2019 wade pp presentation. dr. alicic. updatedwadepage.org/files/2019conf/2019 wade pp... ·...
TRANSCRIPT
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SGLTinhibitionandDiabeticKidneyDisease
RadicaAlicic,MD,FHM,FACPAssociatedProfessorofMedicine
UniversityofWashingtonSchoolofMedicineProvidenceHealthCare,Spokane,Washington
WADEConferenceApril27,2019
DisclosuretoParticipants
NoticeofRequirementsforSuccessfulCompletion:Forsuccessfulcompletion,participantsarerequiredtobeinattendanceinthefullactivityandcompletetheprogramevaluationattheconclusionoftheeducationalevent.PresenterConflictsofInterest/FinancialRelationshipsDisclosures:Noconflictsexist.DisclosureofRelevantFinancialRelationshipsandMechanismtoIdentifyandResolveConflictsofInterest:Noconflictsofinterest.Non-EndorsementofProducts:AccreditedstatusdoesnotimplyendorsementbyAADE,ANCC,ACPEorCDRofanycommercialproductsdisplayedinconjunctionwiththiseducationalactivity.Off-labelUse:ParticipantswillbenotifiedbyspeakerstoanyproductusedforapurposeotherthanthatforwhichitwasapprovedbytheFoodandDrugAdministration.
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Outline
• Diabetickidneydiseaseepidemiology• Roleofthekidneyinglucosehomeostasis• Sodiumglucosecontransporters(SGLT)• ReviewofthekidneyoutcomesinCardiovascularOutcomesTrials(CVOT)
• OverviewofCREDENCE• FieldguideforuseofSGLT-2inhibitorscircamid-2019
• FutureofSLGTsinhibitors
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DiabeticKidneyDisease(DKD)
• Apersistentelevatedurinaryalbuminexcretion(UAE)≥30mg/g,apersistentreductioninestimatedglomerularfiltrationrate(eGFR)<60ml/min/1.73m2,orboth
• Epidemiologicaldatashowthatabout30%ofpatientswithDM1,andabout40%ofDM2patientshaveDKD
• Post-mortemhumanstudiesshowthatupto60%ofdiabeticpatientshavestructuralchangesofDKD
KidneyDiseaseImprovingGlobalOutcomeswww.kdigo.org
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NaturalHistoryofDKD
AlicicRZetal.ClinJAmSocNephrol,2017;12:2032–2045.etal.CJASN2017;12:2032-2045
DiabeticKidneyDisease(DKD)
• WorldwideleadingcauseofESKD(inUSabout44%ofalldialysispatientshavediabetes)
• ESKDandneedforKRT=deathsentenceinlargepartoftheworld
• TheglobalnumberofdeathsattributedtoDKDroseby94%between1990-2012
CourserWGetal.KidneyInt2011;80:1258LozanoRetal.Lancet2012;380:2095
Mortality and Morbidity of DKD Patients
• Theprevalenceofcardiovascular(CV)disease:70%amongpatientsaged66andolderwhohaveCKDcomparedwith35%amongthosewhodon’thaveCKD
• DiabeticpatientswithESKDhave10to100-foldhighermortalityrisk
• Mostoftheexcessall-causeandCVdeathriskindiabetesisattributabletothepresenceofdiabetickidneydisease
UnitedStatesRenalDataSystem;www.usrds.orgAdleretal.KidneyInt.2003,63:225–232Afkarianetal.JAmSocNephrol.2003,24:302-308.
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MortalityRates
Adleretal,KidneyInt,2003;63(1):225–232
PrevalenceofDiabeticKidneyDiseaseisIncreasingDespiteContemporaryManagement
AllDiabeticKidneyDisease
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4
2
01988-1994 1999-2004 2005-2008
Prevalence(MillionsofCases)
DeBoeretal.JAMA.305:2532-2539,2011
KidneysandGlucoseHomeostasisPhysiologicconditions-Gluconeogenesis(20%-25%)-Reabsorptionofglucoseinthekidney(160-180g/d)- Uptakeofglucosefromthecirculation(10%)
Indiabetes- Postabsorptivegluconeogenesis- Reabsorptionofglucoseinthekidney
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NeumillerJJetal.JASN.2017,12:2263-2274
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1980s
French chemist isolates phlorizin from apple tree bark
Joseph von Mering demostrates that ingestion ofhigh doses of phlorizin causes glycosuria
First-in-human testing of phlorizin
Discovery of tissue distribution of SGLT1/2
Phlorizin inhibits SGLT1 and SGLT2
First SGLT2 inhibitor FDA approved
First dual SGLT1/2 inhibitorpending approval
1886 19331835 1995 2014 2019
efferentarteriole
normal PGC
afferentarteriole
maculadensa
proximalconvoluted
tubule
distalconvoluted
tubule
collectingduct
connectingtubule
descendinglimb ofHenle
ascendinglimb ofHenle
Bowman’scapsule
high PGC afferentvasodilation
reducedfeedback from
maculadensa
increased NaCl andglucose reabsorption
via SGLT-2
decreaseddistal delivery
of NaCl
increased NaCl andglucose filtration
~90% glucoseresorption via SGLT-2
~10% glucoseresorption via SGLT-1
Sodium-glucose co-transporter-2 (SGLT-2)Sodium-glucose co-transporter-1 (SGLT-1)Sodium (Na)Chloride (Cl)GlucosePGC = pressure in glomerular capillary
A. Normal nephron B. Diabetic nephron
15AdaptedfromAlicicetal.,Diabetes2019;68:248-257.
