| Objective:To assess the efficacy and safety of triple therapy with SGLT-2 inhibitor add-on to DPP-4 inhibitor plus metformin in type 2 diabetes.Method:According to purpose of this systematic review,the appropriate inclusion criteria(including the type of research,participant,intervention,outcome)and detailed search strategy were conducted in accordance with the method of Cochrane systematic review.We searched keywords and the MeSH joint free word respectively,according to the characteristics of different databases,without language restrictions.We searched the Cochrane Library,PUBMED,EMBASE,CBM,CNKI,VIP,WANFANG Database,The National Research Register,American Diabetes Association,European Association for the Study of Diabetes,International Diabetes Federation,American Association of Clinical Endocrinologists and at the same time hand searched relevant journals,from inception to March 2018.Two reviewers independently screened the studies for eligibility,extracted the data from the eligible studies,with the confirmation of cross-check.Different opinions would be decided by the third party.According to criteria for judging risk of bias in the Bias Risk Assessment Tool of the Cochrane Collaboration Network,the risk of bias included trials such as random sequence generation(selection bias),allocation concealment(selection bias),blinding of participants and personnel(performance bias),blinding of outcome assessment(detection bias),incomplete outcome data(attrition bias),selective reporting(reporting bias)and other bias was assessed.Statistical analysis was performed by the RevMan 5.3 software.The heterogeneity would be analyzed before pooling data.After heterogeneity test,data without heterogeneity(p?0.1,I2?50%)could be pooled using fixed effect model,and those with heterogeneity(p?0.1,I2?50%)could be solved by sensitivity analysis,subgroup analysis as well as randomized effect model.We will compare outcome measures for dichotomous(binary)data using relative risks(RR)and continuous data using weighted mean difference(WMD)with 95%confidence intervals(CI).A two-sided P<0.05 was considered significant.We will describe the outcomes when the data cannot be pooled or the raw data of outcomes cannot be acquired.We will evaluate the quality of this systematic review by using the GRADE Proflier 3.6 software.Results:Eight randomized,double-blind,controlled trials involving 3035 patients with type 2 diabetes mellitus were included.The published language of included trials was English.The included trials period was ranged from 24 weeks to 52 weeks.The agents of SGLT-2 inhibitors that included in the study were Dapagliflozin,Canagliflozin,Empagliflozin and Ertugliflozin.The meta-analysis results of effectiveness indicated that the SGLT-2 inhibitor add-on to DPP-4 inhibitor plus metformin produced more effective than DPP-4 inhibitor add-on to metformin in decreasing HbA1c[WMD?-0.63%,95%CI(-0.74,-0.53),P?0.00001],fasting plasma glucose[WMD =-26.50 mg·dL-1,95%CI(-29.61,-23.39),P<0.00001]and postprandial plasma glucose[WMD =-40.55 mg·dL-1,95%CI(-46.82,-34.27),P?0.00001].More patients achieved an HbA1c level of ?7.0%in the triple therapy group[RR=1.88,95%CI(1.70,2.09),P?0.00001].Compared with dual therapy group,no significant differences was observed regarding the occurrence of adverse events,hypoglycemia events and urinary tract infections in triple therapy group(P?0.05).In incidence of genital tract infections,triple therapy group more than dual therapy group[RR=4.37,95%CI(2.62,7.30),P<0.00001].SGLT-2 inhibitor add-on to DPP-4 inhibitor plus metformin significantly decreased the body weight,compared with DPP-4 inhibitor add-on to metformin[WMD =-2.04kg,95%CI(-2.24,-1.83),p?0.00001].In blood pressure,the systolic blood pressure of the triple therapy group decreased significantly compared to the dual therapy group[WMD=-2.69mmHg,95%CI(-3.75,-1.62),P?0.00001].The triple therapy group showed more effective in the drop in diastolic blood pressure compared with the dual therapy group[WMD=-1.26mmHg,95%CI(-1.97,-0.54),P=0.0006].The results of GRADE profliler indicated that the triple therapy group,compared with the dual therapy group,the outcomes of HbA1c and changes in fasting plasma glucose were HIGH quality,the outcomes of postprandial plasma glucose,HbA1c?7.0%,adverse events,hypoglycemic events,body weight,systolic blood pressure,diastolic blood pressure,urinary tract infections,genital tract infections were MODERATE quality.Conclusions:Triple therapy with SGLT-2 inhibitor add-on to DPP-4 inhibitor plus metformin can effectively reduce HbAlc,fasting plasma glucose,postprandial plasma glucose and more patients achieved an HbAlc level of<7.0%in patients whose type 2 diabetes is inadequately controlled with DPP-4 inhibitor plus metformin therapy.The incidence of triple therapy with SGLT-2 inhibitor add-on to DPP-4 inhibitor plus metformin adverse events is relatively lower,and the risk of hypoglycemia and urinary tract infections are lower,but the risk of genital tract infections are higher.Patients with recurrent and ongoing genital tract infections should weigh the pros and cons.SGLT-2 inhibitors can reduce body weight,and has antihypertensive effect,especially for patients with type 2 diabetes mellitus with hypertension.The SGLT-2 inhibitor add-on to DPP-4 inhibitor plus metformin therapy group,compared with the DPP-4 inhibitor add-on to metformin therapy group,the outcomes of HbAlc and changes in fasting plasma glucose were high quality,the outcomes of postprandial plasma glucose,HbA1c?7.0%,adverse events,hypoglycemic events,body weight,systolic blood pressure,diastolic blood pressure,urinary tract infections,genital tract infections were moderate quality. |
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