钠-葡萄糖协同转运蛋白2抑制剂类抗糖尿病新药的研发概况

目前,钠-葡萄糖协同转运蛋白2(SGLT2)抑制剂通过抑制葡萄糖在肾脏近曲小管的重吸收,从而成为治疗糖尿病的新途径。按其结构,SGLT2抑制剂主要分为C-芳基抑制剂、O-芳基抑制剂、S-糖苷抑制剂和N-糖苷抑制剂,而C-芳基抑制剂和O-芳基抑制剂处于研究热点,其中几个新药(dapagliflozin、canagliflozin、ASP1941、BI10773和LX4211)显示出良好的控制血糖水平和减轻体质量的效果,且不良反应较小。综述两类结构中的主要药物研究概况,并分析其研发前景。     

2型糖尿病的克星——SGLT-2抑制剂

SGLT-2抑制剂为非胰岛素依赖型药物,可选择性抑制SGLT-2,抑制肾小管对葡萄糖重吸收,增加尿糖排泄以降低血糖,且不易引起低血糖.SGLT-2抑制剂包括糖苷类及非糖苷类.本文重点介绍已上市药物卡格列净、达格列净、伊格列净、鲁格列净的药动学、药效学、不良反应与药物联用.     

钠-葡萄糖共转运体2抑制剂在糖尿病肾病中的应用

目前降糖药物并不足以延缓糖尿病肾病的进展,既能有效控制血糖、又能保护肾脏的降糖药物值得研发。在糖尿病肾病动物模型中,常规剂量钠-葡萄糖共转运体2(SGLT-2)抑制剂可通过降低肾小球高滤过,改善肾小球、肾小管及肾间质纤维化,抑制炎症反应和氧化应激反应,起到保护肾脏的作用。临床研究显示,SGLT-2抑制剂可降低糖尿病肾病患者的尿蛋白、延缓肾小球滤过率的下降,但已上市的SGLT-2抑制剂肾脏事件风险有所不同。SGLT-2抑制剂对肾脏的确切保护作用及其机制仍需进一步研究探讨,目前几项相关大型随机对照试验正在进行中。     

治疗糖尿病新药:钠-葡萄糖协同转运蛋白抑制剂dapagliflozin

钠-葡萄糖协同转运蛋白2(SGLT-2)是一种跨膜蛋白,主要分布在肾脏近曲小管,将葡萄糖从肾小管液转运入肾小管细胞内,约占肾脏重吸收葡萄糖的90%。SGLT-2抑制剂是治疗糖尿病的新药,可降低SGLT-2活性,减少肾脏对葡萄糖的重吸收量,增加尿糖排出,从而降低血糖。已有的临床试验表明SGLT-2抑制剂dapagliflozin治疗糖尿病有效且安全,患者耐受性良好。SGLT-2抑制剂很可能是未来糖尿病治疗的一个新的突破口。     

SGLT-2抑制剂治疗2型糖尿病的研究进展

钠-葡萄糖协同转运蛋白2抑制剂(SGLT-2i)类药物为近年来出现的一种新型口服糖尿病药物,由于其不依赖于胰岛素的独特降糖机制而日益受到关注。该类药物通过抑制肾脏肾小管中负责从尿液中重吸收葡萄糖的SGLT-2来降低肾糖阈,排出多余的葡萄糖,从而降低血液循环中葡萄糖水平。此外,该类药物还具有降压、减重、减轻尿蛋白等额外获益,在中国2型糖尿病治疗指南(2017版)中被推荐作为单一口服降糖药物效果不佳而采用的二联或三联治疗用药之一。目前,我国临床常见的SGLT-2i抑制剂类药物包括国内批准上市的恩格列净、达格列净和卡格列净。本文对SGLT-2抑制剂类药物的作用机制、降糖效果、降糖外获益等方面进行综述,为临床医师和药师合理用药提供参考。     

SGLT-2选择性抑制剂的代谢调节作用与不良反应

钠-葡萄糖协同转运蛋白2(SGLT-2)抑制剂是一种非胰岛素依赖型的降糖药物,其作用的靶点是肾脏,可以通过抑制肾脏对葡萄糖的重吸收,使过量的葡萄糖从尿液中排出,从而发挥降低血糖的疗效。此类药物对改善血糖和血脂水平,保护胰岛细胞均有确切疗效,且不增加体重,主要的不良反应为生殖器感染、尿路感染和酮症酸中毒。本文通过检索中国知网、万方数据库、维普数据库和PubMed数据库,综述了SGLT-2选择性抑制剂的开发过程、作用机制以及治疗糖尿病的疗效与不良反应,为临床合理用药提供参考。     

