class update: sodium-glucose cotransporter 2 (sglt2 ... · sglt2 inhibitors are the newest class of...

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Author:KathySentena,Pharm.D. Date:January2016

ClassUpdate:Sodium-glucoseCotransporter2(SGLT2)InhibitorsDateofReview:January2016 DateofLastReview:September2015 CurrentStatusofPDLClass:Non-preferredSeeAppendix1. PurposeforClassUpdate:Thesodium-glucosecotransporter2(SGLT2)inhibitorclasswasupdatedinSeptemberaspartofthenon-insulinantidiabeticagentclassreview.NewevidenceonthecardiovasculareffectsofSGLT2inhibitor,empagliflozin,hasbecomeavailable,promptingaclassupdate.ThegoalofthisreviewistoevaluateupdatedevidenceforSGLT2inhibitorsanddetermineifchangesrelatedtocurrentpriorauthorization(PA)criteriatheOregonHealthPlan(OHP)PreferredDrugList(PDL)areneeded.ResearchQuestions:1. IsthereanynewcomparativeevidenceforSGLT2inhibitorspertainingtocardiovascular(CV)benefitsorotherimportantoutcomes(e.g.microvascular,

macrovascularandmortality)?2. IsthereanynewevidenceofcomparativeharmsbetweenSGLT2inhibitorsandothernon-insulinantidiabetictreatments?3. Aretheresubgroupsofpatientswithtype2diabetes(T2DM)whichtheSGLT2inhibitorsmaybemoreeffectiveorassociatedwithlessharm?4. DoesnewevidencenecessitatechangestothePDLorPAcriteriapertainingtotheSGLT2inhibitorclass?Conclusions:• OnerandomizedcontrolledtrialandtwoFoodandDrugAdministration(FDA)safetyupdateshavebeenpublishedsincethelastreview.Therearenonew

systematicreviewsorguidelines.1,2• Inpatientswithahistoryofcardiovasculardisease,therewasmoderatestrengthofevidencethatempagliflozin(pooleddatafrom10mgand25mgdoses)

decreasedtheprimarycompositecardiovascularendpoint(CVdeath,non-fatalmyocardialinfarction[MI],ornon-fatalstroke)withanumberneededtotreat(NNT)of63over3.1years(hazardratio[HR]0.86;95.02%CI,0.74to0.99;P<0.001fornoninferiority;p=0.04forsuperiority).1ReductionintheprimaryendpointwasaresultofasignificantreductioninCVdeath,astherewerenostatisticallysignificantdifferencesbetweenempagliflozinandplaceboinincidenceofnon-fatalMIornon-fatalstroke.Mortalitybenefitswereseenasearlyas3months,whichsuggeststhisoutcomewasnotaresultofreductioninglucose,bloodpressureorweight.Additionally,MIandstrokerateswereunaffected,whichsuggestspossiblecardiovascularbenefitfromthediureticeffectofempagliflozin.ThistheoryissupportedbythereductioninhospitalizationsrelatedtoheartfailureandCVdeath(excludingfatalstroke)observedwithempagliflozin.Nodose-responseeffectofempagliflozinwasobserved,therefore,the10mgdoseisrecommendedformostpatients.Seventy-eightpercentofpatientswereonadditionalantidiabetictherapy,mostcommonlymetformin,insulinandsulfonylureas,74%,48%and43%,respectively.

Author:KathySentena,Pharm.D. Date:January2016

• EmpagliflozinisthefirstdiabetesdrugtoshowCVriskreductioninanadequatelypoweredrandomizedcontrolledtrail(RCT);however,itisunknowniftheriskreductionwouldalsobeseeninT2DMpatientswithoutpreexistingCVdisease.Asystematicreviewandmeta-analysisofdapagliflozinandcanagliflozinstudiesdemonstratedinconclusivefindingsontheeffectofSGLT2inhibitorsoncardiovascularoutcomes(OR0.89;95%CI,0.70to1.14).4ResultsfromongoingstudieswithcanagliflozinanddapagliflozinwillhelptodetermineifthebenefitsseenwithempagliflozinisaSGLT2inhibitorclasseffect,whichislikelybasedonsimilarmechanismofactions,orifitisuniquelyspecifictoempagliflozin.5,6

• Therewasanonsignificantincreaseintherateofnonfatalstrokesinempagliflozin-treatedpatients,whichwarrantsfurtherinvestigation.1AnFDAanalysisreportedhighernonfatalstrokerateswithcanagliflozin,anotherSGLT2inhibitor,comparedtocontrols(HR1.46;95%CI0.83to2.58)4Canagliflozinhasalsobeenassociatedwithincreasedbonefractureratesandthelong-termeffectofSGLT2inhibitorsonbonedensityisstillunknown.2

