SGLT2抑制剂Canagliflozin——Ⅱ型糖尿病治疗的新药

钠依赖的葡萄糖转运蛋白2(sodium-dependent glucose transporters 2,SGLT2)是一种低亲和力、高容量的转运体,主要分布在肾脏近曲小管S1部位,负责肾脏中约90%葡萄糖的重吸收。因此,抑制SGLT2,阻止近曲小管对葡萄糖的重吸收,通过增加尿糖的排出来降低血糖已经成为糖尿病治疗的一种新的策略。文章简述了目前处于临床阶段的SGLT2抑制剂,重点阐述了第1个被FDA批准的SGLT2抑制剂——Canagliflozin,包括它的合成、药动学、药效学、临床研究及不良反应等。     

基于SGLT2受体蛋白的新型糖尿病药物的研究进展

目的钠-葡萄糖共转运蛋白2(SGLT2)是肾小管上负责将尿糖重新吸收为血糖的重要转运蛋白,对该蛋白的抑制可以使糖从血液中转移进入尿液。本文总结了目前各大药物公司在研的SGLT2抑制剂的构效关系及其临床研究进展。方法综述了近年来国内外相关报道,对O,C,N-糖苷类和非糖苷类SGLT2抑制剂的药理、药效和药代学进行讨论,并就其临床研究及开发上市状况进行概述。结果 SGLT2抑制剂的结构与其药理活性和代谢稳定性间的关系是该类药物研发的重点。结论 SGLT2抑制剂与降糖作用的构效关系,对开发新一代治疗糖尿病药物具有重要意义。     

SGLT2抑制剂引起酮症酸中毒的机制及处理

钠-葡萄糖协同转运蛋白-2（SGLT2）抑制剂是一类新型的降糖药物,通过抑制肾小管对葡萄糖的重吸收降低血糖。但临床中发现SGLT2抑制剂可导致血糖不明显升高的酮症酸中毒。本文就SGLT-2抑制剂引起酮症酸中毒的发生机制及处理措施进行了综述。     

糖尿病治疗的新希望——SGLT2抑制剂

钠依赖的葡萄糖运载体(SGLTs)是一类在小肠黏膜和肾近曲小管中发现的转运基因家族,肾脏重吸收葡萄糖的过程主要由SGLTs介导。其中,SGLT1和SGLT2最为重要,SGLT2起主导作用。选择性地抑制SGLT2能显著降低机体对葡萄糖的重吸收,通过增加尿糖的排出从而降低血糖水平。SGLT2抑制剂是一种创造性的治疗策略,其作用靶点和机制与现有降糖药均不同,成为降糖药物研究的热点。文中介绍了SGLT2在调节血糖平衡中的作用,简单介绍了部分在研SGLT2抑制剂,重点综述了Ⅲ期临床药物dapagliflozin的临床试验结果。     

钠-葡萄糖共转运蛋白2抑制剂治疗2型糖尿病的临床研究进展

2 型糖尿病是一种以胰岛素分泌缺陷、胰岛素抵抗或者两者并存所致的高血糖为特征的慢性代谢性疾病。早期血糖控制不佳可以促进微血管并发症的进展,以及大血管风险的发生。虽然有众多的降糖药物在临床使用,但只有约50%的患者能实现血糖控制,传统药物仍存在某些不足,因此,需要开发具有新机制的治疗药物。钠-葡萄糖共转运蛋白2（SGLT2）是近年来发现的具有全新作用机制的一个糖尿病治疗靶点。SGLT2 抑制剂通过抑制肾脏近端小管对葡萄糖的重吸收来增加尿中葡萄糖的排泄而达到控制血糖的目的,其独立于葡萄糖依赖的胰岛素途径,能使低血糖发生风险降低。临床试验数据表明,SGLT2 抑制剂单药治疗和与传统降糖药物联合治疗均可以有效地控制血糖,并改善胰岛素抵抗,同时也有降血压和减少体质量作用。尽管后续的研究显示了SGLT2 抑制剂具有良好的耐受性,该类药物在临床上报道的意想不到的风险仍需要大量和长期的临床数据证实。     

钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂的研究进展

钠-葡萄糖协同转运蛋白2(SGLT2)是最近新发现的糖尿病治疗新靶点,其作用机制是特异性地抑制肾脏对葡萄糖的再吸收,且不依赖于β细胞的功能异常或胰岛素抵抗的程度。其效果也不会随着β细胞功能的衰竭或严重胰岛素抵抗而下降,不会产生传统药物带来的不良反应,是糖尿病治疗的新途径。本文介绍SGLT2在调节体内糖平衡中的作用,总结SGLT2抑制剂在2型糖尿病治疗方面的最新进展,并对已报道的抑制剂化学结构进行总结。     

SGLT2抑制剂在糖尿病患者中的临床应用进展

钠—葡萄糖协同转运蛋白2(SGLT2)是一种新颖的降血糖药物,降低血糖的作用是通过阻断肾脏对尿中葡萄糖的重吸收。越来越多的临床研究发现其降糖效果明显,同时能改善患者的血脂、BMI、收缩压等。但在一些研究中发现其可能导致生殖器及尿道感染风险,同时增加骨折及酮症酸中毒的发生率。本文对SGLT2治疗糖尿病患者的机制及安全性、代谢调控、心血管和肾脏保护作用等方面进行研究进展的综述。     

治疗2型糖尿病药物的合理应用

糖尿病是我国的常见病、多发病。安全、有效、经济地选择降糖药物是糖尿病治疗中的关键组成部分。本文通过介绍口服降糖药和胰岛素的合理选择、不同药物的给药方法、注意事项以及肾功能不全时如何选择降糖药物,强调了降糖药物的合理使用。     

SGLT1/SGLT2双重抑制剂——Sotagliflozin的研究概况

钠-葡萄糖协同转运蛋白2(SGLT2)抑制剂是一类治疗糖尿病的新型药物。SGLT2抑制剂的研发一直致力于相对钠-葡萄糖协同转运蛋白1(SGLT1)高度选择性抑制SGLT2。然而,动物基因组学和药理学研究表明抑制肠道SGLT1也可能成为治疗糖尿病药物靶点。Sotagliflozin是一种SGLT1/SGLT2双重抑制剂,具有独特的非胰岛素依赖型降糖机制,通过抑制SGLT1而减少经胃肠道入血的葡萄糖,也通过抑制SGLT2而增加葡萄糖的排出发挥作用。本文重点综述了其有效性和安全性。     

SGLT2抑制剂研究进展

钠-葡萄糖协同转运蛋白（SGLTs）主要存在于小肠黏膜（SGLTl）和肾近曲小管（SGLT1和SGLT2）的转运基因家族,其表达的膜蛋白负责将葡萄糖、氨基酸、维生素、离子和渗透溶质转运至肾近曲小管的刷状缘细胞及小肠上皮细胞。而SGLT2是一种主要在肾脏特异性表达的高效能．低亲和力转运体。葡萄糖在肾近曲小管的重吸收约有90％由SGLT2完成,因此选择性地阻断SGLT2、减少重吸收、增加尿糖排出这一治疗策略已成为糖尿病领域的又一创新性研究,为糖尿病治疗药物提供了新作用靶点。本文对SGLT2抑制剂在治疗2型糖尿病方面的最新研究进展进行介绍,主要阐述其作用机制、疗效（部分在研SGTL2抑制剂的临床试验结果）和安全性。     

治疗2型糖尿病新药:利西拉肽

利西拉肽是胰高血糖素样肽1(GLP-1)受体激动剂,于2016年7月27日由美国食品和药物管理局批准上市,结合饮食控制和运动以改善2型糖尿病成年患者的血糖水平。利西拉肽在降低糖化血红蛋白方面有良好的疗效,对患者空腹血糖和体重也有一定的降低作用。利西拉肽初始剂量为10μg·d~(-1),应用14 d后可增加维持剂量至20μg·d~(-1)。常见不良反应为恶心、呕吐、头痛、腹泻、眩晕、低血糖,每日1次皮下注射给药,患者耐受性较好。     

The potential of SGLT2 inhibitors in phase II clinical development for treating type 2 diabetes

Introduction: There is now an abundance of anti-diabetic agents. However, only few patients achieve glycemic targets. Moreover, current glucose-lowering agents mainly depend upon insulin secretion or function. Sodium glucose co-transporter type 2 (SGLT2) inhibitors present a novel glucose-lowering therapy, inducing glycosuria in an insulin-independent fashion.

