Chia Chee W, Egan Josephine M
National Institute on Aging, National Institutes of Health, Baltimore, MD 21224-6825, USA.
J Clin Endocrinol Metab. 2008 Oct;93(10):3703-16. doi: 10.1210/jc.2007-2109. Epub 2008 Jul 15.
Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide are incretins secreted from enteroendocrine cells postprandially in part to regulate glucose homeostasis. Dysregulation of these hormones is evident in type 2 diabetes mellitus (T2DM). Two new drugs, exenatide (GLP-1 mimetic) and sitagliptin [dipeptidyl peptidase (DPP) 4 inhibitor], have been approved by regulatory agencies for treating T2DM. Liraglutide (GLP-1 mimetic) and vildagliptin (DPP 4 inhibitor) are expected to arrive on the market soon.
The background of incretin-based therapy and selected clinical trials of these four drugs are reviewed. A MEDLINE search was conducted for published articles using the key words incretin, glucose-dependent insulinotropic polypeptide, GLP-1, exendin-4, exenatide, DPP 4, liraglutide, sitagliptin, and vildagliptin.
Exenatide and liraglutide are injection based. Three-year follow-up data on exenatide showed a sustained weight loss and glycosylated hemoglobin (HbA(1c)) reduction of 1%. Nausea and vomiting are common. Results from phase 3 studies are pending on liraglutide. Sitagliptin and vildagliptin are orally active. In 24-wk studies, sitagliptin reduces HbA(1c) by 0.6-0.8% as monotherapy, 1.8% as initial combination therapy with metformin, and 0.7% as add-on therapy to metformin. Vildagliptin monotherapy lowered HbA(1c) by 1.0-1.4% after 24 wk. Their major side effects are urinary tract and nasopharyngeal infections and headaches. Exenatide and liraglutide cause weight loss, whereas sitagliptin and vildagliptin do not.
The availability of GLP-1 mimetics and DPP 4 inhibitors has increased our armamentarium for treating T2DM. Unresolved issues such as the effects of GLP-1 mimetics and DPP 4 inhibitors on beta-cell mass, the mechanism by which GLP-1 mimetics lowers glucagon levels, and exactly how DPP 4 inhibitors lead to a decline in plasma glucose levels without an increase in insulin secretion, need further research.
胰高血糖素样肽-1（GLP-1）和葡萄糖依赖性促胰岛素多肽是餐后由肠内分泌细胞分泌的肠促胰岛素，部分用于调节葡萄糖稳态。这些激素的失调在2型糖尿病（T2DM）中很明显。两种新药，艾塞那肽（GLP-1类似物）和西他列汀[二肽基肽酶（DPP）4抑制剂]，已获监管机构批准用于治疗T2DM。利拉鲁肽（GLP-1类似物）和维格列汀（DPP 4抑制剂）预计很快上市。
回顾了基于肠促胰岛素治疗的背景以及这四种药物的部分临床试验。使用关键词肠促胰岛素、葡萄糖依赖性促胰岛素多肽、GLP-1、艾塞那肽-4、艾塞那肽、DPP 4、利拉鲁肽、西他列汀和维格列汀在MEDLINE上搜索已发表的文章。
艾塞那肽和利拉鲁肽为注射剂。艾塞那肽的三年随访数据显示体重持续减轻，糖化血红蛋白（HbA1c）降低1%。恶心和呕吐很常见。利拉鲁肽的3期研究结果尚未得出。西他列汀和维格列汀具有口服活性。在24周的研究中，西他列汀作为单一疗法可使HbA1c降低0.6 - 0.8%，作为与二甲双胍的初始联合疗法可降低1.8%，作为二甲双胍的附加疗法可降低0.7%。维格列汀单一疗法在24周后可使HbA1c降低1.0 - 1.4%。它们的主要副作用是尿路感染、鼻咽感染和头痛。艾塞那肽和利拉鲁肽会导致体重减轻，而西他列汀和维格列汀则不会。
GLP-1类似物和DPP 4抑制剂的出现增加了我们治疗T2DM的手段。一些尚未解决的问题，如GLP-1类似物和DPP 4抑制剂对β细胞量的影响、GLP-1类似物降低胰高血糖素水平的机制，以及DPP 4抑制剂究竟如何在不增加胰岛素分泌的情况下导致血糖水平下降，需要进一步研究。
