钠-葡萄糖转运蛋白2抑制剂相关胃肠道反应风险的网状meta分析CSCD

目的系统评价钠-葡萄糖转运蛋白2(SGLT2)抑制剂致2型糖尿病患者胃肠道反应的风险。方法检索国内外有关数据库(截至2022年12月30日),收集SGLT2抑制剂治疗2型糖尿病且结局指标包含胃肠道反应的随机对照试验。采用Cochrane偏倚风险评估工具对纳入的研究进行质量评价。采用Stata 15.1软件贝叶斯方法进行网状meta分析,绘制SGLT2抑制剂不同干预措施胃肠道反应风险的网状证据图、两两比较的联赛图和累积概率排序曲线下面积图(SUCRA),并对SGLT2抑制剂不同干预措施胃肠道反应风险的大小进行排序。胃肠道反应的效应量以相对危险度(RR)及其95%置信区间(CI)表示。结果最终纳入15项研究进行分析,共包括5540例患者。SGLT2抑制剂治疗组3949例,干预药物包括达格列净(1872例)、卡格列净(1100例)、恩格列净(649例)、艾托格列净(219例)、伊格列净(61例)、利格列净(48例);对照组1591例,均给予安慰剂。网状meta分析结果显示,与卡格列净50 mg和卡格列净100 mg相比,艾托格列净10 mg治疗发生胃肠道反应的风险更高(RR=1.37,95%CI:1.02~3.48;RR=2.98,95%CI:1.19~4.09;均P<0.05);SGLT2抑制剂其他干预措施之间的比较差异均无统计学意义。按SUCRA对SGLT2抑制剂不同干预措施胃肠道反应发生风险的排序结果显示,胃肠道反应发生风险从大到小依次为利格列净50 mg、艾托格列净25 mg、艾托格列净10 mg、恩格列净25 mg、伊格列净100 mg、伊格列净300 mg、伊格列净200 mg、艾托格列净5 mg、利格列净10 mg、伊格列净50 mg、恩格列净10 mg、利格列净2.5 mg、达格列净20 mg、达格列净10 mg、恩格列净5 mg、艾托格列净1 mg、达格列净5 mg、安慰剂、卡格列净300 mg、卡格列净200 mg、达格列净2.5 mg、达格列净1 mg、卡格列净100 mg、卡格列净50 mg。结论不同SGLT2抑制剂治疗方案导致2型糖尿病患者发生胃肠道反应的风险不同。卡格列净导致胃肠道反应的风险较小,尤其是卡格列净50 mg方案;而利格列净和艾托格列净容易引起胃肠道反应,尤其在较高剂量治疗时。     

SGLT2抑制剂托格列净的研究进展

托格列净(Tofogliflozin)是一种口服活性小分子SGLT2抑制剂,由日本中外(Chugai)制药开发并用于2型糖尿病(T2DM)的治疗.托格列净对SGLT2的选择性抑制作用是SGLT1的2900多倍,与达格列净、坎格列净、伊格列净、伊帕列净和鲁格列净相比具有更强的选择性.本文对托格列净的发现、药效学、药代动力学、副作用及合成路线进行综述.     

口服降血糖新药-坎格列净

坎格列净(canaglifl ozin)为钠-葡萄糖协同转运蛋白2(SGLT2)抑制剂,于2013年3月美国FDA批准上市,是第1个被批准的SGLT2抑制剂药物,作为成人2型糖尿病的辅助治疗用药。     

达格列净联合用药治疗糖尿病的临床研究进展

糖尿病是一种以高血糖为特征的慢性代谢性疾病,给人类生命健康带来严重危害。当单一降糖药疗效不佳时,常采用2种及2种以上降糖药进行治疗。达格列净是近年新上市的一种钠-葡萄糖共转运蛋白2（sodium-glucose contransporter 2,SGLT2）抑制剂,用于糖尿病疗效显著,不良反应少,应用广泛。临床上糖尿病及其并发症治疗效果不佳时,常将达格列净与胰岛素、二甲双胍、利拉鲁肽、沙格列汀、吡格列酮、阿卡波糖、中药等联用,以增强疗效,降低不良反应发生率。本文通过对达格列净与上述降糖药物联用治疗糖尿病的疗效和安全性进行总结和评价,以期为SGLT2抑制剂联合用药、降糖药合理应用和糖尿病治疗提供参考。     

