基于肠促胰素治疗的药物比较:GLP-1类似物利拉鲁肽的临床优势

胰升糖素样肽1(GLP-1)受体激动剂和二肽基肽酶4(DPP-4)抑制剂是基于肠促胰素治疗2型糖尿病的2类药物,GLP-1受体激动剂可直接激活GLP-1受体,而DPP-4抑制剂通过阻止肠促胰素的酶降解间接发挥作用,二者在临床应用方面的比较是研究的热点.一项头对头比较研究表明,与DPP-4抑制剂西格列汀相比,GLP-1类似物利拉鲁肽降糖、减轻体重和改善β细胞功能的作用更为明显,同时患者的治疗满意度更高,在药物经济学上成本效益更优.利拉鲁肽的这些优势为2型糖尿病患者的临床治疗提供了新的理想选择.     

GLP-1受体激动剂与DPP-4抑制剂对2型糖尿病的疗效对比

目的:比较胰高血糖素样肽1(GLP-1)受体激动剂与二肽基肽酶4(DPP-4)抑制剂治疗2型糖尿病(T2DM)的临床效果。方法:选择2015年1月~2016年1月我院收治的T2DM患者96例。根据随机数字表法,患者被随机均分为GLP-1受体激动剂组(GLP-1组,接受GLP-1受体激动剂利拉鲁肽治疗)和DPP-4抑制剂组(DPP-4组,接受DPP-4抑制剂西格列汀治疗),两组均治疗18周。测量比较两组治疗前后空腹血糖(FBG)、餐后2h血糖(2hPG)水平,以及不良反应发生情况。结果:与治疗前比较,治疗18周后两组FBG、2hPG水平均有显著降低(P0.05或0.01);与DPP-4组比较,GLP-1组治疗后FBG[(7.48±0.45)mmol/L比(6.64±0.28)mmol/L]和2hPG[(11.15±1.01)mmol/L比(9.26±1.82)mmol/L]水平降低更显著,P均0.05。GLP-1组与DPP-4组的总不良反应发生率(29.2%比33.3%)无显著差异,P=0.078。结论:与DPP-4抑制剂比较,GLP-1受体激动剂治疗2型糖尿病在控制血糖和减轻体重方面效果更好,值得推广。     

基于肠促胰素治疗药物在中国或亚洲患者中的应用比较

目的随着对降糖药不良反应和降糖外保护效应的重视不断提高,基于肠促胰素治疗药物的临床应用不断增加。同样作为基于肠促胰素治疗药物——胰升血糖素样肽-1(GLP-1)受体激动剂与二肽基肽酶-4(DPP-4)抑制剂在药理学、疗效和安全性方面存在一些差异,且不同的GLP-1受体激动剂和DPP-4抑制剂间也各有优势和不足。本文将以在中国或亚洲患者中进行的研究为证据,对在我国上市的2种GLP-1受体激动剂和5种DPP-4抑制剂的降糖疗效、降糖外保护效应进行比较,旨在指导临床医生选择合理的降糖药物。     

GLP-1受体激动剂与二肽基肽酶4抑制剂治疗2型糖尿病的比较

随着对肠促胰素在维持葡萄糖稳定作用认识的日益增多,促进了针对2型糖尿病患者肠促胰素活性缺乏治疗药物的研发.根据肠促胰素治疗药物不同的作用机制,可分为以下2类:(1)胰升糖素样肽1(GLP-1)受体激动剂,包括利拉鲁肽(liraglutide)、艾塞那肽每日2次制剂和艾塞那肽每周1次制剂;(2)二肽基肽酶4(DPP-4)抑制剂,包括西格列汀(sitagliptin)、利拉利汀(linagliptin)、沙格列汀(saxagliptin)和维格列汀(vildagliptin),DPP-4抑制剂可限制内源性GLP-1的降解.这2类药物具有某些共性,如葡萄糖依赖性刺激胰岛素分泌,低血糖发生率低.然而这2类药物在疗效方面的表现却有所不同.本文综述了这2类基于肠促胰素治疗药物的药代动力学及其临床方面的疗效和安全性,阐明了此类药物在2型糖尿病治疗中的地位.     

