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。     

DPP-4抑制剂在2型糖尿病治疗中的作用

2型糖尿病已成为全球范围内发病率增长最快的疾病之一,其发病和进展的重要原因是：胰岛的β细胞胰岛素分泌缺陷和α细胞胰升糖素不适当的分泌造成的胰岛素与胰升糖素比例失调,目前药物治疗不能从根本上阻止β细胞和α细胞的功能恶化.肠促胰素能同时改善胰岛α及β细胞功能,成为治疗糖尿病的新靶点.由于其血浆半衰期仅2 min,很快被二肽基肽酶（DPP-4）降解,口服给药的DPP-4抑制剂成为2型糖尿病治疗的新选择.其作用机制抑制二肽基肽酶的活性,保护内源性肠促胰素活性,发挥葡萄糖依赖性降糖作用.其代表药物有西格列汀、维格列汀、沙格列汀等.其在2型糖尿病中的作用,能够显著降低HbA1c,空腹和餐后血糖,与磺脲类相比DPP-4抑制剂非劣效于磺脲类,由于是葡萄糖依赖性降糖,不会出现低血糖.能改善胰岛素抵抗,同时改善α及β细胞功能障碍,DPP-4抑制剂总体上不增加体重或轻度减轻体重,降低心血管事件的风险,有良好的安全性和耐受性,是2型糖尿病早期治疗的理想药物.     

治疗2型糖尿病药物最新研究进展

2型糖尿病是一种因葡萄糖、脂肪、蛋白质代谢紊乱并最终导致胰岛素抵抗及胰岛素相对分泌不足的内分泌代谢疾病。传统口服降糖药物分别有磺脲类、α-葡糖糖苷酶抑制剂、双胍类、胰岛素增敏剂、格列奈类。近几年随着新的作用机制的发现,出现了多种治疗2型糖尿病的新型药物,如DDP-4和GLP-1。本文章主要阐述其他最新2型糖尿病治疗药物研究进展,包括输送器第二型抑制剂(SGLT2)、11β-HSD-1抑制剂、GRP119、PTP1B抑制剂。     

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。     

吡格列酮对初诊2型糖尿病强化治疗的影响

由于胰岛素抵抗及其相关的代偿性高胰岛素血症是引起胰岛β细胞功能不全进展的病因之一,故纠正或减轻胰岛素抵抗可减慢或防止胰岛素抵抗相关性糖尿病病人胰岛β细胞功能的进一步恶化。由于噻唑烷二酮类药物是减轻胰岛素抵抗的最有效的药物,可以预期这类药物治疗将减慢或防止胰岛β细胞功能的进一步恶化。因此,通过观察胰岛素强化治疗及其与口服噻唑烷二酮类药物联合治疗,了解其对初诊2型糖尿病患者近期血糖控制的影响。     

新型SGLT1/2双靶点抑制剂sotagliflozin

钠-葡萄糖共转运蛋白2(SGLT2)抑制剂是一类新兴的治疗糖尿病的药物。近年来,遗传学和药理学研究发现,胃肠道SGLT1蛋白也可能成为一个有治疗前景的药物靶点。SGLT1/SGLT2双靶点抑制剂的开发将为糖尿病的治疗提供另一个非胰岛素依赖的途径。临床研究表明,sotagliflozin可以通过双重抑制SGLT1和SGLT2的作用来降低餐后血糖、升高GLP-1和促进尿糖排出。因此,这些特征使得sotagliflozin在对1型和2型糖尿病的治疗方面具有重要临床意义。     

SGLT2抑制剂治疗糖尿病研究进展

近年来,钠-葡萄糖协同转运蛋白2(type 2 sodium glucose co-transporters,SGLT2)抑制剂作为一种新型的治疗糖尿病药物成为研究热点。SGLT2在肾近端小管葡萄糖重吸收中起着非常重要的作用;抑制肾脏SGLT2可以促进Ⅱ型糖尿病人尿糖的排泄,使其血糖恢复正常而不会有低血糖的风险。临床实验表明,SGLT2抑制剂对Ⅱ型糖尿病的治疗效果明显,且具有降低体重、无低血糖风险等优点,目前,许多SGLT2抑制剂已经进入临床评价后期。     

