Cardiac and Renal Protective Effects of SGLT-2 Inhibitors:...

CardiacandRenalProtectiveEffectsofSGLT-2Inhibitors:BenefitsBeyondGlycemicControl

CatlinGrisham-Takac,Pharm.DPGY-2AmbulatoryCarePharmacyResident

CommUnityCareHealthCentersUniversityofTexasatAustinCollegeofPharmacy-October7,2016

https://lh6.googleusercontent.com/-QM0kQhp_Ykc/TXhTohWDZHI/AAAAAAAAAa4/4Q0oNenppBE/s1600/handheartkidneygraphic_withlogo.jpg

Objectives

• Understandtheroleofthesodium-glucoseco-transporter(SGLT)inglucosehomeostasisinnormoglycemicandhyperglycemicstates

• DiscusspleiotropiceffectsobservedwithuseofSGLT-2inhibitorsandexploreproposedpathophysiology• ReviewclinicaldatastudyingrenalandcardioprotectiveendpointsrelatedtoSGLT2inhibition• AnalyzethecardioandrenaloutcomesdrawnfromtheEMPA-REGoutcomestrial

CATLINGRISHAM-TAKAC,PHARMDPLEIOTROPICEFFECTSOFSGLT-2INHIBITORS 2

DiabetesMellitus(DM):AMajorCauseforConcern1-7

1. TypesofDMa. Type1Diabetes(T1DM):Characterizedbyacompletelackofinsulin

i. Makesup10%oftheDMpatientpopulationb. Type2Diabetes(T2DM):Progressivediseasestatecharacterizedbyinsulinresistance

i. Makesup90%oftheDMpatientpopulationii. Glucotoxicity:prolongedhyperglycemialeadingtoβcelldysfunctionandwidespreadinsulin

resistance2. CDCreportsthatin2012,29.1millionAmericanshaddiabetes(9.3%ofthepopulation)

a. 1.4millionNEWcases/yearb. Estimatedthatevery5minutes,2peopledieofdiabetesrelatedcausesand14adultsarenewly

diagnosed

Figure1.Diabetesassociatedmortalityandthelargestcontributors

3. Goal:Achieveglycemiccontroltopreventorslowprogressionofmicrovascularandmacrovascularcomplications

a. Macrovascular:coronaryheartdiseasei. IncreasedriskforMI,suddencardiacdeath,peripheralarterydiseaseii. Underlinesimportanceforbloodpressurecontrol

b. Microvasculari. Diabeticneuropathyii. Gastrointestinal/genitourinarydysfunctioniii. Diabeticretinopathyiv. Diabeticnephropathy

1. Affects1/3ofallDMpatients:leadingcauseofmortalityandendstagerenaldisease2. Earlypredictors:Hyperfiltrationandenlargedkidney

a. Hyperplasiaofrenaltubulesàtubulointerstitialfibrosis/inflammationi. MediatedbyTGFβ1,IGF1,PDGF,VEGF,EGF

DM:7thleadingcauseofdeath

1.7xmorelikely

1.8xmorelikely

1.5xmorelikely

44%ofallnewcases

CVDeath

MIHospital-ization

StrokeHospital-ization

CKD


3. Progressiontoalbuminuria4. AmericanDiabetesAssociationGuidelineRecommendedManagementofComplications

a. Controlofbloodpressureandbloodglucosei. UKPDS,DCCTandEDICtrialsdemonstrateeffectivenessofachievinggoalinreducing

complicationsb. Screeningfordevelopmentofcomplications

i. YearlymAlb/Cr,dilatedeyeexam,footexam,dentalexamc. RAASinhibition

i. Proventobeeffectiveinslowingprogressiontodiabetickidneydiseaseii. InitiateACE-IorARBinpatientswithmacroalbuminuria(Arecommendation)iii. InitiateACE-IorARBinpatientswithmicroalbuminuria(Brecommendation)

1. Weakevidence:Smalltrialsofnormotensivepatientswithmicroalbuminuria

IntroducingtheConcept:Sodium-GlucoseCo-Transporter(SGLT)Inhibition5,8-12

Table1.Glucosetransportproteins.Theseallowforglucoseutilizationthroughoutthebody.TheSGLTproteinsarefunctionallydifferentthantheGLUTproteinsandareindependentofthepresenceofinsulin Expression Description EnergySource

