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。     

抗2型糖尿病药物DPP-4抑制剂的研究进展

目的对近年来抗2型糖尿病药物二肽基肽酶Ⅳ(DPP-4)抑制剂的最新研究进展进行综述。方法介绍了已上市和处于临床的药物最新情况,并根据化学结构不同,对处于临床前研究的小分子DPP-4抑制剂进行归纳汇总。结果根据文献查阅,已进入市场的DPP-4抑制剂有12种,处于临床研究阶段的有4个药品,此外有许多新型小分子DPP-4抑制剂处于临床前研究阶段。结论相较于传统药物,新型的DPP-4抑制剂具有疗效好,副作用少,不易诱发低血糖等各种优势,因此开发更安全高效的DPP-4抑制剂具有很大的发展前景。     

DPP-4抑制剂治疗2型糖尿病的研究进展及临床应用

DPP-4抑制剂是治疗2型糖尿病的新型药物。较传统的降糖药物而言,DPP-4抑制剂对降低2型糖尿病患者的血糖有更好的疗效,可以降低低血糖的危险,安全性及耐受性良好。本文通过分析DPP-4抑制剂类药物,综述其化学性质、物理作用、临床研究和当前待解决的问题,对DPP-4抑制剂类药物的研究进展及临床应用疗效进行探究和展望。     

DPP-4抑制剂治疗糖尿病的临床疗效

目的探讨DPP-4抑制剂治疗糖尿病的临床疗效。方法选取2013年3月—2015年3月晋中市第一人民医院收治的84例糖尿病患者,分为对照组和观察组,每组42例。对照组患者接受双胍类(二甲双胍)药物治疗,观察组患者在对照组基础上接受DPP-4抑制剂(西格列汀)治疗。比较两组患者的临床疗效及不良反应发生情况。结果观察组患者空腹血糖(FPG)、餐后2h血糖(2h PG)及糖化血红蛋白(Hb A1c)低于对照组,总有效率高于对照组,不良反应发生率低于对照组,差异有统计学意义(P<0.05)。结论 DPP-4抑制剂治疗糖尿病的临床疗效显著,不良反应少,安全性高。     

不同DPP-4抑制剂的构效关系和药代动力学特征

二肽基肽酶-4（DPP-4）抑制剂是治疗2型糖尿病的新靶点,强效和选择性DPP-4抑制剂已成为糖尿病治疗新药的开发热点。本文主要对已在国内上市的西格列汀、沙格列汀、维格列汀和利格列汀4种DPP-4抑制剂的构效关系以及药代动力学特点,吸收、分布、代谢、消除进行综述。     

DPP-4抑制剂治疗糖尿病国内研究现状

二肽基肽酶-4（DPP-4）抑制剂是一类新型口服降糖药物,其通过抑制DPP-4酶活性,提高体内内源性胰升糖素样肽1（GLP-1）水平,增强肠促胰素作用进而发挥降糖作用。DPP-4抑制剂除了能有效的控制血糖水平,还能保护胰岛功能,延缓疾病进程,在临床上已被广泛用于治疗糖尿病。本文通过查阅国内相关文献及资料,对相关科研成果进行总结归纳,就DPP-4抑制剂治疗糖尿病在国内的研究状况做一综述。     

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。     

DPP-4抑制剂联合阿卡波糖治疗2型糖尿病的疗效分析

目的探讨DPP-4抑制剂联合阿卡波糖治疗2型糖尿病的疗效。方法选取2015年3月至2017年3月我院收治的应用阿卡波糖降糖治疗血糖尚未达标的2型糖尿病患者64例为研究对象,在继续应用阿卡波糖的基础上加用DPP-4抑制剂降糖治疗。1个月后与加药前进行对比分析。结果加药后患者的糖化血红蛋白水平、空腹及餐后2 h血糖低于加药前。加药后,患者的NO高于加药前,ET-1低于加药前。结论 DPP-4抑制剂联合阿卡波糖治疗2型糖尿病的应用效果显著,症状和指标得到改善,提高了治疗效果,值得应用。     

