Copyright© AE&M all rights reserved. 629 million diabetic patientsby2045. About87% will be likelyto havediabetesworldwide.There were that, some425million(8.8%) adults,20-79yearsold, DiabetesFederation(IDF)hasestimated International urbanization, T2DMison the risealloverworld. therapideconomicdevelopment and With prevalence. T INTRODUCTION 478 DOI: 10.20945/2359-3997000000146 Accepted on8/Apr/2019 Received onOct/8/2018 [email protected] Chen Yu Correspondence to: Liaoning Province, China Medical University, Shenyang, ofChina Shengjing Hospital 1 original article original DepartmentofEndocrinology, chronic and progressive diseasewithhigh andprogressive chronic ype 2 mellitus (T2DM) is a kind of Efficacy andsafety ofsodium- Sodium-glucose co-transporter2inhibitors;;typediabetesmellitus; meta-analysis Keywords body weightandloweringbloodpressure. to achieve glycemiccontrolwithmetforminalone,basedonitseffects onglycemic control,reducing plus metforminmayprovide anattractive treatmentoptiontothose T2DM patientswhoareunable events. related adverse No significantdifference was foundintheriskof hypoglycemia, urinarytractinfectionor volume metformin grouphadhigherriskofgenitalinfection[RR=3.98,95%CI(2.38,6.67),p<0.00001]. 95% CI(-2.40,-1.07), comparedwithmetforminmonotherapy. However, p<0.00001] SGLT2-i plus andDBP[MD=-1.74,(-2.05, -1.39), SBP[MD=-4.44,95%CI(-5.45,-3.43),p<0.00001] p<0.00001], FPG[MD=-1.12,< 0.00001], 95%CI(-1.38, bodyweight[MD=-1.72, -0.87),p<0.00001], 95%CI SGLT2-i plus metformin had higher reduction level in HbA1C [MD = -0.50, 95% CI (-0.62, -0.38), p safety endpoints. The heterogeneitywas evaluatedbyI². eventsfor andriskratios (RR)toevaluatetheadverse of glycemicandotherclinicalparameters, and Cochrane database. Collaborative We usedmeandifferences (MD)toassesstheefficacy methods: mellitus (T2DM)patientswithinadequateglycemiccontrolmetforminalone. transporter (SGLT2-i), 2inhibitors asacombinationtreatmentwithmetforminintype2diabetes Objectives: ABSTRACT http://orcid.org/0000-0001-9682-7894 Chen Yu http://orcid.org/0000-0002-3465-3443 Li Ping http://orcid.org/0000-0002-0150-9146 Liu Cong http://orcid.org/0000-0002-1940-8693 Li Ling http://orcid.org/0000-0001-5567-4262 Zhang Jingfan metformin: ameta-analysis inadequate glycemiccontrol on in type2diabetes mellituswith glucose cotransporter-2 inhibitors 1 1 1 1 We have searched randomized controlledtrials(RCTs)inthedatabase:MEDLINE,Embase To provide ameta-analysis oftheclinicalefficacy andsafetyofsodiumglucoseco- 1 Conclusions: most commonly initialoralmedicationworldwide (1). asthe willbeusuallytreated blood glucose,metformin levelsof notabletocontrol are of T2DMtreatment, ). Ifattemptstochange lifestyle,thecornerstone to (thebodycannot fullyrespond and insulinresistance inadequateinsulinsecretion the followingtworeasons: income countries(1). T2DMinhigh probably to 91%diabeticpatientsare Simplistically, inT2DM,hyperglycemia iscausedby Although the risk of genital infection may increase, SGLT2-i Arch EndocrinolMetab. 