GLUT-1 Brain,erythrocytes,endothelialcells

Constitutiveglucosetransporter

Facilitateddiffusiondownaglucose-concentration

gradient

GLUT-2 Kidney,smallintestine,liver,pancreaticβcells

Lowaffinityglucosetransporter,sensesglucosein

isletcells

GLUT-3 Neurons,placenta Highaffinityglucosetransporter

GLUT-4 Skeletal/cardiacmuscle,adiposecells

Insulinresponsiveglucosetransporter

GLUT-5 Smallintestine,sperm,kidney,brain,adiposecells,muscle

Fructosetransporter,lowaffinityforglucose

SGLT-1 Distalsegmentoftheproximaltubule,intestine

Highaffinity,lowcapacityglucosetransport

Responsiblefor~10%ofrenalglucosereabsorption

Activetransport:Nacotransportandagainstglucose-concentration

gradientSGLT-2Earlyconvolutedsegmentofproximaltubules,pancreatic

αcells

Lowaffinity,highcapacityglucosetransport

Responsiblefor80-90%ofrenalglucosereabsorption


Figure2.DescriptionofsodiumandglucosereabsorptioninarenaltubulecellviaSGLT-210,12

1.Sodiumistransportedacrosstheluminalmembraneandcreatesanenergygradient.2.Glucoseisthenallowedtofollowacrosstheluminalmembraneviapassivetransport.3.ATPasemediatedNa/KpumpreturnstheNatotheblood,creatingaconcentrationgradient.4.GlucosediffusesthroughGLUT2andbackintothebloodstream

RoleofSGLT-2inGlucoseHomeostasis1. Innormoglycemic,non-diabeticpatients

a. SGLTtransporthelpstomaintainaconsistentfastingplasmaglucoseb. Transportthresholdmaintainedatbloodglucoseof180-200mg/dlc. Atbloodglucoselevels>200mg/dl,glycosuria

2. Inpatientswithimpairedfastingglucoseandbothtypesofdiabetesmellitus(seeFigure3)a. Processbecomesamaladaptivemechanismb. Potentiateshyperglycemiaandencouragesdevelopmentofhyperfiltrationc. Unknownifitnormalizesonceeuglycemiaisachieved

3. Systemically,prolongedhyperglycemiatriggersneurohormonalactivationa. ActivatedRAAS/SNSpathwaysleadstoincreasedbloodpressureandincreasedarterialstiffnessb. Provensurrogateendpointscontributingtodevelopmentofrenalandcardiovascularcomplications

Figure3.IllustrationofthemaladaptiveglucosehomeostasismechanisminIFGandDMProlongedhyperglycemialeadstoupregulationofSGLT-2proteinsintherenaltubules,increasingthereabsorptionofglucoseandthuspotentiatinghyperglycemia.Simplyput,thismechanismleadstoahyperfilteringnephron.

12

3

4

↑filteredglucoseinproximaltubule

UpregulationofSGLT2transporters

ProlongedHyperglycemicState

RAASandSNSactivationNitricoxidesuppression

↑Bloodpressure↑Arterialstiffness

Hyperfiltration


Figure4.TGFandinteractionwithSGLT-210,12

(a)Representstheoveralleffectofanormaltubuloglomerularfeedbackloopwhereappropriatetoneoftheafferentarterioleismaintained.(b)AnexampleoftheimpairedtubuloglomerularfeedbackloopasaresultofexcessiveNareabsorptionintheproximaltubule.(c)RepresentstherestorationofTGFwithinhibitionofSGLT2.

SGLT-2Inhibitors:Mechanismofaction

1. Normalizesthresholdforglycosuriaresultinginexcretionofexcessglucosethroughtheurinea. UpregulationofSGLT1inthedistalsegmentoftheproximaltubuleb. About50%ofglucoseisreabsorbedcomparedto100%whennotinhibitedc. Resultsinnormalization/reductionofbloodglucose

i. Decreasedgluconeogenesis/totalhepaticglucoseii. Increasedinsulinsensitivity(improvedinsulinsignaling)

a. Restorestubuloglomerularfeedback(TGF)aspicturedinFigure4.

Table2.SGLT-2Inhibitors:AtaGlance11,13-16

Brand Generic Availabledosing(mg) Efficacy(A1clowering) ADEs**

Invokana® canagliflozin 100-300

-0.7%-0.42%ifCrCl30-

59ml/min

• DKA,ketosis• Genitalmycotic

infections• UTI• Slight↑LDL• Bonefracture• Bladdercancer

Farxiga® dapagliflozin 5-10

Jardiance® empagliflozin 10-25

Suglat® ipragliflozin* 25-100

*availableinJapanonly,**ThereissomethoughtthatDKAandbladdercancerweresubjecttoreportingbias.PatientswhomayhaveexperiencedincreasedUTIsormycoticinfectionswouldlikelyhavebeensubjecttomorescreeningthanthosewithoutUTIsormycoticinfections.DKAmaynothavebeenreportedinthosepatients,exceptforthepresenceoftherapywithSGLT-2inhibitors.


