·06; treatment difference −0·16%, 0·07, 95% CI −0·29 to −0·03). 12 (5%) of 233 patients allocated to exenatide and two (1%) of 223 taking insulin glargine discontinued participation because of adverse events (p=0·012). A planned extension period (up to 2·5 years' duration) is in progress.

Interpretation

Once weekly exenatide is an important therapeutic option for patients for whom risk of hypoglycaemia, weight loss, and convenience are particular concerns.

Funding

Amylin Pharmaceuticals; Eli Lilly and Company.

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.

Section snippets

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

References (32)

  • DC Klonoff et al.

    Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years

    Curr Med Res Opin

    (2008)
  • Declaration of Helsinki: ethical principles for medical research involving human subjects

    JAMA

    (2000)
  • H Yki-Jarvinen et al.

    Initiate Insulin by Aggressive Titration and Education (INITIATE): a randomized study to compare initiation of insulin combination therapy in type 2 diabetic patients individually and in groups

    Diabetes Care

    (2007)
  • JB McGill et al.

    Circulating 1,5-anhydroglucitol levels in adult patients with diabetes reflect longitudinal changes of glycemia: a U.S. trial of the GlycoMark assay

    Diabetes Care

    (2004)
  • RL Kolotkin et al.

    Development of a brief measure to assess quality of life in obesity

    Obes Res

    (2001)
  • EuroQol—a new facility for the measurement of health-related quality of life

    Health Policy

    (1990)
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