DPP-4抑制剂的药代动力学特点

DP P-4抑制剂作为治疗2型糖尿病的新型药物正在崭露头角,目前已上市的DPP-4抑制剂有西格列汀、维格列汀和沙格列汀.本文就这3种DP P-4抑制剂的主要药代动力学特点,吸收、分布、代谢和排泄进行综述.     

DPP-4抑制剂维格列汀的心血管效应

抗糖尿病药物的心血管安全性及作用备受关注。传统降糖药物,如磺脲类及噻唑烷二酮类均可能出现心血管不良反应。新型口服降糖药物DPP-4抑制剂维格列汀存在对心血管的潜在获益,在糖尿病治疗中的心血管安全性已经得到充分验证。     

市售DPP-4抑制剂类抗糖尿病药物的比较研究

DPP-4抑制剂是近年来上市的一类高效、高选择性抗2型糖尿病药物,通过检索文献,综述已上市的五种DPP-4抑制剂在结构、药代药动、选择性、药物相互作用、副作用等方面的差异.     

DPP-4的基因组学研究进展与DPP-4抑制剂的临床应用

二肽基肽酶IV(DPP-4)是一种分布广泛的膜相关性丝氨酸蛋白酶,能够影响糖代谢、脂质代谢、免疫调节、神经调节、信号转导、癌症发展等多种生理功能。随着全基因组关联研究(GWAS)的发展,DPP-4基因的基因多态性,主要是单核苷酸多态性已被证实影响血脂水平和mRNA表达,还影响心血管疾病的易感性,可能与DPP-4抑制剂在血脂紊乱和心血管疾病方面的疗效具有密切关系,这在2型糖尿病的治疗中具有重要意义。本文对国内外所有关于DPP-4基因多态性的研究进行综述,并在此基础上探讨其对DPP-4抑制剂在2型糖尿病治疗中的影响。     

从指南的变迁看DPP-4抑制剂的临床地位

二肽基肽酶（DPP-4）抑制剂的研究广受关注,多项临床研究证实其有效性及安全性,包括能有效控制糖化血红蛋白,低血糖和体重增加发生率较低。不少国际性糖尿病组织制定的2型糖尿病治疗指南已将此类新降糖药列入治疗流程。虽和经典降糖药物相比,其临床应用时间较短,在治疗策略中的地位仍存有争议,但在不远将来,更多临床数据或可证明长期使用DPP-4抑制剂的安全性和有效性,从而进一步提高其临床地位。     

DPP-4抑制剂的心血管保护作用

二肽基肽酶-4（DPP-4）抑制剂作为一类新上市用于治疗2型糖尿病的药物,最新的荟萃分析结果显示[1],DPP-4抑制剂可以有效地降低糖化血红蛋白（HbA1c）0.6%～1.1%,与安慰剂相比不易出现低血糖,且不易引起严重不良反应。     

DPP-4抑制剂研究进展

DPP-4抑制剂是一类用于治疗2型糖尿病的口服降糖新药,可改善血糖控制,并且不会诱发低血糖和增加体重。与原有药物相比,DPP-4抑制剂在用药安全性方面具有显著的优势。本综述介绍已上市的DPP-4抑制剂及其作用机理和临床研究。     

维格列汀与西格列汀降糖疗效对比

目的:比较维格列汀和西格列汀的降糖效果。方法:受试者随机分配维格列汀组,或者西格列汀组。先后分服两药,使用动态血糖监测(CGM)测定24h的平均血糖、平均血糖波动幅度(MAGE)、空腹血糖、餐后血糖、HbA1c、GA、1,5AG、IRI、CPR、BNP、PAI-1以及尿C肽。结果:维格列汀组的24h平均血糖低于西格列汀组(142.1±35.5vs.153.2±37.0mg/dL;P=0.012)。与西格列汀相比,服用维格列汀的患者,MAGE下降(110.5±33.5vs.129.4±45.1mg/dL;P=0.040),晚餐后血糖峰值也下降(206.1±40.2vs.223.2±43.5mg/dL;P=0.015),早餐后3h内AUC≥180mg/dL也下降(484.3vs.897.9mg/min/dL;P=0.025),尿CPR显著上升(97.0±41.6vs.85.2±39.9μg/day;P=0.008)。两组间HbA1c,GA,1,5AG,IRI,CPR,BNP,或PAI-1均无意义。结论:与西格列汀比较,维格列汀的降糖效果更好,副作用更小,对心血管的保护作用更佳,值得临床推广应用。     