• Thereishighstrengthofevidencethatgenitalinfectionsaremorecommonwithempagliflozincomparedtoplacebo(6.4%vs.1.8%,respectively(p<0.001).1,4Incidenceofhypoglycemia,bonefracturesandvolumedepletionweresimilarbetweenempagliflozinandplacebotreatedpatients.1

• SGLT2inhibitorsareconsideredasecond-lineoptionbytheAmericanDiabetesAssociation(ADA).7TheAmericanAssociationofClinicalEndocrinologists(AACE)andAmericanCollegeofEndocrinology(ACE)recommendsthemasanoptionforpatientspresentingwithalllevelsofA1C.8,9TheNationalInstituteforHealthandCareExcellence(NICE)recommendsempagliflozinandcanagliflozinfordualtherapyifasulfonylurea(SU)iscontraindicatedandasathirdagentinpatientsalreadytakingmetforminandaSU.10,11

Recommendations:• ModifycurrentPAcriteriatoallowuseofSGLT2inhibitorsasathirdlineoptionbehindmetforminandsulfonylureas(Appendix4).• NochangestothePDLarerecommendeduntilresultsoftrialsfromotherSGLT2inhibitorscanagliflozinanddapagliflozinareavailable.PreviousConclusions:• Thereisinsufficientnewcomparativeevidenceforefficacy/effectivenessondifferencesofmicrovascularoutcomes(retinopathy,nephropathyand

neuropathy)betweendifferenttreatmentsfortype2diabetesmellitus(T2DM).12Evidence-basedrecommendationsinnewclinicalpracticeguidelinesfromtheAmericanDiabetesAssociation(ADA),InstituteforClinicalSystemsImprovement(ICIS),andtheNationalInstituteforHealthandCareExcellence(NICE),

AmericanAssociationofClinicalEndocrinologists(AACE)andAmericanCollegeofEndocrinology(ACE)andasystematicreviewdraftreportfromtheAgencyforHealthcareResearchandQuality(AHRQ),supportthecurrentstatusofnon-insulinantidiabetictherapiesonthepreferreddruglist(PDL).12

• Highqualityevidencesuggestpatientsonmetformin,pioglitazone,metforminplusadipeptidylpeptidase-4(DPP-4)inhibitor,ormetforminplusaSGLT-2inhibitorhavesimilarratesofall-causemortality,basedononesystematicreview.12

• Thereishighqualityevidencethatmonotherapywitheithermetformin,athiazolidinedione(TZD)orasulfonylurea(SU)resultsinsimilarloweringofA1Cbasedononesystematicreview.12

• ThereismoderatequalityevidencethatDPP-4inhibitorslowerA1Clessthanmetforminandglimepiridebasedontwosystematicreviews(oneforeach• comparison).12• Moderatequalityevidence,fromonefairandonegoodqualitytrial,suggeststhatDPP-4inhibitorsdonotreducemajorCVoutcomescomparedto

placebo.12DatafromtheEXAMINEandTECOSfoundthesedrugstobenon-inferiortoplacebowhenacompositeofCVoutcomeswereevaluated.12• Moderatequalityevidencefromtwometa-analysesshowedastatisticallysignificantincreaseinHFoutcomeswithDPP-4inhibitorscomparedtoplaceboor

activetreatment.12Studiesincludedinthemeta-analyseswereofshortdurationandthemajorityofincludedoutcomeswerelimitedto2trialsonly[SAVORTIMI53(saxagliptin)andEXAMINE(alogliptin)].12

Author:KathySentena,Pharm.D. Date:January2016

• HighqualityevidencesuggesthypoglycemiaratesarehigherwithSUthancomparativeT2DMtherapybasedontwosystematicreviews.12• Evidencefromarecentsystematicreviewandmeta-analysisfoundglyburidetobeassociatedwithatleastoneepisodeofhypoglycemiacomparedto

secretagogues[relativerisk(RR)1.52,95%CI1.21to1.92]andcomparedtootherSUs(RR1.83,95%CI1.35to2.49).12• Thereislowqualityevidencetorecommendmetforminuseinpatientswithmildtomoderatekidneydiseasebasedononesystematicreview.Evidence

fromthisreviewsuggestsmetforminissafeinpatientswithmildtomoderatechronickidneydisease(eGFR>30-60mL/minper1.73m2)withoutincreasedriskoflacticacidosis,basedonevidencefromprimarilynon-clinicaltrialdata.ThefrequencyoflacticacidosisinthesettingofmetformintherapyisverylowandnumericallysimilartowhatappearstobethebackgroundrateinthepopulationwithT2DM.12

