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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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6

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