Proposed Scope of Work for KDIGO Clinical ... - KIDNEY DISEASE€¦ · Management of Diabetes and...

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ProposedScopeofWorkforKDIGOClinicalPracticeGuidelineonthe

ManagementofDiabetesandChronicKidneyDisease

Introduction

KidneyDisease:ImprovingGlobalOutcomes(KDIGO)isanot-for-profitorganizationestablishedtodevelopandimplementglobalclinicalpracticeguidelinesforpatientswithkidneydisease.Sinceitsinceptionin2003,KDIGOhaspublishedtenguidelines,beginningwiththeKDIGOClinicalPracticeGuidelineforthePrevention,Diagnosis,Evaluation,andTreatmentofHepatitisCinChronicKidneyDisease(CKD).ThisproposedScopeofWorkisdesignedtobrieflydescribetherationalefordevelopmentofaguidelineonthemanagementofpatientswithdiabetesandCKDandtooutlinethetopicsthatthisguidelineintendstoaddress.WearenowseekingpubliccommentsontheproposedScopeofWorkpresentedheretoensurethatfeedbackfromallrelevantstakeholdersofthisglobalguidelineisdulyconsideredbeforeaformalsystematicreviewoftheliteratureisundertaken.

Background

Theprevalenceofdiabetesaroundtheworldhasreachedepidemicproportions.Whilediabetesisalreadyestimatedtoaffectmorethan8%oftheglobalpopulation−morethan425millionpeople−thisisprojectedtogrowtoover629millionpeopleby2045.1Ithasalsobeenestimatedthat40%ormoreofpeoplewithdiabeteswilldevelopCKD,includingasignificantnumberwhowilldevelopend-stagekidneydisease(ESKD)requiringdialysisandtransplantation.2PreventionofCKDindiabetesisthereforeahighpriority.DiabetesisalreadytheleadingcauseofESKDinmostdevelopedcountries,andthegrowthinthenumberofpeoplewithESKDaroundtheworldoverrecentdecadeshasbeendrivenprimarilybygrowthinthenumberofpeoplewithdiabetesastheunderlyingcause.3,4Inpeoplewithdiabetes,increasingalbuminuriaanddecliningGFR

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canbeduetoclassicdiabeticglomerulopathy.However,reducedGFRwithoutalbuminuriaisanincreasinglyrecognizedphenotypethatmayhavedifferentunderlyingmechanisms,andpeoplewithdiabetescandevelopkidneydiseaseforreasonsotherthandiabetesitself.Assuchtheneedfordiagnosticandprognostickidneybiopsiesinpeoplewithdiabetesremainsamatterofdiscussion.Thepresenceofkidneydiseaseisassociatedwithamarkedlyincreasedriskofcardiovasculardiseaseanddeathinpeoplewithdiabetes.5,6ThereforeaggressiveinterventionagainstcardiovascularriskfactorsisveryimportantinpeoplewithdiabetesandCKD.7Recentdatademonstratedeclineinincidenceofcardiovascularandothercomplicationsinsomepopulationsprobablyduetobetterscreeningforandtreatmentofriskfactors,butdespitethis,adeclineinESKDismuchlessapparent.8

AsprovisionofdialysistopeoplewithESKDconsumesapproximately6%ofallhealthcarecostsintheUSandmoreinsomeothercountries,4thereisastrongeconomicimperativetoimproveoutcomesforpeoplewithdiabetesandkidneydiseaseinadditiontothestrongpersonalandsocietalhealthrationale.Whiletheidentificationofrenin-angiotensinblockadeasaneffectivestrategyforthepreventionofESKDintype1andtype2diabetesmellitusalmost2decadesagowasamajorstepforward,9-11subsequentresearchhashadlimitedsuccessatmostinbuildinguponthesegains.Anumberofpromisingtreatmentshavebeenfoundtobeineffectiveorharmful,manyofwhichhavenowbeenabandonedinthispopulation.Ontheotherhand,anumberofnewagentsarecurrentlybeingtested,whichmayhopefullyimproveoutcomesforpeoplewithdiabetesandkidneydisease.TreatinghyperglycemiainpeoplewithdiabetesandCKDischallengingduetotheriskofhypoglycemiaandtheneedtoadjustselectionanddosingofmedicationsaccordingtolevelofGFR.Furthermore,assessingmeanbloodglucoseiscomplicatedinadvancedCKDbecauseoflimitationsofhemoglobinA1c(HbA1c).

