恩格列净治疗2型糖尿病的系统评价

余彬¹, 饶友义¹, 余江平¹, 任琳¹, 周虹², 黄毅岚³^,

1.四川省绵阳市中心医院药学部,绵阳 621000

2.四川省绵阳市中心医院烧伤整形科,绵阳 621000

3.西南医科大学附属医院药学部,泸州 646000

YU Bin¹, RAO Youyi¹, YU Jiangping¹, REN Lin¹, ZHOU Hong², HUANG Yilan³^,

1.Department of Pharmacy, Mianyang Central Hospital, Sichuan Province, Mianyang 621000,China

2. Department of Burn and Plastic Surgery, Mianyang Central Hospital, Sichuan Province, Mianyang 621000, China

3.Department of Pharmacy, the Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China

作者简介:余彬(1989-),男, 四川泸州人,药师,硕士,研究方向:循证药学与药物代谢动力学。电话:0816-2222821,E-mail:455131008@qq.com。

通信作者:黄毅岚(1970-),女, 四川泸州人,教授,硕士生导师,硕士,主要从事临床药学研究。电话:0830-3165787,E-mail:75332015@qq.com。

中图分类号: R977.15;R969.3 文献标识码: B 文章编号: 1004-0781(2018)05-0613-07

摘要: 目的评价恩格列净治疗2型糖尿病(T2DM)的有效性和安全性。方法计算机检索PubMed、Embase、Medline、Cochrane图书馆、CNKI、万方、维普等数据库,时间:建库至2016年5月,筛选恩格列净与活性降糖药物对照比较治疗T2DM有效性和安全性的随机对照试验(RCT)。根据Cochrane系统评价员手册进行质量评价,采用RevMan 5.3 版与STATA 12版软件对数据进行Meta分析。结果共纳入7项研究,患者4 135例。Meta分析结果显示,单用恩格列净,在降低糖化血红蛋白(HbA1c)方面,恩格列净10 mg劣于二甲双胍 (P=0.03),恩格列净25 mg与二甲双胍相当 (P=0.34),但优于二肽基肽酶4(DPP-4)抑制药(P=0.04);联用二甲双胍,在降低HbA1c方面,恩格列净10 mg与DPP-4抑制药差异无统计学意义(P=0.13);25 mg剂量组优于DPP-4抑制药和格列美脲 (P=0.01)。在降低空腹血糖(FPG)方面,恩格列净 10,25 mg与二甲双胍相似,优于DPP-4抑制药和格列美脲;在降低体质量、血压方面,恩格列净2个剂量组均优于对照组。在安全性方面,恩格列净2个剂量组低血糖风险与DPP-4抑制药相似,低于格列美脲,生殖器感染的风险高于活性降糖药物。结论恩格列净治疗T2DM安全、有效。

关键词: 恩格列净 ; 钠-葡萄糖转运蛋白类 ; 糖尿病 ; 2型 ; 系统评价

Abstract:

Objective To evaluate the effectiveness and safety of empagliflozin (EMPA) for type 2 diabetes (T2DM). Methods PubMed, Embase, Medline, Cochrane, CNKI, Wanfang and VIP were searched. Randomized controlled trials(RCTs)on efficacy and safety of EMPA compared with other antidiabetic drugs in T2DM were selected. Quality of the studies were evaluated according to the notebook of Cochrane system investigator. Meta-analysis of data was pooled by the RevMan 5.3 software and STATA 12 software. Results A total of 7 RCTs involving 4 135 patients were included. Result of the Meta analyis showed that in monotherapy, 10 mg EMPA was inferior to metformin (MET) in terms of HbA1c (P=0.03);EMPA 25 mg was similar to MET (P=0.34), but was superior to DPP-4 inhibitors in HbA1c (P=0.04). As add-on to MET, there was no statistically significant difference between DPP-4 inhibitors and 10 mg EMPA in HbA1c (P=0.13), 25 mg EMPA was superior to DPP-4 inhibitors (P=0.01) and glimepiride (P=0.01). Both doses of EMPA were similar to MET, but superior to DPP-4 inhibitors and glimepiride in fasting blood glucose (FPG). In addition, EMPA provided a significantly greater reduction in weight and blood pressure comparing to the control group. In the aspect of safety, the risk of hypoglycaemia in two groups of EMPA were similar to DPP-4 inhibitor, but was lower than glimepiride. Compared with control group, the risk of genital tract infections were higher in EMPA group. Conclusion EMPA is safe and effective in the treatment of T2DM.

Key words: Empagliflozin ; Sodium-glucose transport proteins ; Diabetes ; type 2 ; Systematic review

钠-葡萄糖协同转运蛋白2(sodium-glucose cotransporters 2,SGLT2)主要表达于肾近曲小管前S1节段,负责90%葡萄糖在肾脏的重吸收,SGLT2抑制药通过阻断SGLT,抑制肾脏对葡萄糖重吸收,增加尿糖排泄而降低血糖^[1,2];在降糖的同时,减少低血糖发生的风险和减轻体质量,并在不同程度上降低收缩压和舒张压^[3,4]。目前已被美国食品药品监督管理局(FDA)批准上市的SGLT-2抑制药有dapagliflozin^[5]、canagliflozin^[6]和恩格列净(empagliflozin)^[7]。恩格列净作为第3个SGLT-2抑制药,于2014年8月被FDA批准上市,推荐使用剂量为每日10或25 mg^[7]。

2015美国糖尿病学会和欧洲糖尿病研究学会(ADA /EASD) 2型糖尿病(T2DM)管理指南更新推荐药物治疗首选二甲双胍^[8],如二甲双胍单药治疗失败,则联合其他口服降糖药治疗,推荐联用的二线药物有磺脲类、噻唑烷二酮类、二肽基肽酶4(DPP-4)抑制药、SGLT-2抑制药、GLP-1(胰高血糖素样肽)受体激动药、胰岛素。《2013年中国2型糖尿病防治指南》T2DM高血糖治疗路径的二线药物治疗没有包括SGLT-2抑制药。THOMSEN 等^[9]和正在进行的GRADE研究^[10]是2个旨在比较二线药物实际应用的临床试验,比较了与二甲双胍联合使用的4个类别(磺酰脲类、DPP-4 抑制药、GLP-1 受体激动药和胰岛素)降糖药的疗效,而这2个试验均没包括 SGLT2 抑制药。本研究拟采用系统评价的方法,对恩格列净对照阳性药(二甲双胍、西格列汀、利格列汀、格列美脲)治疗T2DM的临床试验进行分析,以期为其治疗T2DM提供循证依据。

1 资料与方法

1.1 纳入与排除标准

1.1.1 研究类型入选研究均为随机对照试验(RCT)。

1.1.2 研究对象患者年龄>18岁,以WHO或ADA标准确诊为T2DM,疗程>12周。排除严重心、肝、肾功能异常,严重心功能不全,以及妊娠和哺乳期患者。

1.1.3 干预措施试验组使用恩格列净,或者恩格列净联用二甲双胍,对照组使用其他口服降糖药物,或者其他口服降糖药物联用二甲双胍。除生活方式干预外,两组均没有其他降糖背景治疗。

1.1.4 结局指标主要结局指标:糖化血红蛋白(HbA1c)。次要结局指标:空腹血糖(FPG)、体质量、收缩压(SBP)、舒张压(DBP)、不良反应。

1.2 检索策略

计算机检索PubMed、Embase、Medline、Cochrane图书馆、CNKI、万方、维普等数据库,检索时间从建库至2016年5月。英文检索词包括:Empagliflozin、BI 10773、Jardiance、Metformin、T2DM、type 2 diabetes;中文检索词包括:恩格列净、二甲双胍、2型糖尿病。检索策略采用主题词与自由词相结合的方式。

1.3 资料提取及质量评价

两名研究人员独立评价文献质量和提取数据,如遇分歧则与第3位研究者协商后解决。数据提取文献基本信息、受试者基本信息、研究质量基本信息、干预措施基本信息、结局指标基本信息。对于使用不同单位的结局指标,应换算为同一单位后再进行统计分析。根据Cochrane系统评价手册中的“偏倚风险评估工具”对纳入的研究进行方法学质量评价^[10],评价内容包括:随机方法是否正确;是否进行分配隐藏;是否采用盲法;数据是否完整;是否对失访人数进行报道;是否进行意向治疗(ITT)分析。并采用修改后的Jadad量表对文献质量进行评分。其中随机、分配隐藏和双盲分别占2分;退出或失访描述为1分,未进行描述者为0分,总分在4分以下提示文献质量较低。

1.4 统计学方法

采用Cochrane协作网提供的RevMan 5.3版软件对数据进行Meta分析。采用χ²检验对纳入研究进行异质性检验,若P>0.1,I²<50%,认为各研究结果间无统计学异质性,采用固定效应模型分析,否则采用随机效应模型。连续性变量采用加权均数差(weighted mean difference,WMD)为效应量,分类变量采用相对危险度(relative risk,RR)为效应量,区间估计采用95%可信区间(95%CI),以P<0.05为差异有统计学意义。

2 结果

2.1 文献检索结果

初检获得230篇相关文献,剔除重复文献后通过阅读题名、摘要及全文,排除药动学研究、动物实验、综述、恩格列净单药治疗、安慰药对照等不符合纳入标准的文献,最后纳入文献7篇^{[10,11,12,13,14,15,16]},共4 135例T2DM患者。其中单用恩格列净与二甲双胍对照的文献1篇,单用恩格列净与西格列汀对照的文献2篇,恩格列净+二甲双胍与格列本脲+二甲双胍对照的文献1篇,恩格列净+二甲双胍与DPP4抑制药(西格列汀、利格列汀)+二甲双胍对照的文献3篇,均为英文发表。纳入研究的基本特征见表1。表1

纳入研究的基本特征

Tab.1

General characteristics of the included studies

文献第一作者及发表年份	干预措施	例数	年龄/ 岁	HbA1c基线水平/%	FPG基线水平/ (mmol·L^-1)	体质量基线水平/kg	疗程/ 周
ROSENSTOCK,2013^[10]	二甲双胍+恩格列净10 mg	71	59.0±9.0	7.90±0.7	9.61±2.00	87.9±14.4
	二甲双胍+恩格列净25mg	70	59.0±8.1	8.1±0.8	10.00±2.70	90.5±16.9
	二甲双胍+西格列汀100 mg	71	58.1±10.1	8.1±0.9	9.89±2.40	88.0±15.0	12
DEFRONZO,2013^[11]	二甲双胍+恩格列净10 mg	137	56.1±10.5	8.02±0.83	8.98±1.93	85.7±18.4
	二甲双胍+恩格列净25 mg	140	55.5±10.0	8.00±0.93	8.88±2.10	87.7±17.6
	二甲双胍+利格列汀5 mg	128	56.2±10.0	8.02±0.90	8.68±1.02	85.0±18.3	52
RIDDERSTRALE,2014^[12]	二甲双胍+恩格列净25 mg	765	56.2±10.3	7.92±0.81	8.32±1.77	82.5±19.2
	二甲双胍+格列美脲1~4 mg	780	55.7±10.4	7.92±0.86	8.32±1.98	83.0±19.2	104
FERRANNINI,2013^[13]	二甲双胍+恩格列净10 mg	166	60(33~77)	7.88±0.74	9.77±2.09	89.6±15.0
	二甲双胍+恩格列净25 mg	166	60(34~79)	7.91±0.78	9.91±2.17	89.5±16.2
	二甲双胍+西格列汀100 mg	56	60(32~75)	8.03±8.09	9.97±2.38	88.6±14.9	78
RODEN,2015^[14]	恩格列净10 mg	224	56.2±11.6	7.87±0.88	8.60±1.82	78.4±18.7
	恩格列净25 mg	224	52.8±11.8	7.96±0.85	8.40±1.91	77.8±18.3
	西格列汀100 mg	223	55.2±10.0	7.85±0.80	8.20±1.61	79.3±20.4	76
RODEN,2013^[15]	恩格列净10 mg	224	56.2±11.6	7.87±0.88	8.50±1.80	78.4±18.7
	恩格列净25 mg	224	53.8±11.6	7.86±0.85	8.50±1.90	77.8±18.0
	西格列汀100 mg	223	55.1±9.9	7.85±0.79	8.20±1.60	79.3±20.4	24
FERRANNINI,2013^[16]	恩格列净10 mg	81	58.0(30~76)	8.00±0.8	9.90±2.60	76.8(45.5~118.0)
	恩格列净25 mg	82	57.0(30~79)	7.80±0.80	9.50±1.40	81.2(49.1~130.0)
	二甲双胍1 000 mg	80	58.0(34~73)	8.10±0.90	9.80±2.40	81.1(42.0~126.0)	12