G LP-1类似物与D PP-4抑制剂对肥胖2型糖尿病患者疗效观察

目的分析GLP-1类似物与DPP-4抑制剂在肥胖2型糖尿病治疗中的临床效果。方法选取2017年1月—2019年1月在该院接受治疗的肥胖2型糖尿病患者共106例分为DPP-4抑制剂组和GLP-1类似物组,DPP-4抑制剂组应用口服药物西格列汀进行治疗,GLP-1类似物组应用注射药物利拉鲁肽进行治疗,比较两组用药方式对患者血糖以及血脂的影响。结果治疗后GLP-1类似物组的FPG、TC、腰围、体重以及SBP显著低于DPP-4抑制剂组,不良反应发生率显著高于DPP-4抑制剂组,组间差异有统计学意义(P0.05)。其他血糖、血脂、血压以及用药安全性指标,两组相比较差异无统计学意义(P0.05)。结论 GLP-1类似物与DPP-4抑制剂在肥胖2型糖尿病治疗中均具有良好的疗效。     

DPP-4抑制剂对糖尿病肾病的保护作用

高血糖是糖尿病肾病发病的重要原因之一.二肽基肽酶-4（DPP-4）抑制剂可减少胰高血糖素样肽-1（GLP-1）降解,改善机体高血糖状态,从而延缓糖尿病肾病病程的进展.此外,DPP-4抑制剂还可影响其他与糖尿病肾病相关的非GLP-1底物,如基质细胞衍生因子-1α、脑钠尿肽及金属内肽酶的表达,继而发挥GLP-1非依赖性的肾脏保护作用.研究DPP-4抑制剂对糖尿病患者肾脏的保护作用及其机制,将为其在糖尿病肾病治疗中的应用提供新的认识.     

DPP-4抑制剂在2型糖尿病中的研究进展

2型糖尿病是一种慢性进展性疾病,诊断初期患者的胰岛β细胞功能即损失50％以上.肠促胰岛激素效应的发现和应用是近年来糖尿病治疗方面较新的研究领域之一,它是人类进食后由肠道内分泌L细胞分泌的一类激素,主要包括胰升糖素样肽1(GLP-1)和葡萄糖依赖性促胰岛素分泌多肽(GIP),可以帮助机体产生部分餐后胰岛素效应.GLP-1是目前已知的最强的刺激胰岛素释放的物质之一,但是由于GLP-1的血浆半寿期很短(＜2分钟),体内一种蛋白酶-二肽基肽酶4(DPP-4)可裂解GLP-1氨基端的脯氨酸和丙氨酸,从而使GLP-1迅速降解,生物活性丧失.随着对糖尿病病理生理机制和肠促胰岛激素生理作用的深入研究,DPP-4抑制剂作为一种基于肠促胰岛激素机制的药物,给2型糖尿病的治疗提供了新的方法.我们就DPP-4抑制剂在2型糖尿病中的应用和研究进展作一综述.     

从LIRA—DPP-4i研究看利拉鲁肽的早期临床应用

胰升血糖素样肽-1（GLP-1）受体激动剂（含GLP-1类似物）和二肽基肽酶-Ⅳ（DPP-Ⅳ）抑制剂是目前与肠促胰素有关的治疗T2DM的药物。LIRA-DPP-4i研究表明,利拉鲁肽与西格列汀相比,具有更有效降（HbA1c、FPG降幅更大）、更明显减轻体重和更显著改善β细胞功能的特点。利拉鲁肽还可降低糖尿病前期发病率,早期应用更早获益。     

胰高糖素样肽1在心力衰竭治疗方面的研究进展

糖尿病作为一种慢性系统性疾病,已成为包括心力衰竭在内的心血管疾病的重要危险因素,且糖尿病合并心力衰竭的患者日益增多。胰高糖素样肽1(GLP-1)是肠道L细胞分泌的一种肠促胰激素,可通过多种机制调节葡萄糖代谢。GLP-1受体激动剂及二肽基肽酶4(DPP-4)抑制剂是新型抗糖尿病药物。现已知其具有抗氧化、减轻缺血性心肌损伤、降压、保护内皮细胞等多种心脏保护作用,本文就GLP-1在心力衰竭治疗方面的研究进展做一综述。     

新型降糖药物在三种常见青少年的成年起病型糖尿病亚型上的应用

青少年的成年起病型糖尿病(maturity-onset diabetes of the young, MODY)是一种异质性的单基因糖尿病,其中MODY1、MODY2和MODY3是常见的MODY亚型。近年来胰升糖素样肽1受体激动剂(GLP-1RA)、二肽基肽酶4抑制剂(DPP-4i)、钠-葡萄糖共转运蛋白2抑制剂(SGLT2i)与葡萄糖激酶激动剂(GKA)等新型降糖药物在治疗糖尿病方面取得了良好的进展,本文结合目前最新的基础及临床证据,对上述三种MODY的发病机制、临床特征、关于新型降糖药物的诊疗进展作一综述,旨在为MODY的诊疗开拓更为安全有效的新方法。     

Incretin therapy and its effect on body weight in patients with diabetes

Glucagon-like peptide 1 (GLP-1) analogues and dipeptidyl peptidase-4 (DPP-4) inhibitors are two classes of treatments for type 2 diabetes, which enhance the well-known 'incretin effect' of increased insulin secretion in response to food intake. This concise review introduces both types of incretin-based therapies and focuses on the extra-pancreatic effect of GLP-1 on body weight. As well as improving glycaemic control in subjects with type 2 diabetes, these treatments have the additional benefits of improving weight management in these patients, with GLP-1 receptor agonists causing weight loss and DPP-4 inhibitors being weight neutral.     