SGLT2抑制剂不良反应信号的挖掘与评价

目的:挖掘和评价钠-葡萄糖共转运蛋白2(SGLT2)抑制剂卡格列净、达格列净、恩格列净上市后的不良反应(ADR)信号,为临床合理用药提供参考。方法:采用比例报告比法(PRR)和报告比值比法(ROR)对2013年第2季度至2020年第3季度美国FDA不良事件报告系统自发呈报系统中接收的卡格列净、达格列净、恩格列净等3种SGLT2抑制剂的ADR进行信号挖掘,分析ADR报告中对应患者的基本信息(包括性别、年龄、上报年份、上报国家、严重ADR)和安全警告信号。结果:收集到的6029375份ADR报告中,SGLT2抑制剂为伴随和怀疑药物的ADR报告有43807份,其中卡格列净ADR报告19301份、达格列净ADR报告10960份、恩格列净ADR报告13546份。除性别未知和年龄缺失的ADR报告外,纳入报告患者的性别分布均衡,主要集中在50~75岁范围内,上报年份主要在2018年,主要上报国家为美国,以“住院或住院时间延长”为主要的严重ADR。共挖掘得到ADR信号573个,累及系统26个,主要集中在代谢与营养类疾病、内分泌失调、肾脏及泌尿系统疾病、感染及侵扰类疾病等方面。卡格列净、达格列净、恩格列净ADR频数排序前10位的主要ADR信号共14个,达格列净、恩格列净的ADR信号中强度最强的信号都依次为酮症酸中毒(PRR值分别为119.64、140.11,ROR值的95%CI下限分别为148.28、178.78)和真菌感染(PRR值分别为47.76、34.77,ROR值的95%CI下限分别为50.69、36.28);而卡格列净除上述2个信号较强外,截趾(PRR值为489.79,ROR值的95%CI下限为520.15)和骨髓炎(PRR值为61.42,ROR值的95%CI下限为65.38)的信号也较强。结论:SGLT2抑制剂在代谢与营养类疾病、内分泌失调、肾脏及泌尿系统疾病、感染及侵扰类疾病方面的安全风险较高。达格列净、卡格列净、恩格列净易引起酮症酸中毒、真菌感染等ADR,卡格列净还易引起截趾、骨髓炎等ADR。     

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.     

基于模型荟萃分析5个SGLT2抑制剂在单用和 联合用药治疗2型糖尿病的临床疗效

目的：采用基于模型的荟萃分析（MBMA）方法,建立钠-葡萄糖共转运蛋白2抑制剂（SGLT2i）的药物效应模型,定量分析不同SGLT2i单用、或SGLT2i联合二甲双胍、联合二肽基肽酶-4抑制剂（DPP4i）、联合DPP4i和二甲双胍,共四种治疗方式对于2型糖尿病（T2DM）的临床疗效。方法：通过ClinicalTrials.gov和Web of Science（MEDLINE）进行文献检索,纳入5个SGLT2i（卡格列净、达格列净、恩格列净、埃格列净、依格列净）临床研究,选择糖化血红蛋白（HbA1c）的相对基线变化值作为药效学指标,建立药物效应模型。结果：最终纳入54篇文献,涵盖167组研究的24802名受试者,最终建立以时间、剂量描述的SGLT2i药物效应模型。SGLT2i按疗效顺序为依格列净>卡格列净>埃格列净>恩格列净>达格列净。相比单药治疗,72周各药联合二甲双胍使得HbA1c变化值再降0.13%,联合DPP4i可再降0.09%。SGLT2i联合二甲双胍和DPP4i可分为两个亚组：因DPP4i和二甲双胍控制不足而联用的人群比单药组可再降0.02%,而因二甲双胍控制不足而联用的人群可再降0.75%。目前各药推荐剂量几乎已达到最大降糖效果。未来同类药物的开发可以卡格列净和依格列净作为对照药物,衡量新化合物开发是否具有良好的临床优势性。结论：采用MBMA方法量化SGLT2i在单用、二联、三联不同治疗方式的降糖作用,按药物疗效高低排序依次为依格列净、卡格列净、埃格列净、恩格列净、达格列净。     