2.2 纳入研究的方法学质量评价结果

见表2。

表2

纳入研究的质量评价结果

Tab.2

Results of quality evaluation on the included studies

纳入研究及发表年份	随机方法	分配隐藏	盲法	数据完整	是否报道存在失访和退出	ITT分析	Jadad 评分/分
ROSENSTOCK,2013^[10]	是	是	否	是	是	否	5
DEFRONZO,2013^[11]	是	是	是	是	是	否	7
RIDDERSTRALE,2014^[12]	是	是	是	是	是	否	7
FERRANNINI,2013^[13]	不清楚	不清楚	否	是	是	否	1
RODEN,2015^[14]	是	是	否	是	是	否	5
RODEN,2013^[15]	是	是	是	是	是	否	7
FERRANNINI,2013^[16]	是	是	否	是	是	否	5

2.3 Meta分析结果

2.3.1 HbA1c ①与二甲双胍比较。1篇文献^[16]报道治疗前后HbA1c水平变化。Meta分析结果显示,单用恩格列净 10 mg组在降低HbAlc方面劣于二甲双胍[WMD=0.27%,95%CI (0.02,0.52),P=0.03];单用恩格列净25 mg组在降低HbAlc方面与二甲双胍相似[WMD=0.12%,95%CI (-0.13,0.37),P=0.34]。见图1,2。

②与DPP-4抑制药比较。5篇文献^{[10-11,13-15]}报道了治疗前后HbA1c水平变化。单用恩格列净 10 mg组在降低HbAlc方面与DPP-4抑制药疗效相似[WMD=0.00%,95%CI (-0.10,0.11),P=0.94];单用恩格列净 25 mg组在降低HbAlc方面优于DPP-4抑制药[WMD=-0.11%,95%CI (-0.22,0.00),P=0.04]。见图1,2。

联合二甲双胍,恩格列净 10 mg组在降低HbAlc方面与DPP-4抑制药疗效相似[WMD=-0.10%,95%CI (-0.23,0.03),P=0.13]。恩格列净25 mg组在降低HbAlc方面优于DPP-4抑制药[WMD=-0.16%,95%CI (-0.30,-0.03),P=0.01]。见图1,2。

③与格列美脲比较。1篇文献^[12]报道了治疗前后HbA1c水平变化。联合二甲双胍,恩格列净25 mg组在降低HbAlc方面优于格列美脲[WMD=-0.11%,95%CI (-0.19,-0.03),P=0.010]。见图1,2。

图1 恩格列净10 mg与活性降糖药物对HbA1c影响的Meta分析

Fig.1 Meta analysis on the effect of 10 mg empagliflozin and active hypoglycemic agents on HbA1c

图2 恩格列净25 mg与活性降糖药对HbA1c影响的Meta分析

Fig.2 Meta analysis on the effect of 25 mg empagliflozin and active hypoglycemic agents on HbA1c

2.3.2 FPG ①与二甲双胍比较。1篇文献^[16]报道了治疗前后FPG水平变化。Meta分析结果显示,单用恩格列净10 mg和25 mg剂量组在降低FPG方面与二甲双胍相似,见表3。

②与DPP-4抑制药比较。5篇文献^{[10,11,13-15]}报道了治疗前后FPG水平变化。单用恩格列净或恩格列净联用二甲双胍,10 mg和25 mg剂量组在降低FPG方面均优于DPP-4抑制药组,见表3。

③与格列美脲比较。1篇文献^[12]报道了治疗前后FPG水平变化。结果表明,联合二甲双胍,恩格列净25 mg在降低FPG方面优于格列美脲,见表3。

2.3.3 体质量 ①与二甲双胍比较。1篇文献^[16]报道了治疗前后体质量变化。Meta分析结果显示,单用恩格列净10 mg和25 mg 剂量组在降低体质量方面均优于二甲双胍,见表3。

②与DPP-4抑制药比较。5篇文献^{[10-11,13-15]}报道了治疗前后体质量变化,单用恩格列净或恩格列净联用二甲双胍,10 mg和25 mg 剂量组在降低体质量方面均优于DPP-4抑制药,见表3。

③与格列美脲比较。1篇文献^[12]报道了治疗前后体质量变化,联合二甲双胍,恩格列净25 mg组在降低体质量方面优于格列美脲,见表3。

2.3.4 对收缩压(SBP)、舒张压(DBP)的影响 ①与DPP-4抑制药比较。5篇文献^{[10-11,13-15]}报道了治疗前后SBP、DBP水平变化,单用恩格列净或恩格列净联用二甲双胍,10 mg和25 mg剂量组在降低SBP、DBP方面均优于DPP-4抑制药,见表3。

表3

其他疗效指标的Meta分析结果

Tab.3

Results of Meta analysis on other therapeutic indexes

结局指标	恩格列净10 mg						恩格列净25 mg
结局指标	研究数量		效应量	95%CI	P	I²/%	研究数量	效应量	95%CI	P	I²/%
FPG
二甲双胍	1	0.05	(-0.50,-0.60)	0.86	—		1	-0.07	(-0.62,0.48)	0.8	—
DPP4	2	-0.81	(-1.01,-0.60)	<0.000 01	0		2	-0.99	(-1.2,-0.79)	<0.000 01	0
DPP4+二甲双胍	3	-0.4	(-0.68,-0.13)	0.004			3	-0.62	(-1.00,-0.24)	0.002	43
格列美脲+二甲双胍	—	—	—	—	—		1	-0.68	(-0.86,-0.50)	<0.000 01	—
体质量
二甲双胍	1	-1.01	(-1.73,-0.29)	0.006	—		1	-1.11	(-1.83,-0.39)	0.002	—
DPP4	2	-2.38	(-2.74,-2.02)	<0.000 01	0		2	-2.63	(-3.00,-2.27)	<0.000 01	0
DPP4+二甲双胍	3	-2.02	(-2.60,-1.44)	<0.000 01	0		3	-2.52	(-3.41,-1.62)	<0.000 01	67
格列美脲+二甲双胍	—	—	—	—	—		1	-4.8	(-5.12,-4.48)	<0.000 01	—
SBP
DPP4	2	-3.6	(-5.18,-2.02)	<0.000 01	0		2	-4.05	(-5.63,-2.47)	<0.000 01	0
DPP4+二甲双胍	3	-3.82	(-5.76,-1.89)	0.000 1	0		3	-4.27	(-6.19,-2.35)	<0.001	12
格列美脲+二甲双胍	—	—	—	—	—		1	-5.6	(-6.73,-4.47)	<0.000 01	—
DBP
DPP4	2	-1.6	(-2.59,-0.61)	0.002	0		2	-2.04	(-3.03,-1.05)	<0.000 1	16
DPP4+二甲双胍	3	-1.43	(-2.66,-0.21)	0.02	0		3	-2.17	(-3.41,-0.93)	0.000 6	31
格列美脲+二甲双胍	—	—	—	—	—		1	-2.7	(-3.40,-2.00)	<0.000 1	—

②与格列美脲比较。1篇文献^[12]报道了治疗前后SBP、DBP水平变化,联合二甲双胍,恩格列净25 mg在降低SBP、DBP方面优于格列美脲,见表3。

2.3.5 不良反应 7篇文献均报道了总不良反应事件的发生。Meta分析结果显示,恩格列净组和对照组在总不良反应发生率、因不良反应退出率、泌尿道感染、鼻咽炎方面差异均无统计学意义(P>0.05)。然而恩格列净组生殖道感染发生率高于对照组。见表4。

表4

安全性指标的Meta分析结果

Tab.4

Results of Meta analysis on security indicators

结局指标	恩格列净10 mg						恩格列净 25 mg
结局指标	研究数量		效应量	95%CI	P	I²/%	研究数量	效应量	95%CI	P	I²/%
总不良反应发生率	6	1.03	(0.95,1.11)	0.51	0		7	1.03	(0.99,1.07)	0.14	0
因不良反应退出率	5	0.87	(0.28,2.75)	0.81	70		6	0.78	(0.41,1.48)	0.45	56
鼻咽炎	3	1.13	(0.77,1.67)	0.52	0		4	0.87	(0.69,1.11)	0.27	0
生殖道感染	6	4.58	(2.37,8.88)	<0.000 01	0		7	4.89	(3.26,7.35)	<0.000 01	0
泌尿道感染	6	0.95	(0.68,1.32)	0.76	0		7	0.98	(0.80,1.20)	0.83	0

低血糖方面,与二甲双胍的比较,恩格列净组与二甲双胍组均未发生低血糖事件。恩格列净10,25 mg在低血糖发生率方面与DPP-4抑制药相似(P>0.05)。格列美脲组发生低血糖事件风险高于恩格列净 25 mg组[RR 0.17,95%CI (0.12,0.24),P<0.000 01)]。

2.4 发表性偏倚风险的评估

因本研究纳入的文献较少,不宜采用Revman 5.3版软件绘制的倒漏斗图来对发表偏倚进行评价。笔者采用STATA 12版软件对HbA1c指标进行Egger检验,检验结果提示,纳入研究间不存在发表偏倚风险(P=0.785)。

3 讨论

2015ADA /EASD 推荐降糖药物联用的选择需个体化,要综合考虑药物的疗效、其他额外的治疗获益、不良反应、药物相互作用、价格以及患者的依从性。恩格列净具有良好的药动学特征:口服生物利用度高,消除半衰期10~19 h,可一天一次口服给药,药物之间相互作用少,患者服药的依从性较好^[17,18]。

本研究表明,单用恩格列净降糖效果不优于二甲双胍,但优于DPP-4抑制药。与二甲双胍联合用药的结果显示:恩格列净10,25 mg在降低FPG方面优于DPP-4抑制药和格列美脲;在降低HbA1c方面,10 mg 剂量组与DPP-4抑制药比较无明显差异;25 mg剂量组与DPP-4抑制药、格列美脲比较均可明显降低HbA1c。从机制上看,一方面SGLT 2 抑制药作用于肾脏表达的SGLT-2,减少了肾脏对葡萄糖重吸收,尿糖排出增多,从而发挥降糖作用。另一方面,SGLT-2抑制药导致胰高血糖素释放增多,从而增加内源性葡萄糖产生(endogenous glucose production,ECP),影响SGLT-2抑制药降糖效果^[19]。而二甲双胍抑制肝糖原的分解,改善外周组织对胰岛素的敏感性,提高外周组织对葡萄糖摄取与利用,抑制ECP。因此SGLT-2抑制药与二甲双胍联用具有机制上的互补,这种联用可能会给患者带来长期的血糖改善^[19,20]。