Preclinical and Clinical Data on Extraglycemic Effects of GLP-1 Receptor Agonists

The diverse actions of the incretin hormone glucagon-like peptide (GLP)-1 include insulinotropic, beta-cell preservative, cardioprotective and vasodilatory effects. This spectrum makes GLP-1 an appealing therapeutic option for patients with type 2 diabetes. However, its rapid metabolism by the enzyme dipeptidyl peptidase (DPP)-4 renders it impractical. Incretin-based analogues have been developed to extend endogenous GLP-1 action (GLP-1 receptor agonists) and to hamper its degradation (DPP-4 inhibitors). Evidence suggests that GLP-1 receptor agonists and DPP-4 inhibitors have different pharmacodynamic and pharmacokinetic effects. For example, GLP-1 receptor agonists deliver supraphysiologic levels of GLP-1 analogues designed to resist inactivation by DPP-4, whereas DPP-4 inhibition conserves native GLP-1 resulting in concentrations within the physiologic range. Furthermore, GLP-1 receptor agonists induce glucose-dependent insulin secretion, beta-cell protection, and other extraglycemic benefits such as weight loss and improvement in markers of cardiovascular risk. In contrast, DPP-4 inhibitors are weight neutral and have modest effects on glucose control. DPP-4 inhibition is dependent on the availability of endogenous GLP-1, which appears to be adversely affected by type 2 diabetes and its progression. Therefore, DPP-4 inhibitors may be better suited for patients with mild hyperglycemia without comorbidities. This review examines the present understanding of the pancreatic effects of endogenous GLP-1, and the extrapancreatic actions it exerts on human bodily systems. Also, it analyzes available preclinical and clinical data on incretin therapies with respect to glycemia, lipids, blood pressure, and weight.     

Impact of glucagon-like peptide-1 on myocardial glucose metabolism revisited

The gut hormone glucagon-like peptide-1 (GLP-1) is an insulinotropic incretin with significant cardiovascular impact. Two classes of medication, GLP-1 analogues and DPP-4 inhibitors, have been developed that circumvent the rapid degradation of GLP-1 by the enzyme dipeptidyl peptidase-4 (DPP-4), both enhance the incretin effect and were developed for the treatment of type 2 diabetes. Several mechanisms suggesting that DPP-4 inhibitors, GLP-1, and analogues could have a protective effect on the cardiovascular risk profile have been forwarded; e.g., reductions of blood glucose, body weight, blood pressure, improvement in left ventricular ejection fraction, myocardial perfusion, atherosclerosis development, and endothelial function. Despite this, the reasons for a decreased risk of developing cardiovascular disease and reduced post-ischaemia damage are still poorly understood. The potentially beneficial effect of GLP-1 stimulation may rely on, among others, improved myocardial glucose metabolism. This review focuses on the dogma that GLP-1 receptor stimulation may provide beneficial cardiovascular effects, possibly due to enhanced myocardial energetic efficiency, by increasing myocardial glucose uptake. The published literature was systematically reviewed and the applied models evaluated since the outcomes of varying studies differ substantially. Reports on the effect of GLP-1R stimulation on myocardial metabolism are conflicting and should be evaluated carefully. There is limited and conflicting information on the impact of these agents in real life patients and while clinical outcome studies investigating the cardiovascular effects of GLP-1 based therapies have been initiated, the first two studies, both on DPP-4 inhibitors, designed specifically to evaluate cardiac safety reported largely neutral outcomes.     