DPP-4抑制剂的有效性和安全性评价

二肽基肽酶4（DPP-4）抑制剂是一类基于肠促胰素的新型的口服降糖药物，其出现为2型糖尿病患者带来新的选择，目前我国已有5种DPP-4抑制剂被SFDA批准上市。多项研究表明其无论单药还是与其他药物联合使用均能降低HbA1c、空腹血糖及餐后血糖，并具有较低低血糖风险，对体重的影响中性，不影响胃排空等特点。具有较高的有效性及良好的安全性和耐受性。但是长期用药的有效性和安全性仍缺乏足够证据。     

从代谢安全性优势看DPP-4抑制剂的治疗依从性

二肽基肽酶-4(DPP-4)抑制剂是治疗2型糖尿病的新靶点,其作用机制是靶向控制餐后和空腹血糖,增强B细胞对于血糖的敏感性,增加血糖依赖性胰岛素分泌。动物试验还观察到,长期使用DPP-4抑制剂,胰岛B细胞量呈剂量依赖性增加,B细胞体积恢复正常,有效改善血糖[1-3]。     

DPP-4抑制剂调节血糖外的作用

DPP-4抑制剂疗效的产生依赖于通过抑制二肽基肽酶Ⅳ使机体内源性的GLP-1水平升高.GLP-1受体分布广泛,除分布在胰岛外,还存在于胃、十二指肠、胰腺外分泌、脑干、丘脑、下丘脑、海马、心、肺、肾、肌细胞、脂肪细胞及肝脏,有证据表明GLP-1受体在内脏传入神经也有表达[1].目前学者们对GLP-1类似物和DPP-4抑制剂在治疗2型糖尿病方面进行了大量研究,本文对DPP-4抑制剂降糖以外的作用进一步进行探讨.     

DPP-4抑制剂的用药方案

2型糖尿病的发病机制包括胰岛素抵抗和进行性B细胞分泌不足两个环节,通过肠促胰岛素(incretin)的作用而改善胰岛B和A细胞分泌功能及胰岛素敏感性,为2型糖尿病的治疗开辟了新的途径.     

DPP-4抑制剂的降糖作用机制

上个世纪三十年代,法国人LaBarre首次提出了＂肠促胰素＂这一概念。近年来的研究加深了人们对肠促胰素的认识,并且催生了一种新型的口服降糖药物——二肽基肽酶-4（DPP-4）抑制剂,它可以提高血液中内源性GLP-1和GIP的浓度,并最终改善血糖控制。目前已有数种DPP-4抑制剂在部分国家上市销售。这些药物的化学结构和药效／代动力学或许各有差异，但它们都能有效地降低血糖（HbAl。降低0．5％～1％）并具有良好的耐受性。本文将着重从A细胞和B细胞的双向调节方面阐述此类药物的作用机制。     

DPP-4 inhibitors in diabetic complications: role of DPP-4 beyond glucose control

Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) are an emerging class of antidiabetic drugs that constitutes approximately fifty percent of the market share of the oral hypoglycemic drugs. Its mechanism of action for lowering blood glucose is essentially via inhibition of the rapid degradation of incretin hormones, such as glucagon-like peptide (GLP)-1 and gastric inhibitory polypeptide (GIP), thus the plasma concentration of GLP-1 increases, which promotes insulin secretion from the pancreatic β cells and suppresses glucagon secretion from the α cells. In addition to the direct actions on the pancreas, GLP-1 exhibits diverse actions on different tissues through its action on GLP-1 receptor, which is expressed ubiquitously. Moreover, DPP-4 has multiple substrates besides GLP-1 and GIP, including cytokines, chemokines, neuropeptides, and growth factors, which are involved in many pathophysiological conditions. Recently, it was suggested that DPP-4 is a new adipokine secreted from the adipose tissue, which plays an important role in the regulation of the endocrine function in obesity-associated type 2 diabetes. Consequently, DPP-4 inhibitors have been reported to exhibit cytoprotective functions against various diabetic complications affecting the liver, heart, kidneys, retina, and neurons. This review outlines the current understanding of the effect of DPP-4 inhibitors on the complications associated with type 2 diabetes, such as liver steatosis and inflammation, dysfunction of the adipose tissue and pancreas, cardiovascular diseases, nephropathy, and neuropathy in preclinical and clinical studies.     

