Elsevier

The Lancet

Volume 372, Issue 9645, 4–10 October 2008, Pages 1240-1250
The Lancet

Articles
Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study

https://doi.org/10.1016/S0140-6736(08)61206-4Get rights and content

Summary

Background

Exenatide is an incretin mimetic that shares glucoregulatory properties with glucagon-like peptide 1 (GLP-1), and improves glycaemic control, with progressive bodyweight reductions, when administered twice a day in patients with type 2 diabetes. We compared the efficacy of a once-weekly formulation of exenatide to that of a twice daily dose.

Methods

A 30-week, randomised, non-inferiority study compared a long-acting release formulation of exenatide 2 mg administered once weekly to 10 μg exenatide administered twice a day, in 295 patients with type 2 diabetes (haemoglobin A1c [HbA1c] 8·3% [SD 1·0], mean fasting plasma glucose 9 [SD 2] mmol/L, weight 102 [SD 20] kg, diabetes duration 6·7 [SD 5·0] years). The patients were naive to drug therapy, or on one or more oral antidiabetic agents. The primary endpoint was the change in HbA1c at 30 weeks. This study is registered with ClinicalTrials.gov, number NCT00308139.

Findings

At 30 weeks, the patients given exenatide once a week had significantly greater changes in HbA1c than those given exenatide twice a day (−1·9 [SE 0·1%] vs −1·5 [0·1%], 95% CI −0·54% to −0·12%; p=0·0023). A significantly greater proportion of patients receiving treatment once a week versus twice a day achieved target HbA1c levels of 7·0% or less (77% vs 61% of evaluable patients, p=0·0039).

Interpretation

Exenatide once weekly resulted in significantly greater improvements in glycaemic control than exenatide given twice a day, with no increased risk of hypoglycaemia and similar reductions in bodyweight.

Funding

Amylin Pharmaceuticals Inc and Eli Lilly and Company.

Introduction

Type 2 diabetes is an increasingly common, complex metabolic disorder, characterised by progressive hyperglycaemia and a high risk of microvascular and macrovascular complications.1, 2, 3, 4 Maintenance of strict glycaemic control, which is crucial for prevention of complications, frequently requires treatment with more than one drug.1, 5, 6, 7, 8 However, despite the introduction of several new classes of drugs, many patients do not achieve recommended glycaemic targets.9, 10 In view of the complex and chronic nature of type 2 diabetes and its increasing prevalence, a need exists for well tolerated and effective agents that provide additional options for optimising glycaemic control.

Two new classes of antidiabetic agents based on potentiation of incretin action have been approved for the treatment of type 2 diabetes: glucagon-like peptide-1 receptor (GLP-1R) agonists or incretin mimetics, and dipeptidyl peptidase-4 (DPP-4) inhibitors or incretin enhancers.11, 12 Exenatide, the first incretin mimetic approved by the Food and Drug Administration and the European Medicines Agency for the treatment of type 2 diabetes, has multiple glucoregulatory effects, including enhancement of glucose-dependent insulin secretion, reduction of glucagon secretion, reduction of food intake, and slowing of gastric emptying.13 In placebo-controlled clinical trials, exenatide administered twice a day significantly improved glycaemic control in patients with type 2 diabetes suboptimally controlled on one or more commonly used oral therapies, including metformin, sulphonylureas, and thiazolidinediones.14, 15, 16, 17 Mean haemoglobin A1c (HbA1c) reductions with exenatide in placebo-controlled trials were roughly 1% from baseline values of 7·9% to 8·4%, whereas open-label comparator studies showed HbA1c reductions of 1·1–1·4% from baseline values of 8·2–9·0%.14, 15, 16, 17, 18, 19, 20

Exenatide lowers fasting and postprandial plasma blood glucose concentrations, and reduces bodyweight in a substantial proportion of treated patients.14, 15, 16, 17 However, its current delivery method requires twice daily subcutaneous injection, and does not provide continuous GLP-1R activation. Furthermore, some evidence exists that the rate of nausea, a transient but commonly reported side-effect of therapy with GLP-1R agonists, could be reduced with long-acting GLP-1R agonists, that achieve peak drug concentrations more slowly over a longer time.

Although GLP-1 is mostly secreted postprandially, several lines of evidence support a role for basal concentrations of GLP-1 in the control of fasting glucose.18, 19 Indeed, blockade of endogenous GLP-1 action increases fasting plasma glucose.20 Moreover, infusion of GLP-1 over 24 h provides better glucose control than a 16 h infusion.18 These observations provide a rationale for exploration of GLP-1R agonists with prolonged pharmacokinetic profiles.

A long-acting release form of exenatide has been developed for use as a once-weekly injection.21 This sustained-release formulation consists of injectable microspheres of exenatide and poly (D,L lactic-co-glycolic acid), a common biodegradable medical polymer with established use in absorbable sutures and extended-release pharmaceuticals, that allows gradual drug delivery at a controlled rate.22 A small pilot study of exenatide once a week over 15 weeks resulted in significant reductions in HbA1c, fasting plasma glucose, postprandial plasma glucose, and bodyweight.21 In the current study, we compared the safety and efficacy of exenatide once a week to that of exenatide given twice daily, over 30 weeks, in patients with type 2 diabetes.

Section snippets

Patients

303 patients were enrolled. Study participants were at least 16 years of age, with type 2 diabetes treated for at least 2 months before screening. Entry criteria included a baseline HbA1c of 7·1–11·0%, fasting plasma glucose of less than 16 mmol/L, body-mass index of 25–45 kg/m2, and therapy with diet modification and exercise, or pharmacological treatment with metformin, a sulphonylurea, a thiazolidinedione, or any combination of two of these agents.

Eligible patients were weight-stable—their

Results

Demographics, baseline characteristics, and disposition by treatment are shown in table 1. Baseline characteristics in the current study were similar to those reported for the 30-week placebo-controlled trials with exenatide twice a day, particularly with respect to age (55 years), sex (42% women), body-mass index (34 kg/m2), and baseline HbA1c (8·4%).14, 15, 16, 17 258 (88%) of the 295 patients randomised in the intention-to-treat population completed 30 weeks of treatment (128 [87%] exenatide

Discussion

Although both exenatide once a week and twice a day resulted in significant reductions in HbA1c and bodyweight from baseline after 30 weeks of treatment, our results show that exenatide once a week produces better glycaemic control than exenatide twice a day: the mean difference in reduction of HbA1c between the two groups was 0·33% (95% CI 0·54% to 0·12%). 77% of patients treated with exenatide once a week achieved HbA1c levels of 7% or less at study endpoint, from an mean baseline HbA1c of

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