恩格列净的其他治疗获益:80%的T2DM患者超重或肥胖,超重和肥胖是产生胰岛素抵抗的重要原因,减轻体质量可以改善胰岛功能和血糖控制^[21,22,23]。研究显示恩格列净减轻体质量的机制可能与其增加尿糖排泄引起渗透性利尿和热量损失有关^[24]。高血压是T2DM的另一个心血管危险因素^[25,26],糖尿病患者高血压的患病率为40%~80%^[27]。恩格列净的降压机制可能与体质量减轻和渗透性利尿有关^[28]。恩格列净上市后一项心血管安全性试验 (恩格列净-REG OUTCOME^TM:NCT01131676) 结果显示,恩格列净组心血管因素死亡率相对风险降低38%^[29]。系统评价结果也显示恩格列净除降低血糖外,还可降低血压和体质量。恩格列净降低患者心血管事件风险的机制也许与其利尿作用有关(起效较快),或降糖、降压、利尿等多种机制的综合作用,但也可能存在其他未被认识的机制。

在安全性方面,恩格列净耐受性较好,与对照组比较,总不良反应发生率、尿路感染方面无显著性差异,生殖器感染的风险高于对照组,但生殖器感染均较轻微或中度,经药物治疗后可缓解。在笔者纳入的研究中,没有糖尿病酮症酸中毒的报道。2015年5月15日,FDA警告SGLT2 抑制药可能有导致糖尿病酮症酸中毒的风险,FDA建议服用SGLT2 抑制药的患者不用常规监测尿酮,但患者一旦有食欲减退、恶心、呕吐、烦躁、嗜睡、呼吸深快等症状,即使血糖正常也应立即到医院就诊^[30]。

综上所述,恩格列净同时具有降低血糖、体质量、血压及低血糖风险较低等特点,随着T2DM的进展,二甲双胍单药治疗失败后,恩格列净可能会为临床提供一种新的选择。

The authors have declared that no competing interests exist.