Glycaemic efficacy of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors as add-on therapy to metformin in subjects with type 2 diabetes-a review and meta analysis

Aims: During recent years, two strategies of incretin-based therapy [glucagon-like peptide-1 (GLP-1) receptor agonism and dipeptidyl peptidase-4 (DPP-4) inhibition] have entered the market for pharmacological management of type 2 diabetes. A main indication for this therapy is as add-on to on-going metformin therapy in subjects with type 2 diabetes who have insufficient glycaemic control with metformin alone. The aim of this study was to compare improvements in glycaemic control and changes in body weight, as well as adverse events, in comparable studies with incretin-based therapy as add-on to metformin. Methods: Studies having a duration of 16-30 weeks were identified from PubMed. Results: A total of 27 study groups in 21 studies fulfilled the criteria of examining incretin-based therapy as add-on to metformin at clinically recommended doses in patients with type 2 diabetes for 16-30 weeks; 7 of these used a short-acting GLP-1 receptor agonist (exenatide BID), 7 used longer acting GLP-1 receptor agonists (liraglutide or exenatide LAR), whereas 14 studies examined DPP-4 inhibitors. In all studies, incretin-based therapy reduced HbA1c concentrations. The reduction in HbA1c was significantly greater in study groups with long-acting GLP-1 receptor agonists than with the other two groups (both p < 0.001), whereas there were no differences between exenatide BID and DPP-4 inhibitors. Across all study groups, there was a negative linear correlation between baseline HbA1c and change in HbA1c (r = -0.70; p < 0.001). Fasting glucose also fell significantly more in study groups given liraglutide or exenatide LAR than in those given exenatide BID or DPP-4 inhibitors (both p < 0.001). Furthermore, body weight was reduced by a similar extent in the two groups with GLP-1 receptor agonists and was not significantly altered in the groups with DPP-4 inhibitors. Lipids, blood pressure and heart rate were not reported consistently, which did not allow general conclusions. Adverse events were rare, apart from increased incidence of nausea and vomiting with GLP-1 receptor agonists. Conclusion: Incretin-based therapy efficiently improves glycaemia when added to metformin in patients with type 2 diabetes, and within 16-30 weeks there is a more pronounced reduction in HbA1c with long-acting GLP-1 receptor agonists (liraglutide and exenatide LAR) than with exenatide BID and DPP-4 inhibitors, although the magnitude of the effect is dependent on the baseline values. Both strategies appear to be associated with a very low risk of adverse events, including hypoglycaemia. Finally, the injectable GLP-1 receptor agonists also reduce body weight (whereas the DPP-4 inhibitors are weight neutral) but are also associated with a greater incidence of gastrointestinal side effects and a tendency to increase heart rate.     

Differentiating among incretin-based therapies in the management of patients with type 2 diabetes mellitus

ABSTRACT: The glucagon-like peptide-1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors have become important options for the management of patients with type 2 diabetes mellitus. While the GLP-1R agonists and DPP-4 inhibitors act on the incretin system to regulate glucose homeostasis, there are important clinical differences among the five agents currently available in the U.S. For example, the GLP-1R agonists require subcutaneous administration, produce pharmacological levels of GLP-1 activity, promote weight loss, have a more robust glucose-lowering effect, and have a higher incidence of adverse gastrointestinal effects. In contrast, the DPP-4 inhibitors are taken orally, increase the half-life of endogenous GLP-1, are weight neutral, and are more commonly associated with nasopharyngitis. Differences in efficacy, safety, tolerability, and cost among the incretin-based therapies are important to consider in the primary care management of patients with type 2 diabetes mellitus.     

Inkretinbasierte Therapien

Incretin-based therapies have become established for the treatment of type 2 diabetes since the introduction in 2006. The injectable glucagon-like peptide 1 receptor-agonists (GLP-1-RA) and the orally active dipeptidyl peptidase 4 (DPP-4) inhibitors have a strict glucose dependent action on insulin and glucagon secretion resulting in a negligible intrinsic hypoglycemia risk. The GLP-1-RAs only act by directly stimulating GLP-1 receptors by receptor ligand concentrations in the pharmacological range. They slow gastric emptying dependent on the duration of action and also act directly by stimulating satiety signals in the central nervous system. These effects lead to a loss of body weight. The DPP-4 inhibitors primarily elevate endogenous GLP-1 plasma concentrations two to threefold. They are body weight neutral as they do not have effects on the central nervous system or gastrointestinal motility. Novel studies suggest beneficial cardiovascular effects of incretin-based therapies. This article gives an overview about novel developments in this therapeutic field.     

Incretin-based therapies in type 2 diabetes: A review of clinical results

GLP-1 analogues (incretin mimetics) and DPP-4 inhibitors (incretin enhancers) represent new classes of anti-diabetic agents for the treatment of type 2 diabetes. The efficacy and safety of the incretin mimetic exenatide and of the DPP-4 inhibitors, sitagliptin and vildagliptin, have been clearly demonstrated by a very large number of clinical trials. Efficacy was demonstrated in terms of reduction of HbA1c, fasting and postprandial glucose. Moreover, exenatide showed a favourable effect on weight, while DPP-4 inhibitors were neutral with respect to this outcome. The low rate of hypoglycemic events seen in all studies confirms the glucose dependent action of incretins.     