PleiotropiceffectsassociatedwithSGLT-2Inhibitors

Weightloss:1-4.5kgobserved4,11,17-201. Lossofcaloriesfromglycosuriaandosmoticdiuresis2. Potentialforreducedinsulinrequirements3. Maintainedpastinitialtherapyperiod

Reductioninuricacid5,6,11,201. IncreasedlevelsassociatedwithHTN,CVDandrenaldisease2. 10-15%reductioninplasmauricacidlevels

a. Clinicalrelevanceunclear

CardiovascularEffect4,11,17,18,20-231. Modestreductioninbloodpressure

a. 2014Meta-analysisbyBakerandcolleaguesi. 27uniqueRCTincluding12,960patientsii. SBP:4mmHgdropconsistentbetweenSGLT-2inhibitorsiii. DBP:1.6mmHgdropconsistentbetweenSGLT-2inhibitors

b. Noincreaseinorthostatichypotensionc. ReducesBPevenin“non-dippers”

i. PatientswithoutnocturnalBPdrop(“dip”)haveanincreasedriskofCVDd. BPreductionobservedeveninpatientswithCKD

2. Reductioninarterialstiffnessa. WellestablishedsurrogatemarkerforCVDb. 8-weekopenlabelprospectivetrial(n=42):T1DMwithempagliflozin25mgvsplacebo

i. Decreasedcarotid-radialpulsewavevelocity(measureofarterialstiffness)undereuglycemicandhyperglycemicconditions

ii. VagaltoneandSNSactivitynotsignificantlychangedc. T2DM:Improvedmarkersofarterialstiffness

i. Pulsepressure,myocardialoxygenconsumption3. Proposedpathophysiologybehindcardiovascularbenefits:multifactorial

a. Proposedpathophysiologyi. Volumecontraction

1. Unclearifvolumecontractionpersiststhroughtreatmentii. Weightlosscorrelation

1. Conflictingdatabetweenstudiesa. BPloweringindependentofweightlossinpatientswithCKD

iii. Neurohormonalchanges-mostareunlikelytoplayasignificantrole1. Increasedplasmaaldosterone,reninandangiotensinIIandurinaryangiotensinogen

(vasoconstriction)2. IncreasedurinaryACE2(vasodilation)

a. Possible:requiresfurtherstudy3. SNSactivityunchanged

iv. Reducedarterialstiffnessb. Metaboliceffects:weightloss,Increasedfatoxidation,increasedglucagonsecretion

i. UnlikelytosupportreductioninCVdeath


ii. Increaseduricacidsecretion1. Benefitnotwellestablished,butmayplayalongtermrole

iii. Weightloss:modest2kgweightlossunlikelytoaccountforearlyreductionsc. Notduetoslowingofatheroscleroticprocesses:nodifferenceinnonfatalstroke,nonfatalMI,unstable

anginad. Bloodpressure:BaselineBPatgoal

i. DecreaseinBPonCVevents:benefitafter1yearii. Reductioninarterialstiffnessanddiuresisà↓centralaorticpressureà↑LVfunction,reduce

workload,myocardialoxygendemand

RenalProtection5,6,9-12,17,19,24

1. Endpointsandsafetyoutcomesobserveda. Decreaseinkidneyweightandglomerularsize(inmousemodels)b. DecreasedeGFRearlyintherapyàeffectstabilizesc. Decreaseinalbuminuriaandprogressiontoalbuminuriad. MaintainedinpatientswithCKDindependentofA1creduction

2. Earlystudiesa. 2013DeFronzoandcolleagues:12T2DMpatients

i. Treatedwith1weekofdapagliflozinà↓eGFRby14%b. 2013Cefaluandcolleagues:1450T2DMpatients

i. CanagliflozinvGlimepiridex52weeksii. Atweek4:greater↓eGFRincanagliflozinvsglimepirideiii. At52weeks:eGFRstabilizedincanagliflozinvssteadydeclineinglimepirideiv. ↓mAlb/Crat1yr:-0.1,-0.9,+0.7in100mg,300mg,placeborespectively

c. 2014ATIRMAtrial:40T1DMpatientsi. Proofofconceptstudyusingempagliflozin25mgii. Compareseffectsinpatientswithnormofiltrationandhyperfiltrationiii. ChangeineGFR(ml/min/1.73m2)

1. Euglycemicconditions:normofiltration(-9)vshyperfiltration(-33)2. Hyperglycemicconditions:normofiltration(-2)vshyperfiltration(-44)

CanSGLT-2inhibitorsprotectpatientswithtype2diabetesfromrenalandcardiovascularcomplications?LiteratureReview

