BMJ Open. Effectiveness and safety of metformin and other glucoselowering

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1 Effectiveness and safety of metformin and other glucoselowering treatments in patients with type diabetes: A cohort study from the Swedish National Diabetes Register (NDR) Journal: Manuscript ID: bmjopen Article Type: Research Date Submitted by the Author: 0-Mar-0 Complete List of Authors: Ekström, Nils; University of Gothenburg, Department of Medicine Schiöler, Linus; Center of Registers in Region Västra Götaland, ; University of Gothenburg, Department of Public Health and Community Medicine Svensson, Ann-Marie; Center of Registers in Region Västra Götaland, Eeg-Olofsson, Katarina; University of Gothenburg, Department of Medicine Miao Jonasson, Junmei; Center of Registers in Region Västra Götaland, Zethelius, Bjorn.; Uppsala University, Public Health/Geriatrics Cederholm, Jan; Uppsala University, Department of Public Health and Caring Sciences / Family Medicine and Clinical Epidemiology Gudbjörnsdottir, Soffia; University of Gothenburg, Department of Medicine; Center of Registers in Region Västra Götaland, Eliasson, Björn; University of Gothenburg, Department of Medicine <b>primary Subject Heading</b>: Diabetes and endocrinology Secondary Subject Heading: Epidemiology, Pharmacology and therapeutics, Cardiovascular medicine Keywords: Diabetes endocrinology < INTERNAL MEDICINE, EPIDEMIOLOGY, THERAPEUTICS, Vascular medicine < INTERNAL MEDICINE, Adverse events < THERAPEUTICS : first published as 0./bmjopen on July 0. Downloaded from on April 0 by guest. Protected by copyright. -

2 Page of Effectivenessandsafetyofmetforminandotherglucoseloweringtreatments inpatientswithtypediabetes: AcohortstudyfromtheSwedishNationalDiabetesRegister(NDR) Authors NilsEkström,LinusSchiöler,,AnnMarieSvensson,KatarinaEegOlofsson,Junmei MiaoJonasson,BjörnZethelius,JanCederholm,SoffiaGudbjörnsdottir,, BjörnEliasson Affiliations CentreofRegistersinRegionVästraGötaland,Gothenburg,Sweden DepartmentofPublicHealthandCommunityMedicine,SahlgrenskaAcademy,University ofgothenburg,sweden DepartmentofMedicine,SahlgrenskaAcademy,UniversityofGothenburg,Sweden DepartmentofPublicHealthandCaringSciences/Geriatrics,UppsalaUniversityand MedicalProductsAgency,Uppsala,Sweden DepartmentofPublicHealthandCaringSciences/FamilyMedicineandClinical Epidemiology,UppsalaUniversity,Sweden Authors addresses NilsEkström(medicalstudent),DepartmentofMedicine,SahlgrenskaUniversityHospital, UniversityofGothenburg,Göteborg,Sweden.Linusschiöler(PhD),Departmentof PublicHealthandCommunityMedicine,SahlgrenskaAcademy,UniversityofGothenburg, Box,00Göteborg,Sweden.AnnMarieSvensson(RN,PhD),NationalDiabetes Register,RegistercentrumVGR,Göteborg,Sweden.KatarinaEegOlofsson(MD,PhD) DepartmentofMedicine,SahlgrenskaUniversityHospital,UniversityofGothenburg, Göteborg,Sweden.JunmeiMiaoJonasson(MD,PhD),NationalDiabetesRegister, RegistercentrumVGR,Göteborg,Sweden.BjörnZethelius(MD,PhD,Assoc.prof.) GeriatricsSection,DepartmentofPublicHealthandCaringSciences,UppsalaUniversity,Box,Uppsala,Sweden.JanCederholm(MD,PhD,Assoc.prof.)FamilyMedicineand ClinicalEpidemiologySection,DepartmentofPublicHealthandCaringSciences,Uppsala University,BMC,Box,Uppsala,Sweden.SoffiaGudbjörnsdottir(MD,PhD,Assoc.! - : first published as 0./bmjopen on July 0. Downloaded from on April 0 by guest. Protected by copyright.

3 Page of prof.),departmentofmedicine,sahlgrenskauniversityhospital,universityofgothenburg, Göteborg,Sweden.BjörnEliasson(MD,PhD,Prof),DepartmentofMedicine, SahlgrenskaUniversityHospital,UniversityofGothenburg,Göteborg,Sweden. Correspondingauthor NilsEkström Phone:+(0)00 nils.ekstrom@gu.se Wordcount Abstract Body! - : first published as 0./bmjopen on July 0. Downloaded from on April 0 by guest. Protected by copyright.

4 Page of Abstract! Objective:Toevaluatetherisksofcardiovasculardisease(CVD),lacticacidosis,serious infectionsandmortalityinalargesampleofpharmacologicallytreatedpatientswithtype diabetesinclinicalpractice,withparticularemphasisonmetformin. Design:Populationbasedretrospectivecohortstudy. Setting:HospitaloutpatientclinicsandprimarycareinSwedenbetweenJuly00and December00. Participants:menandwomenwithtypediabetes,registeredintheSwedish NationalDiabetesRegister(NDR),andoncontinuousglucoseloweringtreatment. Main!outcome!measures:RisksofCVD,acidosis/seriousinfectionandallcausemortality, associatedwitheachtreatmentregimens,wereanalysedinallpatientsandinsubgroups withdifferentestimatedglomerularfiltrationrate(egfr)intervals.covarianceadjustment andpropensityscoreswereusedtoadjustforbaselinecovariates. Results:Insulininmonotherapyshowedanincreasedriskoffatal/nonfatalCVDandall causemortalitycomparedtometformininmonotherapy,hazardratio(hr).(% confidenceinterval:.0to.)and.(.to.0),respectively.metforminshoweda reducedriskofanyacidosis/seriousinfection,hr0.(0.to0.),andallcausemortality, 0.(0.to0.)inpatientswitheGFR0mL/min/.m,andwasnotassociated withincreasedriskofallcausemortality,acidosis/seriousinfectionorcvdinpatientswith renalimpairment. Conclusions:Metforminbasedtherapieswereassociatedwithreducedrisksofsevere endpoints,alsoafterdifferentadjustmentsforpatientcharacteristics.resultswere consistentinpatientswithrenalimpairment,andnoincreasedriskofacidosis/serious infectionwasseen.inclinicalpractice,thebenefitsofmetforminuseclearlyoutbalancethe riskofseveresideeffects.! - : first published as 0./bmjopen on July 0. Downloaded from on April 0 by guest. Protected by copyright.