Importantlysomeofthenewdrugclassesnowavailableforreducingbloodglucoseintype2diabetessuchassodium-glucosecotransportertype2(SGLT2)inhibitorsandglucagon-like-peptide-1(GLP-1)receptoragonistshaveturnedouttohavebeneficialeffectsoncardiovascularoutcomeinpeoplewithpreviouscardiovasculardisease,includingpatientswithmoderateCKD.12,13Inaddition,someoftheseagentsexertedbeneficialeffectsonrenaloutcomeparametersmeasuredassecondaryendpoints.14,15Thisincludedreductioninprogressionofalbuminuria,asurrogateforapotentialrenalbenefit,butforSGLT2inhibitorsareductioninlossofGFRwasalsodemonstrated.16,17

GiventhehighprevalenceofdiabetesandCKD,thelargehealthimpactofESKD,andthestrongrelationshipsofCKDwithcardiovascularmorbidityanddeath,KDIGOhas

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determinedthatthedevelopmentofaclinicalpracticeguidelineforthispatientpopulationistimelyandappropriateinviewofrecentdevelopmentinvariousmanagementandtreatmentoptions.

Topic1:PrimarypreventionofCKDamongpeoplewithdiabetesCKD,asrepresentedbyalbuminuriaorreducedGFR,isacommoncomplicationoftype1andtype2diabetes.Durationofdiabetes,glycemiccontrol,andotherCKDriskfactorsareknowntobeassociatedwiththeprevalenceandincidenceofCKD.Randomizedcontrolledtrialshaveshownthatintensiveglycemiccontrolandspecificglucose-loweringagentsreducetheriskofdevelopingCKDornew-onsetalbuminuria,18whileresultsoftrialsoflifestyleinterventionsandRASblockadeforprimaryCKDpreventionarelessclear.Relevantkeyquestions:HowcanwepreventonsetofCKDinpatientswithdiabetes?Whatistheevidenceforglycemiccontrolandarethereothereffectivestrategies?IsRASblockadeindicatedinpatientswithalbuminuriaA1category(<30mg/gor<3mg/mmol)forCKDprevention,regardlessofbloodpressure?Whatisthedefinitionofdiabetickidneydisease(DKD)?HowisDKDdiagnosedandwhatistheroleofkidneybiopsyindiagnosis?IsthereutilityinthestagingofDKD?Topic2:SecondarypreventionofCKDprogressionamongpeoplewithdiabetesPatientswithdiabetesandeitheralbuminuriaorreducedGFRareatriskofprogressingtoESKD.Infact,diabetesisthemostcommoncauseofESKDinmanycountries.Inaddition,riskofCKDcomplications(includingcardiovasculardisease)increaseswithseverityofCKD.Therefore,interventionstohaltorslowprogressionofCKDareimportanttoimprovetheoutcomesofpeoplewithdiabetesandCKD.Currenttherapeutictargetsincluderenin-angiotensinsystemandbloodpressurecontrol,aswellasglycemiccontrol.Othertherapeuticagentsunderdevelopmentnowtargettheroleofendothelialfunction,oxidativestress,andfibrosis.