参考文献

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[9]	THOMSEN R W,BAGGESEN L M,METTE S,et al.Early glycaemic control in metformin users receiving their first add-on therapy:a population-based study of 4 734 people with type 2 diabetes[J].Diabetologia,2015,38(10):2247-2253. Abstract AIMS/HYPOTHESIS: The aims of this work were to assess glycaemic control in metformin users receiving their first add-on glucose-lowering therapy and to examine the real-life effectiveness of different add-on drugs. METHODS: We carried out a population-based cohort study using healthcare databases in northern Denmark during 2000-2012. We included 4,734 persons who initiated metformin monotherapy and added another glucose-lowering drug within 3 years. Attainment of recommended HbA1c goals within 6 months of add-on was investigated, using Poisson regression analysis adjusted for age, sex, baseline HbA(1c), diabetes duration, complications and Charlson Comorbidity Index. RESULTS: Median metformin treatment duration at intensification was 12 months (interquartile range [IQR] 4-23 months) and pre-intensification HbA(1c) was 8.0% (IQR 7.2-9.2%) (64 [IQR 55-77] mmol/mol). Median HbA(1c) dropped 1.2% (13 mmol/mol) with a sulfonylurea (SU) add-on, 0.8% (9 mmol/mol) with a dipeptidyl peptidase-4 (DPP-4) inhibitor, 1.3% (14 mmol/mol) with a glucagon-like peptide-1 (GLP-1) receptor agonist, 0.9% (10 mmol/mol) with other non-insulin drugs and 2.4% (26 mmol/mol) with insulin. Compared with SU add-on, attainment of HbA(1c) <7% (<53 mmol/mol) was higher with GLP-1 receptor agonists (adjusted RR [aRR] 1.10; 95% CI 1.01, 1.19) and lower with DPP-4 inhibitors (aRR 0.94; 95% CI 0.89, 0.99), other drugs (aRR 0.86; 95% CI 0.77, 0.96) and insulin (aRR 0.88; 95% CI 0.77, 0.99). The proportion of metformin add-on users who attained HbA(1c) <7% (<53 mmol/mol) increased from 46% in 2000-2003 to 59% in 2010-2012, whereas attainment of HbA(1c) <6.5% (<48 mmol/mol) remained 30% among patients aged <65 years without comorbidities. CONCLUSIONS/INTERPRETATION: Among early type 2 diabetes patients receiving their first metformin add-on treatment, HbA(1c) reduction with different non-insulin drugs is similar to, and comparable with, that observed in randomised trials, yet 41% do not achieve HbA(1c) <7% (<53 mmol/mol) within 6 months. DOI:10.1007/s00125-015-3698-1 PMID:26277380 URL [本文引用:1]
[10]	ROSENSTOCK J,SEMAN L J,JELASKA A,et al.Efficacy and safety of empagliflozin,a sodium glucose cotransporter 2(SGLT2) inhibitor,as add-on to metformin in type 2 diabetes with mild hyperglycaemia[J].Diabetes Obes Metab,2013,15(12):1154-1160. AimsTo evaluate the effects of the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin added to metformin for 12090009weeks in patients with type 2 diabetes.MethodsThis dose-ranging, double-blind, placebo-controlled trial randomized 495 participants with type 2 diabetes inadequately controlled on metformin [haemoglobin A1c (HbA1c) >7 to 0909¤10%] to receive 1, 5, 10, 25, or 50090009mg empagliflozin once daily (QD), or placebo, or open-label sitagliptin (100090009mg QD), added to metformin for 12090009weeks. The primary endpoint was change in HbA1c from baseline to week 12 (empagliflozin groups versus placebo).ResultsReductions in HbA1c of 0908080.09 to 0908080.56% were observed with empagliflozin after 12090009weeks, versus an increase of 0.15% with placebo (baseline: 7.80900098.1%). Compared with placebo, empagliflozin doses from 5 to 50090009mg resulted in reductions in fasting plasma glucose (0908082 to 09080828090009mg/dl vs. 5090009mg/dl with placebo; p090009<0900090.0001) and body weight (0908082.3 to 0908082.9090009kg vs. 0908081.2090009kg; p090009<0900090.01). Frequency of adverse events was generally similar with empagliflozin (29.609000948.6%), placebo (36.6%) and sitagliptin (35.2%). Hypoglycaemia rates were very low and balanced among groups. Most frequent adverse events with empagliflozin were urinary tract infections (4.0% vs. 2.8% with placebo) and pollakiuria (2.5% vs. 1.4% with placebo). Genital infections were reported only with empagliflozin (4.0%).ConclusionsOnce daily empagliflozin as add-on therapy to metformin was well tolerated except for increased genital infections and resulted in reductions in HbA1c, fasting plasma glucose and body weight in patients with type 2 diabetes inadequately controlled on metformin monotherapy. DOI:10.1111/dom.12185 PMID:23906374 URL [本文引用:9]
[11]	DEFRONZO R A,LEWIN A,PATEL S,et al.Combination of empagliflozin and linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin[J].Diabetes Care,2013,38(3):384-393. To evaluate the efficacy and safety of combinations of empagliflozin/linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin.Subjects were randomized to a combination of empagliflozin 25 mg/linagliptin 5 mg (n = 137), empagliflozin 10 mg/linagliptin 5 mg (n = 136), empagliflozin 25 mg (n = 141), empagliflozin 10 mg (n = 140), or linagliptin 5 mg (n = 132) as add-on to metformin for 52 weeks. The primary end point was change from baseline in HbA1c at week 24.At week 24, reductions in HbA1c (mean baseline 7.90-8.02% [62.8-64.1 mmol/mol]) with empagliflozin/linagliptin were superior to those with empagliflozin or linagliptin alone as add-on to metformin; adjusted mean (SE) changes from baseline were -1.19% (0.06) (-13.1 mmol/mol [0.7]) with empagliflozin 25 mg/linagliptin 5 mg, -1.08% (0.06) (-11.8 mmol/mol [0.7]) with empagliflozin 10 mg/linagliptin 5 mg, -0.62% (0.06) (-6.8 mmol/mol [0.7]) with empagliflozin 25 mg, -0.66% (0.06) (-7.2 mmol/mol [0.7]) with empagliflozin 10 mg, and -0.70% (0.06) (-7.6 mmol/mol [0.7]) with linagliptin 5 mg (P < 0.001 for all comparisons). In these groups, respectively, 61.8, 57.8, 32.6, 28.0, and 36.1% of subjects with baseline HbA1c 7% (53 mmol/mol) had HbA1c <7% (<53 mmol/mol) at week 24. Efficacy was maintained at week 52. The proportion of subjects with adverse events (AEs) over 52 weeks was similar across treatment arms (68.6-73.0%), with no hypoglycemic AEs requiring assistance.Combinations of empagliflozin/linagliptin as second-line therapy for 52 weeks significantly reduced HbA1c compared with the individual components and were well tolerated. DOI:10.2337/dc14-2364 PMID:25583754 URL [本文引用:7]
[12]	RIDDERSTRALE M,ANDERSEN K R,ZELLER C,et al.Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes:a 104-week randomised,active-controlled,double-blind,phase 3 trial[J].Lancet Diabetes Endocrinol,2014,2(9):691-700. Abstract BACKGROUND: Metformin is the recommended first-line pharmacotherapy for patients with type 2 diabetes. There is no consensus on the optimum second-line pharmacotherapy. We compared the efficacy and safety of the sodium glucose cotransporter 2 inhibitor empagliflozin and the sulfonylurea glimepiride as add-on to metformin in patients with type 2 diabetes. METHODS: In this double-blind phase 3 trial, patients (aged ≥18 years) with type 2 diabetes and HbA1c concentrations of 7-10%, despite metformin treatment and diet and exercise counselling, were randomly assigned in a 1:1 ratio with a computer-generated random sequence, stratified by HbA1c, estimated glomerular filtration rate (eGFR), and region, to empagliflozin (25 mg once daily, orally) or glimepiride (1-4 mg once daily, orally) as add-on to metformin for 104 weeks. Patients and investigators were masked to treatment assignment. The primary endpoint was change from baseline in HbA1c levels at weeks 52 and 104. Differences in the primary endpoint were first tested for non-inferiority (based on a margin of 0·3%). If non-inferiority was shown, differences in the primary endpoint at week 104 were then tested for superiority. Analysis was done on the full-analysis set-ie, patients who were treated with at least one dose of study drug and had a baseline HbA1c value. This study is registered with ClinicalTrials.gov, number NCT01167881 . A 104-week extension is ongoing. FINDINGS: Between August, 2010, and June, 2011, 1549 patients were randomly assigned to receive empagliflozin (n=769) or glimepiride (n=780); four patients in the empagliflozin group did not receive the assigned treatment. Empagliflozin was non-inferior to glimepiride at both timepoints. At week 104, adjusted mean difference in change from baseline in HbA1c with empagliflozin versus glimepiride was -0·11% (95% CI -0·19 to -0·02; p=0·0153 for superiority). Adverse events were reported in 661 (86%) patients treated with empagliflozin and 673 (86%) patients treated with glimepiride. Severe adverse events were reported in 72 (9%) patients in the empagliflozin group and 68 (9%) in the glimepiride group. Serious adverse events were reported in 119 (16%) patients in the empagliflozin group and 89 (11%) in the glimepiride group. Confirmed hypoglycaemic adverse events (plasma glucose ≤3·9 mmol/L or requiring assistance) at week 104 were reported in 19 (2%) patients treated with empagliflozin and 189 (24%) patients treated with glimepiride. INTERPRETATION: Empagliflozin might be an effective and a well tolerated second-line treatment option for patients with type 2 diabetes who have not achieved good glycaemic control on metformin. FUNDING: Boehringer Ingelheim and Eli Lilly. Copyright 08 2014 Elsevier Ltd. All rights reserved. DOI:10.1016/S2213-8587(14)70120-2 PMID:24948511 URL [本文引用:7]
[13]	FERRANNINI E,BERK A,HANTEL S,et al.Long-term safety and efficacy of empagliflozin,sitagliptin,and metformin:an active-controlled,parallel-group,randomized,78-week open-label extension study in patients with type 2 diabetes[J].Diabetes Care,2013,36(12):4015-4021. DOI:10.2337/dc13-0663 URL [本文引用:7]
[14]	RODEN M,MERKER L,CHRISTIANSEN A V,et al.Safety,tolerability and effectson cardiometabolic risk factors of empagliflozin monotherapy in drug-naive patients with type 2 diabetes:a double-blind extension of a phase III randomized controlled trial[J].Cardiovasc Diabetol,2015,14(1):154. DOI:10.1186/s12933-015-0314-0 URL [本文引用:3]
[15]	RODEN M,WENG J P,EILBRACHT J,et al.Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes:a randomised,double-blind,placebo-controlled,phase 3 trial[J].Lancet Diabetes Endocrinol,2013,1(3):208-219. Abstract BACKGROUND: We aimed to investigate the efficacy and tolerability of empagliflozin, an oral, potent, and selective inhibitor of sodium-glucose co-transporter 2, in patients with type 2 diabetes who had not received drug treatment in the preceding 12 weeks. METHODS: In our multicentre, randomised, placebo-controlled, phase 3 trial, we enrolled adults (aged 09090618 years) who had not received oral or injected anti-diabetes treatment in the previous 12 weeks. Eligible patients had HbA1c concentrations of 7-10%. We randomly allocated patients (1:1:1:1) with a computer-generated random sequence, stratified by region, HbA1c, and estimated glomerular filtration rate at screening, to placebo, empagliflozin 10 mg, empagliflozin 25 mg, or sitagliptin 100 mg once daily for 24 weeks. Patients and investigators were masked to treatment assignment. The primary endpoint was change from baseline in HbA1c at week 24 by ANCOVA in all randomly allocated patients who were treated with at least one dose of study drug and had a baseline HbA1c value. This study is completed and registered with ClinicalTrials.gov, number NCT01177813 . FINDINGS: Between Aug 12, 2010, and March 19, 2012, we randomly allocated 228 patients to receive placebo, 224 to receive empagliflozin 10 mg, 224 to receive empagliflozin 25 mg, and 223 to receive sitagliptin. Compared with placebo, adjusted mean differences in change from baseline HbA1c at week 24 were -000·74% (95% CI -000·88 to -000·59; p<000·0001) for empagliflozin 10 mg, -000·85% (-000·99 to -000·71; p<000·0001) for empagliflozin 25 mg, and -000·73% (-000·88 to -000·59; p<000·0001) for sitagliptin. 140 (61%) patients in the placebo group reported adverse events (four [2%] severe and six [3%] serious), as did 123 (55%) patients in the empagliflozin 10 mg group (eight [4%] severe and eight [4%] serious), 135 (60%) patients in the empagliflozin 25 mg group (seven [3%] severe and five [2%] serious), and 119 (53%) patients in the sitagliptin group (five [2%] severe and six [3%] serious). INTERPRETATION: Empagliflozin provides a tolerable and efficacious strategy to reduce HbA1c in patients with type 2 diabetes who had not previously received drug treatment. FUNDING: Boehringer Ingelheim and Eli Lilly. Copyright 0008 2013 Elsevier Ltd. All rights reserved. DOI:10.1016/S2213-8587(13)70084-6 PMID:24622369 URL [本文引用:7]
[16]	FERRANNINI E,SEMAN L,SEEWALDT-BECKER E,et al.A Phase IIb,randomized,placebo-controlled study of the SGLT2 inhibitor empagliflozin in patients with type 2 diabetes[J].Diabetes Obes Metab,2013,15(8):721-728. Abstract AIM: This Phase IIb, randomized, double-blind, placebo-controlled trial evaluated the efficacy, safety, tolerability and pharmacokinetics of empagliflozin in patients with type 2 diabetes. METHODS: Four hundred and eight patients (treatment-na0104ve or after a 4-week wash-out period) were randomized to receive empagliflozin 5, 10 or 25090009mg once daily, placebo or open-label metformin for 12090009weeks. The primary endpoint was change in haemoglobin A1c (HbA1c) after 12090009weeks. RESULTS: After 12090009weeks' treatment, empagliflozin showed dose-dependent reductions in HbA1c from baseline [5090009mg: -0.4%, 10090009mg: -0.5%, 25090009mg: -0.6%; all doses p090009<0900090.0001 vs. placebo (+0.09%)]. Fasting plasma glucose (FPG) decreased with empagliflozin [5090009mg: -1.29090009mmol/l, 10090009mg: -1.61090009mmol/l, 25090009mg: -1.72090009mmol/l; all doses p090009<0900090.0001 vs. placebo (+0.04090009mmol/l)]. Body weight decreased in all empagliflozin groups (all doses p090009<0900090.001 vs. placebo). The incidence of adverse events (AEs) was similar in the placebo (32.9%) and empagliflozin (29.1%) groups. The most frequently reported AEs on empagliflozin were pollakiuria (3.3% vs. 0% for placebo), thirst (3.3% vs. 0% for placebo) and nasopharyngitis (2.0% vs. 1.2% for placebo). AEs consistent with urinary tract infections (UTIs) were reported in four (1.6%) patients on empagliflozin vs. one (1.2%) on placebo. Genital infections were reported in five (2%) patients on empagliflozin vs. 0% on placebo. No UTIs or genital infections led to premature discontinuation. CONCLUSIONS: In patients with type 2 diabetes, empagliflozin resulted in dose-dependent, clinically meaningful reductions in HbA1c and FPG, and reductions in body weight compared with placebo. Empagliflozin was well-tolerated with a favourable safety profile. 0008 2013 Blackwell Publishing Ltd. DOI:10.1111/dom.12081 PMID:23398530 URL [本文引用:6]
[17]	MACHA S,MATTHEUS M,PINNETTI S,et al.Effect of empagliflozin on the steady-state pharmacokinetics of ethinylestradiol and levonorgestrel in healthy female volunteers[J].Clin Drug Investig,2013,33(5):351-357. Background Empagliflozin is a potent, selective inhibitor of sodium glucose cotransporter 2 in development for the treatment of patients with type 2 diabetes mellitus. Oral contraceptives may be co-administered with antidiabetic agents over long periods of time, therefore potential drug-drug interactions between oral contraceptives and antidiabetic drugs should be investigated. Objective The effect of multiple oral doses of empagliflozin 2502mg once daily (qd) on the steady-state pharmacokinetics of the combined oral contraceptive ethinylestradiol (EE) 3002μg/levonorgestrel (LNG) 15002μg qd was investigated. Study Design This was a phase I, open-label, two-period, fixed sequence study. Setting The study was performed at the Human Pharmacology Centre/Department of Translational Medicine , Boehringer Ingelheim, Biberach, Germany. Participants Eighteen healthy premenopausal women participated in the study. Intervention There was a mandatory run-in period in which participants received EE 3002μg/LNG 15002μg02qd for 21–4802days followed by a treatment-free interval of 702days. Participants then received EE 3002μg/LNG 15002μg qd for 1402days (reference; period 1), followed by EE 3002μg/LNG 15002μg qd plus empagliflozin 2502mg qd for 702days (test; period 2). Main Outcome Measures The pharmacokinetics of EE and LNG at steady state based on the primary endpoints of area under the steady-state plasma concentration-time curve during a dosage interval τ (AUC τ,ss ) and maximum steady-state plasma concentration during a dosage interval ( C max,ss ) were the main outcome measures. Results The pharmacokinetics of EE and LNG were not affected by co-administration with empagliflozin. Geometric mean ratios (9002% CI) of AUC τ,ss and C max,ss for EE were 102.8202% (97.58, 108.35) and 99.2202% (93.40, 105.39), respectively. For LNG, these values were 101.9402% (98.54, 105.47) and 105.8102% (99.47, 112.55), respectively. The 9002% CIs were within the standard bioequivalence boundaries of 80–12502%. There were no relevant changes in the time to reach peak levels ( t max,ss ) or terminal elimination half-life ( t 05,ss ) of EE and LNG between test and reference treatments. Ten women in each treatment had at least one adverse event (AE). Severe AEs were reported by three women in the reference period and one woman in the test period. There were no serious AEs or premature discontinuations. Conclusion The combination of EE 3002μg/LNG 15002μg and empagliflozin 2502mg was well tolerated. Based on standard bioequivalence criteria, empagliflozin had no effect on the pharmacokinetics of EE and LNG, indicating that no dose adjustment of EE 3002μg/LNG 15002μg is required when empagliflozin is co-administered. DOI:10.1007/s40261-013-0068-y PMID:23512637 URL [本文引用:1]
[18]	MACHA S,MATTHEUS M,PINNETTI S,et al.Pharmaco-kinetics of empagliflozin,a sodium glucose cotransporter 2 inhibitor,and glimepiride following co-administration in healthy volunteers:a randomised,open-label,crossover study[J].J Diab Res Clin Metab,2012,1(1):1-7. [本文引用:1]
[19]	NESCHEN S,SCHEERER M,SEELIG A,et al.Metformin supports the antidiabetic effect of a sodium glucose cotransporter 2 inhibitor by suppressing endogenous glucose production in diabetic mice[J].Diabetes,2015,64(1):284-290. Combined use of metformin and a sodium glucose cotransporter 2 inhibitor (SGLT2I) is a promising treatment strategy for type 2 diabetes. The mechanism by which combination treatment provides better glycemic control than metformin or SGLT2I monotherapy remains elusive. Therefore, we investigated the physiological mechanism by which both compounds lower blood glucose concentrations in diabetic mice. We compared the potential of metformin and the SGLT2I AVE2268 alone or in combination to mitigate hyperglycemia and modulate glucose fluxes in db/db and diabetic Tallyho/JngJ mice. SGLT2I treatment alone elicited a rapid decline in circulating blood glucose levels, which appeared to induce endogenous glucose production. Supplementation of metformin dampened this counterresponse, and therefore, combination therapy more efficiently maintained glycemic control. Finally, combination treatment blunted postprandial glucose excursions and improved HbA1c levels within 2 weeks. We conclude that coapplication of metformin enhances the glucose-lowering actions of SGLT2I by restraining endogenous glucose production, which may provide long-term improvement of glycemic control in type 2 diabetic patients. DOI:10.2337/db14-0393 PMID:25071027 URL [本文引用:2]
[20]	MEROVCI A,SOLIS-HERRERA C,DANIELE G,et al.Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production[J].J Clin Invest,2014,124(2):509-514. Elsevier’s Scopus, the largest abstract and citation database of peer-reviewed literature. Search and access research from the science, technology, medicine, social sciences and arts and humanities fields. DOI:10.1172/JCI76184 PMID:24463448 URL [本文引用:1]
[21]	FOX C S,PENCINA M J,WILSON P W,et al.Lifetime risk of cardiovascular disease among individuals with and without diabetes stratified by obesity status in the Framingham heart study[J].Diabetes Care,2008,31(8):1582-1584. OBJECTIVE—We assessed the lifetime risk of cardiovascular disease (CVD) among individuals with and without obesity and diabetes. RESEARCH DESIGN AND METHODS—Participants were drawn from the original and offspring cohorts of the Framingham Heart Study. Lifetime (30-year) risk of CVD was assessed using a modified Kaplan-Meier approach adjusting for the competing risk of death, beginning from age 50 years. RESULTS—Over 30 years, the lifetime risk of CVD among women with diabetes was 54.8% among normal-weight women and 78.8% among obese women. Among normal-weight men with diabetes, the lifetime risk of CVD was 78.6%, whereas it was 86.9% among obese men. CONCLUSIONS—The lifetime risk of CVD among individuals with diabetes is high, and this relationship is further accentuated with increasing adiposity. DOI:10.2337/dc08-0025 PMID:1101974 URL [本文引用:1]
[22]	BAVENHOLM P N,KUHL J,PIGON J,et al.Insulin resistance in type 2 diabetes:association with truncal obesity,impaired fitness,and atypical malonyl coenzyme A regulation[J].J Clin Endocrinol Metab,2003,88(1):82-87. Abdominal obesity and physical inactivity are associated with insulin resistance in humans and contribute to the development of type 2 diabetes. Likewise, sustained increases in the concentration of malonyl coenzyme A (CoA), an inhibitor of fatty-acid oxidation, have been observed in muscle in association with insulin resistance and type 2 diabetes in various rodents. In the present study, we assessed whether these factors are present in a defined population of slightly overweight (body mass index, 26.2 kg/m2), insulin-resistant patients with type 2 diabetes. Thirteen type 2 diabetic men and 17 sex-, age-, and body mass index-matched control subjects were evaluated. Insulin sensitivity was assessed during a two-step euglycemic insulin clamp (infusion of 0.25 and 1.0 mU/kg x min). The rates of glucose administered during the low-dose insulin clamp were 2.0 +/- 0.2 vs. 0.7 +/- 0.2 mg/kg body weight x min (P < 0.001) in the control and diabetic subjects, respectively; rates during the high-dose insulin clamp were 8.3 +/- 0.7 vs. 4.6 +/- 0.4 mg/kg body weight x min (P < 0.001) for controls and diabetic subjects. The diabetic patients had a significantly lower maximal oxygen uptake than control subjects (29.4 +/- 1.0 vs. 33.4 +/- 1.4 ml/kg x min; P = 0.03) and a greater total body fat mass (3.7 kg), mainly due to an increase in truncal fat (16.5 +/- 0.9 vs. 13.1 +/- 0.9 kg; P = 0.02). The plasma concentration of free fatty acid and the rate of fatty acid oxidation during the clamps were both higher in the diabetic subjects than the control subjects (P = 0.002-0.007). In addition, during the high-dose insulin clamp, the increase in cytosolic citrate and malate in muscle, which parallels and regulates malonyl CoA levels, was significantly less in the diabetic patients (P < 0.05 vs. P < 0.001). Despite this, a similar increase in the concentration of malonyl CoA was observed in the two groups, suggesting an abnormality in malonyl CoA regulation in the diabetic subjects. In conclusion, the results confirm that insulin sensitivity is decreased in slightly overweight men with mild type 2 diabetes and that this correlates closely with an increase in truncal fat mass and a decrease in physical fitness. Whether the unexpectedly high levels of malonyl CoA in muscle, together with the diminished suppression of plasma free fatty acid, explains the insulin resistance of the diabetic patients during the clamp remains to be determined. DOI:10.1210/jc.2002-020330 PMID:12519834 URL [本文引用:1]
[23]	MAGGIO C A,PI-SUNYER F X.The prevention and treat-ment of obesity.Application to type 2 diabetes[J].Diabetes Care,1997,20(11):1744-1766. Division of Endocrinology, Diabetes, and Nutrition, St. Luke's-Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, New York, New York 10025, USA. DOI:10.2337/diacare.20.11.1744 PMID:9353619 URL [本文引用:1]
[24]	BARNETT A H.Impact of sodium glucose cotransporter 2 inhibitors on weight in patients with type 2 diabetes mellitus[J].Postgrad Med,2013,125(5):92-100. Most patients with type 2 diabetes mellitus (T2DM) are overweight or obese. Both T2DM and overweight/obesity are associated with increased patient risk of cardiovascular events and mortality. Despite being the recognized cornerstone of treatment, weight loss and maintenance of weight loss are difficult for patients with T2DM, particularly as treatments for T2DM may cause weight gain. Sodium glucose cotransporter 2 (SGLT2) inhibitors, a new class of drug for the treatment of patients with T2DM, reduce renal glucose reabsorption, resulting in urinary glucose excretion. Due to the caloric loss associated with decreased glucose in urine, treatment with SGLT2 agents offers the benefit of weight loss to patients, as well as reduction in hyperglycemia. Clinical trials of SGLT2 inhibitors in patients with T2DM, ranging in length from 4 to 90 weeks, have shown patient weight reductions from baseline of up to 4.7 kg. Such weight loss may have beneficial effects on adherence to medication, glycemic control, and cardiovascular risk in patients with T2DM. DOI:10.3810/pgm.2013.09.2698 PMID:24113667 URL [本文引用:1]
[25]	American Diabetes Association.Standards of medical care in diabetesd 2012[J].Diabetes Care,2012,35(Suppl 1):S11-S63. DOI:10.2337/dc12-s011 URL [本文引用:1]
[26]	CEDERHOLM J,GUDBJORNSDOTTIR S,ELIASSON B,et al.Blood pressure and risk of cardiovascular diseases in type 2 diabetes:further findings from the Swedish National Diabetes Register (NDR-BP II)[J].J Hypertens,2012,30(10):2020-2030. DOI:10.1097/HJH.0b013e3283577bdf URL [本文引用:1]
[27]	SOWERS J R,EPSTEIN M,FROHLICH E D.Diabetes,hypertension,and cardiovascular disease:an update[J].Hypertension,2001,37(4):1053-1059. DOI:10.1161/01.HYP.37.4.1053 URL [本文引用:1]
[28]	BASILE J N.The potential of sodium glucose cotransporter 2 (SGLT2) inhibitors to reduce cardiovascular risk in patients with type 2 diabetes (T2DM)[J].J Diabetes Complications,2013,27(3):280-286. Type 2 diabetes mellitus (T2DM) significantly increases morbidity and mortality from cardiovascular disease (CVD). Treatments for patients with T2DM have the potential to reduce cardiovascular (CV) risk. This review focuses on the potential of a new class of antidiabetic agents, the sodium glucose cotransporter 2 (SGLT2) inhibitors, to reduce CV risk in patients with T2DM through reductions in hyperglycemia, blood pressure (BP), and body weight. The results of clinical trials of SGLT2 inhibitors are summarized and discussed. DOI:10.1016/j.jdiacomp.2012.12.004 PMID:23375850 URL [本文引用:1]
[29]	ZINMAN B,WANNER C,LACHIN J M,et al.Empagliflo-zin,cardiovascular outcomes,and mortality in type 2 diabetes[J].N Engl J Med,2015,373(22):2117-2128. DOI:10.1056/NEJMoa1504720 URL [本文引用:1]
[30]	FDA.Warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood[EB/OL].[2014-01-08].. URL [本文引用:1]