5 Page of Article(summary( ( Article(focus( ( To(evaluate(the(risks(of(cardiovascular(disease((CVD),(acidosis/serious(infection(and( mortality(associated(with(metformin(and(other(glucose?lowering(treatments,(in(a(cohort(of( ((type((diabetes(patients,(and(in(subgroups(with(different(degrees(of(renal( impairment.((( ( Key(messages( ( Metformin(was(associated(with(reduced(risk(of(CVD,(acidosis/serious(infection(and(all?cause( mortality(compared(to(insulin,(and(a(reduced(risk(of(all?cause(mortality(compared(to(other( oral(hypoglycemic(agents.( ( The(effects(were(consistent(in(patients(with(renal(impairment((eGFR(?0(mL/min/.(m ),( and(there(were(no(increased(risk(of(acidosis/serious(infection(even(in(patients(with(low(renal( function.( Strengths(and(limitations(of(this(study( A(large(cohort(with(comprehensive(data(on(patient(characteristics(was(studied.( A(composite(endpoint(including(diagnosis(of(acidosis,(shock,(acute(renal(failure(and(serious( infections(was(used(to(evaluate(the(occurrence(of(lactic(acidosis.( ( : first published as 0./bmjopen on July 0. Downloaded from on April 0 by guest. Protected by copyright. -

6 Page of Introduction Typediabetesmellitus(DM)isacommondisease,whichcausesmajormorbidityand mortalityduetomicroandmacrovascularcomplications().arangeofglucoselowering agentswithdifferentpropertiesaimsatpreventingthesecomplications.theukprospective DiabetesStudy(UKPDS)demonstratedareductionincardiovasculardisease(CVD)andall causemortalityinthesubgroupofobesedmpatientstreatedwithmetformincomparedto sulfonylureas,insulinordietalone(,).furtherbeneficialeffectswithmetforminhavealso beenrecognized(,).onaccountofthis,internationaltreatmentguidelinesrecommend metforminasfirstlinepharmacologicaltreatmentindmpatients(). Metforminhavebeenconsideredcausingincreasedriskoflacticacidosis.Consequently, metformintreatmenthavebeencontraindicatedinpatientsatriskofdevelopinglactic acidosis,e.g.patientswithcardiovascularandrenaldisease(0).giventhehighprevalence ofmicroandmacrovasculardiseaseinthedmpopulation(),arelativelylarge proportionwascomprehendedbythecontraindications.however,severalstudieshave suggestedthisconcerntobeexaggerated(). Inthelightofthesefindings,mostguidelineshavebecomelessstricttowardsmetformin treatmentinthesepatients(,).however,thereisstillagreatneedforclinicaland epidemiologicalstudiesinvestigatingtheoveralleffectsofmetformininpatientsconsidered vulnerabletosuchtreatment.therefore,theaimofthissurveywastoinvestigatebenefits andrisksassociatedwithdifferentglucoseloweringmedications,inacohortofdm patientsinclinicalpractice,andinsubgroupsofpatientswithdifferentdegreesofrenal impairment. MaterialandMethods Inthispopulationbased,longitudinalstudyinformationwaslinkedfromfournational registersinsweden;thenationaldiabetesregister(ndr),theprescribeddrugregister(), thepatientregister,andthecauseofdeathregister(,).ndrisbasedandadministered ingöteborg,sweden.sincetheestablishmentin,ndrhasbeenworkingwith systematicqualityimprovement,researchanddevelopmentinthefieldofdiabetesmellitus.! - : first published as 0./bmjopen on July 0. Downloaded from on April 0 by guest. Protected by copyright.

7 Page of In00,NDRcoveredpatientswithtypediabetesmellitus(DM)andDM( ).Physiciansandnursesinhospitaloutpatientclinicsandprimaryhealthcareclinicsreport tothendratleastannually,viatheinternetorviadirecttransferofdatafrommedical recordsdatabases.allincludedpatientshaveagreedtoberegisteredbeforeinclusion. Studypopulation Thisstudy,approvedbythecentralethicalreviewboardattheUniversityofGothenburg, comprisesdmpatients.alldmpatientsaged 0to<years,andregisteredin thendrbetweenjuly,00anddecember,00wereeligibleforinclusioninthe study(appendixfigure).dmwasdefinedastreatmentwithdietonly,ororal hypoglycemicagents(oha)only,oronsetageofdiabetes 0yearsandtreatmentwith insulinonlyorcombinedwithoha.patientshadtoberegisteredinthendroneyearprior toandoneyearfollowingtheirfirstprescriptionofglucoseloweringtreatment.inorderto achieveadequatelengthofthefollowupperiod,theyhadtobeinitiatedonglucose loweringtreatmentbefore00tobeincluded. Baselineoccurredtwelvemonthsafterthefirstprescriptionofglucoseloweringmedication. Onlypatientswhohadfilledatleastthreeprescriptionsorfillsofmultidosedispensed drugsduringthistwelvemonthsperiodwereincludedinthestudy.patientswhohad collectedbothordinaryprescriptionsandmultidosedispenseddrugswereexcluded.thus, twelvemonthsofcontinuousglucoseloweringmedicationatbaselinewasensured.the patientswereclassifiedaccordingtoglucoseloweringtreatment,andclinicalcharacteristics wereanalysedatbaseline.patientsmissingvaluesforbaselinecharacteristicswereexcluded fromtheanalysis.otherohaconsistedofpatientstreatedwithallohasotherthan metformin.thevastmajorityofthisgroup,however,wastreatedwithsulphonylureas(su). Baseline VariablesassessedatbaselinearepresentedinTable.Historyofcongestiveheartfailure (CHF),andCVDweredefinedasatleastoneeventofCHForCVDrespectively,anytime betweentheyearofandthestartofthestudy.historyofseriousinfectionswas definedasatleastonesevereinfectionwithinsixmonthspriortobaseline,andthevariable! - : first published as 0./bmjopen on July 0. Downloaded from on April 0 by guest. Protected by copyright.

8 Page of previoushospitalizationashospitalizationforatleastthreeconsecutivedayswithinsix monthspriortobaseline. Thepatientswerescreenedusinglocalmethods,butguidelineswereavailabletoensurethe useofsimilarmethodologyinallcentres.bodymassindex(bmi)wascalculatedasweightin kilogramsdividedbyheightinmeterssquared.asmokerwasapatientsmokingoneormore cigarettesperday,orapipedaily,orwhohadstoppedsmokingwithinthepastthree months.cumulativemicroalbuminuriawasdefinedasurinealbuminexcretion>0 g/min intwooutofthreeconsecutivetests.laboratoryanalyses,includingtotalcholesterol(tc) andhdlcholesterol(hdlc)werecarriedoutatlocallaboratories.hbacanalysesare qualityassuredinswedenbyregularcalibrationwithmonos,ahplcmethod.hbacvalues wereconvertedtothenationalglycohemoglobinstandardizationprogram(ngsp)standard levels().nonhdlcholesterol(nonhdlc)wascalculatedbysubtractinghdlcfromtc. Estimatedglomerularfiltrationrate(eGFR)wascalculatedusingtheMDRD(Modificationof DietinRenalDisease)!equation(). Followup Allpatientswerefollowedfrombaselineuntiltheoccurrenceofanendpointevent,or otherwise,untilcensordateofdecember,00.patientswhoexperiencedanendpoint eventbetweenfirstprescriptionandbaselinewereexcludedfromtheanalysisofthat specificendpoint.patientschangingtreatmentduringthestudywerenotcensored,and endpointeventswereattributedtheongoingtreatmentatthetimeoftheevent.mean followupwas.years.thefiveendpointsanalysedwerefatal/nonfatalcvd,fatalcvd, acidosis/seriousinfection,fatalacidosis/seriousinfectionandallcausemortality.cvdwas definedasdiagnosisofmyocardialinfarction,anginapectoris,intracerebralhaemorrhage, cerebralinfarction,unspecifiedstroke,peripheralvasculardisease(pvd),orintervention withpercutaneouscoronaryintervention(pci)orcoronaryarterybypassgrafting(cabg), whicheveroccurredfirst.acidosis/seriousinfectionwasdefinedasdiagnosisofacidosis, seriousinfection,shock,oracuterenalfailure,whichwereregardedassignsoflactic acidosis.seriousinfectionsrequiringhospitalizationforantiinfectioustreatmentaswellas acidosis,shock,andacuterenalfailurerequiringtreatmentinhospital,usuallyintensivecare thus,registeredintheinpatientregister,wereincludedinthecompositeendpoint.the! - : first published as 0./bmjopen on July 0. Downloaded from on April 0 by guest. Protected by copyright.