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]。     

新型降糖药DPP-4抑制剂研究进展

二肽基肽酶-4 (dipeptidyl peptidase-4, DPP-4)是研发新型降糖药物的热门靶点。目前,已经发现许多DPP-4抑制剂,其中一些化合物已经进入临床应用。本文介绍了DPP-4抑制剂在降糖药中的地位及作用机制,综述了近年来不同结构类型DPP-4抑制剂的研究进展。     

The safety of DPP-4 inhibitor and SGLT2 inhibitor combination therapies

Introduction: Type 2 diabetes (T2D), a multifactorial and chronic disease, requires in an elevated percentage of patients the association of several antidiabetic drugs to achieve optimal glycemic control. Dipeptidyl peptidase-4 inhibitors (DPP-4i) and sodium–glucose cotransporter inhibitors (SGLT2i) are new classes of oral antidiabetic drugs developed over the last years.

Areas covered: This paper summarizes the safety of DPP-4i and SGLT2i combination therapies. Relevant studies were identified through searches in PubMed.

Expert opinion: DPP4i and SGLT2i are antidiabetic drugs that lower blood glucose without causing hypoglycaemia or weight increase. More importantly, cardiovascular trials have clearly demonstrated the cardiovascular safety of DPP4i and a reduction in cardiovascular events with SGLT2i (empagliflozin and canagliflozin). Therefore, the association of both therapeutic groups could be an attractive option to achieve optimal blood glucose control in T2D because of their complementary mechanism of action. Clinical trials evaluating the combination of SGLT2i and DPP4i show that the co-administration of these drugs in fixed-dose combinations in comparison to separate tablets does not carry additional safety concerns that each individual drug, but increases therapeutic effects. Therefore, this antidiabetic combination is a safe and effective therapy for patients with T2D.     

二肽基肽酶4抑制剂在控制2型糖尿病透析患者代谢指标中的作用

目的：研究3种不同二肽基肽酶4（DPP-4）抑制剂对终末期肾病合并2型糖尿病患者代谢参数的影响。方法：对200例应用DPP-4抑制剂（西格列汀、维格列汀或利格列汀）治疗2型糖尿病的终末期肾病患者进行前瞻性队列研究。DPP-4抑制剂治疗12周前后评估糖化血红蛋白（HbA1c）、空腹血糖和代谢指标的变化。结果：西格列汀、维格列汀、利格列汀治疗组HbA1c水平下降无显著性差异（分别为-0.74±1.57、-0.39±1.45和-0.08±1.40，P=0.076），空腹血糖及血脂变化亦无显著差异。在血液透析患者（n=115）中，3组间HbA1c水平变化无差异。相比之下，腹膜透析患者（n=85）用西格列汀治疗12周后，HbA1c比用维格列汀和利格列汀治疗12周降低得更多（分别为-1.58±0.95，-0.46±0.98，-0.04±1.22，P=0.001）。结论：在终末期肾病患者中使用不同DPP-4抑制剂的降糖作用差异无显著性。在腹膜透析患者中，西格列汀比其他DPP-4抑制剂可使HbA1c水平降低更多。     

胰高血糖素样肽-1受体激动剂和二肽基肽酶-4抑制剂联用二甲双胍治疗2型糖尿病的疗效与安全性对比的系统评价

目的：比较胰高血糖素样肽-1（GLP-1）受体激动剂和二肽基肽酶-4（DPP-4）抑制剂联用二甲双胍治疗2型糖尿病的疗效和安全性。方法：计算机检索Pubmed,Embase,Cochrane Library,CNKI,WanFang,VIP,CBM数据库,纳入GLP-1受体激动剂和DPP-4抑制剂联用二甲双胍比较治疗2型糖尿病的随机对照试验（RCT）,检索时间截止至2016年6月1日。由两位研究者根据纳入排除标准筛选文献、提取资料以及对文献质量进行评价,采用Rev-Man 5.3.5软件对数据进行分析。结果：共纳入14篇RCT。Meta分析结果显示：GLP-1受体激动剂+二甲双胍在降低糖化血红蛋白,降低空腹血糖,减轻体重,降低收缩压方面均优于DPP-4抑制剂+二甲双胍,差异具有统计学意义;在降低舒张压方面,2组并无差别;DPP-4抑制剂+二甲双胍组不良反应发生率更低,差异具有统计学意义;在低血糖方面,2组发生率相当,没有统计学差异。结论：GLP-1受体激动剂+二甲双胍在降低2型糖尿病患者的血糖,体质量控制以及降低收缩压方面优于DPP-4抑制剂+二甲双胍,但是不良反应发生率更高。     