Glucose handling by the kidney

2011

... 钠-葡萄糖协同转运蛋白2(sodium-glucose cotransporters 2,SGLT2)主要表达于肾近曲小管前S1节段,负责90%葡萄糖在肾脏的重吸收,SGLT2抑制药通过阻断SGLT,抑制肾脏对葡萄糖重吸收,增加尿糖排泄而降低血糖^[1,2];在降糖的同时,减少低血糖发生的风险和减轻体质量,并在不同程度上降低收缩压和舒张压^[3,4].目前已被美国食品药品监督管理局(FDA)批准上市的SGLT-2抑制药有dapagliflozin^[5]、canagliflozin^[6]和恩格列净(empagliflozin)^[7].恩格列净作为第3个SGLT-2抑制药,于2014年8月被FDA批准上市,推荐使用剂量为每日10或25 mg^[7]. ...

The role of the kidneys in glucose homeostasis:a new path towards normalizing glycaemia

2012

Empagliflozin monotherapy with sitagliptin as an activecomparator in patients with type 2 diabetes:a randomised,double-blind,placebo-controlled,phase 3 trial

2013

Empagliflo-zin as add-on to basal insulin for 78 weeks improves glycemic control with weight loss in insulin-treated type 2 diabetes (T2DM)

2013

FDA.Advisory committee recommends approval of dapagli-flozin for treatment of adults with type 2 diabetes

2014

FDA.Advisory committee recommends approval of canagli-flozin for treatment of adults with type 2 diabetes

2013

FDA.Advisory committee recommends approval of Empagli-flozin for treatment of adults with type 2 diabetes

2014

... [7]. ...

Management of hyperglycemia in type 2 diabetes,2015:a patient-centered approach:update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes

2015

... 2015美国糖尿病学会和欧洲糖尿病研究学会(ADA /EASD) 2型糖尿病(T2DM)管理指南更新推荐药物治疗首选二甲双胍^[8],如二甲双胍单药治疗失败,则联合其他口服降糖药治疗,推荐联用的二线药物有磺脲类、噻唑烷二酮类、二肽基肽酶4(DPP-4)抑制药、SGLT-2抑制药、GLP-1(胰高血糖素样肽)受体激动药、胰岛素.《2013年中国2型糖尿病防治指南》T2DM高血糖治疗路径的二线药物治疗没有包括SGLT-2抑制药.THOMSEN 等^[9]和正在进行的GRADE研究^[10]是2个旨在比较二线药物实际应用的临床试验,比较了与二甲双胍联合使用的4个类别(磺酰脲类、DPP-4 抑制药、GLP-1 受体激动药和胰岛素)降糖药的疗效,而这2个试验均没包括 SGLT2 抑制药.本研究拟采用系统评价的方法,对恩格列净对照阳性药(二甲双胍、西格列汀、利格列汀、格列美脲)治疗T2DM的临床试验进行分析,以期为其治疗T2DM提供循证依据. ...

Early glycaemic control in metformin users receiving their first add-on therapy:a population-based study of 4 734 people with type 2 diabetes

2015

Efficacy and safety of empagliflozin,a sodium glucose cotransporter 2(SGLT2) inhibitor,as add-on to metformin in type 2 diabetes with mild hyperglycaemia

2013

... 两名研究人员独立评价文献质量和提取数据,如遇分歧则与第3位研究者协商后解决.数据提取文献基本信息、受试者基本信息、研究质量基本信息、干预措施基本信息、结局指标基本信息.对于使用不同单位的结局指标,应换算为同一单位后再进行统计分析.根据Cochrane系统评价手册中的“偏倚风险评估工具”对纳入的研究进行方法学质量评价^[10],评价内容包括:随机方法是否正确;是否进行分配隐藏;是否采用盲法;数据是否完整;是否对失访人数进行报道;是否进行意向治疗(ITT)分析.并采用修改后的Jadad量表对文献质量进行评分.其中随机、分配隐藏和双盲分别占2分;退出或失访描述为1分,未进行描述者为0分,总分在4分以下提示文献质量较低. ...

... 初检获得230篇相关文献,剔除重复文献后通过阅读题名、摘要及全文,排除药动学研究、动物实验、综述、恩格列净单药治疗、安慰药对照等不符合纳入标准的文献,最后纳入文献7篇^{[10,11,12,13,14,15,16]},共4 135例T2DM患者.其中单用恩格列净与二甲双胍对照的文献1篇,单用恩格列净与西格列汀对照的文献2篇,恩格列净+二甲双胍与格列本脲+二甲双胍对照的文献1篇,恩格列净+二甲双胍与DPP4抑制药(西格列汀、利格列汀)+二甲双胍对照的文献3篇,均为英文发表.纳入研究的基本特征见表1. 表1

纳入研究的基本特征 ...

