In a recent head-to-head comparison, glycemic control was better with the glucagon-like peptide-1 (GLP-1) exenatide twice daily than with the sulfonylurea glimepiride once daily in patients with type 2 diabetes who are inadequately controlled with metformin, said Guntram Schernthaner, MD, Head of the Department of Medicine, Rudolfstiftung Hospital, Vienna, Austria, at the 2012 ADA annual meeting. Dr Schernthaner reported the results of the European Exenatide trial known as EUREXA, which was simultaneously published in the Lancet (Gallwitz B, et al. Lancet. 2012;379:2270-2278).
Comparing Sulfonylurea and GLP-1
A sulfonylurea is a common choice as second-line therapy after metformin failure in many countries in patients with type 2 diabetes, because sulfonylureas are inexpensive and have a rapid effect, Dr Schernthaner noted. Glycemic control subsequently deteriorates with a sulfonylurea, however, because its effect is not glucose-dependent, and the risk for hypoglycemia may limit the dosage of the sulfonylurea used in clinical practice, he said.
The EUREXA trial was conducted at 128 centers in 14 European countries and included 1029 adults with type 2 diabetes who were overweight or obese and whose hemoglobin (Hb) A1c level was between 6.5% and 9.0%, despite stable and maximally tolerated doses of metformin.
The study tested the following 2 hypotheses: (1) that exenatide is noninferior to glimepiride on time to treatment failure, and (2) if noninferiority is demonstrated, exenatide would prove superior to glimepiride.
Treatment failure was defined as treatment with the maximally tolerated dose of antidiabetic agents and 1 of 2 situations—the HbA1c level remains above 7% at 2 consecutive office visits 3 months apart, or the HbA1c level is more than 9% at any visit after 3 months of treatment.
In this open-label study, participants were assigned to receive exenatide injected subcutaneously within 60 minutes before breakfast and evening meals—starting at 5 mcg twice daily for 5 weeks and followed by 10 mcg twice daily for the remaining study period—or to glimepiride 1 mg daily immediately before breakfast.
“Exenatide twice daily was associated with lower A1c levels over time compared with glimepiride,” said Dr Schernthaner.
Treatment failure occurred in 41% of patients in the exenatide group versus 54% of those in the glimepiride group, a risk difference of 12.4%, which corresponded to a 25% reduction in the risk of treatment failure with exenatide.
Exenatide met the criterion for noninferiority and separately showed superiority over glimepiride as an add-on treatment to metformin.
Reduced HbA1c Levels and Weight
The median time to inadequate glycemic control was 180 weeks in the exenatide group versus 142 weeks in the glimepiride group. Overall, 45% of the patients assigned to exenatide achieved an HbA1c concentration <7% compared with 31% of the patients assigned to glimepiride.
Fasting plasma glucose concentration was significantly lower in the exenatide group at years 1, 2, and 3 compared with the glimepiride group. Glucose levels during oral glucose tolerance tests were also significantly lower with exenatide versus glimepiride at these time points.
“Exenatide-treated patients experienced significantly greater weight loss over time,” said Dr Schernthaner. Patients in the exenatide group lost 3.32 kg of body weight from baseline through the last visit compared with a gain of 1.15 kg in those randomized to glimepiride.
The incidence of hypoglycemia was lower in patients receiving exenatide twice daily than in those receiving glimepiride, he said. Hypoglycemia of any type was reported by 36% of patients in the exenatide group and by 67% in the glimepiride group; documented symptomatic hypoglycemia occurred in 7% of the exenatide group versus 12% of the glimepiride group.
Gastrointestinal and injection-site reactions were more common in patients receiving exenatide twice daily than in patients receiving glimepiride once daily.