Elsevier

The Lancet

Volume 379, Issue 9833, 16–22 June 2012, Pages 2270-2278
The Lancet

Articles
Exenatide twice daily versus glimepiride for prevention of glycaemic deterioration in patients with type 2 diabetes with metformin failure (EUREXA): an open-label, randomised controlled trial

https://doi.org/10.1016/S0140-6736(12)60479-6Get rights and content

Summary

Background

Glycaemic control deteriorates progressively over time in patients with type 2 diabetes. Options for treatment escalation remain controversial after failure of first-line treatment with metformin. We compared add-on exenatide with glimepiride for durability of glycaemic control in patients with type 2 diabetes inadequately controlled by metformin alone.

Methods

We did an open-label, randomised controlled trial at 128 centres in 14 countries between Sept 5, 2006, and March 29, 2011. Patients aged 18–85 years with type 2 diabetes inadequately treated by metformin were randomly assigned via a computer-generated randomisation sequence to receive exenatide twice daily or glimepiride once daily as add-on to metformin. Randomisation was stratified by predetermined categories of glycated haemoglobin (HbA1C) concentration. The primary outcome was time to inadequate glycaemic control and need for alternative treatment, defined as an HbA1c concentration of more than 9% after the first 3 months of treatment, or more than 7% at two consecutive visits after the first 6 months. Analysis was by intention to treat. This trial is registered with EudraCT, number 2005-005448-21, and ClinicalTrials.gov, number NCT00359762.

Findings

We randomly assigned 515 patients to the exenatide group and 514 to the glimepiride group, of whom 490 versus 487 were the intention-to-treat population. 203 (41%) patients had treatment failure in the exenatide group compared with 262 (54%) in the glimepiride group (risk difference 12·4 [95% CI 6·2–18·6], hazard ratio 0·748 [0·623–0·899]; p=0·002). 218 (44%) of 490 patients in the exenatide group, and 150 (31%) of 487 in the glimepiride group achieved an HbA1c concentration of less than 7% (p<0·0001), and 140 (29%) versus 87 (18%) achieved concentrations of 6·5% and less (p=0·0001). We noted a significantly greater decrease in bodyweight in patients given exenatide than in those given glimepiride (p<0·0001). Five patients in each treatment group died from causes unrelated to treatment. Significantly fewer patients in the exenatide group than in the glimepiride group reported documented symptomatic (p<0·0001), nocturnal (p=0·007), and non-nocturnal (p<0·0001) hypoglycaemia. Discontinuation because of adverse events (mainly gastrointestinal) was significantly higher (p=0·0005) in the exenatide group than in the glimepiride group in the first 6 months of treatment, but not thereafter.

Interpretation

These findings provide evidence for the benefits of exenatide versus glimepiride for control of glycaemic deterioration in patients with type-2 diabetes inadequately controlled by metformin alone.

Funding

Eli Lilly and Company; Amylin Pharmaceuticals.

Introduction

Metformin is widely used as a first-line glucose-lowering drug;1, 2 however, selection of the most appropriate treatment after metformin failure is poorly established. Sulphonylureas are commonly chosen as add-on treatment because of their rapid effect and low cost.1, 3, 4 Although these drugs can improve the short-term function of β cells, glycaemic control subsequently deteriorates; furthermore, because effects are not glucose-dependent, risk of hypoglycaemia might be increased, which can restrict doses used in clinical practice.5

Glucagon-like peptide (GLP)-1 receptor agonists have become established as treatments for type 2 diabetes.6, 7 They improve glycaemic control, with glucose-dependent stimulation of insulin secretion and no increased risk of hypoglycaemia, and have been associated with weight loss and improvements in biomarkers of cardiovascular risk.8, 9, 10, 11 These drugs have shown protective action in β cells, and findings from clinical trials have noted improved β-cell function,12, 13, 14 thus raising expectations that GLP-1 receptor agonists might delay disease progression.15, 16

We aimed to assess durability of glycaemic control achieved with GLP-1 receptor agonist exenatide twice a day and sulphonylurea glimepiride in patients with type 2 diabetes inadequately controlled by metformin alone.

Section snippets

Study design and participants

We undertook this open-label, randomised controlled European Exenatide (EUREXA) trial at 128 centres in 14 countries (Austria, Czech Republic, Finland, France, Germany, Hungary, Ireland, Israel, Italy, Mexico, Poland, Spain, Switzerland, and the UK) between Sept 5, 2006, and March 29, 2011. The rationale and baseline characteristics of the EUREXA phase 3, multinational study have been described previously.17 Eligible participants had type 2 diabetes; were overweight to obese (body-mass index

Results

Figure 1 shows the trial profile. We randomly assigned 1029 of 1404 screened patients to receive either exenatide or glimepiride as add-on treatment to metformin. The intention-to-treat population consisted of 490 patients in the exenatide group and 487 in the glimepiride group; conclusions from the as-treated population were not different from those from the intention-to-treat analysis and are therefore not presented. Of patients who met the primary endpoint, five of those in the exenatide

Discussion

Our findings show that exenatide twice daily as add-on to metformin reduced worsening of glycaemic control and rate of hypoglycaemia compared with add-on glimepiride in patients with type 2 diabetes inadequately controlled by metformin alone. Furthermore, exenatide was more effective than glimepiride for fasting glucose, glucose excursions after meals, and HbA1c concentration. Overall, safety and tolerability of both drugs was consistent with the known safety profiles. The most frequently

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