... General characteristics of the included studies

文献第一作者及发表年份	干预措施	例数	年龄/ 岁	HbA1c基线水平/%	FPG基线水平/ (mmol·L^-1)	体质量基线水平/kg	疗程/ 周
ROSENSTOCK,2013^[10]	二甲双胍+恩格列净10 mg	71	59.0±9.0	7.90±0.7	9.61±2.00	87.9±14.4
	二甲双胍+恩格列净25mg	70	59.0±8.1	8.1±0.8	10.00±2.70	90.5±16.9
	二甲双胍+西格列汀100 mg	71	58.1±10.1	8.1±0.9	9.89±2.40	88.0±15.0	12
DEFRONZO,2013^[11]	二甲双胍+恩格列净10 mg	137	56.1±10.5	8.02±0.83	8.98±1.93	85.7±18.4
	二甲双胍+恩格列净25 mg	140	55.5±10.0	8.00±0.93	8.88±2.10	87.7±17.6
	二甲双胍+利格列汀5 mg	128	56.2±10.0	8.02±0.90	8.68±1.02	85.0±18.3	52
RIDDERSTRALE,2014^[12]	二甲双胍+恩格列净25 mg	765	56.2±10.3	7.92±0.81	8.32±1.77	82.5±19.2
	二甲双胍+格列美脲1~4 mg	780	55.7±10.4	7.92±0.86	8.32±1.98	83.0±19.2	104
FERRANNINI,2013^[13]	二甲双胍+恩格列净10 mg	166	60(33~77)	7.88±0.74	9.77±2.09	89.6±15.0
	二甲双胍+恩格列净25 mg	166	60(34~79)	7.91±0.78	9.91±2.17	89.5±16.2
	二甲双胍+西格列汀100 mg	56	60(32~75)	8.03±8.09	9.97±2.38	88.6±14.9	78
RODEN,2015^[14]	恩格列净10 mg	224	56.2±11.6	7.87±0.88	8.60±1.82	78.4±18.7
	恩格列净25 mg	224	52.8±11.8	7.96±0.85	8.40±1.91	77.8±18.3
	西格列汀100 mg	223	55.2±10.0	7.85±0.80	8.20±1.61	79.3±20.4	76
RODEN,2013^[15]	恩格列净10 mg	224	56.2±11.6	7.87±0.88	8.50±1.80	78.4±18.7
	恩格列净25 mg	224	53.8±11.6	7.86±0.85	8.50±1.90	77.8±18.0
	西格列汀100 mg	223	55.1±9.9	7.85±0.79	8.20±1.60	79.3±20.4	24
FERRANNINI,2013^[16]	恩格列净10 mg	81	58.0(30~76)	8.00±0.8	9.90±2.60	76.8(45.5~118.0)
	恩格列净25 mg	82	57.0(30~79)	7.80±0.80	9.50±1.40	81.2(49.1~130.0)
	二甲双胍1 000 mg	80	58.0(34~73)	8.10±0.90	9.80±2.40	81.1(42.0~126.0)	12

...

... Results of quality evaluation on the included studies

纳入研究及发表年份	随机方法	分配隐藏	盲法	数据完整	是否报道存在失访和退出	ITT分析	Jadad 评分/分
ROSENSTOCK,2013^[10]	是	是	否	是	是	否	5
DEFRONZO,2013^[11]	是	是	是	是	是	否	7
RIDDERSTRALE,2014^[12]	是	是	是	是	是	否	7
FERRANNINI,2013^[13]	不清楚	不清楚	否	是	是	否	1
RODEN,2015^[14]	是	是	否	是	是	否	5
RODEN,2013^[15]	是	是	是	是	是	否	7
FERRANNINI,2013^[16]	是	是	否	是	是	否	5

...

... ②与DPP-4抑制药比较.5篇文献^{[10-11,13-15]}报道了治疗前后HbA1c水平变化.单用恩格列净 10 mg组在降低HbAlc方面与DPP-4抑制药疗效相似[WMD=0.00%,95%CI (-0.10,0.11),P=0.94];单用恩格列净 25 mg组在降低HbAlc方面优于DPP-4抑制药[WMD=-0.11%,95%CI (-0.22,0.00),P=0.04].见图1,2. ...

... ②与DPP-4抑制药比较.5篇文献^{[10,11,13-15]}报道了治疗前后FPG水平变化.单用恩格列净或恩格列净联用二甲双胍,10 mg和25 mg剂量组在降低FPG方面均优于DPP-4抑制药组,见表3. ...

... ②与DPP-4抑制药比较.5篇文献^{[10-11,13-15]}报道了治疗前后体质量变化,单用恩格列净或恩格列净联用二甲双胍,10 mg和25 mg 剂量组在降低体质量方面均优于DPP-4抑制药,见表3. ...

... 2.3.4 对收缩压(SBP)、舒张压(DBP)的影响 ①与DPP-4抑制药比较.5篇文献^{[10-11,13-15]}报道了治疗前后SBP、DBP水平变化,单用恩格列净或恩格列净联用二甲双胍,10 mg和25 mg剂量组在降低SBP、DBP方面均优于DPP-4抑制药,见表3. ...

Combination of empagliflozin and linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin

2013

纳入研究的基本特征 ...

... General characteristics of the included studies

文献第一作者及发表年份	干预措施	例数	年龄/ 岁	HbA1c基线水平/%	FPG基线水平/ (mmol·L^-1)	体质量基线水平/kg	疗程/ 周
ROSENSTOCK,2013^[10]	二甲双胍+恩格列净10 mg	71	59.0±9.0	7.90±0.7	9.61±2.00	87.9±14.4
	二甲双胍+恩格列净25mg	70	59.0±8.1	8.1±0.8	10.00±2.70	90.5±16.9
	二甲双胍+西格列汀100 mg	71	58.1±10.1	8.1±0.9	9.89±2.40	88.0±15.0	12
DEFRONZO,2013^[11]	二甲双胍+恩格列净10 mg	137	56.1±10.5	8.02±0.83	8.98±1.93	85.7±18.4
	二甲双胍+恩格列净25 mg	140	55.5±10.0	8.00±0.93	8.88±2.10	87.7±17.6
	二甲双胍+利格列汀5 mg	128	56.2±10.0	8.02±0.90	8.68±1.02	85.0±18.3	52
RIDDERSTRALE,2014^[12]	二甲双胍+恩格列净25 mg	765	56.2±10.3	7.92±0.81	8.32±1.77	82.5±19.2
	二甲双胍+格列美脲1~4 mg	780	55.7±10.4	7.92±0.86	8.32±1.98	83.0±19.2	104
FERRANNINI,2013^[13]	二甲双胍+恩格列净10 mg	166	60(33~77)	7.88±0.74	9.77±2.09	89.6±15.0
	二甲双胍+恩格列净25 mg	166	60(34~79)	7.91±0.78	9.91±2.17	89.5±16.2
	二甲双胍+西格列汀100 mg	56	60(32~75)	8.03±8.09	9.97±2.38	88.6±14.9	78
RODEN,2015^[14]	恩格列净10 mg	224	56.2±11.6	7.87±0.88	8.60±1.82	78.4±18.7
	恩格列净25 mg	224	52.8±11.8	7.96±0.85	8.40±1.91	77.8±18.3
	西格列汀100 mg	223	55.2±10.0	7.85±0.80	8.20±1.61	79.3±20.4	76
RODEN,2013^[15]	恩格列净10 mg	224	56.2±11.6	7.87±0.88	8.50±1.80	78.4±18.7
	恩格列净25 mg	224	53.8±11.6	7.86±0.85	8.50±1.90	77.8±18.0
	西格列汀100 mg	223	55.1±9.9	7.85±0.79	8.20±1.60	79.3±20.4	24
FERRANNINI,2013^[16]	恩格列净10 mg	81	58.0(30~76)	8.00±0.8	9.90±2.60	76.8(45.5~118.0)
	恩格列净25 mg	82	57.0(30~79)	7.80±0.80	9.50±1.40	81.2(49.1~130.0)
	二甲双胍1 000 mg	80	58.0(34~73)	8.10±0.90	9.80±2.40	81.1(42.0~126.0)	12

...

... Results of quality evaluation on the included studies

纳入研究及发表年份	随机方法	分配隐藏	盲法	数据完整	是否报道存在失访和退出	ITT分析	Jadad 评分/分
ROSENSTOCK,2013^[10]	是	是	否	是	是	否	5
DEFRONZO,2013^[11]	是	是	是	是	是	否	7
RIDDERSTRALE,2014^[12]	是	是	是	是	是	否	7
FERRANNINI,2013^[13]	不清楚	不清楚	否	是	是	否	1
RODEN,2015^[14]	是	是	否	是	是	否	5
RODEN,2013^[15]	是	是	是	是	是	否	7
FERRANNINI,2013^[16]	是	是	否	是	是	否	5

...

Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes:a 104-week randomised,active-controlled,double-blind,phase 3 trial

2014

纳入研究的基本特征 ...

... General characteristics of the included studies

文献第一作者及发表年份	干预措施	例数	年龄/ 岁	HbA1c基线水平/%	FPG基线水平/ (mmol·L^-1)	体质量基线水平/kg	疗程/ 周
ROSENSTOCK,2013^[10]	二甲双胍+恩格列净10 mg	71	59.0±9.0	7.90±0.7	9.61±2.00	87.9±14.4
	二甲双胍+恩格列净25mg	70	59.0±8.1	8.1±0.8	10.00±2.70	90.5±16.9
	二甲双胍+西格列汀100 mg	71	58.1±10.1	8.1±0.9	9.89±2.40	88.0±15.0	12
DEFRONZO,2013^[11]	二甲双胍+恩格列净10 mg	137	56.1±10.5	8.02±0.83	8.98±1.93	85.7±18.4
	二甲双胍+恩格列净25 mg	140	55.5±10.0	8.00±0.93	8.88±2.10	87.7±17.6
	二甲双胍+利格列汀5 mg	128	56.2±10.0	8.02±0.90	8.68±1.02	85.0±18.3	52
RIDDERSTRALE,2014^[12]	二甲双胍+恩格列净25 mg	765	56.2±10.3	7.92±0.81	8.32±1.77	82.5±19.2
	二甲双胍+格列美脲1~4 mg	780	55.7±10.4	7.92±0.86	8.32±1.98	83.0±19.2	104
FERRANNINI,2013^[13]	二甲双胍+恩格列净10 mg	166	60(33~77)	7.88±0.74	9.77±2.09	89.6±15.0
	二甲双胍+恩格列净25 mg	166	60(34~79)	7.91±0.78	9.91±2.17	89.5±16.2
	二甲双胍+西格列汀100 mg	56	60(32~75)	8.03±8.09	9.97±2.38	88.6±14.9	78
RODEN,2015^[14]	恩格列净10 mg	224	56.2±11.6	7.87±0.88	8.60±1.82	78.4±18.7
	恩格列净25 mg	224	52.8±11.8	7.96±0.85	8.40±1.91	77.8±18.3
	西格列汀100 mg	223	55.2±10.0	7.85±0.80	8.20±1.61	79.3±20.4	76
RODEN,2013^[15]	恩格列净10 mg	224	56.2±11.6	7.87±0.88	8.50±1.80	78.4±18.7
	恩格列净25 mg	224	53.8±11.6	7.86±0.85	8.50±1.90	77.8±18.0
	西格列汀100 mg	223	55.1±9.9	7.85±0.79	8.20±1.60	79.3±20.4	24
FERRANNINI,2013^[16]	恩格列净10 mg	81	58.0(30~76)	8.00±0.8	9.90±2.60	76.8(45.5~118.0)
	恩格列净25 mg	82	57.0(30~79)	7.80±0.80	9.50±1.40	81.2(49.1~130.0)
	二甲双胍1 000 mg	80	58.0(34~73)	8.10±0.90	9.80±2.40	81.1(42.0~126.0)	12

...