9 Page of internationalclassificationsofdiseases0codesforallendpointsaregiveninappendix Materials.Fatalitywasdefinedasaneventfollowedbydeathinthesubsequentdays. StatisticalMethods Baselinecharacteristicswerecompared,unadjusted,usingANOVAandlogisticregression (Table).PropensityscoreswereestimatedusingboostedCART(),sincelogistic regressiondidnotachievegoodbalance.baselinecharacteristicswerethencomparedusing logisticregressionorolsregression,adjustedforoctilesofthepropensityscore(appendix Table).Unadjustedsurvivaloftheendpointsbytreatmentgroupsinallpatientswas estimatedwiththekaplanmeierestimator(figure). Coxregressionmodelswereusedtoestimatehazardratios(HR)forallendpointsingroups ofpatientswithdifferentglucoseloweringtreatments,andmetforminonlyasreference. Adjustmentsweremadeforage,sex,diabetesduration,HbAc,nonHDLC,BMI,smoking, egfr,multidosedispensation,previoushospitalization,historyofcvdandchf, microalbuminuria,andtreatmentwithantihypertensiveagents,lipidloweringagentsand cardiacglycosides(table).hrwerealsoestimatedinpatientswithinsulinonlyorother OHAonlycomparedtometforminonly,adjustedbystratificationforoctilesofpropensity scoresasdescribedabove(table).hrwereestimatedinsubgroupswithdifferentegfr intervals(table),formetformin,insulinorotheroha,withanyotherglucoselowering treatmentasreference.adjustmentwasmadeforsamecovariatesasintable. FunctionalformofcontinuouscovariateswerecheckedusingaKolmogorovtypesupremum test()andinsomemodelsitwasfoundsuitabletoaddaquadratictermforageor diabetesduration.theproportionalhazards(ph)assumptionwascheckedbyincludingthe interactionbetweencovariatesandlogoffollowuptime.violationsofthephassumption werehandledbystratifyingontheviolatingcovariate,orbymodellingtheeffectastime dependent().additionalchecksoftheformofthetimedependenceweremadeusing plotsofscaledschoenfeldresiduals(). AllstatisticalanalyseswereperformedwithSASversion.(SASInstitute,Cary,NC,USA), exceptkaplanmeiercurvesproducedinspssversion(spssinc.,chicago,usa),and! - : first published as 0./bmjopen on July 0. Downloaded from on April 0 by guest. Protected by copyright.

10 Page of propensityscoresestimatedusingthepackagetwanginr(rfoundationforstatistical Computing,Vienna,Austria).AtwosidedPvalue<0.0wasconsideredstatistically significant. Roleofthefundingsource TheRegionVästraGötalandandtheSwedishAssociationofLocalAuthoritiesandRegions fundthendr.thisstudywasalsosupportedbyanunrestrictedresearchgrantfrombms, France.Thefundershadnoroleinstudydesign,datacollectionandanalysis,decisionto publish,orpreparationofthemanuscript. Results Patients Tablegivesthedistributionbetweentreatmentsandclinicalcharacteristicsatbaseline, unadjusted.thetotalpopulationpresentedamean(±sd)ageof.±.yearswithmean diabetesdurationof.±.0years,andameanhbacof.±.%.theproportionof femaleswere.%and.0%ofthepopulationweresmokers.meanbmiwas.±. kg/m,meansystolicbloodpressure0mmhg,meannonhdl.mmol/l,andmean egfr.±.ml/min/.m..%hadhistoryofcvd,.%historyofchf,and.% historyofseriousinfections.therewerestatisticallysignificantdifferencesbetweenthe groupsinallvariables.patientsoninsulinbasedtreatmentspresentedlongerdiabetes duration,highermeanhbac,moreoftenmicroalbuminuriaandhistoryofcvd,chfand seriousinfectionsthanthepopulationingeneral. PatientstreatedwithmetformingenerallypresentedhigheGFRandBMI.Patientson metformininmonotherapyweretheyoungestparticipants,withtheshortestdiabetes duration,andhadalowmeanhbac.theyalsorelativelyseldomhadhistoryofcvd,chfor seriousinfections.patientstreatedwithotherohainmonotherapypresentedthehighest meanage,thelowestmeanhbacandthelowestmeanbmi.afteradjustmentwith propensityscore,alldifferencesinbaselinecharacteristicsexceptforhistoryofchf,and BMIwereerased(AppendixTable).CHFandBMIwerefurtheradjustedforwith stratificationandasacovariate,respectively.! - : first published as 0./bmjopen on July 0. Downloaded from on April 0 by guest. Protected by copyright.

11 Page 0 of Tablegivestimeofexposuretotheglucoseloweringagentsandproportionsofpatients changingtreatment,ineachgroup.theproportionschangingtreatmentrangedbetween.%and.%.comparisonofbaselinecharacteristicsinpatientswhochanged treatmentandpatientswhodidnotchangetreatment,showedsignificantdifferences,with e.g.morefrequenthistoryofcvd,chfandseriousinfectionsinpatientswhodidnotchange treatment,(p<0.0). Outcomes Figureshowsunadjustedtimetoaneventofallcausemortality,anyCVD,andany acidosis/seriousinfectionineachtreatmentgroup.thesteepestdecreasesofcurveswere seenwithinsulinonlyandinsulinincombinationwithotheroha.tablegiveshrwith% confidenceintervals(ci)forallendpoints,adjustedforcovariatesasgiveninthetable.all treatmentswereassociatedwithsignificantlyincreasedrisksofallcausemortalityandany CVDcomparedtometforminonly,withHRrangingfrom.(%CI:.to.)to. (.0to.)forallcausemortalityandfrom.0(.to.)to.(.0to.0)for anycvd.insulinonlyandotherohaonlyalsoshowedasignificantlyincreasedriskoffatal CVD.AlltreatmentsexceptmetforminincombinationwithotherOHAwereassociatedwith asignificantlyincreasedriskofanyacidosis/seriousinfection,andinsulinonlyorin combinationwithmetforminshowedanincreasedriskoffatalacidosis/seriousinfection. Relativelyfewfataleventsoccurredduringfollowup(Table),contributingtothewider confidenceintervalsfortheseriskestimates. TablegivesHRwith%CIforallendpointswithinsulinonlyorotherOHAonlycompared tometforminonly,adjustedforpropensityscore.insulinwasassociatedwithsignificantly increasedrisksofanycvd,hr.(.0to.),allcausemortality,hr.(.to.0), andalsoacidosis/seriousinfectionandfatalacidosis/seriousinfection,hr.(.to.) and.(.0to.).whencomparingotherohaonlytometforminonly,aborderline significantlyincreasedriskwasseenforallcausemortality,hr.(.0to.). TablegivesHRwith%CIforanyCVD,anyacidosis/seriousinfectionandallcause mortality,insubgroupsofpatientswithdifferentegfrintervals,adjustedforcovariatesas giveninthetable.treatmentswithmetformin,insulin,orotherohainanycombination! - : first published as 0./bmjopen on July 0. Downloaded from on April 0 by guest. Protected by copyright.