钠-葡萄糖共转运蛋白-2抑制剂对2型糖尿病患者肾脏结局的系统评价和Meta分析

目的：通过系统评价探讨糖尿病患者使用钠-葡萄糖共转运蛋白-2抑制剂（SGLT-2I）对肾脏的影响,为临床用药提供循证依据。方法：系统检索中国知网、万方、维普、中国生物医学文献数据库、Medline(Ovid)、EMBASE(Ovid)以及CENTRAL数据库,检索时间为建库至2022年11月9日,纳入被明确诊断为2型糖尿病的患者,并对符合标准的随机对照试验进行质量评估和数据提取,并使用Stata16 MP对数据进行分析。结果：研究共纳入文献12篇,包含8个随机对照试验以及4个预先设定的包含肾脏结局的亚组分析研究,涉及60 767例患者,系统评价结果显示与安慰剂组相比,接受SGLT-2I治疗显著改善了糖尿病患者肾脏恶化、终末期肾脏疾病或肾脏死亡的复合肾脏结局的发生风险[RR=0.63,95%CI (0.57～0.69)],而且这种获益在慢性肾疾病患者中也依然存在。结论：SGLT-2I对糖尿病患者具有显著的肾脏保护作用。     

钠-葡萄糖共转运蛋白2抑制剂相关的药物相互作用

钠-葡萄糖共转运蛋白2(sodium-glucose cotransporter 2,SGLT-2)抑制剂是治疗2型糖尿病的新型口服药物。SGLT-2抑制剂通过降低肾糖阈,增加尿葡萄糖排泄,同时排出部分能量;由于SGLT-2抑制剂的降糖机制依赖于血液和尿液中葡萄糖的浓度差,因此,在血糖较低的时候其效用就大大减弱,从而降低了低血糖发生风险。在降血糖外,SGLT-2抑制剂还有诸多获益,包括降低收缩压、舒张压,改变血液动力学,提高血细胞比容;降低体质量,减少内脏脂肪和皮下脂肪;降低尿酸;对心脏、肾脏还有保护作用。本文就我国批准使用的SGLT-2抑制剂恩格列净、达格列净和卡格列净的药物相互作用进行综述,以期为临床医师和药师合理用药提供参考。     

2型糖尿病治疗药物——SGLT-2抑制剂研究进展

钠-葡萄糖协同转运蛋白-2抑制剂通过减少人体肾脏对葡萄糖的重吸收,增加尿糖的排泄,达到降低血液中葡萄糖水平的目的,从而成为治疗2型糖尿病的新途径。近年来,SGLT-2抑制剂类药物也不断的问世,给2型糖尿病患者的治疗带来了新的希望。     

基于心血管获益浅谈SGLT-2抑制药在2型糖尿病管理中的价值

摘 要心血管疾病的风险管控是糖尿病管理过程中非常重要的环节。国内外权威机构和指南对降糖药物对心血管结局的要求非常严格。多项心血管结局研究显示,钠 葡萄糖协同转运蛋白2(SGLT-2)抑制药能显著降低心血管事件风险,降低心血管死亡率。SGLT-2抑制药心血管获益的机制不仅来自于对血糖、体质量等因素的改善,可能还源于对多重心血管风险因素的控制。在目前糖尿病管理追求个体化、以患者为中心的策略下,随着心血管结局研究的不断发布,SGLT-2抑制药在指南中的地位越来越高,在糖尿病的管理中的价值越来越大。本文通过SGLT-2抑制药心血管获益的研究及指南推荐的变迁,阐述SGLT-2抑制药在糖尿病管理中的价值,并简要分析SGLT-2抑制药带来心血管获益的可能机制。     

Diabetes and kidney disease: the role of sodium–glucose cotransporter-2 (SGLT-2) and SGLT-2 inhibitors in modifying disease outcomes

Patients with type 2 diabetes (T2D) often have coexisting chronic kidney disease (CKD). However, healthy renal function is crucial in maintaining glucose homeostasis, assuring that almost all of the filtered glucose is reabsorbed by the sodium glucose cotransporters (SGLTs) SGLT-1 and SGLT-2. In diabetes, an increased amount of glucose is filtered by the kidneys and SGLT-2 is upregulated, leading to increased glucose absorption and worsening hyperglycemia. Prolonged hyperglycemia contributes to the development of CKD by inducing metabolic and hemodynamic changes in the kidneys. Due to the importance of SGLT-2 in regulating glucose levels, investigation into SGLT-2 inhibitors was initiated as a glucose-dependent mechanism to control hyperglycemia, and there are three agents currently approved for use in the United States: dapagliflozin, canagliflozin, and empagliflozin. SGLT-2 inhibitors have been shown to reduce glycated hemoglobin (A1C), weight, and blood pressure, which not only affects glycemic control, but may also help slow the progression of renal disease by impacting the underlying mechanisms of kidney injury. In addition, SGLT-2 inhibitors have shown reductions in albuminuria, uric acid, and an increase in magnesium. Caution is advised when prescribing SGLT-2 inhibitors to patients with moderately impaired renal function and those at risk for volume depletion and hypotension. Published data on slowing of the development, as well as progression of CKD, is a hopeful indicator for the possible renal protection potential of this drug class. This narrative review provides an in-depth discussion of the interplay between diabetes, SGLT-2 inhibitors, and factors that affect kidney function.     

