GLP-1 receptor agonists (GLP-1 RAs), with exenatide b.i.d. first approved for the treatment of type 2 diabetes in 2005, have been further developed to yield effective compounds/preparations, which have overcome the original problem of rapid elimination (short half-life), initially necessitating short intervals between injections (twice daily for exenatide b.i.d.). Today, GLP-1 RAs are injected twice daily (exenatide b.i.d.), once daily (lixisenatide, liraglutide) or once weekly (exenatide once weekly, dulaglutide, albiglutide, semaglutide). A daily oral preparation of semaglutide, which has shown a clinical effectiveness close to the once-weekly subcutaneous preparation, has recently been approved. All GLP-1 RAs share common mechanisms of action: augmentation of hyperglycaemia-induced insulin secretion, suppression of glucagon secretion at hyper- or euglycaemia, deceleration of gastric emptying preventing large post-meal glycaemic increments, reduction in calorie intake and body weight. Short-acting agents (exenatide b.i.d., lixisenatide) have reduced effectiveness on overnight and fasting plasma glucose, but maintain their effect on gastric emptying in long-term treatment. Long-acting GLP-1 RAs (liraglutide, exenatide once-weekly, dulaglutide, albiglutide, and semaglutide) have more profound effects on overnight and fasting plasma glucose and HbA_1c, both on a background of oral glucose-lowering agents and in combination with basal insulin. Effects on gastric emptying decrease over time (tachyphylaxis). Given a similar, if not superior, effectiveness for HbA_1c reduction with additional weight reduction and no intrinsic risk for hypoglycaemic episodes, GLP-1RAs are recommended as the preferred first injectable glucose-lowering therapy in type 2 diabetes, even before insulin treatment. However, GLP-1 RAs can be combined with (basal) insulin in either free or fixed-dose preparations. More recently developed agents, in particular semaglutide, are characterized by greater efficacy with respect to lowering plasma glucose as well as body weight. Since 2016, several cardiovascular (CV) outcomes studies have shown that GLP-1 RAs can effectively prevent CV events like acute myocardial infarction or stroke, and associated mortality. Therefore, guidelines particularly recommend treatment with GLP-1 RAs in patients with pre-existing atherosclerotic vascular disease (e.g., previous CV events). The evidence for similar effects in lower risk subjects is not quite as strong. Since sodium/glucose cotransporter-2 (SGLT-2) inhibitors treatment reduces CV events as well (with the effect mainly driven by a reduction of heart failure complications), the individual risk of ischaemic or heart failure complications should guide the choice of treatment. GLP-1 RAs may also help to prevent renal complications of type 2 diabetes. Other areas of active research in the field of GLP-1 RAs are the definition of subgroups within the type 2 diabetes population, who particularly benefit from treatment with GLP-1 RAs. This includes pharmacogenomic approaches and a characterization of non-responders. Novel indications for GLP-1 RAs outside type 2 diabetes, like type 1 diabetes, neuro-degenerative diseases, and psoriasis, are being explored. Thus, within 15 years of their initial introduction, GLP-1 RAs have become a well-established class of glucose-lowering agents which has the potential for further development and growing impact for the treatment of type 2 diabetes and potentially other diseases.

GLP-1受体激动剂（GLP-1 RA），艾塞那肽于2005年首次批准用于治疗2型糖尿病，经过进一步开发，产生了有效的化合物/制剂，克服了原来快速消除的问题（短半数） -life），最初需要较短的注射间隔（艾塞那肽每日两次）。如今，GLP-1 RA 每天注射两次（艾塞那肽 bid）、每天一次（利西拉肽、利拉鲁肽）或每周一次（艾塞那肽每周一次、度拉鲁肽、阿必鲁肽、索马鲁肽）。每日口服索马鲁肽制剂最近已获得批准，其临床效果接近每周一次皮下注射制剂。所有 GLP-1 RA 都有共同的作用机制：增加高血糖诱导的胰岛素分泌、抑制高血糖或正常血糖时的胰高血糖素分泌、减缓胃排空以防止餐后血糖大幅增加、减少热量摄入和体重。短效药物（艾塞那肽 bid、利西拉来）降低隔夜和空腹血糖的疗效，但在长期治疗中保持其对胃排空的作用。长效 GLP-1 RA（利拉鲁肽、艾塞那肽每周一次、度拉鲁肽、阿必鲁肽和索马鲁肽）对夜间和空腹血糖和 HbA1c 具有更深远的影响_，无论是在口服降糖药的背景下还是与联合用药联合使用基础胰岛素。对胃排空的影响随着时间的推移而减弱（快速耐受）。_对于HbA1c而言，即使不是更优越，也具有相似的效果由于 GLP-1RA 不仅能进一步减轻体重，而且没有低血糖发作的内在风险，因此被推荐作为 2 型糖尿病的首选注射降糖疗法，甚至在胰岛素治疗之前也是如此。然而，GLP-1 RA 可以与（基础）胰岛素联合制成游离或固定剂量制剂。最近开发的药物，特别是索马鲁肽，其特征在于在降低血浆葡萄糖和体重方面更有效。自 2016 年以来，多项心血管 (CV) 结局研究表明，GLP-1 RA 可以有效预防急性心肌梗死或中风等心血管事件以及相关死亡率。因此，指南特别建议对既往患有动脉粥样硬化性血管疾病（例如既往心血管事件）的患者使用 GLP-1 RA 进行治疗。在低风险受试者中显示类似效果的证据并不那么有力。由于钠/葡萄糖协同转运蛋白 2 (SGLT-2) 抑制剂治疗也可减少心血管事件（其效果主要是通过减少心力衰竭并发症来驱动），因此缺血性或心力衰竭并发症的个体风险应指导治疗的选择。GLP-1 RA 还可能有助于预防 2 型糖尿病的肾脏并发症。GLP-1 RA 领域的其他活跃研究领域是 2 型糖尿病人群中亚组的定义，这些亚组特别受益于 GLP-1 RA 治疗。这包括药物基因组学方法和无反应者的表征。2 型糖尿病以外的 GLP-1 RA 的新适应症（如 1 型糖尿病、神经退行性疾病和牛皮癣）正在探索中。因此，在首次推出后的 15 年内，GLP-1 RA 已成为一类成熟的降糖药物，具有进一步开发的潜力，并在 2 型糖尿病和其他潜在疾病的治疗中产生越来越大的影响。