钠-葡萄糖协同转运蛋白2抑制剂治疗晚期心力衰竭1例

目的 探讨晚期心力衰竭治疗策略。方法 报告钠-葡萄糖协同转运蛋白2(SGLT2)抑制剂治疗晚期心力衰竭病人1例。该晚期心力衰竭病人合并多种并发症,应用多种利尿剂效果不佳后给予口服50 mg卡格列净,每日1次。结果 病人心力衰竭症状得以改善,N末端-B型钠尿肽前体（NT-proBNP）短期内下降及肾小球滤过率（eGFR）短期上升。结论 SGLT2抑制剂对晚期心力衰竭病人的治疗,短期有效,前景可期。     

一类全新机制的2型糖尿病治疗药物SGLT2抑制剂

钠-葡萄糖协同转运蛋白(SGLT2)抑制剂是一类作用于新靶点的降糖药物,目前已进入临床使用,美国FDA已经批准上市的有6种,中国CFDA也相继批准了达格列净(dapagliflozin)及恩格列净(empagliflozin)在我国上市。为了使临床医师及药师更好地了解和使用该类全新机制的糖尿病治疗药物,本文从该类药物的来源、化学结构、药理作用机制、药物代谢动力学特点、临床疗效与应用、不良反应及安全性进行了综述,以供参考。     

钠-葡萄糖转运蛋白2抑制剂与2型糖尿病患者恶性肿瘤发生风险的Meta分析

目的： 系统评价钠-葡萄糖转运蛋白2（sodium-glucose transporter 2 inhibitors,SGLT2）抑制剂的使用与2型糖尿病患者肿瘤发病的关系,为明确二者之间关系提供循证医学依据。方法： 以"钠-葡萄糖转运蛋白2（SGLT2）抑制剂、达格列净（dapagliflozin）、坎格列净（canagliflozin）、恩格列净（empagliflozin）、2型糖尿病、肿瘤"等为关键词,通过PubMed、Embase、Web of Science、Cochrane Library及万方、中国知网（CNKI）、维普中文期刊（VIP）等数据库检索2021年2月以前发表的中英文文献,确定符合条件的随机对照试验（randomized controlled trials,RCTs）。运用RevMan 5.3和Stata 15.0软件进行统计学处理。结果： 最终纳入17篇文献,共35 299例患者,其中1 072例2型糖尿病患者罹患恶性肿瘤。Meta分析结果表明,与对照组相比,SGLT2抑制剂与总体肿瘤风险增加无显著相关性（RR=0.98,95% CI：0.96~1.36）。不同SGLT2抑制剂对肿瘤发生的风险无显著相关性（RR=0.92,95% CI：0.81~1.04）。结论： 目前来自短期随机对照试验的证据并未表明使用SGLT2抑制剂的2型糖尿病患者有增加发生恶性肿瘤的风险。     

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。     

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.     

Practical considerations for the use of sodium–glucose co-transporter type 2 inhibitors in treating hyperglycemia in type 2 diabetes

Sodium–glucose co-transporter type 2 (SGLT2) inhibitors are a new class of oral anti-diabetic agents with a unique, insulin-independent mode of action. In patients with diabetes who have adequate renal function, SGLT2 inhibitors reduce hyperglycemia by blocking renal glucose reabsorption and increasing urinary glucose excretion. These agents are indicated for the treatment of hyperglycemia in type 2 diabetes mellitus (T2DM), as an adjunct to diet and exercise. In terms of efficacy, they are comparable to most other oral agents, and carry a low risk of hypoglycemia unless combined with sulfonylureas or insulin. They may be used in combination regimens with metformin, sulfonylureas, or insulin. Beyond glucose lowering, SGLT2 inhibitors are associated with modest weight loss and mild anti-hypertensive effects. Emerging cardiovascular and renal outcomes data suggest other potentially beneficial non-glycemic effects, although these findings await confirmation from further studies. The main adverse effects are increased risk of volume depletion and of genitourinary infections, although these can be managed with standard interventions. Rare cases of euglycemic ketoacidosis have been reported in a subset of patients treated with these agents, an issue currently under investigation. SGLT2 inhibitors represent a promising alternative treatment option for T2DM patients in whom the effectiveness of oral anti-hyperglycemic therapy is limited by the risk of hypoglycemia, weight gain, or other adverse effects. Safety and efficacy (up to 4 years) have been demonstrated in a range of T2DM patient populations, although more studies will be needed to determine whether treatment with SGLT2 inhibitors improves patient-important outcomes in the longer term.     