• InDecemberof2014liraglutideinjection(Saxenda)wasapprovedforchronicweightmanagementinadditiontoareduced-caloriedietandphysicalactivity.TreatmentsforweightlossarenotfundedbytheOHP.12

PreviousRecommendations:• Makeexenatide(Byetta®)apreferredagentbutsubjecttocurrentpriorauthorization(PA)forGLP1receptorantagonists.• Makeempagliflozin/linagliptin(Glyxambi®)non-preferreddrugsubjecttocurrentPAforSGLT-2inhibitors.• ReorganizePDLclassesfornon-insulinantidiabeticagentstothefollowing:

o DPP-4Inhibitorso GLP-1ReceptorAntagonistso MiscellaneousAntidiabeticAgents(metformin,pramlintide,meglitinides,others).o SGLT-2Inhibitorso Sulfonylureaso Thiazolidinediones

• RemoveclinicalPAforpramlintideduetolowoverallutilizationandcurrentFDA-mandatedRiskEvaluationMitigationStrategy(REMS)alreadyinplacetopromotesafeusethrougheducation.

• ModifySGLT-2inhibitorclinicalPAtorequiremonitoringrenalfunctionevery6months.• ContinueclinicalPAcriteriaforallDPP-4inhibitorsandallGLP-1RAs.

Background:SGLT2inhibitorsarethenewestclassofantidiabeticagentsforpatientswithT2DM.SGLT2inhibitorsincreaseurinaryglucoseexcretionbydecreasingrenalabsorptionofglucose.13Becauseoftheirmechanismofaction,SGLT2inhibitorsposelowriskforhypoglycemiabutincreasethelikelihoodofurinarytractandgenitalinfections.AdditionalbenefitsofSGLT2inhibitorsareweightlossandreducedbloodpressure,likelythroughtheirdiureticeffect.SGLT2inhibitorsareassociatedwithmodestA1Cloweringofapproximately0.5%inplacebo-controlledcomparisons.14TherearecurrentlythreeSGLT2inhibitorsavailable,offeredasmonotherapyorincombinationformulationswithmetformin:canagliflozin(Invokana),dapagliflozin(Farxiga),andempagliflozin(Jardiance).Cardiovasculardiseaseistheprimarycomplicationinpatientswithdiabetesmellitus(DM).15ItiswelldocumentedthatloweringA1Cisassociatedwithreducedmicrovascularoutcomes,howevertheevidenceformacrovascularbenefitsareuncertain.Additionally,someantidiabetictherapieshavebeenassociatedwithadditionalCVrisk,promptingtheFDAtorequirestudiestoevaluatetheimpactofnewantidiabetictherapiesoncardiovascularoutcomes.EvidencesuggestsmetforminislikelytoreducetheincidenceofCVDbasedondatafromtheUnitedKingdomProspectiveDiabetesStudy(UKPDS).7TheTECOStrial(DPP-4

