Exenatide Exhibits Dose-Dependent Effects on Glycemic Control over 12 Weeks in Japanese Patients with Suboptimally Controlled Type 2 Diabetes

Abstract

Abstract. This study assessed the dose-dependent efficacy and safety of exenatide over 12 weeks in Japanese patients with type 2 diabetes suboptimally controlled despite therapeutic doses of sulfonylurea (SU), SU plus biguanide, or SU plus thiazolidinedione. Patients were randomly assigned to placebo (N = 40), 2.5 µg (N = 38), 5 µg (N = 37), or 10 µg (N = 38) exenatide administered subcutaneously twice daily (bID). Patients randomly assigned to 10 µg exenatide received 5 µg bID for the first 4 weeks, with the dose escalated to 10 µg bID for the final 8 weeks. Patients were 60.3 ± 9.7 years old, with body mass index 25.3 ± 4.3 kg/m 2 and hemoglobin a1c (Hba1c) 8.0 ± 0.8%. baseline-to-endpoint Hba1c changes (%) were +0.02 ± 0.1 (placebo), -0.9 ± 0.1 (2.5 µg), -1.2 ± 0.1 (5 µg), and -1.4 ± 0.1 (10 µg) (all p < 0.001 vs. placebo). Of patients with baseline HbA1c ≥7%, 5.1% (placebo), 50.0% (2.5 µg), 71.4% (5 µg), and 79.4% (10 µg) achieved Hba1c <7% at endpoint (p < 0.001, trend test). baseline-to-endpoint fasting plasma glucose changes (mg/dL) were +6.0 ± 4.8 (placebo), -18.6 ± 5.7 (2.5 µg), -25.0 ± 7.0 (5 µg), and -28.9 ± 5.9 (10 µg) (all p ≤ 0.001 vs. placebo). Treatment-emergent adverse events were mostly mild; dose-dependent increases in incidence were observed for hypoglycemia, nausea, anorexia, decreased appetite, and diarrhea (all p ≤ 0.044, trend test). Over 12 weeks, exenatide dose-dependently improved glycemic control in Japanese patients with type 2 diabetes.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Exenatide Once Weekly in Japanese Patients with Type 2 Diabetes

“…The incidences of nausea and vomiting with exenatide QW in the current study were similar to those observed during previous studies of exenatide QW in primarily Caucasian populations [14,15], and generally lower than those observed during previous studies of exenatide BId in japanese and primarily Caucasian populations [13,[18][19][20][21]. Gradual dose escalation with exenatide BId has been shown to reduce the proportion of patients experiencing doselimiting nausea and vomiting [22].…”

“…By su, Tzds, and insulins, can cause weight gain in patients with T2d [30]. The reasons for the unexpected weight loss (-1.6 kg at Week 10) with placebo observed in this study are not known; however, a similar placebo effect and apparent neutral effect of exenatide on body weight, as compared with placebo, have also been observed previously in a study of exenatide BId in japanese patients with T2d [13]. This observed neutral effect of exenatide on body weight in japanese patients, regardless of exenatide formulation, may be due to the relative leanness of japanese patients with T2d [13] as compared with Caucasians [14,15,[18][19][20][21].…”

“…additionally, the improvements were generally greater than those from previous studies of similar or longer duration evaluating exenatide BId in japanese and primarily Caucasian populations [13,[18][19][20][21]. The degree of Hba 1c reduction in the current study was also notable given the patients' relatively low mean Hba 1c values of 7.3%-7.5% at baseline.…”

“…Exenatide twice daily (BId), administered as a subcutaneous injection, has been shown to reduce hemoglobin a 1c (Hba 1c ), fasting glucose, and postprandial glucose in japanese patients with T2d [12,13]. However, exenatide BId does not provide continuous activation of GLP-1 receptors.…”

Exenatide once weekly: clinical outcomes and patient satisfaction

“…66 This effect was seen in earlier exenatide twice daily studies in Japanese subjects. 70 The authors hypothesize that the leanness of the Japanese cohort could contribute to this apparent neutral effect on weight.…”