Areas covered: In this review, the authors discuss the key efficacy and safety data from phase II clinical trials in type 2 diabetes mellitus (T2DM) of the main SGLT2 inhibitors approved or currently in development, and provide a rationale for their use in T2DM.

Expert opinion: Despite the very promising characteristics of this new therapeutic class, a number of issues await consideration. One important question is what to expect from head-to-head comparison data. We also need to know if dual inhibition of SGLT1/SGLT2 is more efficacious in reducing HbA_1c and how this therapy affects metabolic and cardiovascular parameters. Additionally, several SGLT2 agents that have not yet come to market have hitherto been evaluated in Asian populations, whereas approved SGLT2 inhibitors have been frequently studied in other populations, including Caucasian subjects. Thus, we need more information on the potential role of ethnicity on their efficacy and safety.     

SGLT2 inhibitors: a promising new therapeutic option for treatment of type 2 diabetes mellitus

Background Hyperglycemia is an important pathogenic component in the development of microvascular and macrovascular complications in type 2 diabetes mellitus. Inhibition of renal tubular glucose reabsorption that leads to glycosuria has been proposed as a new mechanism to attain normoglycemia and thus prevent and diminish these complications. Sodium glucose cotransporter 2 (SGLT2) has a key role in reabsorption of glucose in kidney. Competitive inhibitors of SGLT2 have been discovered and a few of them have also been advanced in clinical trials for the treatment of diabetes. Objective To discuss the therapeutic potential of SGLT2 inhibitors currently in clinical development. Key findings A number of preclinical and clinical studies of SGLT2 inhibitors have demonstrated a good safety profile and beneficial effects in lowering plasma glucose levels, diminishing glucotoxicity, improving glycemic control and reducing weight in diabetes. Of all the SGLT2 inhibitors, dapagliflozin is a relatively advanced compound with regards to clinical development. Summary SGLT2 inhibitors are emerging as a promising therapeutic option for the treatment of diabetes. Their unique mechanism of action offers them the potential to be used in combination with other oral anti‐diabetic drugs as well as with insulin.     

2型糖尿病治疗新药沙格列汀的药理及临床评价

二肽基肽酶(DPP-4)抑制剂沙格列汀是一种具有新型作用机制的2型糖尿病治疗药物,2009年7月31日,获美国FDA批准上市,2011年5月17日,在中国获得上市批准(商品名:安立泽)。研究证实,沙格列汀作为单药治疗或与二甲双胍的联合治疗,能有效改善血糖控制,没有明显的体重改变,发生低血糖的风险较低。现就其作用机制、药代动力学、临床研究及不良反应等做一综述。     

Better response to the SGLT2 inhibitor dapagliflozin in young adults with type 2 diabetes

Background and aim: A variation of the response to Sodium glucose co-transporter 2 (SGLT2) inhibitors with age has not been investigated in patients with diabetes. The aim of this study was to assess renal threshold of glucose (RTg) before and after administration of an SGLT2 inhibitor in young adult patients (≤40 years) and older adult patients (>40 years) with type 2 diabetes (T2DM). Subjects and methods: Twenty Japanese patients with T2DM were enrolled. Baseline data were obtained on the first day and dapagliflozin (5 mg) was administered at 6:00 on the second day. Glucose excursions were assessed by continuous glucose monitoring and urine samples were collected every hour during the daytime (7:00 to 15:00) on both days. RTg was estimated from the regression line of the scatter plot of the hourly mean glucose concentrations. Results: After a single dose of dapagliflozin, RTg decreased from 121.5 to 6.1 mg/dl in the young adult group and from 151.0 mg/dl to ?15.8 mg/dl in the older group. After dapagliflozin, the slope of the regression line was significantly steeper in the young adult group. Conclusion: Dapagliflozin was more effective in young patients because they showed a larger response of urinary glucose excretion.     