2019;63(5):478-86 Results: Finally 9studieswereincluded. Arch Metab. Endocrinol 2019;63/5 Materials and Arch Metab. Endocrinol 2019;63/5 ‘SGLT2 inhibitors’, thenamesofindividual available 2inhibitors’, ‘sodiumglucoseco-transporter terms: Collaborative database,based onthefollowingsearch Embase (1974toNovember 2017)andCochrane in thedatabase:MEDLINE (1978 toNovember2017), We trials(RCTs) randomizedcontrolled havesearched MATERIALS ANDMETHODS alone. inmetformin glycemic control inT2DMpatientswithinadequate on tometformin andsafetyofSGLT2-i, asadd- synthesize theefficacy We meta-analysistoupdateand conductedthepresent stilllacking. of SGLT2-i are combinedwithmetformin However, andsafety large trialsevaluatingtheefficacy luseogliflozin, ipragliflozin,andtofogliflozin(7-9). including canagliflozin, dapagliflozin, empagliflozin, Union,theUnitedStates,and Japan)atleast, European inonemajormarket (suchasthe have beenapproved SGLT2 gene(6).Uptonow, thefollowingSGLT2-i by controlled and weight gain are hyperfiltration glomerular because thatthefactorsofhypertension, blood glucosewithoutcausingtheabovesideeffects of SGLT2-i thecontrol can improve Nevertheless, maybenegated. bythetreatments glycemic control the benefits of Therefore, occurred. gain, frequently suchas hypoglycemiaandweight the sideeffects, them (5,6).DuringthetraditionaltherapyforT2DM, with SGLT2-i, which include exogenousinsulinin other kindsofantidiabeticagentscanbecombined all (5,6).Asaresult, theglycemiccontrol improved of theamountorsensitivityinsulin,consequently glycated hemoglobin(HbA1C)levelsirrespective thebloodglucose levelsand could decrease (4). SeveralhumantrialsdemonstratedthatSGLT2-i thebloodglucose glucose,thusreducing of urinary the excretion tubules, increasing proximal in renal SGLT2-i isbasedoninhibitingglucosereabsorption of the yearof2015(3).Theantidiabeticeffect Association fortheStudyofDiabetes(EASD)in American DiabetesAssociation(ADA)andEuropean as second-lineagentsinT2DMmanagementby target. SGLT2-iunmet control wasrecommended those T2DMpatients a newwaytotreat provide (SGLT2-i), asanovelkindofantidiabeticdrugs, target (2). orcholesterol control failed tomeetglycemictarget, aswellbloodpressure still33–49%diabeticpatients are there Nevertheless, Sodium glucose co-transporter 2inhibitors Sodium glucoseco-transporter AEs-hypotension/dehydration/ hypovolemia. suggestive ofgenitalinfection(GI),andvolumerelated tractinfection(UTI),AEs suggestive ofurinary (AEs) ofSGLT2-i includedhypoglycemiaAEs,AEs adverse events (DBP), special interest blood pressure (SBP)anddiastolic change ofsystolicbloodpressure the changeofHbA1C,bodyweight, thechangeoffastingplasmaglucose (FPG), reported: ≥ 12weeks,[4]Thefollowingdatawascompletely [3]Treatmentcombined withmetformin, duration SGLT2-i withplacebo compared asadd-ontometformin [2]Studies onmetformin, inadequate glycemiccontrol [1] RCTsadult patients of T2DM with recruited ‘metformin’. ‘ipragliflozin’, ‘IPRA’ and‘tofogliflozin’,‘TOFO’) ‘DAPA’, ‘empagliflozin’,‘EMPA’, ‘luseogliflozin’, SGLT2-i (‘canagliflozin’,‘CANA’, ‘dapagliflozin’, FPG and body weight, since statistical heterogeneity FPG and body weight, since statistical heterogeneity the assessmentofcontinuous variablesofHbA1C, of heterogeneity. We modelin usedRandom-effects SGLT2-i agentstoevaluate theconfoundingeffect individual analyses of different subgroup performed among trials (10).Weevaluate theheterogeneity to asubstantiallevelofheterogeneity) 50% reveal test (significantlevelatp<0.05)andI²tests(I² ≥ dehydration/ hypovolemia).We Q-statistic performed AEs-hypotension/ AEs ofGI,andvolumerelated the dichotomousvariables(hypoglycemia,AEsofUTI, safety, weusedriskratio(RR)with95%CI toassess body weight,SBPandDBP. of Forthemeasurement