Euglycaemic diabetic ketoacidosis as a complication of SGLT-2 inhibitors: epidemiology,pathophysiology, and treatment

ABSTRACT

Introduction

Sodium-glucose co-transporters 2 (SGLT-2) inhibitors are a relatively novel class of oral medications for the treatment of Type 2 Diabetes Mellitus, which lower plasma glucose by inhibiting glucose reabsorption in the proximal renal tubule. Apart from their hypoglycemic action, recent data suggest these agents have additional major cardioprotective and nephroprotective properties.     

Sodium-glucose co-transporter-2 inhibitors as add-on therapy to insulin: rationale and evidences

Sodium-glucose co-transporter-2 inhibitors (SGLT-2I) are recently approved class of anti-hyperglycaemic agents for the treatment of type 2 diabetes mellitus (T2DM). SGLT-2I inhibits renal glucose reabsorption, thereby ensuing urinary glucose excretion in a dose-dependent manner. This caloric loss and osmotic diuresis, secondary to increased urinary glucose excretion, has a unique potential to counter insulin induced weight gain and fluid retention, with little potential of hypoglycemic exacerbation. Also, as these agents act independently of insulin secretion or action, they are effective even in long-standing diabetes with depleted β-cell reserve. Improvement in insulin sensitivity, as observed with SGLT-2I can also facilitate insulin action. Furthermore, significant reduction in total daily insulin dosage and reduction of body weight as observed during combination therapy renders SGLT-2I, a near-ideal partner to insulin. This review aims to evaluate the safety and efficacy of currently used SGLT-2I as an add-on to insulin therapy in the treatment of T2DM.     

新型抗2型糖尿病药物钠-葡萄糖协同转运蛋白2抑制剂研究进展

钠-葡萄糖协同转运蛋白（SGLT）是一类位于小肠黏膜（SGLT1）和肾近曲小管（SGLT2和SGLT1）中的葡萄糖转运基因家族。其中,SGLT2是一种低亲和力的转运蛋白,在肾脏中特异性表达并且在近曲小管葡萄糖重吸收中发挥非常重要的作用。它可以选择性地抑制SGLT2,即可通过增加尿糖的排出来治疗2型糖尿病,是一种创造性的治疗策略。本文介绍了SGLT2抑制剂在2型糖尿病治疗研究方面的最新进展,重点综述了SGLT2抑制剂的作用机制、部分在研SGLT2抑制剂的生物活性数据及临床试验结果。     

Sodium–glucose cotransporter 2 inhibitors: an evidence-based practice approach to their use in the natural history of type 2 diabetes

Objective The sodium–glucose cotransporter 2 (SGLT-2) inhibitors are an important addition to available treatments for patients with type 2 diabetes (T2D) as an adjunct to modifications in diet and exercise. SGLT-2 inhibitors may be prescribed alone or as add-on treatment in patients receiving metformin, sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, and/or insulin across the natural history of the disease. Inhibition of SGLT-2, which is responsible for approximately 90% of renal glucose reabsorption, increases urinary glucose excretion and lowers blood glucose concentrations. The objective of this review is to discuss the pathophysiology of diabetes and the contribution of the kidney to glucose homeostasis and to provide an evidence-based practice approach to clinical applications of SGLT-2 inhibitors in the treatment of T2D.

Methods PubMed and Google Scholar databases were searched to identify literature published from 1990 through September 2015 examining the pathophysiology of T2D, the role of the kidney in regulating glucose concentrations, and clinical evidence for the efficacy and safety of SGLT-2 inhibitors in T2D.

Results There is a need for early treatment in patients with T2D to minimize the risk of cardiovascular complications that increase morbidity and mortality. SGLT-2 inhibitors improve glycemic control, reduce body weight and blood pressure, and are associated with a low risk of hypoglycemia. Adverse events associated with SGLT-2 inhibitors include mild to moderate urinary tract and genital infections and mild dehydration potentially leading to orthostatic hypotension.

Conclusions An evidence-based practice approach to examining the importance of early, proactive treatment of T2D using SGLT-2 inhibitors from initiation of pharmacotherapy to increasingly more complicated combination therapy regimens, including insulin, suggests that this treatment strategy maximizes benefits and minimizes potential side effects. The SGLT-2 inhibitors augment the arsenal of available antidiabetes agents, facilitating the ability of clinicians to design tailored treatment regimens that help patients achieve therapeutic goals.     

Development of sodium-dependent glucose co-transporter 2 inhibitors as potential anti-diabetic therapeutics

The kidney plays an important role in the regulation of plasma glucose. It is estimated that greater than 99% of the renal glucose filtered by kidney glomerulus is resorbed by sodium-dependent glucose co-transporters (SGLTs), and that SGLT2 located in the proximal renal tubule achieves the most of this assignment. Studies of SGLT2 inhibitors indicate that raising renal glucose excretion by inhibiting SGLT2 helps effectively normalize the plasma glucose levels in individuals with type 2 diabetes mellitus (T2DM). This review discusses the discovery of SGLT2 inhibitors and the related structure-activity relationship (SAR) studies. The clinical trial data of dapagliflozin is also involved.