Author:KathySentena,Pharm.D. Date:January2016

inhibitors)andELIXAstudy(GLP-1agonists)haveshownaneutralimpactoncardiovascularmarkers.16,17Thisreviewwillfocusontherecentevidenceonthebenefitsofempagliflozinoncardiovascularoutcomes.Twoadditionaltrialsareunderwaywithcanagliflozin(CANVAS)anddapagliflozin(DECLARE)todeterminethecardiovascularimpactofthesetherapies.5,6ThesestudieswillprovidevaluableevidenceonhowtobestmanagetheincreasedriskofCVdiseaseseeninpatientswithT2DM.Methods:AMedlineliteraturesearchfornewsystematicreviewsandrandomizedcontrolledtrials(RCTs)assessingclinicallyrelevantoutcomestoactivecontrols,orplaceboifneeded,wasconducted.TheMedlinesearchstrategyusedforthisreviewisavailableinAppendix3,whichincludesdates,searchtermsandlimitsused.TheOHSUDrugEffectivenessReviewProject,AgencyforHealthcareResearchandQuality(AHRQ),CochraneCollection,NationalInstituteforHealthandClinicalExcellence(NICE),DepartmentofVeteransAffairs,BMJClinicalEvidence,andtheCanadianAgencyforDrugsandTechnologiesinHealth(CADTH)resourcesweremanuallysearchedforhighqualityandrelevantsystematicreviews.Whennecessary,systematicreviewsarecriticallyappraisedforqualityusingtheAMSTARtoolandclinicalpracticeguidelinesusingtheAGREEtool.TheFDAwebsitewassearchedfornewdrugapprovals,indications,andpertinentsafetyalerts.Finally,theAHRQNationalGuidelineClearinghouse(NGC)wassearchedforupdatedandrecentevidence-basedguidelines.Theprimaryfocusoftheevidenceisonhighqualitysystematicreviewsandevidence-basedguidelines.Randomizedcontrolledtrialswillbeemphasizedifevidenceislackingorinsufficientfromthosepreferredsources.NewSystematicReviews:Nonewsystematicreviewsidentified.NewGuidelines:Nonewguidelinesidentified.NewSafetyAlerts:InSeptemberofthisyear,theFoodandDrugAdministration(FDA)releasedawarningofanincreasedriskofbonefracturesanddecreasedbonemineraldensityassociatedwiththeuseofcanagliflozin,alsoaSGLT2inhibitor.2ItisunknownifthisisaclasseffectandtheFDAiscontinuingtoevaluateifotherSGLT2inhibitorsconveythissamerisk.TheFDAreleasedadrugsafetycommunicationinDecemberonlabelingchangesfortheSGLT2inhibitorclassfortheriskofketoacidosisandseriousurinarytractinfections,potentiallyleadingtohospitalizations.PostmarketingstudiesarebeingrequiredfromthemanufacturersoftheSGLT2inhibitorstogainadditionalclarityontherisk.3NewFormulationsorIndications:Nonewformulations.RandomizedControlledTrials:

Author:KathySentena,Pharm.D. Date:January2016

Twenty-threecitationsweremanuallyreviewedfromtheliteraturesearch.Afterfurtherreview,22trialswereexcludedbecauseofwrongstudydesign(observational),comparator(placebo),outcomestudied(non-clinical)oroutsidethesearchdates.Theremainingtrialisdescribedbelow.ThefullabstractisincludedinAppendix2.EMPA-REGOUTCOMETrialThecardiovasculareffectsandmortalityassociatedwithempagliflozintreatmentwasstudiedindouble-blind,placebocontrolled,randomizedcontrolledtrial.1Adultpatients(n=7020)withT2DMwererandomizedtoreceiveadailydoseofempagliflozin10mg,empagliflozin25mgorplaceboandwerefollowedforamedian3.1years.Themediantreatmentdurationwas2.6years.Patientswereameanageof63yearsold,predominatelymale(71%),white(72%)andhadapriorhistoryofCVdisease.ThemostcommonCVriskfactorwascoronaryarterydisease(CAD)(75%)followedbymulti-vesselCAD(47%)andhistoryofMI(47%).BaselineA1Clevelswere8.07%.Backgroundantidiabetictherapieswereallowed.1Metformin,insulinandsulfonylureasweremostcommonlyusedwithsimilarratesacrossalltreatmentgroups.Angiotensin-convertingenzymeinhibitors(ACE)orangiotensinreceptorblockers(ARBs)wereusedby81%ofpatients.Twenty-sixpercentofpatientshadmoderaterenalinsufficiency(<60mL/min/1.73m2).1Theprimarycompositeoutcomewasdeathfromcardiovascularcauses,nonfatalmyocardialinfarction,ornonfatalstroke.Theprimaryoutcomeplushospitalizationforunstableanginawasakeysecondaryoutcome.Patientswereanalyzedusingamodifiedintention-to-treatanalysisofpooledempagliflozindataversusplacebo.1Thenoninferioritythresholdfortheprimaryoutcomecomparisonbetweenempagliflozinandplacebowassetatamarginof1.3forthehazardratio.Atwo-sidedPvalueof0.0498,orless,wasusedforstatisticalsignificanceandtheconfidenceinterval(CI)wascalculatedat95.02%fortheprimaryoutcome.Empagliflozin(pooleddatafrombothdoses)wasfoundtosignificantlylowertheincidenceofthecompositeprimaryoutcomecomparedtoplacebo(hazardratio[HR]0.86;95.02%CI,0.74to0.99;p<0.001fornoninferiorityandp=0.04forsuperiority).1Emapagliflozinwasnoninferior,butnotstatisticallysuperior,toplaceboforthekeysecondarycompositeoutcome,whichwastheprimarycompositeoutcomeplushospitalizationsforunstableangina(12.8%vs14.4%,respectively(HR0.89;95%CI,0.78to1.01;p<0.001fornoninferiorityandp=0.08forsuperiority)).Whenindividualendpointswereanalyzed,patientsonempagliflozinhadstatisticallysignificantlowerincidenceofdeathfromcardiovascularcauses,all-causemortality,andhospitalizationsforheartfailure(Table1).RatesofMIandfatalornonfatalstrokeweresimilarbetweenbothgroups.1Fatalornonfatalstrokerateswerehigherwithempagliflozincomparedtoplacebo(HR1.18;95%CI,0.89to1.56;p=0.26).Empagliflozinwasalsoassociatedwithanincreasedriskofnonfatalstroke(HR1.24;95%CI,0.92to1.67;p=0.16)Therewasnosignificantdifferenceincardiovascularoutcomesbetweentheempagliflozin10mgandempagliflozin25mgdoses.DifferencesisA1Creductionbetweenthe10mgand25mgdosesandplacebowerealsosimilar(-0.54%[95%CI,-0.58to-0.49]inthe10mggroupand-0.60%[95%CI,-0.64to-0.55]inthe25mggroup).1However,byweek206thedifferencehaddecreasedto-0.24%forempagliflozin10mgand-0.36%forempagliflozin25mg,comparedtoplacebo.Changesincardiovascularriskfactorswithempagliflozincomparedtoplaceboincludereductionsinthefollowing;smallchangesinweight,waistcircumference,uricacidlevels,andsystolicanddiastolicbloodpressure.SmallincreasesinLDLandHDLcholesterolwereseenwithempagliflozinincomparisontoplacebo.1TherewasnosubstantialdifferenceinA1Cloweringbetweenempagliflozin10mgandempagliflozin25mg,suggestingtreatmentwiththe10mgdosetobeadequateformostpatients.Adverseeventsleadingtodiscontinuationwerelowerinthepooledempagliflozingroupcomparedtoplacebo,17.3%and19.4%,respectively.1Genitalinfectionswerethemostcommonadverseeffectassociatedwithempagliflozintreatment,whichoccurredatasignificantlyhigherratethanplacebo(6.4%vs,1.8%,