12 Page of werecomparedtoanyothertreatment.metforminbasedtreatmentswereassociatedwith reducedrisksofanyacidosis/seriousinfectionhr0.(0.to0.)andallcausemortality HR0.(0.to0.)inthesubgroupofpatientswitheGFR0mL/min/.m.Similar resultswereseeninthesubgroupwithegfr>0ml/min/.m,hr0.(0.to0.)for anyacidosis/seriousinfectionand0.(0.to0.)forallcausemortality.bothinsulinand otherohawereassociatedwithincreasedriskofallcausemortalityinpatientswithegfr >0mL/min/.m.Insulinwasalsoassociatedwithincreasedriskofanyacidosis/serious infectioninpatientswithegfr0,or>0ml/min/.m,andincreasedriskofanycvd inpatientswithegfr0,0,or>0ml/min/.m. Discussion Thispopulationbasedobservationalstudydemonstratespronouncedbeneficialeffectsof metformininclinicalpractice.asexpected,thereweresignificantdifferencesinclinical characteristicsbetweenthegroups.thesedifferences,however,disappearedafter adjustmentwithpropensityscores.still,metformininmonotherapyshowedasignificantly reducedriskofanycvd,allcausemortality,anyacidosis/seriousinfectionandfatal acidosis/seriousinfectioncomparedtoinsulininmonotherapy.aborderlinesignificantrisk reductionofallcausemortalitywasalsoshowncomparedtootherohainmonotherapy. Theincreasedriskassociatedwithinsulintreatmentcouldbeduetothesepatients presentingamoreseveredisease.however,anincreasedriskcausedbyinsulinper$se cannotberuledout.othershavereportedsimilareffectsassociatedwithinsulintreatment (),buttheliteratureisnotconsistentinthismatter().resultsfromalargeclinical trialinvestigatingtheeffectsofinsulintreatmentoncvd()areexpectedtobepresented inthenearfuture,andwillhopefullybringclarityinthismatter. Thebeneficialeffectsofmetformin,showninthissurvey,areconsistentwithprevious findings.theukpdsdemonstratedareductioninallcausemortalityinthesubgroupof obesedmpatientstreatedwithmetformincomparedtodiet,insulinorsu().the sustainabilityoftheeffectwasconfirmedinatenyearpostinterventionalfollowup(). AnotherclinicaltrialindicatedreducedriskofmacrovasculareventsininsulintreatedDM! : first published as 0./bmjopen on July 0. Downloaded from on April 0 by guest. Protected by copyright.

13 Page of patientswhenaddingmetformincomparedtoplacebo(). Subgroupanalyseswithpatientspresentingdifferentdegreesofrenalimpairmentwere conducted,anddidnotshowanyincreasedriskofcvd,acidosis/seriousinfectionorall causemortalityassociatedwithmetforminbasedtreatmentsinpatientswithegfr0, 0,or>0mL/min/.m.Rather,metforminbasedtreatmentswereassociatedwith reducedrisksofallcausemortalityandacidosis/seriousinfectioninpatientswithegfr 0or>0mL/min/.m.Theprevalenceofrenalimpairmentdifferedbetweenthe groups,withpatientspresentinganegfr<ml/min/.m beingrareinmetformin basedtreatments.however,theprevalenceofegfr0ml/min/.m rangedbetween 0.%and.%inthesepatients(Table),anddidnotdiffermuchfromotherpatients. Consequently,thesubgroupwitheGFR0mL/min/.m wasbasedonasurprisingly largematerial,whilethesubgroupwithegfr0ml/min/.m constitutedrelatively fewpatients. Arecentlypublishedobservationalstudy()examinedtheeffectsofmetformininpatients withadvancedcardiovasculardisease,thusconsideredvulnerabletometformin.theresults indicatedsignificantlyreducedriskofallcausemortalityinpatientstreatedwithmetformin comparedtootherglucoseloweringtreatments.resultswereconsistentinasubgroupof patientswithrenalimpairment(egfr00ml/min/.m ).Thesurvey,however,only analysedallcausemortality,andcouldthereforenotdetectpotentialcasesoflacticacidosis. Furthermore,glucoseloweringtreatmentswereonlyspecifiedasmetforminuseornot,and noadjustmentsforcrucialcovariatessuchashbacordiabetesdurationweremade. SeveralstudieshavefailedtodemonstrateincreasedincidencerateoflacticacidosisinDM patientstreatedwithmetformin.thus,dmwithitscomorbiditiesoranyglucoselowering treatmentratherthanmetforminuseper$sehavebeensuggestedtoberiskfactorsforlactic acidosis(). Thelargepopulation,DMpatients,andcomprehensiveadjustmentsforcovariates areapparentstrengthsofthepresentsurvey.dataarecollectedfromthendrdatabase withacurrentlyestimatedcoverageofmorethan0%ofallpatientsinhospitaloutpatient clinicsandalmost0%ofallpatientsinprimarycareinsweden,suggestingittobehighly! - : first published as 0./bmjopen on July 0. Downloaded from on April 0 by guest. Protected by copyright.

14 Page of representativeofclinicalpractice.riskcalculationsweremade,adjustedforcovariateswith propensityscoresandincoxregressionmodels.thepropensityscoreachievedperfectly wellbalancedgroupsregardingbaselinecharacteristicsindicatingtherobustnessofthis statisticalanalysis.thecoxregressionmodelsenabledmorecomprehensivecomparisons betweenseveralglucoseloweringregimens.wealsopresentedexposuretimeforthe differentglucoseloweringtreatments,butunfortunatelytherewasnousefulinformation aboutdoses. Despitecomprehensiveadjustments,covariatesofpossibleimportancecouldhavebeen missed.thus,thepresenceofallocationbiasmaynotbefullyavoided.furthermore, patientswhochangedglucoseloweringtreatmentduringthestudywerenotcensored.it couldbethatpatientswithadvancingdiseasemorefrequentlychangedtoaspecificglucose loweringmedication,dilutingtheresultsobserved.comparisonofbaselinecharacteristics indicatedhigherproportionsofhistoryofcvd,chfandseriousinfectionsinpatients changingtreatment.thiscouldhaveaffectedtheresults,eventhoughtheproportionsof patientschangingtreatmentwerehighinallgroups.veryfeweventsofdiagnosedlactic acidosisoccurredduringthefollowup,andthusanalyseswithlacticacidosisasanendpoint wouldnotprovidedesirablestrength.therefor,acompositeendpoint(acidosis/serious infections)includingdiagnosisofacidosis(n=),shock(n=),acuterenalfailure(n=) andseriousinfections(n=),wasused.thiscomplicatestheevaluationoflacticacidosis per$se,althoughthisdiagnosisinpracticeonlyoccursincombinationwithsevereinfections orcvd.furthermore,lacticacidosisreportedwithuseofbiguanidesmostlyinvolve phenformine,whichwaswithdrawnfromthemarket,aslacticacidosiswas0timesmore frequentthanwithmetformin().thepatientgrouptreatedwithotheroha,weremainly treatedwithsuandtoaverylimiteddegreewithglitazones,acarboseordppinhibitors duringthestudyperiod.investigationoftheindividualeffectivenessoftheseagentswould howeverbeofinterestinthefuture. Inconclusion,thisnationwideobservationalstudyofDMpatientssupportsthe previouslyobservedeffectivenessofmetformin.metforminwasassociatedwithreduced riskofallcausemortalitycomparedtobothinsulinandotheroha,andforseveral additionalendpointscomparedtoinsulin.theresultswereconsistentinasubgroupof! - : first published as 0./bmjopen on July 0. Downloaded from on April 0 by guest. Protected by copyright.

15 Page of patientswithrenalimpairment,andnoincreasedriskofacidosis/seriousinfectionwasseen. Togetherwithpreviousfindings,thisconstitutesevidentsupporttothelessstrictapproach tometformintreatmentinpatientswithrenalimpairment,advocatedinmostguidelines. Thus,considerablymoreDMpatientsmaybeconsideredfortreatmentwithmetformin.! - : first published as 0./bmjopen on July 0. Downloaded from on April 0 by guest. Protected by copyright.

