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

Model-Based Meta-Analysis of Clinical Efficacy of Five SGLT2 Inhibitors in Monotherapy and In Combination for Type 2 Diabetes Mellitus

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。

Objective:Model-based meta-analysis(MBMA)was used to establish a drug effect model of sodium-glucose cotransporter 2 inhibitors(SGLT2i),quantifying the efficacies of SGLT2i monotherapy,SGLT2i in combination with metformin,SGLT2i in combination with dipeptidyl peptidase-4 inhibitors(DPP4i)and SGLT2i in combination with metformin and DPP4i in the treatment of type 2 diabetes mellitus(T2DM).Methods:A literature search was conducted through ClinicalTrials.gov and Web of Science(MEDLINE)to summarize clinical studies of five SGLT2i(canagliflozin,dapagliflozin,empagliflozin,ertugliflozin and ipragliflozin).The HbA1c change from baseline was selected as an indicator to establish the drug effect model.Results:A total of 54 literatures were included,and a pharmacodynamic model was established with 24,802 subjects from 167 groups of studies.The therapeutic efficacy order of SGLT2i from high to low was ipragliflozin>canagliflozin>empagliflozin>ertugliflozin>dapagliflozin.Compared with the change of HbA1c level with SGLT2 monotherapy at week 72,each drug combined with metformin can reduce another 0.13%,SGLT2i combined with DPP4i can reduce another 0.09%.SGLT2i in combination with metformin and DPP4i can be divided into two subgroups:those treated with inadequate control by DPP4i and metformin in combination had an additional 0.02%reduction,and those treated with inadequate control by metformin monotherapy an additional 0.75%reduction.At present,the recommended dose of each drug has almost reached the maximum hypoglycemic effect.In the future development of similar drugs,canagliflozin and ipragliflozin can be used as control drugs to measure whether the development of new compounds have clinical advantages.Conclusions:The MBMA method can be used to quantify the hypoglycemic effects of SGLT2i in single,double and triple treatment regimens,and the order of drug efficacy from high to low is ipragliflozin,canagliflozin,empagliflozin,ertugliflozin and dapagliflozin.