Clinical Efficacy of Different Doses of Canagliflozin Combined with Metformin in the Treatment of Type 2 Diabetes Mellitus: a Meta-analysis

doi:10.12114/j.issn.1007-9572.2022.0073

Chinese General Practice ›› 2022, Vol. 25 ›› Issue (15): 1888-1896,1905.DOI: 10.12114/j.issn.1007-9572.2022.0073

Special Issue: 内分泌代谢性疾病最新文章合辑

• Evidence-based Medicine • Previous Articles Next Articles

Clinical Efficacy of Different Doses of Canagliflozin Combined with Metformin in the Treatment of Type 2 Diabetes Mellitus: a Meta-analysis

1. NHC Key Laboratory of Hormones and Development/Tianjin Key Laboratory of Metabolic Diseases/Tianjin Institute of Endocrinology, Tianjin 300134, China
2. Tianjin Medical University Chu Hsien-I Memorial Hospital, Tianjin 300134, China

Received:2022-01-19 Revised:2022-02-26 Published:2022-03-17 Online:2022-04-07
Contact: Daiqing LI
About author:
CHEN Y Y, LI X D, TANG Y Z, et al. Clinical efficacy of different doses of canagliflozin combined with metformin in the treatment of type 2 diabetes mellitus: a meta-analysis[J]. Chinese General Practice, 2022, 25 (15) : 1888-1896, 1905.

不同剂量卡格列净联合二甲双胍治疗2型糖尿病临床疗效的Meta分析

1. 300134　天津市，国家卫生健康委员会激素与发育重点实验室　天津市代谢性疾病重点实验室　天津市内分泌研究所
2. 300134　天津市，天津医科大学朱宪彝纪念医院

通讯作者: 李代清
作者简介:
陈玉英，李晓冬，汤云昭，等.不同剂量卡格列净联合二甲双胍治疗2型糖尿病临床疗效的Meta分析[J].中国全科医学，2022，25（15）：1888-1896，1905. [www.chinagp.net] 作者贡献：陈玉英负责提出研究思路和方案；陈玉英、李晓东负责检索文献、收集文献、绘制森林图及结果解读；陈玉英负责论文撰写和修订；汤云昭、李代清负责文章质量控制和审校，对整体文章负责，监督管理；所有作者确认了论文的最终稿。
基金资助:
国家自然科学基金青年基金资助项目(81600628/H0713); 天津市自然科学基金资助项目(16JCYBJC25700)

Abstract

Abstract:

Background

Canagliflozin (CANA) and metformin (MET) can both be used in the treatment of type 2 diabetes (T2DM) , but the clinical efficacy of combined use remains to be further clarified.

Objective

To elevate the efficacy and safety of CANA combined with MET in the treatment of T2DM, and to provide clinical reference for the treatment of T2DM.

Methods

A systematic review of published randomized controlled trials (RCTs) of 100 mg and/or 300 mg CANA combined with MET for T2DM performed in PubMed, Cochrane Library, EMBase, Clinical Trials.gov, CNKI Database, VIP Database, Wanfang Databases from inception to 18 April 2021 were retrieved by computer, and the included references were retrieved manually. After literature screening, data extraction and quality evaluation, meta-analysis was performed using RevMan 5.3 software.

Results

A total of 9 RCTs with 6 224 patients were included. Meta-analysis results showed that the levels of glycosylated hemoglobin (HbA_1c) , fasting blood glucose (FPG) , body weight, systolic blood pressure (SBP) , diastolic blood pressure (DBP) , and triacylglycerol (TG) in the 100 mg CANA combined with MET group and the 300 mg CANA combined with MET group were lower than placebo control group (P<0.05) . The levels of pancreatic β-cell function index (HOMA-β) , low-density lipoprotein cholesterol (LDL-C) , and high-density lipoprotein cholesterol (HDL-C) in the 100 mg CANA combined with MET group were higher than those in the placebo control group (P<0.05) . The levels of HbA_1c and SBP in the 300 mg CANA combined with MET group were lower than those in the active control group, and the level of HOMA-β was higher than that in the active control group (P<0.05) . The FPG, body weight, DBP and TG in the 100 mg CANA combined with MET group and 300 mg CANA combined with MET group were lower than those in the active control group, and the levels of LDL-C and HDL-C were higher than those in the active control group (P<0.05) . The incidence of reproductive system infection (female) in the 100 mg CANA combined with MET group was higher than that in the placebo control group (P<0.05) . The incidence of reproductive system infection (female) and osmotic diuresis-related adverse events in the 300 mg CANA combined with MET group was higher than that in the placebo control group (P<0.05) . The incidence of reproductive system infection (male) , reproductive system infection (female) , and osmotic diuresis in the 100 mg CANA combined with MET group and 300 mg CANA combined with MET group was higher than that in the active control group (P<0.05) .