16 Page of Datasharing Noadditionaldataavailable. Copyrightstatement I[NilsEkström]theCorrespondingAuthorofthisarticlecontainedwithintheoriginal manuscriptwhichincludesanydiagramsphotographs,otherillustrativematerial,video, filmoranyothermaterialhowsoeversubmittedbythecontributor(s)atanytimeand relatedtothecontribution( thecontribution )havetherighttograntonbehalfofall authorsanddograntonbehalfofallauthors,alicencetothebmjpublishinggroupltdand itslicensees,topermitthiscontribution(ifaccepted)tobepublishedinbmjopenandany otherbmjgroupproductsandtoexploitallsubsidiaryrights,assetoutinthelicenceat: ( Authorcontributions NE,LS,BZ,JC,AMS,JMJ,KEO,SGandBEcontributedtotheconceptionanddesign.LS,JC andamscontributedtotheacquisitionofdataandperformedthecalculations.ls,ne,jc, BZ,SG,AMSandBEcontributedtotheanalysisandinterpretationofdata.NEandBE contributedtodraftingthearticle.ne,be,bz,jz,ams,ls,keo,sgandjmjcontributedto revisingthearticlecriticallyforimportantintellectualcontentandfinalapprovalofthe versiontobesubmitted. Acknowledgements Wethankthepatients,regionalNDRcoordinatorsandallparticipatingnursesand physicians.thendrissupportedbytheswedishsocietyfordiabetology,andtheswedish DiabetesAssociation. Funding TheRegionVästraGötalandandtheSwedishAssociationofLocalAuthoritiesandRegions fundthendr.thisstudywasalsosupportedbyanunrestrictedresearchgrantfrombms, France.Thefundershadnoroleinstudydesign,datacollectionandanalysis,decisionto publish,orpreparationofthemanuscript.! - : first published as 0./bmjopen on July 0. Downloaded from on April 0 by guest. Protected by copyright.

17 Page of Conflictofinterest BEhasservedasalecturerforallpharmacologicalcompaniesmanufacturingglucose loweringagentsandparticipatedinadvisoryboardsforelilillyswedenabandelilillyco, Sanofiaventis,Sweden,BoehringerIngelheimAB,Sweden,andMSD,Sweden. Disclaimer BjörnZethelius(BZ)isemployedbytheMedicalProductsAgency(MPA),UppsalaSweden. BZhasnotreceivedanyfinancialsupportorotherbenefitsfromBMSFranceorany commercialsponsor.resultsandviewsofthepresentstudyrepresenttheauthorsandnot necessarilyanyofficialviewsofthempawherebzisemployed.! - : first published as 0./bmjopen on July 0. Downloaded from on April 0 by guest. Protected by copyright.

18 Page of Figurelegends Table:Baselinecharacteristicsinall,typediabetespatientsandingroupsbasedon glucoseloweringtreatments.means±onestandarddeviation(sd)andfrequencies(%)are given.therewerestatisticallysignificantdifferences(p<0.00)inallvariablesbetweenthe groups.! Table:Timeofexposure(months)tospecificglucoseloweringagents,andproportions changingtreatment(%)ineachgroup. Table:Adjustedhazardratios(HR)with%confidenceintervals(CI)foranyCVD,fatal CVD,anyacidosis/seriousinfection,fatalacidosis/seriousinfection,andallcausemortalityin allpatients,ineachtreatmentgroup,andwithmetforminonlyasreference.adjustments weremadeforage,sex,diabetesduration,hbac,nonhdlc,bmi,smoking,egfr,multi dosedispensation,previoushospitalization,historyofcvdandchf,microalbuminuria,and treatmentwithantihypertensiveagents,lipidloweringagentsandcardiacglycosides. Table:Numbersandfrequencies(%)ofendpointeventsineachtreatmentgroup.!! Table:Adjustedhazardratioswith%confidenceintervalsforanyCVD,fatalCVD,any acidosis/seriousinfection,fatalacidosis/seriousinfection,andallcausemortalityinpatients withinsulinonlyandpatientswithmetforminonlyasreference,orinpatientswithother OHAonlyandpatientswithmetforminonlyasreference.Eachcomparisonwasadjustedby stratificationwithoctilesofpropensityscores.! Table:Adjustedhazardratios(HR)with%confidenceintervalsforanyCVD,any acidosis/seriousinfection,andallcausemortalityinsubgroupsofpatientswithdifferent egfrintervals.hrassociatedwiththeexaminedagentinanycombinationisgivenwithany otherglucoseloweringtreatmentasreference.adjustmentsweremadeforage,sex, diabetesduration,hbac,nonhdlc,bmi,smoking,egfr,multidosedispensation, previoushospitalization,historyofcvdandchf,microalbuminuria,andtreatmentwith antihypertensiveagents,lipidloweringagentsandcardiacglycosides.!! - : first published as 0./bmjopen on July 0. Downloaded from on April 0 by guest. Protected by copyright.

19 Page of Figure:Time(months)toeventofallcausemortality(a),anyCVD(b),andany acidosis/seriousinfection(c)ineachtreatmentgroup,unadjusted. AppendixTable:Baselinecharacteristicsingroupsofpatientstreatedwithmetforminonly, insulinonly,orotherohaonly,appliedincoxregressionanalysespresentedintable. Means±standarddeviation(SD)andproportions(%)ofclinicalvariablesatbaseline.P valuesaregivenforcomparisonbetweenmetforminonlyandinsulinonly,andbetween metforminonlyandotherohaonly,unadjustedandafteradjustmentbystratificationfor octilesofpropensityscoresappliedforeachcomparison. AppendixFigure:Enrollmentofpatients.! - : first published as 0./bmjopen on July 0. Downloaded from on April 0 by guest. Protected by copyright.

20 Page of References. ZimmetP,AlbertiKG,ShawJ.Globalandsocietalimplicationsofthediabetes epidemic.nature.00;:.. Effectofintensivebloodglucosecontrolwithmetforminoncomplicationsin overweightpatientswithtypediabetes(ukpds).ukprospectivediabetesstudy (UKPDS)Group.Lancet.;:.. HolmanRR,PaulSK,BethelMA,etal.0yearfollowupofintensiveglucose controlintypediabetes.nengljmed.00;:.. KahnSE,HaffnerSM,HeiseMA,etal.Glycemicdurabilityofrosiglitazone, metformin,orglyburidemonotherapy.nengljmed.00;:.. KooyA,deJagerJ,LehertP,etal.Longtermeffectsofmetforminon metabolismandmicrovascularandmacrovasculardiseaseinpatientswithtypediabetes mellitus.archinternmed.00;:.. NathanDM,BuseJB,DavidsonMB,etal.Medicalmanagementof hyperglycemiaintypediabetes:aconsensusalgorithmfortheinitiationandadjustmentof therapy:aconsensusstatementoftheamericandiabetesassociationandtheeuropean AssociationfortheStudyofDiabetes.DiabetesCare.00;:0.. HandelsmanY,MechanickJI,BlondeL,etal.AmericanAssociationofClinical EndocrinologistsMedicalGuidelinesforClinicalPracticefordevelopingadiabetesmellitus comprehensivecareplan.endocrpract.0;suppl:.. TypeDiabetes:NationalClinicalGuidelineforManagementinPrimaryand SecondaryCare(Update).London:RoyalCollegeofPhysiciansofLondon.;00.. Nationalguidelinesfordiabetescare.00[cited0June,];Available from: 0. BaileyCJ,TurnerRC.Metformin.NEnglJMed.;:.. IsomaaB,AlmgrenP,TuomiT,etal.Cardiovascularmorbidityandmortality associatedwiththemetabolicsyndrome.diabetescare.00;:.. SalpeterSR,GreyberE,PasternakGA,etal.Riskoffatalandnonfatallactic acidosiswithmetforminuseintypediabetesmellitus.cochranedatabasesystrev. 00:CD00.! - : first published as 0./bmjopen on July 0. Downloaded from on April 0 by guest. Protected by copyright.

