College of Pharmacy, Washington State University, Spokane, Washington 99210-1495, USA.
Clin Ther. 2011 May;33(5):528-76. doi: 10.1016/j.clinthera.2011.04.024.
Increased understanding of the role of incretin hormones in maintaining glucose homeostasis has enabled the development of pharmacotherapies that target deficient incretin activity in type 2 diabetes mellitus (T2DM). Incretin therapies are premised on 1 of 2 approaches: (1) augmenting the activity of the hormone glucagon-like peptide (GLP)-1 (GLP-1 receptor agonists) and (2) inhibiting the degradation of GLP-1 by dipeptidyl peptidase (DPP)-4 (DPP-4 inhibitors).
This review discusses the pharmacokinetic properties and clinical profiles of the GLP-1 receptor agonists (exenatide twice daily, liraglutide once daily, exenatide once weekly, taspoglutide, and albiglutide) and the DPP-4 inhibitors (sitagliptin, saxagliptin, vildagliptin, and alogliptin) available for use or in late-stage development.
A search of PubMed for literature published between 2000 and mid-2010 was conducted using the names of each agent as key words. Phase III and IV studies were included in the review of efficacy and tolerability. Supplemental searches of abstracts from major diabetes conferences provided additional information on pharmacokinetic properties. Searches of all reference lists were performed to identify additional references of interest.
The PubMed search identified multiple randomized, controlled clinical studies of the GLP-1 receptor agonists and the DPP-4 inhibitors administered as monotherapy or in combination regimens. Reductions from baseline in glycosylated hemoglobin ranged from 0.4% to 1.5% with exenatide 5 to 10 μg/d (7 studies), 0.6% to 1.5% with liraglutide 0.6 to 1.8 mg/d (6 studies), 0.3% to 1.0% with sitagliptin 25 to 200 mg/d (9 studies), 0.5% to 0.9% with saxagliptin 2.5 to 10 mg/d (3 studies), 0.4% to 1.0% with vildagliptin 50 to 100 mg/d (6 studies), and 0.4% to 0.8% with alogliptin 12.5 to 25 mg/d (4 studies). Dosage adjustments and caution in prescribing incretin therapies are recommended in patients with renal disease, with those recommendations varying based on the agent and the degree of dysfunction. Incretin therapies have been associated with few interactions with commonly used antihyperglycemic and cardiovascular therapies.
Based on the pharmacokinetic and therapeutic characteristics described in previously published Phase III and IV studies of incretin therapies, these agents may provide an option for the management of T2DM.
人们对肠促胰岛素激素在维持葡萄糖内稳态中的作用的认识不断加深，这使得针对 2 型糖尿病（T2DM）中肠促胰岛素活性不足的药物疗法得以发展。肠促胰岛素疗法基于以下两种方法之一：（1）增强激素胰高血糖素样肽（GLP）-1 的活性（GLP-1 受体激动剂），和（2）抑制二肽基肽酶（DPP）-4 对 GLP-1 的降解（DPP-4 抑制剂）。
本文讨论了 GLP-1 受体激动剂（每日两次给予艾塞那肽、每日一次给予利拉鲁肽、每周一次给予艾塞那肽、替西帕肽和阿必鲁肽）和 DPP-4 抑制剂（西他列汀、沙格列汀、维格列汀和阿格列汀）的药代动力学特性和临床特征，这些药物已被应用或处于后期开发阶段。
在 2000 年至 2010 年中期，使用每个药物的名称作为关键词，在 PubMed 上进行了文献搜索。在对疗效和耐受性进行综述时，纳入了 III 期和 IV 期研究。对主要糖尿病会议的摘要进行补充搜索，提供了关于药代动力学特性的更多信息。对所有参考文献列表进行搜索，以确定其他感兴趣的参考文献。
PubMed 搜索确定了多项关于 GLP-1 受体激动剂和 DPP-4 抑制剂的随机对照临床研究，这些药物作为单药或联合治疗方案给药。与基线相比，艾塞那肽 5 至 10 μg/d 可使糖化血红蛋白降低 0.4%至 1.5%（7 项研究），利拉鲁肽 0.6 至 1.8 mg/d 可使糖化血红蛋白降低 0.6%至 1.5%（6 项研究），西他列汀 25 至 200 mg/d 可使糖化血红蛋白降低 0.3%至 1.0%（9 项研究），沙格列汀 2.5 至 10 mg/d 可使糖化血红蛋白降低 0.5%至 0.9%（3 项研究），维格列汀 50 至 100 mg/d 可使糖化血红蛋白降低 0.4%至 1.0%（6 项研究），阿格列汀 12.5 至 25 mg/d 可使糖化血红蛋白降低 0.4%至 0.8%（4 项研究）。建议在肾功能受损的患者中调整肠促胰岛素治疗的剂量并谨慎处方，这些建议基于药物和功能障碍的程度而有所不同。肠促胰岛素疗法与常用的抗高血糖和心血管治疗药物之间的相互作用很少。
根据之前发表的关于肠促胰岛素疗法的 III 期和 IV 期研究中的药代动力学和治疗特征，这些药物可能为 T2DM 的治疗提供一种选择。
