Interim Analysis of the Effects of Exenatide Treatment on A1C, Weight and Cardiovascular Risk Factors over 82 weeks in 314 Overweight Patients with Type 2 Diabetes

Blonde L, Klein EJ, Zhang B, et al. Diabetes Obes Metab. 2006;8:435-447.

Exenatide is one of a new class of drugs called incretin mimetics and has glucoregulatory effects comparable to the GI hormone glucagon-like peptide-1 (GLP-1). Previous studies have shown advantageous results with exenatide for reduction in A1C and weight. This study was an extension of prior trials and aimed to analyze the effects of exenatide on glycemic control, weight, and selected cardiovascular risk factors over a period of 82 weeks in patients with type 2 diabetes who were unable to attain good glycemic control with a sulfonylurea (SU), metformin, or a combination of both.

The initial exenatide clinical studies were stratified, balanced, randomized, double-blind, placebo-controlled, parallel-group, 30-week clinical trials designed to evaluate glycemic control in 1,446 patients through A1C and safety measures. A total of 1,125 patients completed these studies, in which patients on the highest dose of exenatide (10 mcg BID) had a mean A1C reduction of 1%, and 40% of patients with baseline
A1C >7 achieved A1C values ≤7%. These patients also demonstrated a significant reduction in weight.
Of these patients, 974 chose to enter the 82-week, open-label, uncontrolled extension study.

Inclusion criteria for the extension study consisted of age between 16 and 75 years; type 2 diabetes treated for at least 3 months prior to screening with the maximally effective dose (1500 mg/day) of SU, metformin, or combination of both; A1C between 7.1% and 11.0%; fasting plasma glucose (FPG) <13.3 mmol/L; body mass index (BMI) between 27 and 45 kg/m²; no abnormal laboratory tests (relative to type 2 diabetes populations); and completion of the antecedent 30-week study. The primary objective of the 82-week study was to evaluate safety and change from baseline to each visit for A1C. Secondary endpoints included changes from baseline to each visit for weight, FPG levels, BMI, and lipid concentrations. Safety endpoints included adverse events occurring at the time of or soon after the first exenatide dose during the placebo-controlled study and throughout the 82-week extension study. All the safety analyses were performed using the 82-week intent-to-treat (ITT) group, defined as those people who received at least 1 injection in the extension study and whose enrollment timing permitted completion of the 82-week extension study. Demographic characteristics of the 82-week completer cohort were similar to the 82-week ITT population and the initial placebo-controlled study. Patients eligible to participate in the 82-week study initially received 5 mcg exenatide BID for 4 weeks, followed by 10 mcg exenatide thereafter. Study medication was subcutaneously injected into the abdomen 15 minutes prior to meals in the morning and evening.  

A total of 314 patients completed the study. The completer cohort A1C decreased (-0.9±0.1% from baseline) in the first 30 weeks of the extension study; the A1C reduction was maintained until the end of the 82 weeks, with a total reduction of -1.1±0.1%. Approximately 48% of patients reached an A1C ≤7% at 82 weeks. Additionally, the decrease in FPG was maintained for 82 weeks (change from baseline of placebo-controlled study = -0.9±0.2 mmol/L). The change in body weight from baseline to 82 weeks was progressive and reached -4.4±0.3 kg (4.4% of baseline body weight); 81% of patients had lost weight. Moreover, weight was also significantly reduced with the use of adjunct medications; there was a 5.3-kg loss with metformin and exenatide, 3.9-kg loss with SU and exenatide, and 4.1-kg loss with SU, metformin, and exenatide.
To assess for potential bias, the ITT group was analyzed for reduction in A1C and weight, with results of
-0.08±0.1% and -3.5±0.2 kg, respectively.

Exenatide was well tolerated overall, with nausea and hypoglycemia being the most frequent adverse events. Hypoglycemia occurred in approximately 10% of patients, and was generally mild to moderate. Four cases of severe hypoglycemia were reported, all in conjunction with SU use. Although nausea stabilized, weight loss did not, indicating that the occurrence of weight loss was independent of nausea. There was also a significant reduction in cardiovascular risk factors with the use of exenatide. Decreases in HDL-C, triglycerides, and sitting diastolic blood pressure were 0.12 mmol/L, -0.43 mmol/L, and -2.7 mm/Hg, respectively. Other parameters such as total cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, and systolic blood pressure also showed improvements.

The current analysis had a few limitations, including the absence of a comparison group, the changing nature of the study, and small study sample. However, the overall study results were promising and demonstrate that exenatide treatment is associated with a significant and progressive reduction in weight and A1C and notable improvements in some cardiovascular risk factors.