21 Page 0 of EurichDT,McAlisterFA,BlackburnDF,etal.Benefitsandharmsofantidiabetic agentsinpatientswithdiabetesandheartfailure:systematicreview.bmj.00;:.. RousselR,TravertF,PasquetB,etal.Metforminuseandmortalityamong patientswithdiabetesandatherothrombosis.archinternmed.00;0:.. WettermarkB,HammarN,ForedCM,etal.ThenewSwedishPrescribedDrug Registeropportunitiesforpharmacoepidemiologicalresearchandexperiencefromthefirst sixmonths.pharmacoepidemioldrugsaf.00;:.. MerloJ,LindbladU,PessahRasmussenH,etal.Comparisonofdifferent procedurestoidentifyprobablecasesofmyocardialinfarctionandstrokeintwoswedish prospectivecohortstudiesusinglocalandnationalroutineregisters.eurjepidemiol. 000;:.. TunstallPedoeH,KuulasmaaK,AmouyelP,etal.Myocardialinfarctionand coronarydeathsintheworldhealthorganizationmonicaproject.registrationprocedures, eventrates,andcasefatalityratesinpopulationsfromcountriesinfourcontinents. Circulation.;0:.. EegOlofssonK,CederholmJ,NilssonPM,etal.Riskofcardiovasculardisease andmortalityinoverweightandobesepatientswithtypediabetes:anobservationalstudy in,0patients.diabetologia.00;:.. EegOlofssonK,CederholmJ,NilssonPM,etal.Glycemiccontroland cardiovasculardiseasein,patientswithtypediabetes:anobservationalstudyfrom theswedishnationaldiabetesregister(ndr).diabetescare.00;:0. 0. EliassonB,SvenssonAM,MiftarajM,etal.Clinicaluseandeffectivenessof lipidloweringtherapiesindiabetesmellitusanobservationalstudyfromtheswedish nationaldiabetesregister.plosone.0;:e.. LindM,BouniasI,OlssonM,etal.Glycaemiccontrolandincidenceofheart failurein0patientswithtypediabetes:anobservationalstudy.lancet.0.. HoelzelW,WeykampC,JeppssonJO,etal.IFCCreferencesystemfor measurementofhemoglobinacinhumanbloodandthenationalstandardizationschemes intheunitedstates,japan,andsweden:amethodcomparisonstudy.clinchem. 00;0:.! - : first published as 0./bmjopen on July 0. Downloaded from on April 0 by guest. Protected by copyright.

22 Page of LeveyAS,BoschJP,LewisJB,etal.Amoreaccuratemethodtoestimate glomerularfiltrationratefromserumcreatinine:anewpredictionequation.modificationof DietinRenalDiseaseStudyGroup.AnnInternMed.;0:0.. LeeBK,LesslerJ,StuartEA.Improvingpropensityscoreweightingusing machinelearning.statisticsinmedicine.00;:.. LINDY,WEILJ,YINGZ.CheckingtheCoxmodelwithcumulativesumsof martingalebasedresiduals.biometrika.;0:.. CollettD.Modellingsurvivaldatainmedicalresearch.ed.BocaRaton:CRC press;00.. GRAMBSCHPM,THERNEAUTM.Proportionalhazardstestsanddiagnostics basedonweightedresiduals.biometrika.;:.. ColaycoDC,NiuF,McCombsJS,etal.ACandcardiovascularoutcomesintype diabetes:anestedcasecontrolstudy.diabetescare.0;:.. MargolisDJ,HoffstadO,StromBL.Associationbetweenseriousischemic cardiacoutcomesandmedicationsusedtotreatdiabetes.pharmacoepidemioldrugsaf. 00;:. 0. CurrieCJ,PetersJR,TynanA,etal.SurvivalasafunctionofHbA(c)inpeople withtypediabetes:aretrospectivecohortstudy.lancet.00;:.. GambleJM,SimpsonSH,EurichDT,etal.Insulinuseandincreasedriskof mortalityintypediabetes:acohortstudy.diabetesobesmetab.00;:.. MellbinLG,MalmbergK,NorhammarA,etal.Theimpactofglucoselowering treatmentonlongtermprognosisinpatientswithtypediabetesandmyocardial infarction:areportfromthedigamitrial.eurheartj.00;:.. MellbinLG,MalmbergK,NorhammarA,etal.Prognosticimplicationsof glucoseloweringtreatmentinpatientswithacutemyocardialinfarctionanddiabetes: experiencesfromanextendedfollowupofthediabetesmellitusinsulinglucoseinfusionin AcuteMyocardialInfarction(DIGAMI)Study.Diabetologia.0;:0.. MalmbergK,RydenL,WedelH,etal.Intensemetaboliccontrolbymeansof insulininpatientswithdiabetesmellitusandacutemyocardialinfarction(digami):effects onmortalityandmorbidity.eurheartj.00;:0.. MalmbergK,RydenL,EfendicS,etal.Randomizedtrialofinsulinglucose infusionfollowedbysubcutaneousinsulintreatmentindiabeticpatientswithacute! : first published as 0./bmjopen on July 0. Downloaded from on April 0 by guest. Protected by copyright.

23 Page of myocardialinfarction(digamistudy):effectsonmortalityatyear.jamcollcardiol. ;:.. EegOlofssonK,CederholmJ,NilssonPM,etal.NewaspectsofHbAcasarisk factorforcardiovasculardiseasesintypediabetes:anobservationalstudyfromthe SwedishNationalDiabetesRegister(NDR).JInternMed.00;:.. GersteinH,YusufS,RiddleMC,etal.Rationale,design,andbaseline characteristicsforalargeinternationaltrialofcardiovasculardiseasepreventioninpeople withdysglycemia:theorigintrial(outcomereductionwithaninitialglargine Intervention).AmHeartJ.00;:,e.. ChanNN,BrainHP,FeherMD.Metforminassociatedlacticacidosis:arareor veryrareclinicalentity?diabetmed.;:.! - : first published as 0./bmjopen on July 0. Downloaded from on April 0 by guest. Protected by copyright.