以钠-葡萄糖同向转运体为靶标的糖尿病治疗药物

钠-葡萄糖同向转运体(SGLT)是一种仅在肾小管和肠道基底外侧膜表达的膜蛋白。研究发现，注射SGLT的竞争性抑制剂根皮苷可通过诱导糖尿病啮齿类动物的尿糖增加而发挥降血糖作用。近期开发的根皮苷衍生物T-1095口服后可经肠道有效吸收进入血液循环。与根皮苷相似，口服T-1095可抑制肾脏SGLT的功能，增加尿中葡萄糖的排出而使血糖降低；持续应用T-1095可改善胰岛8细胞的胰岛素分泌量及高血糖诱导的肌肉和肝脏对胰岛素的抵抗；该药可能还有助于预防和治疗糖尿病并发症。因此，口服SGLT抑制剂是一类具有前景的糖尿病治疗药物。     

短期胰岛素联合二甲双胍治疗早期2型糖尿病

2型糖尿病是一种缓慢进展性疾病,其发病的中心环节是胰岛素抵抗和胰岛β细胞功能缺陷,改善胰岛素抵抗和保护胰岛β细胞功能是治疗2型糖尿病的关键.早期2型糖尿病患者的部分胰岛β细胞功能是可逆转的,故对其短期使用胰岛素强化治疗使血糖得到满意控制,可恢复胰岛β细胞功能.     

新型降血糖药物钠-葡萄糖共转运蛋白2抑制剂的不良反应及其预防

钠-葡萄糖共转运蛋白2(sodium-glucose cotransporter 2,SGLT2)抑制剂是一类新型非胰岛素依赖性降血糖药物,其主要通过抑制近端肾小管对葡萄糖的重吸收,促进葡萄糖从尿液排泄,从而产生降低患者血糖水平的作用.SGLT2抑制剂不仅能改善2型糖尿病患者的高血糖状态,且还具有减轻体质量,降低血压,...     

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。     

Mechanistic evaluation of the effect of sodium-dependent glucose transporter 2 inhibitors on delayed glucose absorption in patients with type 2 diabetes mellitus using a quantitative systems pharmacology model of human systemic glucose dynamics

Sodium-dependent glucose transporter (SGLT) 2 is specifically expressed in the kidney, while SGLT1 is present in the kidneys and small intestine. SGLT2 inhibitors are a class of oral antidiabetic drugs that lower elevated plasma glucose levels by promoting the urinary excretion of excess glucose through the inhibition of renal glucose reuptake. The inhibition selectivity for SGLT2 over SGLT1 (SGLT2/1 selectivity) of marketed SGLT2 inhibitors is diverse, while SGLT2/1 selectivity of canagliflozin is relatively low. Although canagliflozin suppresses postprandial glucose levels, the degree of contribution for SGLT1 inhibition to this effect remains unproven. To analyze the effect of SGLT2 inhibitors on postprandial glucose level, we constructed a novel quantitative systems pharmacology (QSP) model, called human systemic glucose dynamics (HSGD) model, integrating intestinal absorption, metabolism, and renal reabsorption of glucose. This HSGD model reproduced the postprandial plasma glucose concentration–time profiles during a meal tolerance test under different clinical trial conditions. Simulations after canagliflozin administration showed a dose-dependent delay of time (T_max,glc) to reach maximum concentration of glucose (C_max,glc), and the delay of T_max,glc disappeared when inhibition of SGLT1 was negated. In addition, contribution ratio of intestinal SGLT1 inhibition to the decrease in C_max,glc was estimated to be 23%–28%, when 100 and 300 mg of canagliflozin are administered. This HSGD model enabled us to provide the partial contribution of intestinal SGLT1 inhibition to the improvement of postprandial hyperglycemia as well as to quantitatively describe the plasma glucose dynamics following SGLT2 inhibitors.     

钠–葡萄糖协同转运蛋白2抑制剂对心肌梗死影响的研究进展

钠–葡萄糖协同转运蛋白2(SGLT2)抑制剂是近年来应用于临床的新型口服抗糖尿病药物,主要通过抑制分布在肾脏肾小管处的SGLT2来阻止多余葡萄糖的重吸收,促进尿糖排泄,从而降低循环血糖水平,同时发挥利钠、利尿作用,对充血性心力衰竭也是一种新的治疗选择。随着越来越多的人群受用,研究发现SGLT2抑制剂还具有降低心血管结局等多种心血管保护作用,不仅可使心衰患者受益,对心肌梗死也呈现出多效性,尽管相关机制目前只是推测。主要对SGLT2抑制剂治疗心肌梗死的相关研究进行综述。     

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。     

Sodium glucose cotransporter SGLT1 as a therapeutic target in diabetes mellitus

Introduction: Glycemic control is important in diabetes mellitus to minimize the progression of the disease and the risk of potentially devastating complications. Inhibition of the sodium–glucose cotransporter SGLT2 induces glucosuria and has been established as a new anti-hyperglycemic strategy. SGLT1 plays a distinct and complementing role to SGLT2 in glucose homeostasis and, therefore, SGLT1 inhibition may also have therapeutic potential.