Conclusion

100 mg and 300 mg of CANA combined with MET can effectively reduce HbA_1c and FPG levels, body weight, blood pressure and TG levels, and increase LDL-C and HDL-C levels in T2DM patients. For patients with T2DM poorly controlled by MET, it may be considered in combination with CANA, but attention should be paid to infection of the reproductive system. Therefore, high-quality large-sample trials are still needed to confirm the long-term safety of different doses of CANA combined with MET.

Key words: Diabetes mellitus, type 2, Canagliflozin, Metformin, Treatment outcome, Meta-analysis

摘要：

背景

卡格列净（CANA）和二甲双胍（MET）均可用于治疗2型糖尿病（T2DM），但联合使用的临床疗效有待进一步明确。

目的

评价CANA联合MET治疗T2DM的疗效和安全性，为T2DM的治疗提供临床参考。

方法

计算机检索PubMed、Cochrane Library、EMBase、Clinical Trails.gov、中国知网、维普网、万方数据知识服务平台，检索有关100 mg和/或300 mg的CANA联合MET治疗T2DM的随机对照试验（RCTs）（CANA联合MET组给予CANA联合MET，安慰剂对照组给予单用MET或者安慰剂联合MET/活性对照组给予其他口服降糖药物联合MET），检索时间为建库至2021-04-18，同时手工检索纳入文献的参考文献。经文献筛选、提取数据和质量评价后，采用RevMan 5.3软件进行Meta分析。

结果

共纳入9篇RCTs，6 224例患者。Meta分析结果显示，100 mg CANA联合MET组和300 mg CANA联合MET组糖化血红蛋白（HbA_1c）、空腹血糖（FPG）、体质量、收缩压（SBP）、舒张压（DBP）、三酰甘油（TG）水平均低于安慰剂对照组（P<0.05），胰岛β细胞功能指数（HOMA-β）、低密度脂蛋白胆固醇（LDL-C）、高密度脂蛋白胆固醇（HDL-C）水平高于安慰剂对照组（P<0.05）。300 mg CANA联合MET组HbA_1c、SBP均低于活性对照组，HOMA-β水平高于活性对照组（P<0.05）。100 mg CANA联合MET组和300 mg CANA联合MET组FPG、体质量、DBP、TG均低于活性对照组，LDL-C、HDL-C水平均高于活性对照组（P<0.05）。100 mg CANA联合MET组生殖系统感染（女性）发生率高于安慰剂对照组（P<0.05）；300 mg CANA联合MET组生殖系统感染（女性）、渗透利尿相关不良事件发生率均高于安慰剂对照组（P<0.05）；100 mg CANA联合MET组和300 mg CANA联合MET组生殖系统感染（男性）、生殖系统感染（女性）、渗透利尿相关不良事件发生率均高于活性对照组（P<0.05）。

结论

100 mg和300 mg CANA联合MET能有效降低T2DM患者HbA_1c、FPG，减轻体质量，降低血压和TG水平，提高LDL-C、HDL-C水平。对于MET控制不佳的T2DM患者，可考虑与CANA联合使用，但要注意生殖系统的感染。后期仍需要高质量的大样本试验，以确认不同剂量的CANA联合MET的长期安全性。

关键词: 糖尿病，2型, 坎格列嗪, 二甲双胍, 治疗结果, Meta分析

Yuying CHEN,Xiaodong LI,Yunzhao TANG, et al. Clinical Efficacy of Different Doses of Canagliflozin Combined with Metformin in the Treatment of Type 2 Diabetes Mellitus: a Meta-analysis[J]. Chinese General Practice, 2022, 25(15): 1888-1896,1905. DOI: 10.12114/j.issn.1007-9572.2022.0073.
陈玉英,李晓冬,汤云昭等. 不同剂量卡格列净联合二甲双胍治疗2型糖尿病临床疗效的Meta分析[J]. 中国全科医学, 2022, 25(15): 1888-1896,1905. DOI: 10.12114/j.issn.1007-9572.2022.0073.