Comparison of liraglutide versus other incretin-related anti-hyperglycaemic agents

The two classes of incretin-related therapies, dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs), have become important treatment options for patients with type 2 diabetes. Sitagliptin, saxagliptin, vildagliptin and linagliptin, the available DPP-4 inhibitors, are oral medications, whereas the GLP-1 RAs-twice-daily exenatide, once-weekly exenatide and once-daily liraglutide-are administered subcutaneously. By influencing levels of GLP-1 receptor stimulation, these medications lower plasma glucose levels in a glucose-dependent manner with low risk of hypoglycaemia, affecting postprandial plasma glucose more than most other anti-hyperglycaemic medications. Use of GLP-1 RAs has been shown to result in greater glycaemic improvements than DPP-4 inhibitors, probably because of higher levels of GLP-1 receptor activation. GLP-1 RAs can also produce significant weight loss and may reduce blood pressure and have beneficial effects on other cardiovascular risk factors. Although both classes are well tolerated, DPP-4 inhibitors may be associated with infections and headaches, whereas GLP-1 RAs are often associated with gastrointestinal disorders, primarily nausea. Pancreatitis has been reported with both DPP-4 inhibitors and GLP-1 RAs, but a causal relationship between use of incretin-based therapies and pancreatitis has not been established. In clinical trials, liraglutide has shown efficacy and tolerability and resulted in certain significant benefits when compared with exenatide and sitagliptin.     

Gemeinsamkeiten und Unterschiede inkretinbasierter Therapien

The options to treat type 2 diabetes with incretin-based therapies were introduced approximately 5 years ago. The options comprise injectable glucagon-like peptide 1 receptor agonists (GLP-1 RA) and orally active dipeptidylpeptidase?4 (DPP-4) inhibitors. Both classes of drugs stimulate insulin secretion and inhibit glucagon secretion in a glucose-dependent manner. For these reasons they do not possess an intrinsic risk for hypoglycemia. The GLP-1 RAs lead to a sustained rise of GLP-1 concentrations to levels approximately 5- to 10-fold higher than the physiological plasma concentrations. They exert their pharmacological effects exclusively by stimulating the GLP-1 receptor. The GLP-1 RAs additionally slow gastric emptying and stimulate the feeling of satiety in the central nervous system (CNS) and not only improve glycemic parameters but also induce weight loss. The inhibition of DPP-4 results in a 2- to 3-fold elevation of endogenous GLP-1 concentration additionally the degradation of gastric inhibitory polypeptide (GIP) and other peptides is inhibited and prolonged. No effects on gastric emptying are observed and DPP-4 inhibitors are weight neutral. This article gives an overview on the similarities and differences of GLP-1 RA and DPP-4 inhibitor actions and the developments to be expected in this field.     

GLP-1 based therapies: differential effects on fasting and postprandial glucose

Glucagon-like peptide-1 (GLP-1), a gut-derived hormone secreted in response to nutrients, has several glucose and weight regulating actions including enhancement of glucose-stimulated insulin secretion, suppression of glucagon secretion, slowing of gastric emptying and reduction in food intake. Because of these multiple effects, the GLP-1 receptor system has become an attractive target for type 2 diabetes therapies. However, GLP-1 has significant limitations as a therapeutic due to its rapid degradation (plasma half-life of 1-2 min) by dipeptidyl peptidase-4 (DPP-4). Two main classes of GLP-1-mediated therapies are now in use: DPP-4 inhibitors that reduce the degradation of GLP-1 and DPP-4-resistant GLP-1 receptor (GLP-1R) agonists. The GLP-1R agonists can be further divided into short- and long-acting formulations which have differential effects on their mechanisms of action, ultimately resulting in differential effects on their fasting and postprandial glucose lowering potential. This review summarizes the similarities and differences among DPP-4 inhibitors, short-acting GLP-1R agonists and long-acting GLP-1R agonists. We propose that these different GLP-1-mediated therapies are all necessary tools for the treatment of type 2 diabetes and that the choice of which one to use should depend on the specific needs of the patient. This is analogous to the current use of modern insulins, as short-, intermediate- and long-acting versions are all used to optimize the 24-h plasma glucose profile as needed. Given that GLP-1-mediated therapies have advantages over insulins in terms of hypoglycaemic risk and weight gain, optimized use of these compounds could represent a significant paradigm shift for the treatment of type 2 diabetes.