| Objective:To evaluate the efficacy and safety of sodium-gl ucose cotransporter-2 inhibitors in patients with type 2 diabetes mell itus.Methods: We developed the search strategies based on the PICOS principle to search Medline(via Pub Med),Embase,CENTRAL and Cli nical Trials.gov from inception to October,2018,then identified rando mized double-blind controlled trials meeting inclusion and exclusion criterias.We extracted the basic information and outcomes,assessed the quality of included studies according to Cochrane risk of bias tool.Network meta-analysis and conventional meta-analysis were per formed by Stata 14.0,continuous variables were calculated by SMD and 95% CIs,discontinuous variables were calculated by RR and 95% CIs.Results: A total of 56 English studies,of these,12 for canagliflozin,14 for empagliflozin,18 for dapagliflozin,6 for ipragliflozin,6 for ertu gliflozin,involving 28760 patients were eligible for our meta-analysis.Network meta-analysis showed:(1)All SGLT2 inhibitors obviously re duced Hb A1 c more than placebo,ranging from dapagliflozin 2.5mg(SMD:-0.51%,95%CI:-0.89~-0.13)to canagliflozin 300mg(SMD:-1.32%,95%CI:-1.62~-1.02).Except for ipragliflozin 50 mg and canagliflozin 100 mg,canagliflozin 300 mg significantly reduced Hb A1 c more th an other SGLT2 inhibitors,ranging from empagliflozin 25mg(SMD:-0.56%,95%CI:-0.96~-0.16)to dapagliflozin 2.5mg(SMD:-0.81%,95%C I:-1.29~-0.32);(2)All SGLT2 inhibitors were more effective than pl acebo for achieving Hb A1c<7%,ranging from dapagliflozin 2.5mg(RR:1.42,95%CI:1.17~1.73)to empagliflozin 25mg(RR:2.45,95%CI:2.13~2.82).Empagliflozin 25 mg was more effictive than other SGLT2 inhibitors about achieving Hb A1c<7%,with RRs from empagliflozi n 10mg(RR:1.18,95%CI:1.05~1.32)to dapagliflzoin 2.5mg(RR:1.72,95%CI:1.3.5~2.17),except for canagliflozin 300 mg and ertugliflozin 15 mg.Canagliflozin 300 mg also was more valid than other SGLT2 i nhibitors on achieving Hb A1c<7%,ranging from dagpagliflozin 10 m g(RR:1.22,95%CI:1.04~1.43)to dapagliflozin 2.5mg(RR:1.70,95%CI:1.36~2.11);(3)Compared with placebo,all SGLT2 inhibitors significantl y decreased fasting plasma glucose(FPG),with SMDs from dapaglifl ozin 2.5mg(SMD:-0.47mmol/L,95%CI:-0.69~-0.25)to ipragliflozin 50mg(SMD:-0.96mmol/L,95%CI:-1.21~-0.72);(4)All SGLT2 inhibitors w ere more effictive than placebo for reducing body weight,with SM Ds from canagliflozin 100mg(SMD:-0.38 kg,95%CI:-0.5~-0.26)to ipra gliflozin 50mg(SMD:-0.89 kg,95%CI:-1.05~-0.73).Compared other S GLT2 inhibitors,ipragliflozin 50 mg clearly decreased body weight,r anging from empagliflozin 25mg(SMD:-0.27 kg,95%CI:-0.46~-0.08)tocanagliflozin 100mg(SMD:-0.51 kg,95%CI:-0.71~-0.31);(5)When Com pared placebo,all SGLT2 ihibitors led to greater systolic blood pres sure(SBP)reduction,ranging from dapagliflozin 2.5mg(SMD:-0.22 m m Hg,95%CI:-0.36~-0.09)to canagliflozin 300mg(SMD:-0.35 mm Hg,95%CI:-0.42~-0.28);(6)All SGLT2 inhibitors visibly improved diastolic blood pressure than placebo,ranging from ertugliflozin 5mg(SMD:-0.13 mm Hg,95%CI:-0.25~-0.02)to canagliflozin 300mg(SMD:-0.34 mm Hg,95%CI:-0.41~-0.27);(7)Canagliflozin 300 mg and dapagliflozin 10 mg were associated with higher risk of AEs leading to discontinuati on than placebo(RR=1.28,1.26,P<0.05),however ipragliflozin 50 mg was lower risk than placebo(RR=0.44,P<0.05).Ipragliflozin 50 mg w as associated with lower risk of AEs leading to discontinuation than other SGLT2 inhibitors,with RRs from empagliflozin 25mg(RR:2.06,95%CI:1.21~3.52)to canagliflozin 300mg(RR:2.92,95%CI:1.64~5.19);(8)Canagliflozin