... Results of quality evaluation on the included studies

纳入研究及发表年份	随机方法	分配隐藏	盲法	数据完整	是否报道存在失访和退出	ITT分析	Jadad 评分/分
ROSENSTOCK,2013^[10]	是	是	否	是	是	否	5
DEFRONZO,2013^[11]	是	是	是	是	是	否	7
RIDDERSTRALE,2014^[12]	是	是	是	是	是	否	7
FERRANNINI,2013^[13]	不清楚	不清楚	否	是	是	否	1
RODEN,2015^[14]	是	是	否	是	是	否	5
RODEN,2013^[15]	是	是	是	是	是	否	7
FERRANNINI,2013^[16]	是	是	否	是	是	否	5

...

... ③与格列美脲比较.1篇文献^[12]报道了治疗前后HbA1c水平变化.联合二甲双胍,恩格列净25 mg组在降低HbAlc方面优于格列美脲[WMD=-0.11%,95%CI (-0.19,-0.03),P=0.010].见图1,2. ...

... ③与格列美脲比较.1篇文献^[12]报道了治疗前后FPG水平变化.结果表明,联合二甲双胍,恩格列净25 mg在降低FPG方面优于格列美脲,见表3. ...

... ③与格列美脲比较.1篇文献^[12]报道了治疗前后体质量变化,联合二甲双胍,恩格列净25 mg组在降低体质量方面优于格列美脲,见表3. ...

... ②与格列美脲比较.1篇文献^[12]报道了治疗前后SBP、DBP水平变化,联合二甲双胍,恩格列净25 mg在降低SBP、DBP方面优于格列美脲,见表3. ...

Long-term safety and efficacy of empagliflozin,sitagliptin,and metformin:an active-controlled,parallel-group,randomized,78-week open-label extension study in patients with type 2 diabetes

2013

纳入研究的基本特征 ...

... General characteristics of the included studies

文献第一作者及发表年份	干预措施	例数	年龄/ 岁	HbA1c基线水平/%	FPG基线水平/ (mmol·L^-1)	体质量基线水平/kg	疗程/ 周
ROSENSTOCK,2013^[10]	二甲双胍+恩格列净10 mg	71	59.0±9.0	7.90±0.7	9.61±2.00	87.9±14.4
	二甲双胍+恩格列净25mg	70	59.0±8.1	8.1±0.8	10.00±2.70	90.5±16.9
	二甲双胍+西格列汀100 mg	71	58.1±10.1	8.1±0.9	9.89±2.40	88.0±15.0	12
DEFRONZO,2013^[11]	二甲双胍+恩格列净10 mg	137	56.1±10.5	8.02±0.83	8.98±1.93	85.7±18.4
	二甲双胍+恩格列净25 mg	140	55.5±10.0	8.00±0.93	8.88±2.10	87.7±17.6
	二甲双胍+利格列汀5 mg	128	56.2±10.0	8.02±0.90	8.68±1.02	85.0±18.3	52
RIDDERSTRALE,2014^[12]	二甲双胍+恩格列净25 mg	765	56.2±10.3	7.92±0.81	8.32±1.77	82.5±19.2
	二甲双胍+格列美脲1~4 mg	780	55.7±10.4	7.92±0.86	8.32±1.98	83.0±19.2	104
FERRANNINI,2013^[13]	二甲双胍+恩格列净10 mg	166	60(33~77)	7.88±0.74	9.77±2.09	89.6±15.0
	二甲双胍+恩格列净25 mg	166	60(34~79)	7.91±0.78	9.91±2.17	89.5±16.2
	二甲双胍+西格列汀100 mg	56	60(32~75)	8.03±8.09	9.97±2.38	88.6±14.9	78
RODEN,2015^[14]	恩格列净10 mg	224	56.2±11.6	7.87±0.88	8.60±1.82	78.4±18.7
	恩格列净25 mg	224	52.8±11.8	7.96±0.85	8.40±1.91	77.8±18.3
	西格列汀100 mg	223	55.2±10.0	7.85±0.80	8.20±1.61	79.3±20.4	76
RODEN,2013^[15]	恩格列净10 mg	224	56.2±11.6	7.87±0.88	8.50±1.80	78.4±18.7
	恩格列净25 mg	224	53.8±11.6	7.86±0.85	8.50±1.90	77.8±18.0
	西格列汀100 mg	223	55.1±9.9	7.85±0.79	8.20±1.60	79.3±20.4	24
FERRANNINI,2013^[16]	恩格列净10 mg	81	58.0(30~76)	8.00±0.8	9.90±2.60	76.8(45.5~118.0)
	恩格列净25 mg	82	57.0(30~79)	7.80±0.80	9.50±1.40	81.2(49.1~130.0)
	二甲双胍1 000 mg	80	58.0(34~73)	8.10±0.90	9.80±2.40	81.1(42.0~126.0)	12

...

... Results of quality evaluation on the included studies

纳入研究及发表年份	随机方法	分配隐藏	盲法	数据完整	是否报道存在失访和退出	ITT分析	Jadad 评分/分
ROSENSTOCK,2013^[10]	是	是	否	是	是	否	5
DEFRONZO,2013^[11]	是	是	是	是	是	否	7
RIDDERSTRALE,2014^[12]	是	是	是	是	是	否	7
FERRANNINI,2013^[13]	不清楚	不清楚	否	是	是	否	1
RODEN,2015^[14]	是	是	否	是	是	否	5
RODEN,2013^[15]	是	是	是	是	是	否	7
FERRANNINI,2013^[16]	是	是	否	是	是	否	5

...

Safety,tolerability and effectson cardiometabolic risk factors of empagliflozin monotherapy in drug-naive patients with type 2 diabetes:a double-blind extension of a phase III randomized controlled trial

2015

纳入研究的基本特征 ...

... General characteristics of the included studies

文献第一作者及发表年份	干预措施	例数	年龄/ 岁	HbA1c基线水平/%	FPG基线水平/ (mmol·L^-1)	体质量基线水平/kg	疗程/ 周
ROSENSTOCK,2013^[10]	二甲双胍+恩格列净10 mg	71	59.0±9.0	7.90±0.7	9.61±2.00	87.9±14.4
	二甲双胍+恩格列净25mg	70	59.0±8.1	8.1±0.8	10.00±2.70	90.5±16.9
	二甲双胍+西格列汀100 mg	71	58.1±10.1	8.1±0.9	9.89±2.40	88.0±15.0	12
DEFRONZO,2013^[11]	二甲双胍+恩格列净10 mg	137	56.1±10.5	8.02±0.83	8.98±1.93	85.7±18.4
	二甲双胍+恩格列净25 mg	140	55.5±10.0	8.00±0.93	8.88±2.10	87.7±17.6
	二甲双胍+利格列汀5 mg	128	56.2±10.0	8.02±0.90	8.68±1.02	85.0±18.3	52
RIDDERSTRALE,2014^[12]	二甲双胍+恩格列净25 mg	765	56.2±10.3	7.92±0.81	8.32±1.77	82.5±19.2
	二甲双胍+格列美脲1~4 mg	780	55.7±10.4	7.92±0.86	8.32±1.98	83.0±19.2	104
FERRANNINI,2013^[13]	二甲双胍+恩格列净10 mg	166	60(33~77)	7.88±0.74	9.77±2.09	89.6±15.0
	二甲双胍+恩格列净25 mg	166	60(34~79)	7.91±0.78	9.91±2.17	89.5±16.2
	二甲双胍+西格列汀100 mg	56	60(32~75)	8.03±8.09	9.97±2.38	88.6±14.9	78
RODEN,2015^[14]	恩格列净10 mg	224	56.2±11.6	7.87±0.88	8.60±1.82	78.4±18.7
	恩格列净25 mg	224	52.8±11.8	7.96±0.85	8.40±1.91	77.8±18.3
	西格列汀100 mg	223	55.2±10.0	7.85±0.80	8.20±1.61	79.3±20.4	76
RODEN,2013^[15]	恩格列净10 mg	224	56.2±11.6	7.87±0.88	8.50±1.80	78.4±18.7
	恩格列净25 mg	224	53.8±11.6	7.86±0.85	8.50±1.90	77.8±18.0
	西格列汀100 mg	223	55.1±9.9	7.85±0.79	8.20±1.60	79.3±20.4	24
FERRANNINI,2013^[16]	恩格列净10 mg	81	58.0(30~76)	8.00±0.8	9.90±2.60	76.8(45.5~118.0)
	恩格列净25 mg	82	57.0(30~79)	7.80±0.80	9.50±1.40	81.2(49.1~130.0)
	二甲双胍1 000 mg	80	58.0(34~73)	8.10±0.90	9.80±2.40	81.1(42.0~126.0)	12

...

... Results of quality evaluation on the included studies

纳入研究及发表年份	随机方法	分配隐藏	盲法	数据完整	是否报道存在失访和退出	ITT分析	Jadad 评分/分
ROSENSTOCK,2013^[10]	是	是	否	是	是	否	5
DEFRONZO,2013^[11]	是	是	是	是	是	否	7
RIDDERSTRALE,2014^[12]	是	是	是	是	是	否	7
FERRANNINI,2013^[13]	不清楚	不清楚	否	是	是	否	1
RODEN,2015^[14]	是	是	否	是	是	否	5
RODEN,2013^[15]	是	是	是	是	是	否	7
FERRANNINI,2013^[16]	是	是	否	是	是	否	5

...

Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes:a randomised,double-blind,placebo-controlled,phase 3 trial

2013

纳入研究的基本特征 ...

... General characteristics of the included studies

文献第一作者及发表年份	干预措施	例数	年龄/ 岁	HbA1c基线水平/%	FPG基线水平/ (mmol·L^-1)	体质量基线水平/kg	疗程/ 周
ROSENSTOCK,2013^[10]	二甲双胍+恩格列净10 mg	71	59.0±9.0	7.90±0.7	9.61±2.00	87.9±14.4
	二甲双胍+恩格列净25mg	70	59.0±8.1	8.1±0.8	10.00±2.70	90.5±16.9
	二甲双胍+西格列汀100 mg	71	58.1±10.1	8.1±0.9	9.89±2.40	88.0±15.0	12
DEFRONZO,2013^[11]	二甲双胍+恩格列净10 mg	137	56.1±10.5	8.02±0.83	8.98±1.93	85.7±18.4
	二甲双胍+恩格列净25 mg	140	55.5±10.0	8.00±0.93	8.88±2.10	87.7±17.6
	二甲双胍+利格列汀5 mg	128	56.2±10.0	8.02±0.90	8.68±1.02	85.0±18.3	52
RIDDERSTRALE,2014^[12]	二甲双胍+恩格列净25 mg	765	56.2±10.3	7.92±0.81	8.32±1.77	82.5±19.2
	二甲双胍+格列美脲1~4 mg	780	55.7±10.4	7.92±0.86	8.32±1.98	83.0±19.2	104
FERRANNINI,2013^[13]	二甲双胍+恩格列净10 mg	166	60(33~77)	7.88±0.74	9.77±2.09	89.6±15.0
	二甲双胍+恩格列净25 mg	166	60(34~79)	7.91±0.78	9.91±2.17	89.5±16.2
	二甲双胍+西格列汀100 mg	56	60(32~75)	8.03±8.09	9.97±2.38	88.6±14.9	78
RODEN,2015^[14]	恩格列净10 mg	224	56.2±11.6	7.87±0.88	8.60±1.82	78.4±18.7
	恩格列净25 mg	224	52.8±11.8	7.96±0.85	8.40±1.91	77.8±18.3
	西格列汀100 mg	223	55.2±10.0	7.85±0.80	8.20±1.61	79.3±20.4	76
RODEN,2013^[15]	恩格列净10 mg	224	56.2±11.6	7.87±0.88	8.50±1.80	78.4±18.7
	恩格列净25 mg	224	53.8±11.6	7.86±0.85	8.50±1.90	77.8±18.0
	西格列汀100 mg	223	55.1±9.9	7.85±0.79	8.20±1.60	79.3±20.4	24
FERRANNINI,2013^[16]	恩格列净10 mg	81	58.0(30~76)	8.00±0.8	9.90±2.60	76.8(45.5~118.0)
	恩格列净25 mg	82	57.0(30~79)	7.80±0.80	9.50±1.40	81.2(49.1~130.0)
	二甲双胍1 000 mg	80	58.0(34~73)	8.10±0.90	9.80±2.40	81.1(42.0~126.0)	12

...