Empagliflozin added to metformin and sulfonylurea therapy in patients with sub-optimally controlled type 2 diabetes mellitus

The combination of metformin and a sulfonylurea is commonly used in type 2 diabetes mellitus. Many patients on this combination therapy do not achieve or maintain glycemic targets and require the addition of a third antihyperglycemic agent. Among the options are the sodium glucose cotransporter 2 (SGLT2) inhibitors, a recently developed class of medications that effectively improve glycemic control and are associated with reduction in body weight and blood pressure. This article evaluates a 24-week, randomized, placebo-controlled study of the SGLT2 inhibitor empagliflozin, added to metformin plus sulfonylurea regimens. Empagliflozin led to significant reductions in glycated hemoglobin and fasting plasma glucose, as well as body weight and systolic blood pressure. Adverse events typically recorded with SGLT2 inhibitors were observed; notably, genital infections occurred in more patients on empagliflozin than placebo. Overall, empagliflozin was well tolerated. These results indicate that SGLT2 inhibitors can be successfully added to metformin plus sulfonylurea regimens. SGLT2 inhibitors are not the only therapeutic option in this clinical situation; however, based on the secondary effects observed in this and other studies, they appear to be of particular value for patients who are obese or overweight.     

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.     

Differentiating sodium-glucose co-transporter-2 inhibitors in development for the treatment of type 2 diabetes mellitus

Introduction: Sodium-glucose co-transporter-2 (SGLT2) inhibitors are a novel class of agents for the treatment of type 2 diabetes mellitus (T2DM). By inhibiting SGLT2, they prevent renal glucose reabsorption, resulting in glucosuria.

Areas covered: The rationale for development of SGLT2 inhibitors is reviewed, with particular focus on the nine SGLT2 inhibitors currently in development. The authors compare the potency and SGLT2 selectivity of the agents, as well as the results from both animal and clinical studies, considering the potential implications they may have for clinical use.

Expert opinion: Current evidence suggests that SGLT2 inhibitors have similar efficacy in terms of glycemic control and also demonstrate benefits beyond glycemic reductions, including reductions in body weight and modest reductions in blood pressure. Additionally, they appear to preserve beta-cell function and improve insulin sensitivity. Their mechanism of action allows for combination of SGLT2 inhibitors with other antidiabetic drugs and use across the treatment continuum for T2DM. Potential differences in safety and efficacy based on observed differences in potency and selectivity among the SGLT2 inhibitors, particularly versus SGLT1, remain to be seen. Further long-term data, including post-marketing surveillance, are required to fully determine the safety profile of SGLT2 inhibitors in large patient groups.     

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。     

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。     

Evolution of sodium glucose co-transporter 2 inhibitors as anti-diabetic agents

Background: A critical factor for maintenance of glucose balance is the renal recovery of glucose from the glomerular filtrate mediated primarily by sodium glucose co-transporter 2 (SGLT2). This capacity can be modulated by SGLT2 inhibitors thereby providing a unique insulin independent method of treatment of diabetes. Objective/method: A discussion of the evolution of SGLT inhibitors as inferred from patents published from 2005 to 2009 is prefaced by a brief review of the role of SGLT in glucose transport and the clinical findings illustrating the therapeutic potential of SGLT inhibitors as anti-diabetic agents. These compounds comprise O, C and N-glycosides generated by attachment of an appropriate lipophilic aglycone component to a suitable glucose analogue. Conclusion: The realization that the in vivo potency of O-glucosides was markedly less than that of C-glucosides necessitated a shift in medicinal chemistry focus of the pharmaceutical companies pursuing SGLT2 inhibitors. Particular emphasis is placed on the strategy that each used to circumvent the constraints imposed by prior art while utilizing a common pharmacophore. The role of SGLT2 inhibitors for treatment of diabetes will be established by the outcome of the five compounds in advanced clinical trials.