Early Pharmacodynamic Effects of Exenatide Once Weekly in Type 2 Diabetes Are Independent of Weight Loss: A Pooled Analysis of Patient-level Data

详细信息    查看全文

• 作者：Michael E. Trautmann ; MD¹ ; ^{metraut@gmail.com" class="auth_mail" title="E-mail the corresponding author} ; Jenny Han ; MS² ; James Ruggles ; PhD³
• 关键词：diabetes mellitus ; early response ; exenatide ; glucagon-like peptide-1 receptor agonist ; HbA1c ; pharmacokinetics
• 刊名：Clinical Therapeutics
• 出版年：2016
• 出版时间：June 2016
• 年：2016
• 卷：38
• 期：6
• 页码：1464-1473
• 全文大小：373 K

文摘

Exenatide once weekly, a glucagon-like peptide-1 receptor agonist (GLP-1RA), is approved as an adjunct to diet and exercise for the treatment of adults with type 2 diabetes mellitus. Exenatide acts by binding to and activating glucagon-like peptide-1 receptors, thereby stimulating glucose-dependent insulin secretion, suppressing glucose-dependent glucagon secretion, slowing gastric emptying, and increasing feelings of satiety. Gradual increases in drug level (“autotitration”) after the initiation of a fixed exenatide 2-mg weekly dose achieve minimal effective (~50 pg/mL) and steady-state (~300 pg/mL) concentrations by 2 weeks and 6 to 8 weeks, respectively. The purpose of this study was to examine pharmacodynamic outcomes with exenatide once weekly and to determine whether changes are secondary to weight loss and thus delayed by the sequential nature of responses.

Methods

This post hoc analysis evaluated trials in the exenatide once-weekly development program. Outcomes included glycosylated hemoglobin (HbA_1c), weight, fasting serum or plasma glucose (FG), lipids, and blood pressure (BP) at weeks 2, 4, and 24. Relationships between changes from baseline in these outcomes and changes in weight were examined. The effect of nausea and vomiting (adverse events characteristic of GLP-1RAs) on weight loss was also assessed.

Findings

Pooled data were analyzed from 12 trials in which 2190 patients received exenatide once weekly. Patients had a mean HbA_1c level of 8.4% and weight of 87 kg at baseline. Exenatide once weekly produced significant improvements in HbA_1c, FG, weight, and systolic BP at weeks 2 and 4, with continuous improvements through week 24. There were no clinically meaningful correlations between weight loss and improvements in pharmacodynamic outcomes at weeks 2, 4, or 24. Patients had significant reductions in weight at weeks 2, 4, and 24 regardless of whether they experienced nausea and/or vomiting during the study, although patients with at least 1 nausea/vomiting event had greater weight loss at week 24 than those who did not.

Implications

Improvements in pharmacodynamic end points occurred early in treatment with exenatide once weekly, before steady-state plasma concentrations. These early effects did not seem to be secondary to weight loss and are likely the direct effects of exenatide.