Areas covered: This review focuses on the physiology of SGLT1 in the small intestine and kidney and its pathophysiological role in diabetes. The therapeutic potential of SGLT1 inhibition, alone as well as in combination with SGLT2 inhibition, for anti-hyperglycemic therapy are discussed. Additionally, this review considers the effects on other SGLT1-expressing organs like the heart.

Expert opinion: SGLT1 inhibition improves glucose homeostasis by reducing dietary glucose absorption in the intestine and by increasing the release of gastrointestinal incretins like glucagon-like peptide-1. SGLT1 inhibition has a small glucosuric effect in the normal kidney and this effect is increased in diabetes and during inhibition of SGLT2, which deliver more glucose to SGLT1 in late proximal tubule. In short-term studies, inhibition of SGLT1 and combined SGLT1/SGLT2 inhibition appeared to be safe. More data is needed on long-term safety and cardiovascular consequences of SGLT1 inhibition.     

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。     

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.     

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。     

Sotagliflozin as a potential treatment for type 2 diabetes mellitus

Introduction: SGLT1 is the primary transporter responsible for the absorption of glucose and galactose in the intestine, while SGLT2 and SGLT1 are both involved in the renal reabsorption of glucose. SGLT2 inhibitors are a new class of oral antidiabetic drugs, acting by increasing urinary glucose excretion (UGE). They offer the advantages of a reduced risk of hypoglycaemia, a decrease in body weight and blood pressure and an efficacy at all stages of type 2 diabetes (T2DM).

Areas covered: Herein, the authors focus specifically on sotagliflozin (LX4211), the first-in-class dual SGLT1/SGLT2 inhibitor. Original publications in English were selected as the basis of this review. Clinical trials were identified using the Clinicaltrial.gov database.

Expert opinion: By a potential additional mechanism of action on intestinal glucose absorption linked to SGLT1 inhibition, sotagliflozin differentiates from SGLT2 inhibitors by reducing postprandial glucose excursion and insulin secretion, as well as by increasing GLP-1 secretion. Despite a weaker effect on UGE than selective SGLT2 inhibitors, sotagliflozin is as effective as SGLT2 inhibitors on HbA1C reduction, with a similar safety profile in short-term studies. While sotagliflozin was first assessed in T2DM, it is now in phase 3 development as an adjuvant treatment in patients with T1DM after positive results from a pilot study.     

Physiologically based pharmacokinetic–pharmacodynamic modeling to predict concentrations and actions of sodium‐dependent glucose transporter 2 inhibitor canagliflozin in human intestines and renal tubules

Canagliflozin is a recently developed sodium‐glucose cotransporter (SGLT) 2 inhibitor that promotes renal glucose excretion and is considered to inhibit renal SGLT2 from the luminal side of proximal tubules. Canagliflozin reportedly inhibits SGLT1 weakly and suppresses postprandial plasma glucose, suggesting that it also inhibits intestinal SGLT1. However, it is difficult to measure the drug concentrations of these assumed sites of action directly. The pharmacokinetic–pharmacodynamic (PK/PD) relationships of canagliflozin remain poorly characterized. Therefore, a physiologically based pharmacokinetic (PBPK) model of canagliflozin was developed based on clinical data from healthy volunteers and it was used to simulate luminal concentrations in intestines and renal tubules. In small intestine simulations, the inhibition ratios for SGLT1 were predicted to be 40%–60% after the oral administration of clinical doses (100–300 mg/day). In contrast, inhibition ratios of canagliflozin for renal SGLT2 and SGLT1 were predicted to be approximately 100% and 0.2%–0.4%, respectively. These analyses suggest that canagliflozin only inhibits SGLT2 in the kidney. Using the simulated proximal tubule luminal concentrations of canagliflozin, the urinary glucose excretion rates in canagliflozin‐treated diabetic patients were accurately predicted using the renal glucose reabsorption model as a PD model. Because the simulation of canagliflozin pharmacokinetics was successful, this PBPK methodology was further validated by successfully simulating the pharmacokinetics of dapagliflozin, another SGLT2 inhibitor. The present results suggest the utility of this PBPK/PD model for predicting canagliflozin concentrations at target sites and help to elucidate the pharmacological effects of SGLT1/2 inhibition in humans. Copyright © 2016 John Wiley & Sons, Ltd.