Discipline of Medicine, Royal Adelaide Hospital, University of Adelaide, North Terrace, Adelaide, SA, 5000, Australia.
Adv Ther. 2013 Feb;30(2):81-101. doi: 10.1007/s12325-013-0009-4. Epub 2013 Feb 13.
"Incretin-based" therapies, such as the glucagon-like peptide-1 (GLP-1) receptor agonists, represent a major advance in type 2 diabetes mellitus (T2DM) treatment. GLP-1 receptor agonists differ substantially in their duration of action, frequency of administration and clinical profile.
This article reviews the mechanisms of action and clinical evidence for GLP-1 receptor targeting and discusses differences between GLP-1 therapies, focusing particularly on clinical data for the GLP-1 receptor agonist, lixisenatide.
GLP-1 therapies target islet cell "defects" of insufficient insulin and excessive glucagon secretion in T2DM, in a glucose-dependent manner, with minimal risk of hypoglycemia. Different GLP-1 therapies exert differential effects on fasting and postprandial glycemia (both being major determinants of glycemic control). They also slow gastric emptying to different extents, probably accounting for different effects to reduce postprandial glycemia. The GetGoal phase 3 studies in T2DM have confirmed the efficacy of once-daily lixisenatide in reducing plasma glucose and glycated hemoglobin (HbA1c), with a pronounced lowering of postprandial plasma glucose (PPG), as monotherapy and as add-on to oral antidiabetic drugs and to basal insulin. Lixisenatide's ability to diminish PPG is probably partly mediated by its marked ability to delay gastric emptying. Lixisenatide is generally well tolerated, with possibly better gastrointestinal tolerability and lower risk of hypoglycemia than exenatide immediate release. Lixisenatide is associated with a beneficial effect on weight, with either no change or a decrease in body weight when administered as add-on therapy to basal insulin in overweight patients with T2DM.
Lixisenatide improves glycemic control, by primarily affecting PPG, while preventing weight gain or reducing body weight with a low risk of hypoglycemia in T2DM. Lixisenatide is likely to represent a significant advance in the management of T2DM, perhaps particularly in those patients with relatively faster gastric emptying and lower levels of HbA1c, including those receiving basal insulin.
“肠促胰岛素类”疗法，如胰高血糖素样肽-1（GLP-1）受体激动剂，是 2 型糖尿病（T2DM）治疗的重大进展。GLP-1 受体激动剂在作用持续时间、给药频率和临床特征方面有很大差异。
本文综述了 GLP-1 受体靶向的作用机制和临床证据，并讨论了 GLP-1 疗法之间的差异，特别关注 GLP-1 受体激动剂利西那肽的临床数据。
GLP-1 疗法以葡萄糖依赖性方式针对 T2DM 中胰岛细胞胰岛素分泌不足和胰高血糖素分泌过多的“缺陷”，低血糖风险极小。不同的 GLP-1 疗法对空腹和餐后血糖（均是血糖控制的主要决定因素）产生不同的影响。它们还以不同的程度减缓胃排空，这可能是降低餐后血糖的不同作用的原因。在 T2DM 中的 GetGoal 阶段 3 研究证实了每日一次利西那肽在降低血浆葡萄糖和糖化血红蛋白（HbA1c）方面的疗效，具有显著降低餐后血糖（PPG）的作用，作为单药治疗以及与口服降糖药和基础胰岛素联合应用。利西那肽降低 PPG 的能力可能部分是通过其显著延缓胃排空的能力介导的。利西那肽通常具有良好的耐受性，与即时释放的艾塞那肽相比，可能具有更好的胃肠道耐受性和更低的低血糖风险。利西那肽与体重的有益影响相关，当在超重的 T2DM 患者中作为基础胰岛素的附加治疗时，体重可能没有变化或减轻。
利西那肽通过主要影响 PPG 来改善血糖控制，同时防止体重增加或减轻体重，且低血糖风险低，在 T2DM 中具有重要意义。利西那肽可能是 T2DM 管理的重大进展，特别是在那些胃排空较快和 HbA1c 水平较低的患者中，包括正在接受基础胰岛素治疗的患者。