Author:KathySentena,Pharm.D. Date:January2016

respectively(p<0.001).Hypoglycemicadverseevents,acuterenalfailure,diabeticketoacidosis,thromboembolicevents,bonefracture,symptomsofvolumedepletionandelectrolytechangesweresimilarbetweenempagliflozinandplacebo.1Table1.DescriptionofRandomizedComparativeClinicalTrialsStudy Comparison Population N Outcomes ARR/N

NTSafetyOutcomes

ARR/NNH

RiskofBias/Applicability

1.Zinman,etal(EMPA-REGOUTCOME)1RCT,DB,DD,PG,Phase3

1.Empagliflozin10mg(E10)2.Empagliflozin25mg(E25)3.Placebo(P)Studyduration:3.1years

Demographics(mean):Age:63yearsMale:71%White:72%Diabetesdiagnosis>10years:57%A1C:8.1%KeyInclusionCriteria:●T2DM●>18yearsofage●Bodymaxindexof<45●eGFR>30ml/min/1.73m2●EstablishedCVD●A1C7-9%onnoglucoseloweringtherapyorA1Cof7-10%on12weeksofastabledoseofglucose-loweringtherapy*KeyExclusionCriteria:●eGFR<30ml/min/1.73m2

ITT:1.23452.23423.2333PP:1.17902.18003.1650Attrition:1.555(24%)2.542(23%)3.683(29%)

PrimaryOutcome:CompositeofCVdeath,non-fatalMI,ornon-fatalstroke):E*:490(10.5%)vs.P:282(12.1%);HR0.86(95.04%CI,0.74to0.99;P<0.001fornoninferiorityandp=0.04forsuperiority)SecondaryOutcomes:CompositeofCVdeath,non-fatalMI,non-fatalstroke,orhospitalizationfromunstableangina):E*:599(12.8%)vs.P:333(14.3%);HR0.89(95.04%CI,0.78to1.01;P<0.001fornoninferiorityandp=0.08forsuperiority)HospitaladmissionforHF:E*:126(2.7%)vs.P:95(4.1%);HR0.65(95%CI,0.50to0.85;P=0.002)Cardiovascularmortality:E*:172(3.7%)vs.P:137(5.9%);HR0.62(95%CI,0.49to0.77;P<0.001)All-causemortality:E*:269(5.7%)vs.P:194(8.3%);HR0.68(95%CI,

6/63NS1.4/712.2/452.6/39

Discontinuationsduetoadverseevents:E*:813(17.3%)vs.P:453(19.4%);P<0.01Anyhypoglycemicevents:E*:1303(27.8%)vs.P:650(27.9%);P-valuenotgivenGenitalinfections:E*:301(6.4%)vs.P:42(1.8%);P<0.001