... Results of quality evaluation on the included studies

纳入研究及发表年份	随机方法	分配隐藏	盲法	数据完整	是否报道存在失访和退出	ITT分析	Jadad 评分/分
ROSENSTOCK,2013^[10]	是	是	否	是	是	否	5
DEFRONZO,2013^[11]	是	是	是	是	是	否	7
RIDDERSTRALE,2014^[12]	是	是	是	是	是	否	7
FERRANNINI,2013^[13]	不清楚	不清楚	否	是	是	否	1
RODEN,2015^[14]	是	是	否	是	是	否	5
RODEN,2013^[15]	是	是	是	是	是	否	7
FERRANNINI,2013^[16]	是	是	否	是	是	否	5

...

A Phase IIb,randomized,placebo-controlled study of the SGLT2 inhibitor empagliflozin in patients with type 2 diabetes

2013

纳入研究的基本特征 ...

... General characteristics of the included studies

文献第一作者及发表年份	干预措施	例数	年龄/ 岁	HbA1c基线水平/%	FPG基线水平/ (mmol·L^-1)	体质量基线水平/kg	疗程/ 周
ROSENSTOCK,2013^[10]	二甲双胍+恩格列净10 mg	71	59.0±9.0	7.90±0.7	9.61±2.00	87.9±14.4
	二甲双胍+恩格列净25mg	70	59.0±8.1	8.1±0.8	10.00±2.70	90.5±16.9
	二甲双胍+西格列汀100 mg	71	58.1±10.1	8.1±0.9	9.89±2.40	88.0±15.0	12
DEFRONZO,2013^[11]	二甲双胍+恩格列净10 mg	137	56.1±10.5	8.02±0.83	8.98±1.93	85.7±18.4
	二甲双胍+恩格列净25 mg	140	55.5±10.0	8.00±0.93	8.88±2.10	87.7±17.6
	二甲双胍+利格列汀5 mg	128	56.2±10.0	8.02±0.90	8.68±1.02	85.0±18.3	52
RIDDERSTRALE,2014^[12]	二甲双胍+恩格列净25 mg	765	56.2±10.3	7.92±0.81	8.32±1.77	82.5±19.2
	二甲双胍+格列美脲1~4 mg	780	55.7±10.4	7.92±0.86	8.32±1.98	83.0±19.2	104
FERRANNINI,2013^[13]	二甲双胍+恩格列净10 mg	166	60(33~77)	7.88±0.74	9.77±2.09	89.6±15.0
	二甲双胍+恩格列净25 mg	166	60(34~79)	7.91±0.78	9.91±2.17	89.5±16.2
	二甲双胍+西格列汀100 mg	56	60(32~75)	8.03±8.09	9.97±2.38	88.6±14.9	78
RODEN,2015^[14]	恩格列净10 mg	224	56.2±11.6	7.87±0.88	8.60±1.82	78.4±18.7
	恩格列净25 mg	224	52.8±11.8	7.96±0.85	8.40±1.91	77.8±18.3
	西格列汀100 mg	223	55.2±10.0	7.85±0.80	8.20±1.61	79.3±20.4	76
RODEN,2013^[15]	恩格列净10 mg	224	56.2±11.6	7.87±0.88	8.50±1.80	78.4±18.7
	恩格列净25 mg	224	53.8±11.6	7.86±0.85	8.50±1.90	77.8±18.0
	西格列汀100 mg	223	55.1±9.9	7.85±0.79	8.20±1.60	79.3±20.4	24
FERRANNINI,2013^[16]	恩格列净10 mg	81	58.0(30~76)	8.00±0.8	9.90±2.60	76.8(45.5~118.0)
	恩格列净25 mg	82	57.0(30~79)	7.80±0.80	9.50±1.40	81.2(49.1~130.0)
	二甲双胍1 000 mg	80	58.0(34~73)	8.10±0.90	9.80±2.40	81.1(42.0~126.0)	12

...

... Results of quality evaluation on the included studies

纳入研究及发表年份	随机方法	分配隐藏	盲法	数据完整	是否报道存在失访和退出	ITT分析	Jadad 评分/分
ROSENSTOCK,2013^[10]	是	是	否	是	是	否	5
DEFRONZO,2013^[11]	是	是	是	是	是	否	7
RIDDERSTRALE,2014^[12]	是	是	是	是	是	否	7
FERRANNINI,2013^[13]	不清楚	不清楚	否	是	是	否	1
RODEN,2015^[14]	是	是	否	是	是	否	5
RODEN,2013^[15]	是	是	是	是	是	否	7
FERRANNINI,2013^[16]	是	是	否	是	是	否	5

...

... 2.3.1 HbA1c ①与二甲双胍比较.1篇文献^[16]报道治疗前后HbA1c水平变化.Meta分析结果显示,单用恩格列净 10 mg组在降低HbAlc方面劣于二甲双胍[WMD=0.27%,95%CI (0.02,0.52),P=0.03];单用恩格列净25 mg组在降低HbAlc方面与二甲双胍相似[WMD=0.12%,95%CI (-0.13,0.37),P=0.34].见图1,2. ...

... 2.3.2 FPG ①与二甲双胍比较.1篇文献^[16]报道了治疗前后FPG水平变化.Meta分析结果显示,单用恩格列净10 mg和25 mg剂量组在降低FPG方面与二甲双胍相似,见表3. ...

... 2.3.3 体质量 ①与二甲双胍比较.1篇文献^[16]报道了治疗前后体质量变化.Meta分析结果显示,单用恩格列净10 mg和25 mg 剂量组在降低体质量方面均优于二甲双胍,见表3. ...

Effect of empagliflozin on the steady-state pharmacokinetics of ethinylestradiol and levonorgestrel in healthy female volunteers

2013

... 2015ADA /EASD 推荐降糖药物联用的选择需个体化,要综合考虑药物的疗效、其他额外的治疗获益、不良反应、药物相互作用、价格以及患者的依从性.恩格列净具有良好的药动学特征:口服生物利用度高,消除半衰期10~19 h,可一天一次口服给药,药物之间相互作用少,患者服药的依从性较好^[17,18]. ...

Pharmaco-kinetics of empagliflozin,a sodium glucose cotransporter 2 inhibitor,and glimepiride following co-administration in healthy volunteers:a randomised,open-label,crossover study

2012

Metformin supports the antidiabetic effect of a sodium glucose cotransporter 2 inhibitor by suppressing endogenous glucose production in diabetic mice

2015

... 本研究表明,单用恩格列净降糖效果不优于二甲双胍,但优于DPP-4抑制药.与二甲双胍联合用药的结果显示:恩格列净10,25 mg在降低FPG方面优于DPP-4抑制药和格列美脲;在降低HbA1c方面,10 mg 剂量组与DPP-4抑制药比较无明显差异;25 mg剂量组与DPP-4抑制药、格列美脲比较均可明显降低HbA1c.从机制上看,一方面SGLT 2 抑制药作用于肾脏表达的SGLT-2,减少了肾脏对葡萄糖重吸收,尿糖排出增多,从而发挥降糖作用.另一方面,SGLT-2抑制药导致胰高血糖素释放增多,从而增加内源性葡萄糖产生(endogenous glucose production,ECP),影响SGLT-2抑制药降糖效果^[19].而二甲双胍抑制肝糖原的分解,改善外周组织对胰岛素的敏感性,提高外周组织对葡萄糖摄取与利用,抑制ECP.因此SGLT-2抑制药与二甲双胍联用具有机制上的互补,这种联用可能会给患者带来长期的血糖改善^[19,20]. ...

... [19,20]. ...

Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production

2014

Lifetime risk of cardiovascular disease among individuals with and without diabetes stratified by obesity status in the Framingham heart study

2008

... 恩格列净的其他治疗获益:80%的T2DM患者超重或肥胖,超重和肥胖是产生胰岛素抵抗的重要原因,减轻体质量可以改善胰岛功能和血糖控制^[21,22,23].研究显示恩格列净减轻体质量的机制可能与其增加尿糖排泄引起渗透性利尿和热量损失有关^[24].高血压是T2DM的另一个心血管危险因素^[25,26],糖尿病患者高血压的患病率为40%~80%^[27].恩格列净的降压机制可能与体质量减轻和渗透性利尿有关^[28].恩格列净上市后一项心血管安全性试验 (恩格列净-REG OUTCOME^TM:NCT01131676) 结果显示,恩格列净组心血管因素死亡率相对风险降低38%^[29].系统评价结果也显示恩格列净除降低血糖外,还可降低血压和体质量.恩格列净降低患者心血管事件风险的机制也许与其利尿作用有关(起效较快),或降糖、降压、利尿等多种机制的综合作用,但也可能存在其他未被认识的机制. ...

Insulin resistance in type 2 diabetes:association with truncal obesity,impaired fitness,and atypical malonyl coenzyme A regulation

2003

PI-SUNYER F X.The prevention and treat-ment of obesity.Application to type 2 diabetes

1997

Impact of sodium glucose cotransporter 2 inhibitors on weight in patients with type 2 diabetes mellitus

2013

Standards of medical care in diabetesd 2012

2012

Blood pressure and risk of cardiovascular diseases in type 2 diabetes:further findings from the Swedish National Diabetes Register (NDR-BP II)

2012

Diabetes,hypertension,and cardiovascular disease:an update

2001

The potential of sodium glucose cotransporter 2 (SGLT2) inhibitors to reduce cardiovascular risk in patients with type 2 diabetes (T2DM)

2013

Empagliflo-zin,cardiovascular outcomes,and mortality in type 2 diabetes

2015

FDA.Warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood

2014

... 在安全性方面,恩格列净耐受性较好,与对照组比较,总不良反应发生率、尿路感染方面无显著性差异,生殖器感染的风险高于对照组,但生殖器感染均较轻微或中度,经药物治疗后可缓解.在笔者纳入的研究中,没有糖尿病酮症酸中毒的报道.2015年5月15日,FDA警告SGLT2 抑制药可能有导致糖尿病酮症酸中毒的风险,FDA建议服用SGLT2 抑制药的患者不用常规监测尿酮,但患者一旦有食欲减退、恶心、呕吐、烦躁、嗜睡、呼吸深快等症状,即使血糖正常也应立即到医院就诊^[30]. ...