24 Page of Table.Baselinecharacteristicsinall,typediabetespatientsandingroupsbasedonglucose<loweringtreatments.! Metformin!Only! Means±onestandarddeviation(SD)andfrequencies(%)aregiven.Therewerestatisticallysignificantdifferences(p<0.00)inallvariables betweenthegroups. Metformin!+! other!oha! Metformin!+! insulin!!!insulin!only!!other!oha!only! Insulin!+!! other!oha! Metformin!+! insulin!+!other! OHA!! N (%) 0(%) 0(%) (%) (0%) (.%) (.%) (00%) Age(Years).(.).(.).(.).(0.).(.).(.).(.).(.) HbAc(%).(.).(.).(.).(.).(.0).(.).(.).(.) <. (.%) (.%) 0(.%) (.%) (.0%) (.%) (.%) 0(.0%).<. 0(.%) (.%) 0(.%) 0(.%) (.%) (.%) (.%) (.%) >. (.%) (.0%) (.%) (.%) (.%) (.%) (.%) (.%) Systolicbloodpressure (mmhg).(.).(.) 0.(.).(.0).(.).(.).(.) 0.(.) Diabetesduration (Years).(.).(.).(.0).(0.).(.).(.).0(.).(.0) egfr(ml/min/.m ).0(0.) 0.(.).(.).(.).(.).(.).(.).(.) < (.%) (.%) (.%) 0(.%) 0(.%) (.%) (.%) (.%) <0 (0.%) (.%) 0(.%) (.%) (.%) (.%) (.%) (.%) >0 (.%) (.%) (.%) (.%) (.0%) (.%) (.0%) (0.%) BMI(Kg/m ) 0.(.).(.).(.0).(.).(.).(.).(.).(.) Non<HDL<C(mmol/L).(.00).(0.).(0.).(0.).0(0.).(.0).(0.).0(0.) Microalbuminuria.0%.%.% 0.%.%.%.%.% Previoushospitalisation.%.%.%.%.%.%.%.% Femalesex.% 0.0%.% 0.%.%.%.%.% HistoryofCVD.%.%.%.%.% 0.%.%.% HistoryofCHF.%.%.%.%.% 0.%.%.% Historyofserious infections.%.%.%.%.%.%.%.% Cardiacglycosides.%.%.%.0%.%.%.%.% Organicnitrates.%.%.%.%.%.0% 0.%.% ASA.%.%.%.%.%.%.%.% Lipidmodifyingagents.%.0%.%.%.%.%.%.% Antihypertensiveagents.%.0%.%.%.%.%.0%.% Multi<dosedispensation.%.%.%.0%.%.%.%.% Smoker.%.0%.%.%.%.%.%.0% - on July 0. Downloaded from on April 0 by guest. Protected by copyright. Total!

25 Table:Timeofexposure(months)tospecificglucose<loweringagents,andproportionschangingtreatment(%)ineachgroup. MeanExposuretimeto metformin MeanExposuretimetoinsulin MeanExposuretimetoOther Oral Metformin! Only! Metformin!+!! other!oha!,,0, Metformin!+! insulin! Insulin!only! Other!OHA! only! Insulin!+!! other!oha!,,,, Metformin!+!! insulin!+!other!oha!!,,,,, Changetreatment(%) 0.% 0.%.%.%.%.%.% - on July 0. Downloaded from on April 0 by guest. Protected by copyright. Page of

26 Page of Table.Adjustedhazardratios(HR)with%confidenceintervals(CI)foranyCVD,fatalCVD,anyacidosis/seriousinfection,fatal acidosis/seriousinfection,andall<causemortalityinallpatients,ineachtreatmentgroup,andwithmetforminonlyasreference * P<0.0 ** P<0.0 *** P<0.00 *Non<proportionalhazards,groupexcludedfromanalysis. Metformin! only! Insulin! only! Other!OHA! only! Insulin!+! other!oha! Metformin!+!! other!oha! Metformin!+!! insulin! Metformin!+! Insulin!+!other!OHA! AnyCVD Reference.(.<.) ***.(.0<.) **.0(.<.) ***.(.0<.0) **.(.<.) ***.(.<.) *** FatalCVD Reference.(.<.) ***.0(.0<.) **.(0.<.) * *.(0.<.) Acidosis/serious infection Fatalacidosis/serious infection Reference,(,<,0) ***,(,0<,) **,(,<,) ***,0(0,<,),0(,0<,) ***,(.00<,)* Reference,(,<,0) ***,(0,<,),(0,<,) 0,(0,<,),(,0<,) *,(0,<,) All<causemortality Reference.(.<.) ***.0(.<.) ***.0(.<.0) ***.(.0<.) **.(.<.) ***.(.<.) *** - on July 0. Downloaded from on April 0 by guest. Protected by copyright.

27 Table:Numbersandfrequencies(%)ofendpointeventsineachtreatmentgroup. Metformin!Only! Metformin!+! other!oha! Metformin!+! insulin! Insulin!only! Other!OHA!only! Insulin!+! other!oha! Metformin+! insulin!+! other!oha!! AnyCVD (.%) (%) (.%) (.%) (.%) (.%) (.%) FatalCVD (0.%) 0(0.%) (%) (.%) (.%) (.%) (0.%) Acidosis/seriousinfection (.%) (.%) (.%) (.%) (.%) (%) (.%) Fatalacidosis/serious infection (0.%) (0.%) (0.%) (0.%) 0(0.%) (0.%) (0.%) All<causemortality (.%) (.%) (.%) 00(.%) (.%) (.%) 0(.%) - on July 0. Downloaded from on April 0 by guest. Protected by copyright. Page of

28 Page of Table.Adjustedhazardratioswith%confidenceintervalsforanyCVD,fatalCVD,anyacidosis/seriousinfection,fatalacidosis/serious infection,andall<causemortalityinpatientswithinsulinonlyandpatientswithmetforminonlyasreference,orinpatientswithotherohaonly andpatientswithmetforminonlyasreference Eachcomparisonwasadjustedbystratificationwithoctilesofpropensityscores. Events/Patients N/N Events/Patients N/N Hazardratio (%CI) Insulin!only! Metformin!only! Insulin!Vs!metformin! P<value Fatal/nonfatalCVD / /.(.0<.) <0.00 FatalCVD / /.(0.<.0) 0. All<causemortality 00/ /.(.<.0) <0.00 Acidosis/seriousinfection /0 /.(.<.) <0.00 Fatalacidosis/seriousinfection / /.(.0<.) 0.0 Other!OHA! Metformin!only! Other!OHA!Vs!metformin! Fatal/nonfatalCVD / /.0(0.<.) 0. FatalCVD / /.0(0.<.) 0.0 All<causemortality / /.(.0<.) 0.0 Acidosis/seriousinfection /0 /.0(0.<.) 0. Fatalacidosis/seriousinfection 0/ /.(0.<.) on July 0. Downloaded from on April 0 by guest. Protected by copyright.

29 Table.Adjustedhazardratios(HR)with%confidenceintervalsforanyCVD,anyacidosis/seriousinfection,andall<causemortalityin subgroupsofpatientswithdifferentegfrintervals.hrassociatedwiththeexaminedagentinanycombinationisgivenwithanyotherglucose< loweringtreatmentasreference. * P<0.0 ** P<0.0! 0!<=!eGFR!<!!!<=!eGFR!<!0! egfr!>=!0! All!patients!! *** P<0.00 *Non<proportionalhazards,groupexcludedfromanalysis. Adjustmentsweremadeforage,sex,diabetesduration,HbAc,non<HDL<C,BMI,smoking,eGFR,multi<dosedispensation,previous hospitalization,historyofcvdandchf,microalbuminuria,andtreatmentwithantihypertensiveagents,lipidloweringagentsandcardiac glycosides. N!! (%!of!total)!!!events!!!(%!of!total)! HR!! (!%!CI)!!N!!!(%!of!total)!!!Events!!!(%!of!total)! HR!! (!%!CI)! Any!CVD! N!! (%!of!total)!!!events!!!(%!of!total)! HR!! (!%!CI)! N! Events! Metformin! 0(.%)! 0(0.%)!.00(0.<.)! (.%)! (.%)! 0.(0.<.0)! 0(.%)! (.%)! 0.(0.<.0)!!! Insulin! 0(.%)! (.%)!.0(.0<.) *! 0(.%)! 0(.%)!.(.0<.) **! (.%)! (.%)!.(.<.) ***! 0!! Other!OHA! 0(.%)! (.%)!.0(0.<.)! 0(.%)! 0(.%)!.0(0.<.)! (.%)! 0(.%)!.0(0.<.0)!!! Total!in!group!!!!!!! 0!!!!! Any!acidosis/serious!infection! Metformin! (.%)! (.%)! 0.(0.<.)! 000(.%)! (.%)! 0.(0.<0.) *! (.%)! (0.%)! 0.(0.<0.) *!!! Insulin! 0(.%)! (.%)!.(.0<.) *! 0(.%)! (.%)!.0(0.<.! (.%)! 0(%)!.(.<.) ***! 0! 0! Other!OHA! (.%)! (.%)! *! (.%)! (.%)! 0.(0.<.00)! (.%)! (.%)!.0(0.<.0)!! 0! Total!in!group! 0! 0!! 0!!! 0! 0!!!! AllUcause!mortality! Metformin! (.%)! (%)!.0(0.<.)! 0(.%)! (.%)! 0.(0.<0.) *! 0(.%)! 0(.%)! 0.(0.<0.) ***!!! Insulin! (.%)! (0.%)!.(0.<.)! 0(.%)! 0(.%)!.(0.<.)! (.%)! (.%)!.(.<.) ***! 000!! Other!OHA! (.%)! (.%)! 0.(0.<.)! (.%)! (.%)! 0.(0.<.)! 0(.%)! (.%)!.0(.0<.) *!! 0! Total!in!group!!!!! 0!!!!!!! - on July 0. Downloaded from on April 0 by guest. Protected by copyright. Page of