Figures/Tables 23

References 33

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第一作者	发表时间（年）	ID	干预措施	样本量（例）	年龄（岁）	T2DM病程（年）	疗程（周）	结局指标
WILDING^[8]	2013	NCT01106625	CANA 100 mg联合MET	157	57.4±10.5	9.0±5.7	26	①②③④⑤⑥⑦⑧⑨⑩
			CANA 300 mg联合MET	156	56.1±8.9	9.4±6.4
			PBO联合MET	156	56.8±8.3	10.3±6.7
SCHERNTHANER^[9]	2013	NCT01137812	CANA 300 mg联合MET	377	56.6±9.6	9.4±6.1	52	①②③④⑤⑥⑦⑧⑨
			SITA 100 mg联合MET	378	56.7±9.3	9.7±6.3
ROSENSTOCK^[10]	2016	NCT01809327	CANA 100 mg联合MET	237	54.2±9.6	2.9±3.3	26	①②③⑤⑥⑦⑧⑨⑩
			CANA 300 mg联合MET	237	55.4±9.8	3.3±3.9
			MET	237	55.2±9.8	3.3±4.5
ROSENSTOCK^[11]	2012	NCT00642278	CANA 100 mg联合MET	64	51.7±8.0	6.1±4.7	12	①②③④⑤⑥⑦⑧⑨⑩
			CANA 300 mg联合MET	64	52.3±6.9	5.9±5.2
			SITA 100 mg联合MET	65	51.7±8.1	5.6±4.7
			PBO联合MET	65	53.3±7.8	6.4±5.0
QIU^[12]	2014	NCT01340664	CANA 100 mg联合MET	93	58.6±8.9	6.7±4.9	18	①②③⑤⑥⑦⑧⑨⑩
			CANA 300 mg联合MET	93	56.7±10.3	7.3±6.0
			PBO联合MET	93	57.0±9.3	7.0±6.4
CEFALU^[13]	2013	NCT00968812	CANA 100 mg联合MET	483	56.4±9.5	6.5±5.5	52	①②③⑤⑥⑦⑧⑨⑩
			CANA 300 mg联合MET	485	55.8±9.2	6.7±5.5
			GIMA联合MET	482	56.3±9.0	6.6±5.0
LAVALLE-GONZÁLEZ^[14]	2013	NCT01106677	CANA 100 mg联合MET	368	55.5±9.4	6.7±5.4	26	①②③⑤⑥⑦⑧⑨
			CANA 300 mg联合MET	367	55.3±9.2	7.1±5.4
			SITA 100 mg联合MET	366	55.5±9.6	6.8±5.2
			PBO联合MET	183	55.3±9.8	6.8±5.3
JI^[15]	2015	NCT01381900	CANA 100 mg联合MET	223	56.5±8.3	6.8±4.5	18	①②③⑤⑥⑦⑧⑨⑩
			CANA 300 mg联合MET	227	56.4±9.2	6.9±4.9
			PBO联合MET	226	55.8±9.4	6.4±4.6
FORST^[16]	2014	NCT01106690	CANA 100 mg联合MET	113	56.7±10.4	10.5±6.6	26	①②③④⑤⑥⑦⑧⑨
			CANA 300 mg联合MET	114	57.0±10.2	11.0±7.6
			PBO联合MET	115	58.3±9.6	10.1±6.6

