Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes
Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes
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DOI：
10.1210/jc.2006-1009
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发表时间：
2006-11-01
影响因子：
5.8
通讯作者：
Wagner, John A.
中科院分区：
文献类型：
--
作者：
Herman, Gary A.;Bergman, Arthur;Wagner, John A.
背景：进餐后，胰高血糖素样肽 1 (GLP-1) 和葡萄糖依赖性促胰岛素肽 (GIP) 被释放并调节血糖控制。通常这些肠降血糖素会被二肽基肽酶-4 (DPP-4) 快速降解。 DPP-4抑制剂是一类新型口服降血糖药，正在开发用于治疗2型糖尿病。评估口服葡萄糖耐量试验（OGTT）后DPP-4抑制的程度和降糖效果所需的活性肠促胰素增强水平。 目的：本研究的目的是检查西格列汀的药效学、药代动力学和耐受性。设计：这是一项随机、双盲、安慰剂对照、三期、单剂量交叉研究。地点：该研究在六个研究地点进行。患者：研究人群包括 58 名未服用降血糖药物的 2 型糖尿病患者。干预措施：干预措施包括西他列汀 25 mg、西他列汀 200 mg 或安慰剂。 主要结果指标：测量包括血浆 DPP-4 活性； OGTT 后血糖漂移；活性和总肠促胰岛素 GIP 水平；胰岛素、C 肽和胰高血糖素浓度；结果：西格列汀在 24 小时内剂量依赖性地抑制血浆 DPP-4 活性，增强活性 GLP-1 和 GIP 水平，增加胰岛素/C-肽，降低胰高血糖素，并在单次口服 25 或 200 mg 西他列汀后 2 和 24 小时进行 OGTT 后血糖波动减少。西格列汀总体耐受性良好，没有出现低血糖事件。 结论：在这项针对 2 型糖尿病患者的研究中，单次口服剂量后西他列汀接近最大降糖功效与血浆 DPP-4 活性抑制 80% 或更高相关，对应于血浆西他列汀浓度为 100 nM 或更高，以及口服剂量后活性 GLP-1 和 GIP 水平增加 2 倍或更高。 OGTT。
Context: In response to a meal, glucagon-like peptide-1 ( GLP-1) and glucose- dependent insulinotropic peptide ( GIP) are released and modulate glycemic control. Normally these incretins are rapidly degraded by dipeptidyl peptidase- 4 ( DPP- 4). DPP- 4 inhibitors are a novel class of oral antihyperglycemic agents in development for the treatment of type 2 diabetes. The degree of DPP- 4 inhibition and the level of active incretin augmentation required for glucose lowering efficacy after an oral glucose tolerance test ( OGTT) were evaluated.Objective: The objective of the study was to examine the pharmacodynamics, pharmacokinetics, and tolerability of sitagliptin. Design: This was a randomized, double- blind, placebo- controlled, three- period, single- dose crossover study. Setting: The study was conducted at six investigational sites.Patients: The study population consisted of 58 patients with type 2 diabetes who were not on antihyperglycemic agents. Interventions: Interventions included sitagliptin 25 mg, sitagliptin 200 mg, or placebo.Main Outcome Measures: Measurements included plasma DPP- 4 activity; post- OGTT glucose excursion; active and total incretin GIP levels; insulin, C- peptide, and glucagon concentrations; and sitagliptin pharmacokinetics.Results: Sitagliptin dose- dependently inhibited plasma DPP- 4 activity over 24 h, enhanced active GLP- 1 and GIP levels, increased insulin/ C- peptide, decreased glucagon, and reduced glycemic excursion after OGTTs administered at 2 and 24 h after single oral 25- or 200- mg doses of sitagliptin. Sitagliptin was generally well tolerated, with no hypoglycemic events.Conclusions: In this study in patients with type 2 diabetes, near maximal glucose- lowering efficacy of sitagliptin after single oral doses was associated with inhibition of plasma DPP- 4 activity of 80% or greater, corresponding to a plasma sitagliptin concentration of 100 nM or greater, and an augmentation of active GLP- 1 and GIP levels of 2- fold or higher after an OGTT.