30 Page of Figure. Time!(months)!to!event!of!allcause!mortality!(a),!any!CVD!(b),!and!any!infecon/acidosis!(c)!in!each!treatment!group,!unadjusted!! a.!allcause!mortality!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!b.!any!cvd Survival,00 0, 0,0 0, 0,0 0 Months! c.!any!acidosis/infecon Survival,00 0, 0,0 0, 0, Survival Functions 0 Months Metformin Only Metformin + other OHA Metformin + Insulin Metformin + Insulin + other OHA Other OHA only Insulin only Insulin + other OHA Metformin Only Metformin + other OHA OHA Other OHA only Metformin + Insulin Insulin only Insulin + other OHA Survival,00 0, 0,0 0, 0,0 0, 0, Months - /bmjopen on July 0. Downloaded from on April 0 by guest. Protected by copyright. 0 0 Metformin Only Metformin + other OHA Other OHA only OHA Metformin + Insulin Insulin only Insulin + other OHA!!!!!!!

31 Page 0 of Appendix Figure. Enrollment of paents DM (*) paents were registered in NDR between st July, - 0 and st December, - 0. Of those, paents were on glucose- lowering medicaon (A0), starng before the year of 00. Of those, paents were between 0 and years old at the me of the first prescripon. Of those, 0 paents had filled at least three prescripons or mul- dose dispensaons in one year. Of those, paents were registered in the NDR ± year from first prescripon, and survived from first prescripon unl baseline. Of those, paents had complete records of all covariates, and were included in the study. * DM is Type Diabetes Mellitus paents were excluded due to non- pharmacological diabetes treatment. paents were excluded because they did not meet the criteria for age. paents were excluded because they did not meet the crieria for connuous medicaon. paents were excluded because they did not meet the criteria registraon and survival unl baseline. paents were excluded because they did not present complete records of all covariates. : first published as 0./bmjopen on July 0. Downloaded from on April 0 by guest. Protected by copyright. -

32 Page of AppendixTable.Baselinecharacteristicsingroupsofpatientstreatedwithmetforminonly,insulinonly,orotherOHAonly,appliedinCox regressionanalysespresentedintable. Means±standarddeviation(SD)andproportions(%)ofclinicalvariablesatbaseline.Pvaluesaregivenforcomparisonbetweenmetforminonly andinsulinonly,andbetweenmetforminonlyandotherohaonly,unadjustedandafteradjustmentbystratificationforoctilesofpropensity scoresappliedforeachcomparison. Metformin!Only! Insulin!only! Other!OHA!only! P!metformin!only/! insulin!only! Unadjusted! P!metformin!only/! insulin!only! Adjusted!for!PS! P!metformin!only/! other!oha!only! Unadjusted! N Age(Years).(.).(0.).(.) < < HbAc(%).(0.) 0.0(.).(.) < Systolicbloodpressure (mmhg).(.).(.0).(.) < Diabetesduration(Years).(.).(0.).(.) < < egfr(ml/min/.m ).0(0.).(.).(.) < < BMI(Kg/m ) 0.(.).(.).(.) < < Non<HDL<C(mmol/L).(.00).(0.).0(0.) < Microalbuminuria.0% 0.%.% < < Previoushospitalisation.%.%.% < < Femalesex.% 0.%.% < < HistoryofCVD.%.%.% < < HistoryofCHF.%.%.% < < Historyofserious infections.%.%.% < < Cardiacglycosides.%.0%.% < Organicnitrates.%.%.% < < ASA.%.%.% Lipidmodifyingagents.%.%.% < < Antihypertensiveagents.%.%.% < Multi<dosedispensation.%.0%.% < Smoker.%.%.% < on July 0. Downloaded from on April 0 by guest. Protected by copyright. P!metformin!only/! other!oha!only! Adjusted!for!PS!

33 Page of Definitions of the endpoints (Appendix Text) Cardiovascular disease (CVD) CVD was defined as diagnosis of myocardial infarction (ICD- 0 code I), angina pectoris (ICD- 0 code I0.0), intracerebral haemorrhage, cerebral infarction, unspecified stroke (ICD- 0 codes I, I, I and I), peripheral vascular disease (PVD, ICD- 0 codes E0, E, E, I0, I, I and I), or intervention with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG), whichever occurred first. Acidosis/serious infection Acidosis/infection was defined as diagnosis of acidosis or chock (ICD- 0 codes E0., E0.A, E0.D, E0.X, E., E.A, E.D, E.X, E., E., E., R., R., R. or R., or diagnosis of serious infection (ICD- 0 codes A00- A0, A- A, A., A- A, A., A, B., I00- I0, I, I, I, J- J, J, J, K, K, K0.0, K0., K0., K, K.0, K, K, M00, M., M., M.0, M., M. or M. or acute renal failure (ICD- 0 codes N0. or N. : first published as 0./bmjopen on July 0. Downloaded from on April 0 by guest. Protected by copyright. -

34 Effectiveness and safety of metformin in patients with type diabetes and different levels of renal function: A cohort study from the Swedish National Diabetes Register Journal: Manuscript ID: bmjopen r Article Type: Research Date Submitted by the Author: 0-May-0 Complete List of Authors: Ekström, Nils; University of Gothenburg, Department of Medicine Schiöler, Linus; Center of Registers in Region Västra Götaland, ; University of Gothenburg, Department of Public Health and Community Medicine Svensson, Ann-Marie; Center of Registers in Region Västra Götaland, Eeg-Olofsson, Katarina; University of Gothenburg, Department of Medicine Miao Jonasson, Junmei; Center of Registers in Region Västra Götaland, Zethelius, Bjorn.; Uppsala University, Public Health/Geriatrics Cederholm, Jan; Uppsala University, Department of Public Health and Caring Sciences / Family Medicine and Clinical Epidemiology Eliasson, Björn; University of Gothenburg, Department of Medicine Gudbjörnsdottir, Soffia; University of Gothenburg, Department of Medicine; Center of Registers in Region Västra Götaland, <b>primary Subject Heading</b>: Diabetes and endocrinology Secondary Subject Heading: Epidemiology, Pharmacology and therapeutics, Cardiovascular medicine Keywords: Diabetes endocrinology < INTERNAL MEDICINE, EPIDEMIOLOGY, THERAPEUTICS, Vascular medicine < INTERNAL MEDICINE, Adverse events < THERAPEUTICS : first published as 0./bmjopen on July 0. Downloaded from on April 0 by guest. Protected by copyright. -