第一作者	发表时间（年）	ID	干预措施	样本量（例）	年龄（岁）	T2DM病程（年）	疗程（周）	结局指标
WILDING^[8]	2013	NCT01106625	CANA 100 mg联合MET	157	57.4±10.5	9.0±5.7	26	①②③④⑤⑥⑦⑧⑨⑩
			CANA 300 mg联合MET	156	56.1±8.9	9.4±6.4
			PBO联合MET	156	56.8±8.3	10.3±6.7
SCHERNTHANER^[9]	2013	NCT01137812	CANA 300 mg联合MET	377	56.6±9.6	9.4±6.1	52	①②③④⑤⑥⑦⑧⑨
			SITA 100 mg联合MET	378	56.7±9.3	9.7±6.3
ROSENSTOCK^[10]	2016	NCT01809327	CANA 100 mg联合MET	237	54.2±9.6	2.9±3.3	26	①②③⑤⑥⑦⑧⑨⑩
			CANA 300 mg联合MET	237	55.4±9.8	3.3±3.9
			MET	237	55.2±9.8	3.3±4.5
ROSENSTOCK^[11]	2012	NCT00642278	CANA 100 mg联合MET	64	51.7±8.0	6.1±4.7	12	①②③④⑤⑥⑦⑧⑨⑩
			CANA 300 mg联合MET	64	52.3±6.9	5.9±5.2
			SITA 100 mg联合MET	65	51.7±8.1	5.6±4.7
			PBO联合MET	65	53.3±7.8	6.4±5.0
QIU^[12]	2014	NCT01340664	CANA 100 mg联合MET	93	58.6±8.9	6.7±4.9	18	①②③⑤⑥⑦⑧⑨⑩
			CANA 300 mg联合MET	93	56.7±10.3	7.3±6.0
			PBO联合MET	93	57.0±9.3	7.0±6.4
CEFALU^[13]	2013	NCT00968812	CANA 100 mg联合MET	483	56.4±9.5	6.5±5.5	52	①②③⑤⑥⑦⑧⑨⑩
			CANA 300 mg联合MET	485	55.8±9.2	6.7±5.5
			GIMA联合MET	482	56.3±9.0	6.6±5.0
LAVALLE-GONZÁLEZ^[14]	2013	NCT01106677	CANA 100 mg联合MET	368	55.5±9.4	6.7±5.4	26	①②③⑤⑥⑦⑧⑨
			CANA 300 mg联合MET	367	55.3±9.2	7.1±5.4
			SITA 100 mg联合MET	366	55.5±9.6	6.8±5.2
			PBO联合MET	183	55.3±9.8	6.8±5.3
JI^[15]	2015	NCT01381900	CANA 100 mg联合MET	223	56.5±8.3	6.8±4.5	18	①②③⑤⑥⑦⑧⑨⑩
			CANA 300 mg联合MET	227	56.4±9.2	6.9±4.9
			PBO联合MET	226	55.8±9.4	6.4±4.6
FORST^[16]	2014	NCT01106690	CANA 100 mg联合MET	113	56.7±10.4	10.5±6.6	26	①②③④⑤⑥⑦⑧⑨
			CANA 300 mg联合MET	114	57.0±10.2	11.0±7.6
			PBO联合MET	115	58.3±9.6	10.1±6.6

结局	干预措施	CANA 100 mg联合MET				CANA 300 mg联合MET
结局	干预措施	文献数量（篇）	I²值（%）	OR（95%CI）	P值	文献数量（篇）	I²值（%）	OR（95%CI）	P值
总不良事件	PBO对照	5^{[8，10,11,12，15]}	0	1.00（0.81，1.23）	1.00	5^{[8，10,11,12，15]}	0	1.15（0.94，1.42）	0.17
	活性对照	2^[11，13]	66	0.91（0.71，1.16）	0.44	3^{[9，11，13]}	0	1.0（0.82，1.23）	1.00
严重不良事件	PBO对照	5^{[8，10,11,12，15]}	0	0.77（0.43，1.38）	0.37	5^{[8，10,11,12，15]}	0	0.76（0.42，1.38）	0.37
	活性对照	2^[11，13]	0	0.63（0.37，1.05）	0.07	3^{[9，11，13]}	27	0.84（0.57，1.23）	0.37
尿路感染	PBO对照	5^{[8，10,11,12，15]}	0	0.90（0.54，1.51）	0.70	5^{[8，10,11,12，15]}	9	1.00（0.61，1.65）	1.00
	活性对照	2^[11，13]	0	1.46（0.85，2.53）	0.17	3^{[9，11，13]}	27	1.09（0.72，1.66）	0.68
生殖系统感染（男性）	PBO对照	4^{[8，10，12，15]}	0	3.37（0.92，12.32）	0.07	4^{[8，10，12，15]}	0	2.74（0.80，9.36）	0.11
	活性对照	1^[13]	-	5.82（1.70，20.01）	0.005	2^[9，13]	0	10.12（3.60，28.42）	<0.000 1
生殖系统感染（女性）	PBO对照	4^{[8，10，12，15]}	0	3.13（1.42，6.88）	0.005	4^{[8，10，12，15]}	0	2.73（1.23，6.06）	0.01
	活性对照	1^[13]	-	5.43（2.07，14.26）	0.000 6	2^[9，13]	0	5.29（2.82，9.91）	<0.000 01
渗透利尿相关不良事件	PBO对照	4^{[8，10，12，15]}	4	1.64（0.67，4.00）	0.27	4^{[8，10，12，15]}	30	3.20（1.47，6.97）	0.003
	活性对照	1^[13]	-	5.47（1.58，18.90）	0.007	2^[9，13]	41	3.18（1.43，7.09）	0.005
容量相关不良事件	PBO对照	4^{[8，10，12，15]}	26	1.45（0.43，4.83）	0.55	4^{[8，10，12，15]}	0	2.03（0.60，6.83）	0.25
	活性对照	1^[13]	-	1.33（0.30，5.99）	0.71	2^[9，13]	25	0.54（0.15，1.97）	0.35

