钠-葡萄糖协同转运蛋白2抑制剂联合胰岛素治疗1型糖尿病疗效与安全性的Meta分析

目的:系统评价钠-葡萄糖协同转运蛋白2(SGLT-2)抑制剂联合胰岛素治疗1型糖尿病(T1DM)的疗效与安全性,为临床T1DM治疗提供循证参考。方法:计算机检索PubMed、Cochrane图书馆、Embase、ClinicalTrials、中国知网、中国生物医学文献数据库与万方数据库,检索时限均为各数据库自建库起至2020年2月,收集在胰岛素基础治疗的基础上,SGLT-2抑制剂(试验组)对比安慰剂(对照组)治疗T1DM的随机对照试验(RCT)。对符合纳入标准的文献进行资料提取,采用Cochrane风险偏倚评估工具5.1.0进行质量评价后,采用Stata 12.0软件进行Meta分析。结果:共纳入11项RCT,合计7003例患者。Meta分析结果显示,试验组患者糖化血红蛋白(HbA1c)水平降低值SMD=-0.49,95%CI(-0.53,-0.44),P<0.001]、HbA1c水平降低值≥0.5%且未发生严重低血糖的患者比例OR=3.93,95%CI(3.49,6.21),P<0.001]、HbA1c水平降低值≥0.5%的患者比例OR=2.65,95%CI(2.25,3.12),P<0.001]、HbA1c水平<7.0%的达标率OR=2.85,95%CI(2.44,3.33),P<0.001]、体质量降低值SMD=-0.83,95%CI(-0.96,-0.70),P<0.001]均显著大于或高于对照组,每日胰岛素用量、空腹血糖、餐后血糖、收缩压、舒张压的降低值均显著大于对照组,差异均有统计学意义(P≤0.011)。试验组患者总体不良反应发生率OR=1.14,95%CI(1.04,1.26),P=0.007]、SGLT-2抑制剂相关的不良反应发生率OR=2.17,95%CI(1.75,2.99),P<0.001]、严重不良反应发生率OR=1.48,95%CI(1.24,1.77),P<0.001]、生殖器感染发生率OR=3.84,95%CI(3.14,4.69),P<0.001]、腹泻发生率OR=1.47,95%CI(1.09,1.97),P=0.011]、体液减少相关不良反应发生率OR=2.05,95%CI(1.37,3.08),P=0.001]、酮症相关不良反应发生率OR=4.18,95%CI(3.15,5.55),P<0.001]、酮症酸中毒发生率OR=4.33,95%CI(3.01,6.23),P<0.001]、严重酮症酸中毒发生率OR=5.06,95%CI(2.61,9.81),P<0.001]均显著高于对照组,差异均有统计学意义;两组患者低血糖、严重低血糖、尿路感染、肾损伤的发生率比较,差异均无统计学意义。结论:SGLT-2抑制剂用于T1DM的联合治疗,可显著改善患者血糖水平,降低体质量、减少每日胰岛素用量、降低收缩压和舒张压,且不增加低血糖、尿路感染、肾损伤的发生风险,但总体不良反应、生殖器感染、腹泻、酮症酸中毒等不良反应的发生风险增加,需予以关注。

Meta-analysis of Efficacy and Safety of SGLT-2 Inhibitors Combined with Insulin for Type 1 Diabetes Mellitus

OBJECTIVE:To systematically evaluate the efficacy and safety of sodium-glucose co-transporter 2(SGLT-2)inhibitors combined with insulin in the treatment of type 1 diabetes mellitus(T1 DM),and to provide evidence-based reference for clinical treatment of T1 DM.METHODS:Retrieved from Pub Med,Cochrane library,Embase,Clinical Trials,CNKI,CBM and Wanfang database,randomized controlled trials(RCT)about SGLT-2 inhibitor(trial group)versus placebo(control group)in the treatment of T1 DM based on insulin treatment were collected during the inception to Feb.2020.After data extraction of literatures met inclusion criteria,Cochrane risk bias evaluation tool 5.1.0 was used to evaluate its quality,and Meta-analysis was perfomed by using Stata 12.0 software.RESULTS:A total of 11 RCTs were included,involving 7003 patients.The results of Meta-analysis showed that the decrease of Hb A1 cSMD=-0.49,95%CI(-0.53,-0.44),P<0.001],the proportion of patients with Hb A1 c≥0.5%and without severe hypoglycemiaOR=3.93,95%CI(3.49,6.21),P<0.001],the proportion of patients with Hb A1 c≥0.5%OR=2.65,95%CI(2.25,3.12),P<0.001],the target rate of Hb A1 c level<7.0%OR=2.85,95%CI(2.44,3.33),P<0.001]and the decrease of body weightSMD=-0.83,95%CI(-0.96,-0.70),P<0.001]in trial group were significantly larger or higher than control group;the decrease values of daily insulin dosage,fasting blood glucose,postprandial blood glucose,systolic blood pressure and diastolic blood pressure in trial group were significantly higher than those in the control group,with statistical significance(P≤0.011).The total incidence of ADROR=1.14,95%CI(1.04,1.26),P=0.007],the incidence of SGLT-2 inhibitor related ADROR=2.17,95%CI(1.75,2.99),P<0.001],the incidence of severe ADROR=1.48,95%CI(1.24,1.77),P<0.001],the incidence of genital infectionOR=3.84,95%CI(3.14,4.69),P<0.001],the incidence of diarrheaOR=1.47,95%CI(1.09,1.97),P=0.011],the incidence of fluid reduction related ADROR=2.05,95%CI(1.37,3.08),P=0.001],the incidence of ketosis related ADROR=4.18,95%CI(3.15,5.55),P<0.001],the incidence of ketoacidosisOR=4.33,95%CI(3.01,6.23),P<0.001]and the incidence of severe ketoacidosisOR=5.06,95%CI(2.61,9.81),P<0.001]were significantly higher than control group,with statistical significance.There was no statistical significance in the incidence of hypoglycemia,severe hypoglycemia,urinary tract infection or kidney injury between 2 groups.CONCLUSIONS:SGLT-2 inhibitors for the treatment of T1 DM can significantly improve the blood glucose,reduce body weight and daily insulin dose,lower systolic blood pressure and diastolic blood pressure,while dose not increase the risk of hypoglycemia,urinary tract infections and renal impairment but increase the risk of total ADR as well as the risk of ADR such as genital infection,diarrhea,ketoacidosis,to which should be paid attention.