the following continuous variables: FPG, HbA1C, baselineof (CI)ofthemeanchangesfrom interval (MD)and 95%confidence weighted meandifferences of efficacy,For the measurement we calculated the allstatisticalanalyses. collaboration) toperform high quality). indicating 0to7(ahighscore rangefrom with scores Jadad’s Scaletoassessthequalityofincludedarticles, published ormostcompletedata.We usedRevised attached tothesametrial,wechosemostrecently were byconsensus.Ifmultiplearticles and confirm inthediscussion investigatorwouldparticipate a third by discussion and consensus. If needed, disagreements We or the discrepancies tried to identify and resolve takenintoaccount. further were articles pertinent, Ifjudged abstractsofarticles. investigators reviewed In order to evaluate the relevance, twoindependent toevaluatetherelevance, In order included: The studiesmetthefollowingcriteriawere We used Review Manger (version 5.3; Cochrane Efficacy andsafety ofSGLT-2i in T2DM 479

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 480 Table 1. and safetywasinadequate.Finally, 9studies(11-19) [4] Duplicate;[5]Thedataaboutoutcomesofefficacy naivepatients; SGLT2-i intreatment withmetformin [3]RCTs usedintreatment; were comparing drugs -Besides SGLT2-i otherantidiabetic ormetformin, asmonotherapy;[2] group against placebocontrolled [1]RCTsthe followingreasons: comparingSGLT2-i excludedfor of thefulltext.However,were 46articles assessedforevaluationindetailbasedonreview further were excluded,55articles were abstracts, 293articles We identified348RCTcitationsinitially,review of after RESULTS and dichotomousvariableswithlittleheterogeneity. in the analyses of continuous variables of SBP and DBP, modelwasused intheanalyses.Fixed-effects presented Efficacy andsafety ofSGLT-2i in T2DM SGLT2-i: sodium-glucoseco-transporter 2inhibitors;MET: metformin;PBO: placebo;IPRA: ipragliflozin;DAPA: dapagliflozin;CANA: canagliflozin; EMPA: empagliflozin. (2016) Lu CH(11) (13) (2013) González FJ Lavalle- (2013) Bailey CJ(12) (2013) (15) Rosenstock J (14) (2012) Wilding JP (2015) Merker L(16) (2015) Ross S(18) (17) (2015) Draeger PM Schumm- (2016) Yang(19) W Study (year) Basic characteristicsofincludedstudies 53.9 ±11.3 58.5 ±10.8 Age (years) 54.4 ±9.4 58.6 ±7.6 55.5 ±9.4 55.5 ±9.9 58.3 ±9.0 53.1 ±9.1 Mean ±SD plus MET 59 ±9.0 SGLT2-i 53.4 ±11.3 53.7 ±10.3 57.9 ±11.2 55.3 ±9.8 57.3 ±8.6 58.5 ±9.4 53.5 ±9.2 plus MET 60 ±8.5 56 ±9.7 PBO Male (%) SGLT2-i 50.6 47.1 47.3 57.6 45.6 50.5 MET plus 50 47 37 plus MET 39.8 51.4 54.5 46.5 51.4 59.3 PBO 55 56 47 duration (weeks) Study 102 24 26 12 76 12 16 24 16 that the SGLT2-i combined with metformin had higher that theSGLT2-i hadhigher combinedwithmetformin results of our meta-analysis showed 2. The efficacy Figure shownin were intheanalysis.Theresults enrolled were of HbA1C,FPGandbodyweight,allthe9articles baseline alone,weanalyzedthechangesfrom metformin on in T2DM patients with inadequate glycemic control monotherapyastreatment andmetformin metformin inTable presented therapyofincludedstudieswere 1. drug on and information characteristics of patients enrolled, studies.Thebasic methodologic qualityoftheenrolled ≥5,whichdemonstratedtheadequate had ascore of 9includedRCTs was5.4,andsevenofninestudies Jadad’sscore the inclusioncriteria.Themeanrevised finally includedinthemeta-analysissincenostudiesmet 1).Noneofluseogliflozinortofogliflozinwere (Figure includedformeta-analysis with total2509patientswere SGLT2-i For the comparison of efficacy betweenSGLT2-i plus For thecomparisonofefficacy MET plus 368 137 217 214 100 147 87 71 68 Number of patients MET PBO plus 137 183 101 207 145 107 83 66 71 CANA 100mg/d EMPA 10mg/d EMPA 10mg/d EMPA 10mg/d IPRA 50mg/d IPRA 50mg/d DAPA 5mg/d DAPA 5mg/d DAPA 5mg/d SGLT2-i Arch Metab. Endocrinol 2019;63/5 Dosage maximum tolerated ≥ 2000mg/d(or (or ≥1000mg/dif unable totolerate prohibited higher according tothe ≥ 1500mg/dor ≥ 1500mg/dor safety concerns maximum dose ≥ 1500mg/d ≥ 1500mg/d ≥ 1500mg/d ≥ 1500mg/d ≥ 1500mg/d ≥ 1500mg/d 1500 mg/dif higher dose) local label doses) dose MET Revised Jadad score 7 7 3 6 5 5 7 6 3 Arch Metab. Endocrinol 2019;63/5 of SGLT2-i plusmetformin showed asignificant effect alone.Theresults on metformin glycemic control inthose T2DMpatientswithinadequate metformin and safetyofSGLT2-i ascombination therapywith We DISCUSSION 4). (Figure placebo plusmetformin of with thegroup (2.38, 6.67),p<0.00001],compared higherriskofAEsGI[RR=3.98,95%CI presented p =0.29].However, SGLT2-i group plusmetformin AEs[RR=1.86,95%CI(0.59,5.90), volume related = 1.19,95%CI(0.89,1.58),p0.25],northeriskof (0.89, 2.32),p=0.13],ortheriskofAEsUTI[RR the incidenceriskof hypoglycemia [RR =1.44,95%CI monotherapyin andthemetformin group metformin between the SGLT2-i plus no significant difference showed 4.The meta-analysis results shown in Figure AEs-hypotension,dehydrationorhypovolemia, related hypoglycemia, AEs of UTI,AEs of GI,and volume AEsofSGLT2-i,ratios ofspecialinterest included 3). monotherapy(Figure with metformin = -1.74,95%CI(-2.40,-1.07),P<0.00001]compared -4.44, 95%CI(-5.45,-3.43),p<.00001]andDBP[MD inSBP[MD= gothigherreduction plus metformin baseline ofSBPandDBP,from andfoundthatSGLT2-i 2).Wemonotherapy (Figure thechanges alsocompared with metformin (I² = 52%) compared heterogeneity = -1.72,95%CI(-2.05,-1.39),p<0.00001],with inbodyweight(kg)[MD (I² =70%);higherreduction quantity of heterogeneity p < 0.00001], but with a great level (mmol/L) [MD=-1.12,95%CI(-1.38,-0.87), in FPG (I²=68%);higher reduction of heterogeneity (-0.62, -0.38),p0.00001],however, quantity withagreat level in HbA1C (%) [MD = -0.50, 95% CI reduction Figure 1. For thecomparisonofsafety, weanalyzedtherisk performed this meta-analysis to examine the efficacy thismeta-analysistoexaminetheefficacy performed Flow diagramofstudyselectionprocess. 348 potentialrelevantarticlesidenti edandretrieved 55 offull-textarticlesassessedforeligibility 9 ofstudiesincludedinquantitative synthesis (meta-analysis)

related AEswasfound.Insummary,related thecombination in theriskofhypoglycemia,UTIorvolume higher riskofgenitalinfection.Nosignificantdifference However, SGLT2-i group plus metformin HbA1C, FPG,bodyweightandbloodpressure. T2DM patients’ inimproving as combinationtreatment in clinical work. Higher doses might overestimate the in clinicalwork. Higherdosesmightoverestimate of SGLT2-ias the most widely used as initial treatment EMPA thesedosages 10mg/d),becauseweregarded (IPRA 50mg/d,DAPA 5mg/d,CANA 100mg/d, SGLT2-i minimum daily doses with recommended study,In thepresent weonlyanalyzedthedataof (25-30). placebo orotherglucose-loweringdrugs with 200–300 kcal/d), compared of approximately loss weight byinducingfavorableglucosuria(urinary of SGLT2-i HbA1C, FPG, and body on