Exenatide Twice Daily Versus Glimepiride for Prevention of Glycemic Deterioration in Patients With Type 2 Diabetes With Metformin Failure (EUREXA): An Open-Label, Randomized Controlled Trial

Study Questions:

What is the comparative efficacy of exenatide versus glimepiride for durability of glycemic control in patients with type 2 diabetes inadequately controlled by metformin alone?

Methods:

The investigators did an open-label, randomized, controlled trial at 128 centers in 14 countries between Sept 5, 2006, and March 29, 2011. Patients ages 18-85 years with type 2 diabetes inadequately treated by metformin were randomly assigned via a computer-generated randomization sequence to receive exenatide twice daily or glimepiride once daily as add-on to metformin. Randomization was stratified by predetermined categories of glycated hemoglobin (HbA1c) concentration. The primary outcome was time to inadequate glycemic 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.

Results:

The investigators 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. A total of 203 (41%) patients had treatment failure in the exenatide group compared with 262 (54%) in the glimepiride group (risk difference, 12.4; 95% confidence interval [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 <7% (p < 0.0001), and 140 (29%) versus 87 (18%) achieved concentrations of 6.5% and less (p = 0.0001). They 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) hypoglycemia. 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.

Conclusions:

The authors concluded that the study findings provide evidence for the benefits of exenatide versus glimepiride for control of glycemic deterioration in patients with type 2 diabetes inadequately controlled by metformin alone.

Perspective:

The study reports that exenatide twice daily as add-on to metformin reduced worsening of glycemic control and rate of hypoglycemia compared with 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. Also, overall, safety and tolerability of both drugs was consistent with their known safety profiles. It appears that exenatide twice a day is a more effective treatment option than glimepiride for patients with metformin failure, and may be considered the preferred strategy.

Clinical Topics: Dyslipidemia, Lipid Metabolism, Nonstatins

Keywords: Venoms, Fish Oils, Mutagens, Diabetes Mellitus, Type 2, Transcription Factors, Hypoglycemia, Hemoglobin A, Glycosylated, Sulfonylurea Compounds, Peptides, Metformin, Blood Glucose, Cardiovascular Diseases, Confidence Intervals


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