Table3.EfficacyandSafetyofEmpagliflozinforType2Diabetes:ASystematicReviewandMeta-Analysis18

Objective Toutilizeavailablestudiestoassessthesafetyandefficacyofempagliflozincomparedwithplaceboorotherantidiabeticagentsinpatientswithtype2diabetes

METHODS

Studyselectionandidentification

• SearchedPubMed,CochraneLibraryandEmbaseforstudieslatestDecember2013;abstractsfromprominentendocrinologymeetingsfrom2009to2013

• Selectedby2reviewers.Anydisagreementsettledbya3rdpartyInclusion• RCTcomparingempagliflozintoplaceboorotherantidiabeticmedication• StudieswithT2DM• Duration≥12weeks


DataExtraction

• 2reviewersindependentlyabstracteddatawitha3rdseniorreviewerresolvingdiscrepancies

Outcomes

• Primary:AbsolutechangeHbA1c(%)• Secondary:Absolutechangeinweight,SBP,DBP,%patientsachievingtarget

A1c<7%• Safety:hypoglycemia,changeineGFR,incidenceofUTI/genitaltractinfections,

volumedepletion

Assessmentofbias

• Keydomains:randomsequencegeneration,allocationconcealmentandincompleteoutcomedata

• Usedmeta-regressionanalysistoassesspublicationtype(fulltextvsabstract)

Dataanalysis

• Assessedbytypeofcomparator,dosage,intentiontotreatanalysis,longestdurationoftreatment

• Continuousoutcomes:weightedmeandifferenceswithinversevarianceweightedrandom-effectsmodel

• Dichotomousoutcomes:oddsratiosviaMantel-Haenzelformulaassumingrandomeffects

• Heterogeneity:Cochran’sQTest(p<0.10=heterogeneity,I2>50%=high)RESULTS

Studycharacteristics

• 10studieswith6203patients:7fulltext,4abstract/e-posterformats• Duration:12-90weeks• BaselineA1c7.8%to8.3%• Backgroundtherapy:4studies-none,3-metformin,1-metformin+SU,1-basal

insulin,1-anyoralantidiabeticdrug,1-metformin+pioglitazone• 8studiesratedhighofbias(usedlastobservationcarriedforwardformissing

A1c).Allreceivedindustryfunding.NoasymmetryinfunnelplotandEggertestdidnotrevealpublicationbias.

VsPlacebo

Measure(changein) Empagliflozin I2(%)%HbA1c(10mg) -0.62(-0.68,-0.57) 0%HbA1c(25mg) -0.66(-0.76,-0.57) 66/38*Weight(10mg),kg -1.85(-2.09,-1.6) 43Weight(25mg),kg -1.84(-2.30,-1.38) 85/66*SBPmmHg -4.19(-5.17,-3.20) 32Hypoglycemia(OR) 1.10(0.87,1.39) 0Genitaltractinfections(OR)

3.31(1.55,7.09) 37

eGFRml/min/1.73m2 -0.84(-2.29,0.62) 59

VsOralAgents

HbA1c(10mg) 0.04(-0.07,0.16) 0HbA1c(25mg) -0.11(-0.25,0.03) 25Weight(10mg) -2.15(-3.03,-1.27) 56Weight(25mg) -2.56(-3.57,-1.55) 66SBP(mmHg) -4.24(-6.08,-2.41) 0Genitaltractinfections(OR)

4.17(1.32,13.15) 0

Resultsrepresentedarethosewiththe25mgdoseandmeanchange(95%confidenceinterval),unlessotherwisespecified)*HeterogeneityreducedbyremovingstudiesincludingCKDpatients.

• HypoglycemiawassimilarbetweenSGLT2,metforminandsitagliptan.• UTInotfoundtobestatisticallydifferentinincidencebetweenanyofthe


groups• CKD2and3a:durableA1creductionvs3b:modestA1creductionvs4:noeffect

onA1creduction• All-causemortality:7trialsreported

o Empagliflozin5deaths(n=2874)o Control5deaths(n=1704)

• NonereportedoncardiovascularoutcomesCONCLUSIONS

Author’sConclusion

BothdosesofempagliflozinareeffectiveatloweringBGinT2DMwhileprovidingbenefitsofweightlossandbloodpressurereduction.Longtermsafetyprofileisunknownandmoretrialsareneededtoassessutilityofthisdrugincombinationwithotheragents.

