Effects of Exenatide (Exendin-4) on Glycemic Control Over 30 Weeks in Sulfonylurea-treated Patients With Type 2 Diabetes

Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD. Diabetes Care. 2004;27:2628-2635.

Exenatide, an incretin mimetic, has been shown to improve glycemic control in patients with type 2 diabetes failing on sulfonylurea in a triple-blind, placebo-controlled study. After a 4-week, lead-in placebo period, patients (n=377) were randomized to receive 5 µg exenatide by twice daily injection (arms A and B) or placebo. After 4 weeks, the dose of exenatide was increased to twice daily 10 µg injections in arm B. The total study duration was 30 weeks. All patients had been receiving monotherapy with a sulfonylurea at the maximally effective dose for a minimum of 3 months prior to screening and continued taking treatment throughout the study. Of the 377 patients randomized to treatment, 260 completed the study. Baseline patient characteristics included 60% male, age 55±11 years, BMI 33±6 kg/m², and A1C 8.6±1.2% (mean±SD).

At the end of the 30-week study period, significant improvement in A1C was observed in patients taking 10 µg exenatide (-0.86±0.11%) and 5 µg exenatide (-0.46±0.12%) compared with placebo (0.12±0.09%; P<.001; ±SE). Of subjects with an A1C>7% at baseline (n=237), more achieved an A1C≤7% in the 10 µg exenatide (41%) and 5 µg exenatide (33%) groups compared with placebo (9%; P<.001). Fasting plasma glucose was found to decrease in the 10 µg exenatide group compared with placebo (-0.6±0.3 vs 0.4±0.3 mmol/L; P<.05). Treatment with exenatide was also associated with weight loss; a mean decrease in weight of -1.6±0.3 kg occurred in the 10 µg exenatide treatment group (P<.05 vs placebo).

The most frequent adverse event was nausea, experienced by 51% of patients in the 10 µg exenatide group, 39% of patients in the 5 µg exenatide group, and 7% of patients in the placebo group. Most episodes of nausea were mild or moderate in intensity. Nausea was most notable when therapy was initiated; subsequent rates of nausea were lower. Mild-to-moderate hypoglycemia was experienced by 36% of patients in the 10 µg exenatide group, 14% of patients in the 5 µg exenatide group, and 3% of patients in the placebo group. There were no occurrences of severe hypoglycemia. The increased incidence of hypoglycemia in patients treated with exenatide may have been due to the increased susceptibility often observed in patients treated with sulfonylurea at lower ambient glycemic levels. No predictive effect of anti-exenatide antibodies (41% at 30 weeks) was found on glycemic control or adverse events.
 
Exenatide is the first in a new class of antiglycemic agents currently being developed for patients with type 2 diabetes not taking insulin and who are not achieving glycemic control through dietary modifications and oral agents. In this study, exenatide was found to reduce A1C and was accompanied with weight loss over a 30-week period in patients with type 2 diabetes not adequately controlled with sulfonylureas.