治疗2型糖尿病的新药维格列汀

2型糖尿病是多基因遗传因素和环境因素共同作用的复杂疾病。维格列汀是一种二肽基肽酶(DPP-Ⅳ)抑制剂,通过增强胰高血糖素样肽(GLP-1)和肠抑胃肽(GIP)的活性而发挥降血糖的作用。作为一种新型的口服降糖药,维格列汀单用或与其他降糖药联合应用控制血糖疗效好、不良反应低、安全且耐受性好。现就其临床药理作用及与其他口服降糖药的联合用药做一综述。     

Remogliflozin etabonate: a novel SGLT2 inhibitor for treatment of diabetes mellitus

Introduction: Inhibitors of sodium-glucose co-transporter type 2 (SGLT2) represent a new class of anti-hyperglycemic agents with a unique mechanism of action. These drugs lower blood glucose by increasing urinary glucose excretion. Remogliflozin etabonate (RE) is a prodrug of remogliflozin, an SGLT2 inhibitor under development.

Areas covered: The following article reviews all of the clinical studies published regarding metabolism, drug interaction, safety and efficacy of RE in healthy subjects, patients with type 1 and type 2 diabetes.

Expert opinion: Available data suggest low potential for RE to interact with other drugs affecting the P450 system. Compared with placebo, RE reduces hemoglobin A1c (HbA1c) levels by an average of 0.5 – 1.0% after 12 weeks of therapy in drug-naive patients with type 2 diabetes. Because of its relatively short half-life, RE may be slightly more effective when used twice daily than once daily. One preliminary study also showed that RE decreased plasma glucose levels in type 1 diabetes. Advantages of RE include modest weight loss of ～ 2 kg, low risk of hypoglycemia, and a trend toward decrease in blood pressure. The commonest adverse effects of RE are genital mycotic infections, urinary tract infections, and dizziness. However, further studies are needed to establish its long-term safety and efficacy, and to determine whether it has specific advantages over currently approved SGLT2 inhibitors.     

治疗上皮样肉瘤新药:zeste基因增强子同源物2抑制剂tazemetostat

tazemetostat(Taz)是一种zeste基因增强子同源物2(EZH2)抑制剂,能够有效抑制多梳蛋白复合体2(PRC2)发挥组蛋白赖氨酸甲基转移酶(HKMT)活性,通过全新的表观遗传调控机制而发挥抗肿瘤活性.2020年1月23日,美国食品和药物管理局(FDA)批准Taz用于不适合完全切除的转移性或局部晚期上皮样...     

SGLT2 inhibitors: a new emerging therapeutic class in the treatment of type 2 diabetes mellitus

The incidence of type 2 diabetes mellitus is increasing worldwide. The existing therapeutic classes of antidiabetic drugs are not adequately effective in maintaining long-term glycemic control in most patients, even when used in combination. One emerging novel therapeutic class of antidiabetic drugs is sodium glucose cotransporter 2 (SGLT2) inhibitors. SGLT2 accounts for 90% of the glucose reabsorption in the kidney. The SGLT2 inhibitors increase urinary excretion of glucose and lower plasma glucose levels in an insulin-independent manner. Dapagliflozin, the most prominent molecule in this class, is currently in a phase III clinical trial. Other members of this class (eg, sergliflozin, remogliflozin) are also in different phases of clinical trials. This class of novel agents can effectively control blood sugar level without producing weight gain or hypoglycemia. Results of ongoing phase III clinical trials are crucial to determine whether the risk-benefit ratio will allow approval of this new class of drugs for the management of type 2 diabetes mellitus.