decreasing SeveralRCTs glycemic control. have found theeffect besides maintaining and body weight control, found tomanifestfavor glucose levelsindependentofinsulinstatusandisalso inhibitionofSGLT2and reversible canlowerblood forT2DMpatients(22-24).Selective results promising SGLT2-i haveshown developeddrugs, the recently , or basal insulin (20,21). Among agonists,SGLT2-i,receptor DPP-4inhibitors, GLP-1 maybefollowedbysulfonylurea, metformin of ClinicalEndocrinologists(AACE)guidelines, totheADAandAmericanAssociation According whichnecessitates add-on treatments. glycemic control adequate itmaynotprovide T2DM progression, However, duetothe after lifestyleinterventions. glycemiccontrol for T2DMpatientswithinsufficient higher riskofgenitalinfection. monotherapy, thanmetformin efficacy althoughwitha better therapy ofSGLT2-i presented andmetformin 5 Datainadequate(n=3) (5) Duplicate(n=5) (4) RCTscomparedintreatmentnaivepatients(n=1O) (3) Otherantidiabeticdrugswereusedintreatment(n=7) (2) RCTscomparedSGLT2-iagainstplaceboasmonotherapy(n=21) (1) 46 offull-textarticlesexcluded,withreasons: 293 articlesexcludedbasedonreviewofabstracts Metformin is recommended as the first line drug asthefirstlinedrug isrecommended Metformin able effects on hypertension onhypertension able effects Efficacy andsafety ofSGLT-2i in T2DM showed 481

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. and/or obesity. especiallythosewithhypertension with metformin, onT2DM benefits topatientshavinginadequatecontrol ofSGLT2-i canprovide treatment andmetformin suggestedthatcombination Theseresults pressure. ofHbA1C,FPG,bodyweightandblood reduction showedasignificant when combinedwithmetformin, SGLT2-iAs shownintheresults, eveninlowdoses, ofSGLT2-i. ortheriskofadverseeffect effectiveness Figure 2. 482 Efficacy andsafety ofSGLT-2i in T2DM Meta-analysis ofefficacy inchangingHbA1C, FPGandweightfrom baseline. growth factor inSGLT2-i patients(32).These growth treated glucose which may act as a potential fungal urinary III trials(31).Itwasthoughttobedueincreased phase afteranalysisofpooleddata from been reported infectionsinSGLT2-i T2DM has of urogenital treated monotherapy.metformin Theslightlyhigherincidence with compared in SGLT2-i group plusmetformin significantly higherincidenceofgenitalinfections Despite the glycemic control, wehavenoteda Despite theglycemiccontrol, Arch Metab. Endocrinol 2019;63/5 Arch Metab. Endocrinol 2019;63/5 Figure 3. authorities to issue a warning (36). However,authorities to issue a warning no related with SGLT-2 inhibitors(35),inducingregulatory duringtreatment hyperglycemia havebeenreported leading to acidosis. Cases of ketosis without severe SGLT2-i ketonemia, couldbeassociatedwithincreased with treatment tubule(38).Asaresult, in therenal inhibition of SGLT-2 stimulates ketonere-absorption the ofketonebodies(37).Furthermore, production the ofglucagon,thusincreasing stimulate therelease ketoacidosis associated with SGLT2-i (35,36). SGLT2-i risk ofinfection. patients aboutgenitalhygieneislikelytominimizethe counseling genitalinfection.What’smore, recurrent or of chronic those women patients with a history SGLT2-i it to patient therapy, when provide especially of we shouldfullyevaluatethebenefitsandharms monotherapy. withmetformin compared However, tractinfectioninSGLT2-i plusmetformin urinary infections (33,34).We didn’tfindthehigherriskof to the