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
CATLINGRISHAM-TAKAC,PHARMDPLEIOTROPICEFFECTSOFSGLT-2INHIBITORS 3
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
CATLINGRISHAM-TAKAC,PHARMDPLEIOTROPICEFFECTSOFSGLT-2INHIBITORS 4
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
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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.
CATLINGRISHAM-TAKAC,PHARMDPLEIOTROPICEFFECTSOFSGLT-2INHIBITORS 6
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
CATLINGRISHAM-TAKAC,PHARMDPLEIOTROPICEFFECTSOFSGLT-2INHIBITORS 7
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
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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
CATLINGRISHAM-TAKAC,PHARMDPLEIOTROPICEFFECTSOFSGLT-2INHIBITORS 9
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)
CATLINGRISHAM-TAKAC,PHARMDPLEIOTROPICEFFECTSOFSGLT-2INHIBITORS 10
• 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
CATLINGRISHAM-TAKAC,PHARMDPLEIOTROPICEFFECTSOFSGLT-2INHIBITORS 11
CONCLUSIONS
Author’sConclusion
DapagliflozinwasfoundtobesuperiortoplaceboinreducingHbA1candachievinga3itemcompositerepresentingreductionincardiovascularriskinapopulationofpatientswithT2DManddocumentedCVD.
Discussion Strengths Weaknesses
• Studydesign• Large%ofpatientsonstandard
therapy• Longfollowupperiod
• Dualprimaryendpoint• Useofsurrogatemarkers• Unclearwhattypeoflipidlowering
therapypatientswereon• LimitedinformationonCHFpatients• Vaguesafetyendpoints
Interpretation
Thistrialdemonstratesthedurabilityofefficacyofdapagliflozininpatientswithcardiovasculardisease.Theendpointsstudiedaresurrogatemarkersandsuggesttheassociationwithtreatmentandcardiovascularbenefits.However,safetyoutcomeswereunclearandnotfullyelucidated.
Figure5.ChangeinSystolicBloodPressureinDapagliflozinComparedwithPlaceboRepresentsdurabledifferencebetweentreatmentgroupsatalltimepointsthroughoutthetrialperiod
CATLINGRISHAM-TAKAC,PHARMDPLEIOTROPICEFFECTSOFSGLT-2INHIBITORS 12
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
CATLINGRISHAM-TAKAC,PHARMDPLEIOTROPICEFFECTSOFSGLT-2INHIBITORS 13
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
CATLINGRISHAM-TAKAC,PHARMDPLEIOTROPICEFFECTSOFSGLT-2INHIBITORS 14
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.
CATLINGRISHAM-TAKAC,PHARMDPLEIOTROPICEFFECTSOFSGLT-2INHIBITORS 15
Discussion Strengths Weaknesses
• Largesamplepopulation• Well-designedoutcomesstudy• Largenumberofpatientson
standardofcare• Gooddistributionofbaselinerenal
function• Fundingsource
• CannotbeextrapolatedtopatientswithlowCVrisks
• BaselineBPandA1cneargoal-limitsexternalvalidity
• Renaloutcomeswereasecondaryendpoint
• FundingsourceInterpretation TheEMPA-REGoutcomesstudyprovidesencouragingdatafortheuseof
empagliflozinasanantidiabeticagentwithpotentialforcardiacandrenalprotectivebenefits.Longtermtherapyappearstobesafeandefficacyismaintainedeveninalongtermsetting.
Figure6.CardiovascularOutcomesfromEMPA-REGstudy18DeathfromcardiovascularcauseandhospitalizationforheartfailurearethetwomostrobustfindingsintheEMPA-REGOutcomestrial.Coxregressioncurvesbelowrepresenttheriskofanevent,whetheritbedeathfromcardiovascularcausesorheartfailurehospitalizationovertime.Benefitsareseenearlyintreatmentandaremaintainedthroughoutthestudyperiod.
CATLINGRISHAM-TAKAC,PHARMDPLEIOTROPICEFFECTSOFSGLT-2INHIBITORS 16
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.
CATLINGRISHAM-TAKAC,PHARMDPLEIOTROPICEFFECTSOFSGLT-2INHIBITORS 17
FinalThoughts
1. Inthisgroupofpatientswithtype2diabeteswhoareathighriskforcardiovasculareventsonstandardoftreatment,empagliflozinappearstobebeneficialinsecondarypreventionofcardiovasculareventsandprogressionofrenaldamage.
2. Itremainstobeseenifempagliflozinmaybebeneficialforprimarypreventioninapopulationinitiatedontherapyearlierindiseaseprogression
3. Furtherstudiesarewarrantedtofullyassessmechanismsbehindtheseimprovements,toclearlyelucidateeffectsinpatientswithoutcardiovasculardiseaseandestablishbenefitasaclass-wideeffect.
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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
CATLINGRISHAM-TAKAC,PHARMDPLEIOTROPICEFFECTSOFSGLT-2INHIBITORS 19
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