治疗2型糖尿病的DPP-4抑制药及其知识产权分析

DPP-4抑制药是近年来研发及上市的新一类口服降糖药物及热点药物,其为2型糖尿病的临床治疗提供了新的选择。国内目前批准及临床应用的治疗2型糖尿病的DPP-4抑制药全部为进口产品。本文对国内外研发与批准上市的DPP-4抑制药知识产权现状进行了详细的研究分析,合理利用好即将专利到期或专利已经失效的DPP-4抑制药相关专利信息,可很好地指导国内针对疗效确切、市场前景好的DPP-4抑制药进行仿创性结合的后续开发,并可产生新的专利,以增强市场竞争力。     

An update on the safety and efficacy of oral antidiabetic drugs: DPP-4 inhibitors and SGLT-2 inhibitors

Introduction: Oral antidiabetic medications are important in many type 2 diabetes care plans

Areas covered: The article summarizes the cardiovascular and renal safety data for DPP-4 inhibitors and SGLT-2 inhibitors and specific safety data particular to each class.

Expert opinion: DPP-4 and SGLT-2 inhibitors provide unique anti-hyperglycemic mechanisms. The cardiovascular safety profiles of DPP-4 inhibitors are promising, but do not show the strong CV risk reduction of empagliflozin and canagliflozin. The heart failure signal associated with DPP-4 inhibitor use is unclear with differing agents, demonstrating increased risk or maybe even protective effects. The risk reduction in cardiovascular disease associated with SGLT-2 inhibitors has translated to recommendations to consider these therapies early in the treatment pathway. Both classes have potential safety concerns that necessitate appropriate patient selection and thorough education on potential side-effects. DPP-4 inhibitors are considered to have neutral or in some studies beneficial renoprotective effects. SGLT-2 inhibitor safety effects on the kidney are more complex. There are reports of acute kidney injury occurring soon after initiating SGLT-2 inhibitor therapy. However, there are large recent studies that have demonstrated the beneficial effect of SGLT-2 inhibitors in slowing the progression of established chronic kidney disease.     

Clinical Effects of Exposure to DPP-4 Inhibitors as Reported to the National Poison Data System

DPP-4 inhibitors (sitagliptin, saxagliptin, and linagliptin) are approved for the treatment of diabetes. They are considered safe due to their hyperglycemia dependent mechanism of action. We examined all isolated exposures to DPP-4 inhibitors reported to the National Poison Database System since 2006 to determine if significant toxicity occurs after exposure with attention to pediatric and intentional overdoses. NPDS data regarding DPP-4 ingestions in all age groups between January 2006 and March 2013 was collected. Cases were reviewed, and the following inclusion criteria applied: (1) reported ingestion of a DPP-4 inhibitor and (2) known clinical outcome. Exclusion criteria included the following: (1) exposure to more than a single substance, (2) no known outcome, and (3) clinical outcome judged to be unrelated to the exposure. One thousand four hundred seventy-six cases were reviewed while 826 were excluded. Of 650 included cases, 562 developed no clinical effects. Mild effects were noted in 77. There were no deaths. Moderate/major effect cases were investigated: two medication-naive nondiabetic individuals with accidental exposures developed clinically significant hypoglycemia requiring treatment. One diabetic patient on a DPP-4 inhibitor developed prolonged hypoglycemia requiring admission and continuous exogenous dextrose. Of 650 included exposures to DPP-4 inhibitors, 639 (98.3%) had either no or minor clinical effects. Three resulted in clinically significant hypoglycemia requiring intervention. None of the moderate or major clinical outcomes were the result of intentional overdoses for the purpose of self-injury. No exploratory ingestions resulted in moderate or major effects. Based on this data, exposure to DPP-4 inhibitors may rarely result in clinically significant hypoglycemia.     

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.     

Design,Synthesis, and in Vitro Evaluation of Novel Aminomethyl-pyridines as DPP-4 Inhibitors

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