Discussion Strengths Weaknesses

• Meta-analysiswithalargenumberofpatients

• Relativelylowoccurrenceofheterogeneitybetweenstudies

• Appropriatestatisticsandmethodsusedtoreducepotentialforbias

• Nodataforempagliflozin10mgavailableforCKDstage3and4

• Limitednumberoftrialsagainstactivecontrols

• Assessedsurrogateendpoints

Interpretation

Thismeta-analysisprovidesavaluablesummationoftheresultsfromaplethoraofearlytrialsstudyingempagliflozininpatientswithT2DM.Empagliflozinappearstobesafeandefficaciouswhileprovidingapotentialtreatmentoptioninpatientswithmoderaterenalimpairment.

Table4.Dapagliflozin’sEffectsonGlycemiaandCardiovascularRiskFactorsinHigh-RiskPatientswithType2Diabetes:A24-Week,Multicenter,Randomized,Double-Blind,

Placebo-ControlledStudywitha28WeekExtension17Objective TodeterminetheefficacyofdapagliflozininloweringHbA1c,bodyweightand

systolicbloodpressureinpatientsdeterminedtobeathighriskforCVDevents.METHODS

StudyDesign• 24weekmulticenter,randomized,double-blind,placebo-controlled,

internationalphase3studyfollowedbya28-weekextensionperiod• Funding:NIHgrantandsupportfromBristol-MyersSquibbandAstraZeneca

StudyPopulation

Inclusion Exclusion• Men≥45orwomen≥50

yearsold• T2DMwithCVD*andHTN• Stableantihyperglycemic

therapyfor4weeks• HbA1c7.2%to≤10.5%

• T1DM• On>3oralantidiabeticmedications• FPG>270mg/dlatscreening• h/oDKA• CVeventwithin2months• SBP≥165mmHg,DBP≥100mmHg• CHFNYHAclassIVorunstableCHF• Severehepaticinsufficiency

*CVD=priordocumentedCHD(h/oMI,revascularization,coronaryarterystenosis>50%)ordocumentedstroke/TIAorPADtreatedwithrevascularization

Intervention • Randomized1:1toDapagliflozin10mgorplacebo+existingstablebackgroundtherapy(notincludingrosiglitazone)


• Ifoninsulinatrandomization:↓insulindoseby25%

EndPoints

• Primary:MeanchangeinHbA1candpercentachieving3itemcomposite(absolute↓A1cof≥0.5%,relative≥3%↓weight,absolute↓≥3mmHgSBP)

• Secondary:meanchangeinSBP,mean%weightchange,proportionofpatientswithBMI≥27kg/m2with≥5%weightloss,A1creductioninthosewithbaselineA1c≥8%and≥9%andindividualcomponentsofcompositeoutcome

• Safety:changeinCVevents,labvalues,EKGresults,vitalsigns,hypoglycemia,eGFR

StatisticalAnalysis

Measure TestMeanchangeinA1c* ANCOVACompositeoutcome Cochran-Mantel-HaenzelmethodContinuousdataat52weeks Repeatedmeasuresmodel*adjustedforbaselineHbA1c,insulinuse,agestratification• Primaryendpoints:Twosidedα<0.025(Bonferroniadjustment),testingwithin

strataα<0.0125• Nostatisticaltestingon52-weekexploratoryendpoints

RESULTS

Baselinecharacteristics

Characteristic Placebo(n=459) Dapagliflozin(n=455)Age(years±SD) 63±7.7 62.8±7.0Female(%) 31.4 32.1White(%) 85.2 82.6

CVevent(%)

CHD 76.0 74.3CVA/TIA 19.4 22.0PAD 3.9 3.3

HbA1c±SD 8.08±0.8 8.18±0.84ACEI/ARB 98.3 98.9Lipidloweringmedications

88.5 84.1

Outcomes

Endpoint Placebo DapagliflozinChangeinA1c(95%CIifprovided)

Allpatients* 0.08(0.01,0.16) -0.38(-0.46,-0.30)A1c≥8 -0.08 -0.56A1c≥9 -0.35 -0.99

3itemcomposite%(95%CI) 0.9(0.0,1.8) 11.7(8.7,14.7)

Weightloss(%)

Week24(kg) -0.30 -2.56BMI≥27*and≥5%loss 4 16.5

ReductioninSBPmmHg(95%CI) -1.03(-2.39,0.32) -2.99(-4.36,-1.61)

Safety(%)

≥1treatmentrelatedAEs 16.2 22Deaths** 0.4 1.5UTI(male/female) 3.2/11.6 3.2/11.4Hypoglycemia 26.2 25.2DecreasedeGFR(52weeks) 0.6 0.4Renalfailure*** 0.6 1.3CHF 0.6 0.2*Stratifiedbybaselinemeasure;**Deathsdeemedtobeunrelatedtotreatment.Dapagliflozin:(3)suddendeath,(1)multi-organfailure,(2)MI,(1)cardiogenicshock)vsplacebo:(1)CVA,(1)pulmonaryembolism;***resolvedwithoutdiscontinuation


CONCLUSIONS

Author’sConclusion

DapagliflozinwasfoundtobesuperiortoplaceboinreducingHbA1candachievinga3itemcompositerepresentingreductionincardiovascularriskinapopulationofpatientswithT2DManddocumentedCVD.