2/48NA5/20

RiskofBias(low/high/unclear):Selectionbias(low):Randomizationwasdoneviaacomputer-generatedrandom-sequenceandinteractivevoice-andWeb-responsesystem.Performancebias(low):Trialwasdouble-blinddesignwithmedicationconcealmentusingdouble-dummydesign.Detectionbias(low):Outcomeassessorswereblindedtorandomizationtreatmentassignments.Outcomeswereadjudicatedbyclinical-eventscommittees.Attritionbias(low):Overallattritionwas25%.mITTanalysiswithLOCFwasusedforalldata.Reportingbias(low):Studyprotocolwasfollowedandoutcomeswerereportedasspecified.Applicability:Patients:Patientswerewellmatched.Ninety-ninepercentofpatientshadahistoryofcardiovasculardisease.Intervention:Pooleddosesofempagliflozin10mgandempagliflozin25mgwasappropriateduetothelowincidenceofexpectedeventsfortheprimaryoutcome.Comparator:Matchedplaceboisanappropriatecomparator.Outcomes:compositeofmajorcardiaceventsisanacceptedoutcomeandrequiredbytheFDAtoensureantidiabetictherapyisnotassociatedwithunacceptablelevelsofcardiacrisk.Inthisstudy,empagliflozinwasshowntoreducecardiovascularoutcomesincluding

Author:KathySentena,Pharm.D. Date:January2016

●Liverdisease●Surgery●Cancer*Glucoseloweringtreatmentatbaseline:-metformin(73.8%)-Insulin(48.0%)-sulfonylureas(43.0%)

0.57to0.82;P<0.001)Fatalornonfatalstroke:E*:164(3.5%)vs.P:69(3.0%);HR1.18(95%CI,0.89to1.56;P=0.26)Nonfatalstroke:E*:150(3.2%)vs.P:60(2.6%);HR1.24(95%CI,0.92to1.67;P=0.16)FatalornonfatalMI:E*:223(4.8%)vs.P:126(5.4%);HR0.87(95%CI,0.70to1.09;P=0.23)E*=Pooleddatafor10mgand25mgdoses.

NSNSNS

deathandall-causemortality.Setting:Forty-twocountriesand590outpatientcenters.

Abbreviations[alphabeticalorder]:A1C=hemoglobinA1C;ACE–angiotensinconvertingenzyme;ARR=absoluteriskreduction;CI=confidenceinterval;CV=cardiovascular;CVD=cardiovasculardisease;DB=double-blind;eGFR=estimatedglomerularfiltrationrate;HR=hazardratio;MI=myocardialinfarction;mITT=modifiedintentiontotreat;N=numberofsubjects;NA=notapplicable;NNH=numberneededtoharm;NNT=numberneededtotreat;NS=notstatisticallysignificant;PP=perprotocol References:

1. ZinmanB,WannerC,LachinJM,etal.Empagliflozin,CardiovascularOutcomes,andMortalityinType2Diabetes.NEnglJMed.2015;373:2103-2116.doi:10.1056/NEJMoal504720.

2. U.S.FoodandDrugAdministration.InvokanaandInvokamet(canagliflozin):FDADrugSafetyCommunication:FDAreviseslabelofdiabetesdrugcanagliflozin(Invokana,Invokamet)toincludeupdatesonbonefractureriskandnewinformationondecreasedbonemineraldensity.FDADrugSafetyCommunication.2015.Availableat:http://www.fda.gov/drugs/drugsafety/ucm461449.htm.AccessedDecember4,2015.

3. U.S.FoodandDrugAdministration.SGLT2Inhibitors:drugsafetycommunication–labelstoincludewarningsabouttoomuchacidinthebloodandseriousurinarytractinfections.FDADrugSafetyCommunication.2015.Availableat:http://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm475553.htm.Accessed:December8,2015.

4. VasilakouD,KaragiannisT,AthanasiadouE,etal.Sodium-glucosecotransporter2inhibitorsfortype2diabetes:asystematicreviewandmeta-analysis.AnnInternMed.2013;159:262-274.

5. NealB,PerkovicV,deZeeuwD,etal.Rationale,design,andbaselinecharacteristicsofthecanagliflozincardiovascularassessmentstudy(CANVAS)–arandomize,placebo-controlledtrial.AmHeartJ.2013;166:217-223.DOI:10.1016/j.ahj.2013.05.007.