DPP-4抑制剂不良反应

糖尿病是一种因胰岛素绝对或相对不足或胰岛素抵抗引起的以糖代谢紊乱为主的慢性综合性疾病,严重影响患者的健康和生活质量.随着对糖尿病发病机制和病理生理的了解,新的治疗糖尿病(主要是2型糖尿病)药物逐渐被开发.二肽基肽酶Ⅳ(DPP-4)抑制剂是近年来用于治疗2型糖尿病的新药之一.肠促胰岛素胰高血糖素样肽-1(GLP-1)等多种激素可增加葡萄糖依赖的胰岛素分泌抑制不适当的胰高血糖素分泌增多.并能增强胰岛素敏感性,延缓胃排空和抑制食欲,从而发挥降血糖作用,然而在体内其很快被DPP-4降解而起不到有效的降血糖效果.     

DPP-4 inhibitors in the treatment of type 2 diabetes

Although being a primary objective in the management of type 2 diabetes, optimal glycaemic control is difficult to achieve and usually not maintained over time. Type 2 diabetes is a complex pathology, comprising altered insulin sensitivity and impaired insulin secretion. Recent advances in the understanding of the physiological functions of incretins and their degrading enzyme dipeptidyl-peptidase (DPP)-4 have led to the 'discovery' of a new class of oral anti-diabetic drugs. Several DPP-4 inhibitors (or gliptins) with different chemical structures are now available. These agents inhibit the degradation of the incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) and hence potentiate glucose-dependent insulin secretion. DPP-4 inhibitors inhibit DPP-4 activity by almost 100% in vitro, maintaining a ≥ 80% inhibition throughout the treatment period in vivo, thus prolonging GLP-1 half-life, and significantly reducing HbA1c generally by -0.7 to 0.8% as well as fasting and post-prandial glycaemia. They are well-tolerated with no weight gain and few adverse effects, and, of particular interest, no increase in hypoglycaemic episodes. Although different by their chemical structure and pharmacokinetic properties, the DPP4 inhibitors currently available have proven similar glucose lowering efficacy.     

DPP-4 inhibitors: focus on safety

Introduction: Dipeptidyl peptidase inhibitors (DPP-4-i) are highly selective inhibitors of the enzyme DPP-4. They act by increasing levels of incretin hormones, which have potent effects on insulin and glucagon release, gastric emptying, and satiety. Our goal is to review the safety issues related to DPP-4-i.

Areas covered: This review is based upon a PubMed search of the literature using keywords alogliptin, linagliptin, saxagliptin, sitagliptin and vildagliptin, DPP-4-i, glucagon-like polypeptide-1 agonists, as well as extensive personal clinical trial experience with each of these agents. The current DPP-4-i have very different chemical structures. Saxagliptin has significant cytochrome P450 metabolism and carries a risk of drug interactions. Linagliptin has primarily entero-hepatic excretion, a benefit in renally impaired patients. A concern arose related to congestive heart failure in the SAVOR TIMI trial of saxagliptin. Several major cardiac studies are underway, with two concluded. Despite lingering uncertainty related to pancreatitis and pancreatic cancer, large randomized trials have not shown an increased risk with DPP-4-i treatment. Cutaneous adverse effects occur with a low frequency with some of these agents.

Expert opinion: DPP-4-i are an additional choice in the group of anti-hyperglycemics. Their principal advantage is a low incidence of hypoglycemia, making these agents desirable in patients such as the elderly and those with cardiac disease. Several large trials have hinted at less cardiac risk with DPP-4-i than with sulfonylureas. The CAROLINA Trial comparing linagliptin and glimepiride may provide a conclusive answer to this question.     

基础胰岛素与二肽基肽酶－4抑制剂联合治疗2型糖尿病的临床观察

目的：观察基础胰岛素与二肽基肽酶－4抑制剂联合治疗2型糖尿病的临床疗效。方法：将80例2型糖尿病患者（空腹血糖＞11．1 mmol／L）以随机数字表法分为观察组与对照组各40例,观察组患者给予地特胰岛素与西格列汀联合治疗,对照组患者给予地特胰岛素与瑞格列奈联合治疗,观察2组患者的临床疗效。结果：观察组患者空腹及餐后2h血糖、糖化血红蛋白、血脂谱、体质量指数较治疗前明显下降（P＜0．05）,且各项指标改善情况均优于对照组（P＞0．05）;2组患者胰岛β细胞功能均较治疗前明显下降,观察组改善情况优于对照组（P＜0．05）;2组患者不良反应均较少,差异无统计学意义（P＞0．05）;2组患者血糖达标率及血糖达标中位时间的差异有统计学意义（P＜0．05）。结论：基础胰岛素与二肽基肽酶－4抑制剂联合治疗2型糖尿病,具有较好的临床疗效,且安全性高,值得推广。