Washington State University College of Pharmacy, Pullman, Washington 99164-6510, USA.
Clin Ther. 2011 May;33(5):511-27. doi: 10.1016/j.clinthera.2011.04.015.
Glucose homeostasis is the result of a complex interaction of a spectrum of hormones, including insulin, glucagon, amylin, and the incretins. Incretins are released by enteroendocrine cells in the intestine in response to a meal. Incretin dysfunction, along with a number of other defects, has been implicated in contributing to the pathogenesis of type 2 diabetes mellitus (T2DM). Therapies that restore incretin activity may reduce the pathophysiologic consequences of diabetes.
The aim of this article was to review incretin physiology and studies of incretin therapy with glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors that were developed to specifically address the blunted incretin response in patients with T2DM.
Relevant English-language publications between 1995 and 2010 were identified through a search of the MEDLINE and EMBASE databases using the search terms incretin, type 2 diabetes mellitus, GLP-1, glucose-dependent insulinotropic polypeptide, and DPP-4. Review articles and preclinical and clinical trials that described relevant details of the epidemiology of diabetes and incretin physiology in health and in T2DM were selected for review and inclusion. Clinical trials were used to describe the clinical efficacy and safety of the GLP-1 receptor agonists and DPP-4 inhibitors in patients with T2DM. An occasional systematic review article and/or meta-analysis summarizing numerous clinical trials of a particular agent was selected for summarizing key data.
Pharmacologic modulation of incretin pathophysiology by GLP-1 receptor agonists and DPP-4 inhibitors significantly improved glycemic control, benefited β-cell function, improved dyslipidemia, and lowered the risk of hypoglycemia compared with insulin and sulfonylureas. Unlike the DPP-4 inhibitors, GLP-1 receptor agonist therapy also produced weight loss, an important consideration given the close association among T2DM, overweight/obesity, and cardiovascular disease. The most common adverse events with GLP-1 receptor agonist therapy included nausea (28%-44%), vomiting (13%-17%), and diarrhea (11%-17%), which generally reduced in incidence and severity with continued therapy. The tolerability profile of the DPP-4 inhibitors was very good, with the incidence of adverse events similar to that of placebo. There was a suggestion of an increased incidence of nasopharyngitis versus placebo (5%-6% vs 3%-4%) with sitagliptin and urinary tract infection (6.8% vs 6.1% with placebo) and headache with saxagliptin (6.5% vs 5.9% with placebo).
The 2 incretin drug classes provided effective and consistent glycemic control with a good tolerability profile. These agents might also improve long-term β-cell function and either reduce body weight or be weight neutral. Their role in the therapeutic armamentarium of T2DM is evolving as their potential strengths and weaknesses become better defined.
葡萄糖稳态是一系列激素（包括胰岛素、胰高血糖素、胰岛淀粉样多肽和肠促胰岛素）复杂相互作用的结果。肠促胰岛素是肠道内分泌细胞在进食后释放的。肠促胰岛素功能障碍以及其他一些缺陷与 2 型糖尿病（T2DM）的发病机制有关。恢复肠促胰岛素活性的疗法可能会降低糖尿病的病理生理后果。
本文旨在综述肠促胰岛素生理学，以及开发用于治疗 T2DM 的胰高血糖素样肽-1（GLP-1）受体激动剂和二肽基肽酶-4（DPP-4）抑制剂的研究。这些药物专门针对 T2DM 患者的肠促胰岛素反应减弱。
通过在 MEDLINE 和 EMBASE 数据库中使用“肠促胰岛素、2 型糖尿病、GLP-1、葡萄糖依赖性胰岛素释放肽和 DPP-4”等搜索词，检索了 1995 年至 2010 年期间的相关英文文献。选择了描述糖尿病和肠促胰岛素生理学在健康和 T2DM 中流行病学的相关细节的综述文章和临床前及临床试验进行综述和纳入。临床研究用于描述 GLP-1 受体激动剂和 DPP-4 抑制剂在 T2DM 患者中的临床疗效和安全性。选择了个别系统评价文章和/或汇总特定药物大量临床试验的荟萃分析，以总结关键数据。
与胰岛素和磺酰脲类药物相比，GLP-1 受体激动剂和 DPP-4 抑制剂对肠促胰岛素病理生理学的药物调节显著改善了血糖控制，有利于β细胞功能，改善了血脂异常，并降低了低血糖风险。与 DPP-4 抑制剂不同，GLP-1 受体激动剂治疗还可导致体重减轻，鉴于 T2DM、超重/肥胖和心血管疾病之间的密切关联，这是一个重要的考虑因素。GLP-1 受体激动剂治疗最常见的不良反应包括恶心（28%-44%）、呕吐（13%-17%）和腹泻（11%-17%），随着持续治疗，这些不良反应的发生率和严重程度通常会降低。DPP-4 抑制剂的耐受性良好，不良反应的发生率与安慰剂相似。与安慰剂相比，西格列汀的不良反应发生率略有增加（5%-6%比 3%-4%），尿路感染（6.8%比安慰剂 6.1%）和头痛（6.5%比安慰剂 5.9%）发生 saxagliptin。
这 2 种肠促胰岛素药物类别提供了有效的、一致的血糖控制，具有良好的耐受性。这些药物还可能改善长期的β细胞功能，或减轻体重，或保持体重不变。随着对它们的潜在优势和劣势的认识不断加深，它们在 T2DM 治疗武器库中的作用正在不断发展。