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SodiumGlucoseCo-Transporters1and2SGLT-1andSGLT-2
• Undernormoglycemiathekidneysreabsorballoftheglucosefromtheglomerularfiltrate
• Energysavingmeasure• SLGT-2isexpressedintheproximal,SGLT-1inthedistaltubule~90%ofglucoseisreabsorbedviaSGLT-2~10%viaSGLT-1
U.S.ApprovedandApproval-PendingSGLT2andSGLT1AndSGLT2Inhibitors
• canagliflozin(Invokana)–March2013• dapagliflozin(Farxiga)–January2014• empagliflozin(Jardiance)–August2014• ertugliflozin(Steglatro)–2017• sotagliflozin(Zynquista)–pending
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MetabolicEffectsofSGLT-2Inhibition
• Glucoselossof70-80g/day• Weightloss• Natriuresisandosmouresiswithcontractionofplasmavolumeandincreaseinhematocritandalbumin
• ReductioninBP• Reductioninuricacidlevel• Concernsofdiabeticketoacidosis• ConcernsofAKIandhyperkalemia
ThomasandCherney(2018)DiabetologiaDOI10.1007/s00125-018-4669-0MazidiMetal.JAmHeartAssoc.2017,6:e004007
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CardioVascularOutcomes(CVO)Trials
• SinceDecember2008,theU.S.FDArequiresthatthecardiovascular(CV)safetyofallnewdrugsfordiabetesbedemonstratedtoexcludeanunacceptableincreasedrelativeCVrisk
• Non-inferioritytrialstoextendminimum2yearsandenrollamorevulnerablepopulationwithDM2
• HigherCVriskare“patientswithrelativelyadvanceddisease,elderlypatients,andpatientswithsomedegreeofrenalimpairment”
HirshbergBetal.,DiabetesCare2011;34:101-106
CV safety trials with drugs for type 2 diabetes.
MannucciEetal.DiabetesCare2016
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CardiovascularOutcomeEventTrialin
Type2DiabetesMellitusPatients(EMPA-REG)
• 7,020DM2participants• 10mg,25mgofempagliflozinorplacebo(1:1:1fashion)
• Meanage63yrs.• Followup:3years• DM2dx>10years• H/OMI(highCVrisk)• eGFR>30ml/min/1.73m²
CanagliflozinCardiovascular
AssessmentStudy(CANVAS)Program
• 10,142DM2participants• Canagliflozinvs.placebo• Meanage63yrs.• Follow-up:2.4years• DM2dx>10yrs.• HighCVrisk• eGFR>30ml/min/1.73m²
ZinmanBetal.NEnglJMed2015;373:2117
CardiovascularOutcomesandDeathfromAnyCauseEMPA-REG
EMPA-REGSub-groupAnalysisKidneyOutcomesinPatientswithDKD
• 2,000participanthadDKD:26%hadaneGFRbetween30-60ml/min/1.73m2,andcloseto40%ofparticipantshadalbuminuria(29%withmicroalbuminuriaand11%withmacroalbuminuria)
• SubgroupanalysesofparticipantswitheGFR<60mL/min/1.73m2ormacroalbuminuria
ZinmanBetal.NEnglJMed2015;373:2117
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WannerCetal.NEnglJMed.2016;375:323
KeyKidneyOutcomesinEMPA-REG
DoublingofSCr44%relativeriskreduction(1.5%vs.2.6%)Progressiontomacroalbuminuria38%relativeriskreductionInitiationofRRT55%relativeriskreductionSlowingGFRdecline0.19±0.11vs.1.67±0.13ml/min/1.73m2/peryear,P<0.001)
NealBetal.NEnglJMed,2017;377:644-657.
CardiovascularOutcomesintheIntegratedCANVASProgram.
NealBetal.NEnglJMed2017;377:644-657.
Effects of Canagliflozin on Cardiovascular, Kidney, Hospitalization, and Death Events in the Integrated CANVAS Program.
HospitalizationforHeartFailure33%relativeriskreductionProgressionofalbuminuria27%relativeriskreductionCompositekidneyoutcome(40%reductionineGFR,RRT,DeathfromKidneycauses40%relativeriskreduction