• Studydesign• Large%ofpatientsonstandard

therapy• Longfollowupperiod

• Dualprimaryendpoint• Useofsurrogatemarkers• Unclearwhattypeoflipidlowering

therapypatientswereon• LimitedinformationonCHFpatients• Vaguesafetyendpoints

Interpretation

Thistrialdemonstratesthedurabilityofefficacyofdapagliflozininpatientswithcardiovasculardisease.Theendpointsstudiedaresurrogatemarkersandsuggesttheassociationwithtreatmentandcardiovascularbenefits.However,safetyoutcomeswereunclearandnotfullyelucidated.

Figure5.ChangeinSystolicBloodPressureinDapagliflozinComparedwithPlaceboRepresentsdurabledifferencebetweentreatmentgroupsatalltimepointsthroughoutthetrialperiod


Table5.TheEMPA-REGOutcomesStudy:CardiovascularandRenalOutcomes5,23

ObjectiveTodeterminethecardiovascularrelatedoutcomesofadjunctiveempagliflozintherapywhenaddedtostandardofcareinpatientswithT2DMandhighcardiovascularrisk.

METHODS

Studydesign

• Randomized,double-blind,placebocontrolled,multinationalandmulticenter• 7028patientsrandomizedfromSeptember2010-April2013• Mediantreatmentduration2.6years/medianobservation3.1years• Funding/oversight:BoehringerIngelheim,EliLilly

Studypopulation

Inclusion Exclusion• ≥18yearsold• UncontrolledT2DMa• BMI≤45kg/m2• eGFR≥30ml/min/1.73m2• Highriskforcardiovasculareventsb• Ondietorexerciseregimenanddrugnaïve

orpre-treatedwithstabletherapyfor12weekspriortorandomization

• Fastingbloodsugar(>240mg/dl)

• Activeliverdisease• Plannedcardiac

surgery/angioplastywithin3months

• eGFR<30ml/min/1.73m2• Acutecoronarysyndrome,

TIAorstrokewithin2months

• Cancertreatmentwithin5years

a)HbA1cbetween7-9%iftreatmentnaïveor7-10%ifondrugtreatment;b)MI>2monthspriortostudyenrollment,multi-vesselCAD,single-vesselCADwithpositivestresstestorrecenthospitalizationforUA,historyofstroke>2monthspriortoconsent,PAD

Intervention

• 2-weekopenlabelplaceborun-inperiodwithstableantihyperglycemictx• Assigned1:1:1to10mgor25mgempagliflozinorplacebooncedaily• 1st12weeks:backgroundtherapytoremainunchangedunlessFPG>240mg/dl

ormedicalnecessity• After12weeks:Freetoadjustbackgroundtherapy• Throughoutstudy:TreatotherCVriskfactorstostandardofcare

Outcomes

Cardiovascularoutcomes• Primaryoutcome:MACE(CVdeath,non-fatalMI,non-fatalstroke)• Keysecondaryoutcome:CompositeofMACE+hospitalizationforUA• Safety:confirmedhypoglycemiaevents,UTI,genitalinfection,volume

depletion,ARF,bonefracture,DKA,thromboemboliceventsRenaloutcomes• Renalmicrovascularoutcomes:incidentorworseningnephropathy

o Progressiontomacroalbuminuria,doublingofserumcreatinine(SCr)witheGFR≤45ml/min/1.73m2,initiationofrenalreplacementtherapy,deathfromrenaldisease

• Others:compositeofincidentorworseningnephropathyordeathfromcardiovascularcauses,individualcomponentsoftheabove,incidentalbuminuriainthosewithpreviouslynormalbaselineurinaryalbumin

• Safety:acutekidneyinjury,hyperkalemia,mycoticinfections,diabeticketoacidosis

Statistical • Noninferiorityfortheprimaryoutcomeanda4stephierarchicaltesting


Analysis strategyforsuperiority• Cox-proportionalhazardsmodel:betweengroupdifferencesandriskofan

outcome• Repeatedmeasuresmixedmodelanalysis:changeinHbA1c,weight,waist

circumference,heartrate,LDL,HDL,uricacid,eGFRfrombaselineRESULTS

BaselineCharacteristics

Characteristic Placebo(n=2333)

Pooledempagliflozin(n=4687)