6. AstraZeneca.Multicentertrialtoevaluatetheeffectofdapagliflozinontheincidenceofcardiovascularevents(DECLARE-TIIMI58).ClinicalTrials.gov.Availableat:www.clinicatrials.gov/ct2/show/NCT01730534?term=declare&rank=2.AccessedDecember5,2015.

Author:KathySentena,Pharm.D. Date:January2016

7. AmericanDiabetesAssociation.2015standardsofmedicalcareindiabetes.DiabetesCare.2015;38(Suppl.1):S4.doi:10.2337/dc15-s003.8. HandelsmanY,BloomgardenZ,GrunbergerG,etal.AmericanAssociationofClinicalEndocrinologistsandAmericanCollegeofEndocrinology–Clinical

PracticeGuidelinesforDevelopingaDiabetesMellitusComprehensiveCareplan–2015.EndocrPract.2015;21(Suppl1).Availableat:https://www.aace.com/files/dm-guidelines-ccp.pdf.

9. AbrahmsonM,BarzilayJ,BlondeL,etal.AACE/ACEComprehensiveDiabetesManagementAlgorithm.EndocrPrac.2015;21:438-447.Availableat:https://www.aace.com/publications/algorithm.

10. NationalInstituteforHealthandCareExcellence.Empagliflozinincombinationtherapyfortreatingtype2diabetes.NiceTechnologyAppraisalGuidance[TA336].2015.Availableat:www.nice.org.uk/guidance/ta336.

11. NationalInstituteforHealthandCareExcellence.Canagliflozinincombinationtherapyfortreatingtype2diabetes.NICETechnologyAppraisalGuidance[TA315]Publisheddate:June2014.Availableat:www.nice.org.uk/guidance/ta315.

12. DrugUseResearchandManagementPrograms.Classupdate:non-insulinantidiabeticagents.Oregondrugusereview/PharmacyandTherapeuticsCommitteeMeeting.September24,2015.Availableat:http://www.orpdl.org/durm/meetings/meetingdocs/2015_09_24/finals/2015_09_24_PnT_Complete.pdf.AccessedDecember3,2015.

13. JardiancePrescribingInformation.BoehringerIngelheimPharmaceuticals,Inc.Ridgefield,CT;2015.14. LiuX,ZhangN,ChenR,etal.Efficacyandsafetyofsodium-glucosecotransporter2inhibitorsintype2diabetes:ameta-analysisofrandomized

controlledtrialsfor1to2years.JDiabetesComplications.2015Jul15.doi:10.1016/j.jdiacomp.2015.07.011.[Epubaheadofprint]15. AlvarezCA,LingvayI,VuylstekeV,etal.Cardiovascularriskindiabetesmellitus:complicationofthediseaseorofantihyperglycemicmedications.Clin

PharmacolandThera.2015;98:145-161.Doi:10.1002/cpt143.16. GreenJ,BethelA,ArmstrongP,etal.Effectofsitagliptinoncardiovascularoutcomesintype2diabetes.NEJM.2015;373:232-42.DOI:

10.1056/NEJMoal1501352.17. PferrerMA,ClaggettB,DiazR,etal.Lixisenatideinpatientswithtype2diabetesandacutecoronarysyndrome.NEnglJMed.2015;373:2247-57.