and empagliflozin reduced the risk of serious AE s,when compared with placebo,with RRs from canagliflozin 100 m g(RR:0.78,95%CI:0.66~0.92)to empagliflozin 25mg(RR:0.93,95%CI:0.87~0.99).Similarly,compared with ertugliflozin 5mg,both of them c an reduce the risk of serious AEs,with RRs from canagliflozin 100mg(RR:0.58,95%CI:0.41~0.82)to empagliflozin 25mg(RR:0.69,95%CI:0.5~0.95);(9)Canagliflozin increased hypoglycaemia risk compared wi th placebo,dapagliflozin 10 mg and empagliflozin,with RRs from dapagliflozin 10mg(RR:1.23,95%CI:1.07~1.40)to empagliflozin 25mg(R R:1.29,95%CI:1.16~1.44);(10)Only canagliflozin 100 mg led to signifi cantly more bone fracture than dapagliflozin 2.5mg(RR:6.48,95%CI:1.01~41.62);(11)Canagliflozin,empagliflozin,dapagliflozin and ertugflo zin were associated with higher risk of genital infections than place bo,with RRs from empagliflozin 25mg(RR:3.30,95%CI:2.59~4.22)t o dapagliflozin 10mg(RR:4.97,95%CI:3.54~6.97),also than ipragliflo zin 50 mg,with RRs from empagliflozin 25mg(RR:5.67,95%CI:1.42~22.68)to dapagliflozin 10mg(RR:8.53,95%CI:2.09~34.78);(12)Dapagli lozin 10 mg was higher risk of urinary tract infections than empaglif lozin,ertugliflozin 5mg and placebo,with RRs from placebo(RR:1.32,95%CI:1.09~1.60)to ertugliflozin 5mg(RR:1.56,95%CI:1.09~2.24).C onventional meta-analysis showed:(1)All SGLT2 inhibitors reduced H b A1c%,fasting blood glucose,body weight,systolic blood pressure and diastolic blood pressure significantly in both overall and subgr oup analyses(P<0.05),but canagliflozin was similar to active drugs for achieving Hb A1c<7%(RR=1.00,95%CI:0.92~1.09).(2)When compa red with control group,canagliflozin increased the risk of AEs lead ing to discontinuation(RR=1.21,95%CI:1.05~1.39),ipragliflozin,howev er,evidently decreased the risk of AEs leading to discontinuation(RR=0.43,95%CI:0.21~0.90);(3)All SGLT2 inhibitors obviously reduced t he risk of serious AEs compared with control group and placebo(RR=0.95,95%CI:0.92~0.98;RR=0.91,95%CI:0.87~0.94).When SGLT2 in hibitors were used in combination with other anti-diabetic drugs,they also significantly reduced the risk of serious AEs compared with c ontrol group(RR=0.95,95%CI:0.92~0.98);(4)SGLT2 inhibitors didn't i ncrease hypoglycaemia risk compared with placebo/control(P<0.05);(5)Overall,SGLT2 inhibitors did not increase the incidence of urinar y tract infections compared with control group,except for dapaglifloz in;(6)SGLT2 inhibitors overtly increased the risk of genital infection s in both overall and subgroup analyses(P<0.05),except for ipraglifl ozin;(7)SGLT2 inhibitors didn't increase the risk of bone fracture(P>0.05).Conclusion:SGLT2 inhibitors had good efficacy,tolerance and safety in treating type 2 diabetes mellitus.All SGLT2 inhibitors significant ly improved Hb A1 c,FPG,body weight,blood pressure.Hb A1 c and blood pressure were the most significantly decreased by canaglifloz in 300 mg.Empagliflozin 25 mg was the most one to achieve Hb A1c<7%.Ipragliflozin 50 mg had the most significant reduction in FPG and body weight.SGLT2 inhibitors reduced the risk of serious AE s,of which the most significant reduction is ipragliflozin 50 mg.All SGLT2 inhibitors,with the exception of ipragliflozin 50 mg,signifi cantly increased genital infection,with the most obvious increase in dapagliflozin 10 mg.SGLT2 inhibitors didn't increase the incidencesof hypoglycemia,withdrawal due to adverse reactions,fractures,an d urinary tract infections. |
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