结局	干预措施	CANA 100 mg联合MET				CANA 300 mg联合MET
结局	干预措施	文献数量（篇）	I²值（%）	OR（95%CI）	P值	文献数量（篇）	I²值（%）	OR（95%CI）	P值
总不良事件	PBO对照	5^{[8，10,11,12，15]}	0	1.00（0.81，1.23）	1.00	5^{[8，10,11,12，15]}	0	1.15（0.94，1.42）	0.17
	活性对照	2^[11，13]	66	0.91（0.71，1.16）	0.44	3^{[9，11，13]}	0	1.0（0.82，1.23）	1.00
严重不良事件	PBO对照	5^{[8，10,11,12，15]}	0	0.77（0.43，1.38）	0.37	5^{[8，10,11,12，15]}	0	0.76（0.42，1.38）	0.37
	活性对照	2^[11，13]	0	0.63（0.37，1.05）	0.07	3^{[9，11，13]}	27	0.84（0.57，1.23）	0.37
尿路感染	PBO对照	5^{[8，10,11,12，15]}	0	0.90（0.54，1.51）	0.70	5^{[8，10,11,12，15]}	9	1.00（0.61，1.65）	1.00
	活性对照	2^[11，13]	0	1.46（0.85，2.53）	0.17	3^{[9，11，13]}	27	1.09（0.72，1.66）	0.68
生殖系统感染（男性）	PBO对照	4^{[8，10，12，15]}	0	3.37（0.92，12.32）	0.07	4^{[8，10，12，15]}	0	2.74（0.80，9.36）	0.11
	活性对照	1^[13]	-	5.82（1.70，20.01）	0.005	2^[9，13]	0	10.12（3.60，28.42）	<0.000 1
生殖系统感染（女性）	PBO对照	4^{[8，10，12，15]}	0	3.13（1.42，6.88）	0.005	4^{[8，10，12，15]}	0	2.73（1.23，6.06）	0.01
	活性对照	1^[13]	-	5.43（2.07，14.26）	0.000 6	2^[9，13]	0	5.29（2.82，9.91）	<0.000 01
渗透利尿相关不良事件	PBO对照	4^{[8，10，12，15]}	4	1.64（0.67，4.00）	0.27	4^{[8，10，12，15]}	30	3.20（1.47，6.97）	0.003
	活性对照	1^[13]	-	5.47（1.58，18.90）	0.007	2^[9，13]	41	3.18（1.43，7.09）	0.005
容量相关不良事件	PBO对照	4^{[8，10，12，15]}	26	1.45（0.43，4.83）	0.55	4^{[8，10，12，15]}	0	2.03（0.60，6.83）	0.25
	活性对照	1^[13]	-	1.33（0.30，5.99）	0.71	2^[9，13]	25	0.54（0.15，1.97）	0.35

Clinical Efficacy of Different Doses of Canagliflozin Combined with Metformin in the Treatment of Type 2 Diabetes Mellitus: a Meta-analysis

不同剂量卡格列净联合二甲双胍治疗2型糖尿病临床疗效的Meta分析

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