Appendix1:CurrentStatusonPreferredDrugList

Author:KathySentena,Pharm.D. Date:January2016

Diabetes,Sodium-GlucoseCo-TransporterInhibitorsROUTE FORMULATION BRAND GENERIC PDLORAL TABLET FARXIGA DAPAGLIFLOZINPROPANEDIOL NORAL TABLET INVOKANA CANAGLIFLOZIN NORAL TABLET JARDIANCE EMPAGLIFLOZIN NORAL TABBP24H XIGDUOXR DAPAGLIFLOZIN/METFORMINHCL NORAL TABLET INVOKAMET CANAGLIFLOZIN/METFORMINHCL NAppendix2:AbstractsofClinicalTrialZinmanB,WannerC,LachinJM,etal.Empagliflozin,CardiovascularOutcomes,andMortalityinType2Diabetes.NEnglJMed.2015Sep17.[Epubaheadofprint].Theeffectsofempagliflozin,aninhibitorofsodium-glucosecotransporter2,inadditiontostandardcare,oncardiovascularmorbidityandmortalityinpatientswithtype2diabetesathighcardiovascularriskarenotknown.MethodsWerandomlyassignedpatientstoreceive10mgor25mgofempagliflozinorplacebooncedaily.Theprimarycompositeoutcomewasdeathfromcardiovascularcauses,nonfatalmyocardialinfarction,ornonfatalstroke,asanalyzedinthepooledempagliflozingroupversustheplacebogroup.Thekeysecondarycompositeoutcomewastheprimaryoutcomeplushospitalizationforunstableangina.ResultsAtotalof7020patientsweretreated(medianobservationtime,3.1years).Theprimaryoutcomeoccurredin490of4687patients(10.5%)inthepooledempagliflozingroupandin282of2333patients(12.1%)intheplacebogroup(hazardratiointheempagliflozingroup,0.86;95.02%confidenceinterval,0.74to0.99;P=0.04forsuperiority).Therewerenosignificantbetween-groupdifferencesintheratesofmyocardialinfarctionorstroke,butintheempagliflozingroupthereweresignificantlylowerratesofdeathfromcardiovascularcauses(3.7%,vs.5.9%intheplacebogroup;38%relativeriskreduction),hospitalizationforheartfailure(2.7%and4.1%,respectively;35%relativeriskreduction),anddeathfromanycause(5.7%and8.3%,respectively;32%relativeriskreduction).Therewasnosignificantbetween-groupdifferenceinthekeysecondaryoutcome(P=0.08forsuperiority).Amongpatientsreceivingempagliflozin,therewasanincreasedrateofgenitalinfectionbutnoincreaseinotheradverseevents.Patientswithtype2diabetesathighriskforcardiovasculareventswhoreceivedempagliflozin,ascomparedwithplacebo,hadalowerrateoftheprimarycompositecardiovascularoutcomeandofdeathfromanycausewhenthestudydrugwasaddedtostandardcare.Appendix3:MedlineSearchStrategy

Author:KathySentena,Pharm.D. Date:January2016

Appendix4:PriorAuthorizationCriteria

Author:KathySentena,Pharm.D. Date:January2016

Sodium-Glucose Cotransporter-2 Inhibitors (SGLT-2 Inhibitors) Goal(s): • Promote cost-effective and safe step-therapy for management of type 2 diabetes mellitus (T2DM). Length of Authorization: • Up to 12 months Requires PA: • All SGLT-2 inhibitors Covered Alternatives: • Preferred alternatives listed at www.orpdl.org/drugs/

Approval Criteria

1. Is this a request for renewal of a previously approved prior authorization?

Yes: Go the Renewal Criteria

No: Go to #2

2. What diagnosis is being treated? Record ICD10 code

3. Does the patient have a diagnosis of type 2 diabetes mellitus?

Yes: Go to #4 No: Pass to RPh. Deny; medical appropriateness

4. Has the patient tried and failed metformin and sulfonylurea therapy or have contraindications to these treatments? (document contraindication, if any)

Yes: Go to #5 No: Pass to RPh; deny and recommend trial of metformin or sulfonylurea. See below for metformin titration schedule.

Author:KathySentena,Pharm.D. Date:January2016

Approval Criteria

5. Is the request for the following treatments (including combination products) with an associated estimated glomerular filtration rate (eGFR): • Canagliflozin and eGFR <45 mL/min/ 1.73 m2, or • Empagliflozin and eGFR <45 mL/min/ 1.73 m2, or • Dapagliflozin and eGFR <60 mL/min/ 1.73 m2?

Yes: Pass to RPh. Deny; medical appropriateness

No: Approve for up to 6 months.

Renewal Criteria

1. Is the request for the following treatments (including combination products) with an associated estimated glomerular filtration rate (eGFR): • Canagliflozin and eGFR <45 mL/min/ 1.73 m2, or • Empagliflozin and eGFR <45 mL/min/ 1.73 m2, or • Dapagliflozin and eGFR <60 mL/min/ 1.73 m2?

Yes: Pass to RPh. Deny; medical appropriateness

No: Approve for up to 6 months.

Initiating Metformin 1. Begin with low-dose metformin (500 mg) taken once or twice per day with meals (breakfast and/or dinner) or 850 mg once per day. 2. After 5-7 days, if gastrointestinal side effects have not occurred, advance dose to 850 mg, or two 500 mg tablets, twice per day (medication to

be taken before breakfast and/or dinner). 3. If gastrointestinal side effects appear with increasing doses, decrease to previous lower dose and try to advance the dose at a later time. 4. The maximum effective dose can be up to 1,000 mg twice per day but is often 850 mg twice per day. Modestly greater effectiveness has been

observed with doses up to about 2,500 mg/day. Gastrointestinal side effects may limit the dose that can be used. Nathan, et al. Medical management of hyperglycemia in Type 2 Diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care. 2008; 31;1-11.

P&T/DUR Review: 1/16 ;9/15; 1/15; 9/14; 9/13 Implementation: TBD; 2/15