Robles Gisela I, Singh-Franco Devada
Nova Southeastern University, College of Pharmacy, Health Professions Division, 3200 South University Drive,Fort Lauderdale, FL 33328, USA.
Drug Des Devel Ther. 2009 Sep 21;3:219-40. doi: 10.2147/dddt.s3321.
Incretin glucagon-like peptide-1 (GLP-1) is a hormone released from cells in the gastrointestinal tract (GI), leading to glucose-dependent insulin release from the pancreas. It also suppresses postprandial hyperglycemia, glucagon secretion and slows gastric emptying. Exenatide (EXE), a functional analog of human GLP-1, was approved by the US FDA in April 2005.
This article reviews current primary literature on the clinical efficacy and safety of EXE in the treatment of type 2 diabetes mellitus (DM) and describes the pharmacokinetics, pharmacodynamics, dosing and administration of EXE.
English-language articles were identified through a search of MEDLINE (1966 to March 2009), International Pharmaceutical Abstracts (1970 to present), and Cochrane Database of Systemic Reviews (1995 to March 2009). Search terms included EXE, diabetes mellitus, postprandial hyperglycemia, gastric emptying, glucagon, pharmacokinetics and pharmacodynamics. Articles were selected for review if their designs were randomized, blinded and of controlled design that focused on clinical outcomes of patients with type 2 DM.
EXE is administered subcutaneously in the thigh, abdomen or upper arm within the 60-minute period before the morning and evening meals. Its C(max) is reached within 2.1 hours, and its T(1/2) in 2.4 hours. EXE's metabolism is primarily through the kidneys. For the patients who received EXE 10 microg SC BID in three, 30-week, placebo-controlled studies with background sulfonylureas (SUs), metformin (MET), or SU + MET, there were significant reductions in HbA(1c) (0.77 to 0.86%), fasting plasma glucose (0.6 mmol/L) and body weight (1.6 to 2.8 kg) (P < or = 0.05 vs PCB) that were sustained in patients who completed two open-label phase trials with an additional 52 weeks of therapy. The use of thiazolidinediones was associated with a slight advantage over EXE in improving HbA(1c) along with increased weight gain; those who received EXE lost weight, but experienced more GI adverse effects. Patients who received EXE lost significant body weight while patients who received insulin gained weight. Patients receiving insulin had lower fasting, prelunch and predinner glucose excursions while patients in the EXE groups had lower postprandial glucose levels. Nausea was most frequently (>20%) reported in patients receiving the highest dose of EXE (10 microg SC BID vs 5 microg SC BID).
EXE at the dose of 10 microg SC BID has been proven to decrease HbA(lc) by 1.3% +/- 0.1% and decrease body weight by up to 5.3 +/- 0.8 kg at week 82. Nausea was the most frequently reported adverse event (>20%) especially in patients being treated with EXE 10 microg SC BID. EXE can be safely added to MET therapy, SU therapy or MET + SU combination to effectively target glycemic goals in patients with type 2 DM. Long-term, head-to-head studies assessing the effect of the EXE +/- oral agents/insulins in patients with HbA(lc) > or = 10% are still needed to fully clarify the role of EXE in poorly controlled patients with type 2 DM.
肠促胰岛素胰高血糖素样肽-1（GLP-1）是一种从胃肠道（GI）细胞释放的激素，可导致胰腺依赖葡萄糖释放胰岛素。它还能抑制餐后高血糖、胰高血糖素分泌并减缓胃排空。艾塞那肽（EXE）是一种人GLP-1的功能类似物，于2005年4月获美国食品药品监督管理局（FDA）批准。
本文综述了关于EXE治疗2型糖尿病（DM）的临床疗效和安全性的当前主要文献，并描述了EXE的药代动力学、药效学、剂量和用法。
通过检索MEDLINE（1966年至2009年3月）、《国际药学文摘》（1970年至今）和Cochrane系统评价数据库（1995年至2009年3月）来识别英文文章。检索词包括EXE、糖尿病、餐后高血糖、胃排空、胰高血糖素、药代动力学和药效学。如果文章设计为随机、双盲且为对照设计，重点关注2型糖尿病患者的临床结局，则选择其进行综述。
EXE在早晚餐前60分钟内于大腿、腹部或上臂皮下注射。其在2.1小时内达到C(max)，T(1/2)为2.4小时。EXE主要通过肾脏代谢。在三项为期30周、以磺脲类药物（SUs）、二甲双胍（MET）或SU + MET为背景治疗的安慰剂对照研究中，接受10μg皮下注射每日两次（SC BID）EXE的患者，糖化血红蛋白（HbA(1c)）显著降低（0.77%至0.86%）、空腹血糖降低（0.6 mmol/L）、体重降低（1.6至2.8 kg）（与安慰剂组相比，P≤0.05），在完成两项开放标签的后续52周治疗期试验的患者中，这些效果得以持续。噻唑烷二酮类药物在改善HbA(1c)方面比EXE略有优势，但体重增加更多；接受EXE治疗的患者体重减轻，但胃肠道不良反应更多。接受EXE治疗的患者体重显著减轻，而接受胰岛素治疗的患者体重增加。接受胰岛素治疗的患者空腹、午餐前和晚餐前血糖波动较低，而EXE组患者餐后血糖水平较低。接受最高剂量EXE（10μg皮下注射每日两次对比5μg皮下注射每日两次）的患者中，恶心是最常报告的（>20%）不良反应。
已证实，在第82周时，10μg皮下注射每日两次的EXE可使HbA(lc)降低1.3%±0.1%，体重减轻多达5.3±0.8 kg。恶心是最常报告的不良事件（>20%），尤其是在接受10μg皮下注射每日两次EXE治疗的患者中。EXE可安全地添加到MET治疗、SU治疗或MET + SU联合治疗中，以有效实现2型糖尿病患者的血糖目标。仍需要进行长期的、直接比较的研究，以评估EXE±口服药物/胰岛素对HbA(lc)≥10%患者的影响，从而充分阐明EXE在控制不佳的2型糖尿病患者中的作用。