Age(years±SD) 63.2±8.8 63.1±8.6Male(%) 72 71.2Whiterace(%) 71.9 72.6BMI(kg/m2±SD) 30.7±5.2 30.6±5.3A1c(%±SD) 8.08±0.84 8.07±0.85CAD(%) 75.6 75.6Heartfailure(%) 10.5 9.9%SBP(mmHg±SD) 135.8±17.2 135.3±16.9

eGFR(%)≥90 20.9 22.460to<90 53.1 51.7<60 26.0 25.9

Urinealbumin:Cr>300mg/g(%) 11.1 10.9Antihypertensivetherapy

ACE-I/ARB 80.1 81.0Βblockers 64.2 65.2

Statin 76.0 77.4

Cardiovascular

Outcomen(%) Placebo(n=2333)

Empagliflozin(n=4687)

Hazardratio

(95%CI)Pvalue

Primaryoutcome 282(12.1) 490(10.5)0.86(0.74-0.99)

0.04*

Keysecondaryoutcome 333(14.3) 599(12.8)

0.89(0.78-1.01)

0.08**

Deathfromanycause 194(8.3) 269(5.7)

0.68(0.57-0.82)

<0.001

DeathfromCVcauses 137(5.9) 172(3.7)

0.62(0.49-0.77)

<0.001

HospitalizationforHF 95(4.1) 126(2.7)

0.65(0.50-0.85)

0.002

Nonfatalstroke 60(2.6) 150(3.2)1.24(0.92-1.67)

0.16

Fatalornonfatalstroke 69(3.0) 164(3.5) 1.18

(0.89- 0.26


1.56)*forsuperiority,noninferiorityp<0.001;**0.08forsuperiority,noninferiority<0.001

• NNT=39overa3-yeartimeframe• 14%reductioninprimaryoutcomedrivenby38%reductionincardiovascular

death• Clearafter3monthsoftherapy(seeFigure6)

Renal(seeFigure7)

Outcome(%) Empagliflozin(n=4124)

Placebo(n=2061)

HazardRatio(95%CI)

IncidentorworseningnephropathyorCVdeath 16.2 23.6 0.61(0.55-0.69)

Incidentorworseningnephropathy 12.7 18.8 0.61(0.53-0.70)

Progressiontomacroalbuminuria 11.2 16.2 0.62(0.54-0.72)

DoublingofSCr 1.5 2.6 0.56(0.39-0.79)Initiationofrenalreplacementtherapy 0.3 0.6 0.45(0.21-0.97)

Incidentalbuminuria 51.5 51.2 0.95(0.87-1.04)Resultsconsistentacrossallpre-specifiedsubgroups(stratificationbyeGFR)andacrossbothdosesofempagliflozin

HbA1c(meandifferencevsplacebo,95%CI)

Timeperiod Empagliflozin10mg(n=2345) Empagliflozin25mg(n=2342)Week12 -0.54(-0.58,-0.49) -0.60(-0.64,-0.55)Week94 -0.42(-0.48,-0.36) -0.47(-0.54,-0.41)Week206 -0.24(-0.40,-0.08) -0.36(-0.51,-0.20)

SafetyOutcomes(%)

Placebo(n=2333)

Pooledempagliflozin(n=4687)

Anyadverseevent 91.7 90.2Confirmedhypoglycemicevent

27.9 27.8

UTI Male 9.4 10.5Female 40.6 36.4

DKA <0.1 0.1Bonefracture 3.9 3.8Acuterenalfailure 6.6 5.2

CONCLUSIONS

Author’sThoughts

Patientswithtype2diabeteswhowereathighcardiovascularriskandreceivedtreatmentwithempagliflozinhadsignificantlylowerratesofcardiovascularrelateddeathswhencomparedtostandardofcare.Empagliflozinalsoappearstobeassociatedwithaslowerprogressionofkidneydiseasedespitestandardtreatments.Whilereducedriskofmanyrenaloutcomeswereobserved,itdidnotpreventincidentalbuminuria.



• Largesamplepopulation• Well-designedoutcomesstudy• Largenumberofpatientson

standardofcare• Gooddistributionofbaselinerenal

function• Fundingsource

• CannotbeextrapolatedtopatientswithlowCVrisks

• BaselineBPandA1cneargoal-limitsexternalvalidity

• Renaloutcomeswereasecondaryendpoint

• FundingsourceInterpretation TheEMPA-REGoutcomesstudyprovidesencouragingdatafortheuseof

empagliflozinasanantidiabeticagentwithpotentialforcardiacandrenalprotectivebenefits.Longtermtherapyappearstobesafeandefficacyismaintainedeveninalongtermsetting.