higher SGLT2-iincidence of genital with regards aboutthesafetytestingof studies have raisedconcerns Some further concerns were generated by reports of generatedbyreports were concerns Some further Meta-analysis ofefficacy inchangingSBPandDBPfrom baseline. outcomes we were interested in, such as the renal effects effects in,suchastherenal interested outcomes wewere those studies,particularly theenrolled outcomes from such kindofbias.Anotherconstraintisthelacksome However, RCTsreported. lowriskof mayhaverelatively likelytobe more bias asthe‘positive’findingswere the publication It mightintroduce in journal. articles collected thedataofmeta-analysisbasedonpublished (19). DAPA withtotal147patients 5mg/dplusMETgroup in reported whilenofracture 145 patientsinthegroup, inMETmonotherapywithtotal onefracture reported accidentinthestudy(17).Yang nofracture reported (17,19).Schumm-DraegerPM the AEsoffractures reported Onlytwoofourincludedarticles concerned. alsobeing ofbonemineralsare transportation ofSGLT2-i tubular ontherenal the possibleeffects didn’t assesstheriskofketoacidosis.Furthermore, we inourincludedarticles, wasreported information concern is related to statistical heterogeneity (I²)which tostatisticalheterogeneity isrelated concern events, ketoacidosis,andsoon.Moreover, another of SGLT2-i theincidenceofcardiovascular treatment, There are limitations in our present study. limitationsinourpresent are There We Efficacy andsafety ofSGLT-2i in T2DM 483

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 484 Figure 4. absent or low. can be attributed This heterogeneity (I² =52%).Whileintheotheranalyses,itwaseither HbA1C (I²=68%),FPG70%)andbodyweight highinthecomparisonofchange was relatively Efficacy andsafety ofSGLT-2i in T2DM Meta-analysis of safetyintheincidenceofspecialinterest adverseevents. or differences in the selection and ascertainment of in the selection and ascertainment or differences duration,and/ extent intheethnicities,treatment insome RCTs, couldbedifferences there different to clinicalandmethodologicalheterogeneity. Across Arch Metab. Endocrinol 2019;63/5 Arch Metab. Endocrinol 2019;63/5 8. 7. 6. 5. 4. 3. 2. 1. REFERENCES was reported. relevant tothisarticle nopotentialconflictofinterest Disclosure: intervention. biotherapy and the potential risk of the therapeutic ofthis efficacy toclarifythelong-term necessary are researches Further and loweringbloodpressure. bodyweight reducing onglycemiccontrol, its effects alone,onaccountof withmetformin glycemic control unable toachieve to thoseT2DMpatientswhoare option anattractivetreatment mayprovide metformin SGLT2-irisk ofgenitalinfectionmayincrease, plus alone.Inconclusion, althoughthe on metformin the T2DMpatientswithinadequateglycemiccontrol monotherapyin withmetformin compared treatment, andsafetyofSGLT2-i plusmetformin effectiveness consequencesofSGLT2-iterm treatment. adverseevents,soastoevaluatethelong- other related safety,renal events,ketoacidosisand cardiovascular dataincluding alltherelated follow-up, andreport therapies inlongertimeandlarger scale,withadequate SGLT2-ishould compare with placebo or other diabetic idealRCTsoverall analysis.Future necessary, are which of patients,whichmightleadtoahighvariabilityinthe smallnumber and eachcentercontributedarelatively multiregional, thetrialswere outcomes. Furthermore,

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