Abstract Objective: This study assessed the pharmacokinetics, pharmacodynamics, and tolerability of single doses of exenatide in adolescent patients with type 2 diabetes mellitus (T2DM). Methods: ...This was a randomized, single-blind, dose-escalation, crossover study in adolescent (age 10–16 years) patients with T2DM who were being treated with diet and exercise or a stable dose of metformin, a sulfonylurea, or a combination of metformin and a sulfonylurea for at least 3 months before screening. Eligible patients were allocated to receive single subcutaneous doses of exenatide 2.5 μg, exenatide 5 μg, and placebo, each followed by a standardized meal, on 3 separate days (maximum interval between first and third doses, 5 weeks). Exenatide 2.5 μg always preceded exenatide 5 μg in each treatment sequence. The primary end points were the pharmacokinetics and safety profile of exenatide; secondary end points included postprandial plasma glucose, serum insulin, and plasma glucagon concentrations. Results: The study enrolled 13 adolescent patients with T2DM (7 females, 6 males; mean SD age, 15 1 years; body mass index, 32.5 5.0 kg/m2 ; glycosylated hemoglobin, 8.2% 1.5%). After administration of exenatide 5 μg, the geometric mean (SE) exenatide AUC0−∞ and Cmax were 339.5 (39.6) pg · h/mL and 85.1 (11.5) pg/mL, respectively (n = 12). The exenatide AUC appeared to be dose dependent, although exenatide was not quantifiable in all patients at the 2.5-μg dose; after administration of exenatide 2.5-μg, the geometric mean AUC0−∞ ) was 159.2 (23.1) pg · h/mL (n = 6) and the geometric mean Cmax was 56.3 (10.1) pg/mL (n = 9). Both exenatide doses were associated with significant reductions in postprandial plasma glucose excursions compared with placebo ( P < 0.01); the incremental mean (SE) AUC15–360min was −3465.6 (1587.3) mg · min/dL for exenatide 2.5 pg, −4422.2 (2434.4) mg · min/dL for exenatide 5 μg, and 3457.4 (1615.5) mg · min/dL for placebo. The 2 exenatide doses were also associated with significant reductions in postprandial plasma glucagon concentrations compared with placebo ( P < 0.01); the respective incremental mean values for AUC15–180min were 125.5 (658.4), −1403.8 (632.1), and 1843.1 (540.6) pg · min/mL. There were no significant differences in serum insulin concentrations between exenatide and placebo. Exenatide was generally well tolerated, with no hypoglycemic events recorded during the study. Conclusions: In these adolescent patients with T2DM, administration of single 2.5- and 5-μg doses of exenatide were associated with dose-dependent increases in plasma exenatide concentrations and improved postprandial glucose concentrations compared with placebo. Both doses appeared to be well tolerated. ClinicalTrials.gov Identifier: NCT00254254.
Abstract Background: Exenatide, an incretin mimetic for adjunctive treatment of type 2 diabetes mellitus (T2DM), reduced glycosylated hemoglobin (HbA1c ) and weight in 30-week placebo-controlled ...trials. Some patients were followed up in open-label extensions to provide ‘real-world’ exenatide clinical experience. Objective: The purpose of this study was to examine the metabolic effects of 2 years of exenatide treatment in patients with T2DM. Methods: For this interim analysis, data were pooled from patients who completed 1 of three 30-week, multicenter, double-blind, placebo-controlled trials and their open-label extensions. In the initial trials, subjects were randomized to BID 5-pg exenatide, 10-pg exenatide, or placebo for 30 weeks. All subjects who enrolled in the extension phase then received 5-pg exenatide BID for 4 weeks, followed by open-label treatment with 10-pg exenatide BID. Subjects continued their existing metformin and/or sulfonylurea regimens. Analyses were conducted on data from all subjects who had the opportunity to achieve 2 years of exenatide exposure, irrespective of their treatment arm in the 30-week placebo-controlled trials. Results: A total of 974 patients entered the open-label, extension phase of the trial. Two hundred eighty-three subjects (mean SD age, 57 10 years; mean SD weight, 100 119 kg; sex, 63% male; mean SD body mass index, 34 6 kg/m2; mean SD HbA1c , 8.3% 1.0%1 completed 2 years of exenatide treatment. Reductions in mean (SE) HbA1c from baseline to week 30 (−0.9% 0.1%) were sustained through 2 years (−1.1% 0.1%; P < 0.05 vs baseline), with 50% of the population achieving HbA1c ≤ 7%. At week 30, exenatide was associated with a significant reduction in mean (SD) body weight from baseline (−2.1 0.2 kg), with progressive reductions after 2 years (−4.7 0.3 kg; P < 0.001 vs baseline). Patients with normal baseline alanine aminotransferase (ALT) (132/283 47%; normal: female ≤19 IU/L; male ≤30 IU/L) had no significant ALT change. However, patients with elevated ALT at baseline (151/283 53%) had a mean (SEM) reduction of ALT (−11 1 IU/L from baseline 38 1 IU/1,; P < 0.05) and 39% achieved normal ALT by week 104. Patients with elevated ALT at baseline lost significantly more weight than patients with normal ALT at baseline ( P = 0.04). However, weight change was minimally correlated with baseline ALT ( r = −0.09) or ALT change ( r = 0.31). Also, homeostasis model assessment of the β-cell function (HOMA-B), blood pressure, and aspartate aminotransferase (AST) all improved. The most frequently reported adverse event was mild-to-moderate nausea. Conclusions: In these patients with T2DM, adjunctive exenatide treatment for 2 years was generally well tolerated and resulted in a sustained reduction of HbA1c , progressive reduction in weight, and improvements in HOMA-B, blood pressure, and the hepatic injury biomarkers, AST and ALT.