Figure6.CardiovascularOutcomesfromEMPA-REGstudy18DeathfromcardiovascularcauseandhospitalizationforheartfailurearethetwomostrobustfindingsintheEMPA-REGOutcomestrial.Coxregressioncurvesbelowrepresenttheriskofanevent,whetheritbedeathfromcardiovascularcausesorheartfailurehospitalizationovertime.Benefitsareseenearlyintreatmentandaremaintainedthroughoutthestudyperiod.


Figure7.KaplanMeiercurvesofselectedrenaloutcomesfromtheEMPA-REGoutcomesRegressioncurvesbelowrepresenttheriskreductionobservedovertimewithempagliflozinascomparedtoplacebo.

FutureStudies20Drugname Studyname Description

Canagliflozin(Invokana®)

CANVAST2DMwithinadequateDMcontrolandCVD• Primary:compositeCVdeath,nonfatalMI,

nonfatalstroke

CANVAS-R Studyingrenalendpointsover78-156weeksTobecompletedApril2017

CREDENCET2DMwithdiabeticnephropathy• Primary:ESRD,doublingofSCr,renalor

cardiovasculardeath

Dapagliflozin(Farxiga®) DECLARE-TIMI58 Primary:MI,ischemicstroke,CVrelateddeathTobecompletedApril2019

SummaryandConclusions

1. SGLT’sroleinglucosehomeostasispresentsaninterestingtargetfornotonlyglucosehomeostasis,burforrenalandcardiacprotection.

2. Pathophysiologyisunclear,butappearstobemultifactorialandrelatedtoreductioninarterialstiffnessandrenaldamage.

3. BenefitsappeartobeindependentofSGLT-2doseorrenalfunctionandindicateclass-widemodificationofearlyendpointsofrenalandcardiovasculardisease.

4. TheEMPA-REGstudydemonstratedcardioprotectiveandrenalprotectiveeffectsindiabeticpatientswithhighcardiovascularriskfactors.


FinalThoughts

1. Inthisgroupofpatientswithtype2diabeteswhoareathighriskforcardiovasculareventsonstandardoftreatment,empagliflozinappearstobebeneficialinsecondarypreventionofcardiovasculareventsandprogressionofrenaldamage.

2. Itremainstobeseenifempagliflozinmaybebeneficialforprimarypreventioninapopulationinitiatedontherapyearlierindiseaseprogression

3. Furtherstudiesarewarrantedtofullyassessmechanismsbehindtheseimprovements,toclearlyelucidateeffectsinpatientswithoutcardiovasculardiseaseandestablishbenefitasaclass-wideeffect.

References:

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AppendixA.Abbreviations

A1c/HbA1chemoglobinA1cACE-IaceinhibitorARBangiotensinreceptorblockerARFacuterenalfailureCKDchronickidneydiseaseCVcardiovascularCVDcardiovasculardiseaseDCCTdiabetescontrolandcomplicationstrialDKAdiabeticketoacidosisDKDdiabetickidneydiseaseDMdiabetesmellitusDNdiabeticnephropathyEDICepidemiologyofdiabetesinterventionsandcomplications

ESRDendstagerenaldiseasemAlb/CrmicroalbumintocreatinineratioMImyocardialinfarctionPADperipheralarterydiseaseRAASrenin-angiotensin-aldosteronesystemSGLTsodiumglucoseco-transporterT1DM/T2DMType1/Type2TGFtubuloglomerularfeedbackUAunstableanginaUKPDSUnitedKingdomprospectivediabetesstudyUTIurinarytractinfection

AppendixB.SupplementalInformationonSGLT2inhibitorsAvailableintheUnitedStates13-15

ChemicalName OralBioavailability Metabolism ExcretionCanagliflozin 65% Glucuronidation 33%renalDapagliflozin 78% Glucuronidation 75%renal

Empagliflozin Rapidandcomplete Glucuronidation 54.4%renal,50%unchanged


Selectadverseeffects11,13-15

1. DKA:<1%a. PotentialreportingbiasasthisisusuallynotreportedinT2DMb. Treatmentshiftsfromcarbohydratemetabolismtolipidoxidation

i. Leadstoketogenesisii. Alsocontributestochangesinlipidpanel(↑HDLandLDL)

2. UTI:6%3. Genitalmycoticinfections:11-12%females/4%males4. Bonefracture/reducedbonemineraldensity:1-2%

a. Minorelevationinserumphosphorusincreasesparathyroidhormonei. Effectsboneturnoverii. Increasedinrenalimpairment

5. Bladdercancer:<1%a. PotentialbiasduetoincreasedmonitoringfromincreaseinUTIandmycoticinfectionsb. Reportedonlyindapagliflozininpostmarketingreports

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