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Relevantkeyquestions:ForwhichpatientswithdiabetesandprevalentCKDisthereastrongindicationforRASinhibition?DoestreatmentofglycemiapreventprogressionofestablishedCKDtoESKD?WhatistheoptimalapproachtoimplementRAASblockadeindiabetesandCKD?IstherearemainingrolefordualRASblockadeamongpatientswithdiabetesandCKD?WhatistheroleofmineralocorticoidreceptorantagonistsinthetreatmentofdiabetesandCKD?ArethereadditionaltreatmentsthatshouldbeconsideredforpreventingprogressionofCKDindiabetes(e.g.,SGLT2inhibitors,dipeptidylpeptidase-4inhibitors,endothelinantagonists,bardoxolone,pentoxifyline,anti-inflammatoryagents,etc.)?Topic3:MeasurementofglycemiainCKDHbA1cistheacceptedtherapeutictargetfortitratingglucosecontrolamongpeoplewithdiabetes.InadvancedCKD,changestohemoglobinkineticscomplicateinterpretationofHbA1c.Alternativebiomarkersofmeanglycemiahavenowbeendevelopedandevaluatedinobservationalstudies.However,itisunclearwhetherusingthesealternativebiomarkersimprovesglycemiamanagement.Withtheadvanceofcontinuousglucosemonitoringtechnology,measuringglucoseitselfhasbeenshowntoimproveglycemiccontrolamongpeoplewithdiabetes(withoutCKD).Oftheseoptionsformeasuringglycemia,theoptimalapproachamongpeoplewithdiabetesandCKDisnotclear.Relevantkeyquestions:DoesCKDmodifytheaccuracyandprecisionofHbA1cinascertainingglycemiaamongpeoplewithdiabetes?InCKDandthoseondialysistherapy,doalternativebiomarkerssuchasglycatedalbuminorfructosaminecorrelatemorepreciselywithglycemiathanHbA1c?

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InCKDandthoseondialysistherapy,doalternativebiomarkerssuchasglycatedalbuminorfructosaminecorrelatemorepreciselywithclinicaldiabetescomplicationsorbetterguideglucose-loweringtreatmentintensitycomparedwithHbA1c?IsselfmonitoredbloodglucoseorcontinuousglucosemonitoringofaddedvalueinpatientswithdiabetesandCKD?Topic4:GlycemiamanagementinCKDIngeneral,intensiveglycemiccontrolreducestheriskofdiabetescomplications(e.g.,CKD,retinopathy,neuropathy,andcardiovasculardisease)attheexpenseincreasedriskofhypoglycemia.Inaddition,individualglucose-loweringmedicationshavespecificbenefitsandrisks.Forexample,someSGLT2inhibitorsandGLP-1receptoragonistsreducetheriskofCKDorcardiovasculareventswithotherbeneficialeffects(e.g.,bloodpressureandweightreduction),thoughadverseeffects(e.g.,hypoglycemia,bonedisease)couldalsovary.InCKD,benefitsandrisksofintensiveglycemiccontrolingeneralandspecificglucose-loweringdrugsmayvary,andsomedrugsrequiredosereductionsorarecontraindicated.TheimpactofCKDonglycemiamanagementalsodiffersacrossthespectrumofCKDseverity,beinglargestamongpatientsondialysistherapy.Therefore,amongpeoplewithdiabetesandCKD,optimalglycemiatargetsandthepreferredagentsusedtoachievethemarenotclear.Relevantkeyquestions:WhatistheoptimaltargetrangeforHbA1c(oralternativeglycemiamarkers)inCKD?DotargetsvaryinaccordancetoseverityofCKD(e.g.,GFRcategories)?Aretherepreferredclasses/agentsfortreatinghyperglycemiainpatientswithdiabetesandCKD?HowdoestheselectionofagentsdifferbyseverityofCKD?Aretherepreferredclasses/agentsinpatientswithdiabetesandCKDtopreventrenal,cardiovascularandothermicrovascularcomplications?WhatistheimpactofhypoglycemiainpatientswithdiabetesandCKD?TowhatextentshouldinsulindosesbemodifiedinadvancedCKD?ShouldtreatmentbechangedwhenpatientswithCKDG5transition/startdialysis?

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Topic5:LifestyleandnutritionamongpeoplewithdiabetesandCKDExercise,weightloss,smokingcessation,andmodificationofdietaryprotein,sodium,andpotassiumareoftenadvisedtopreventCKDprogressionandcardiovascularcomplications.However,effectivenessoftheseinterventionsremainsunclear.Relevantkeyquestions:Isthereevidenceforabenefitoflifestyleintervention(e.g.,weightloss,exercise,physicalactivity)ondeclineinGFRorcardiovascularriskamongpatientswithdiabetesandCKD?Isthereanoptimaldietaryprotein,sodiumandpotassiumintakeinpatientswithdiabetesandCKD?WhatistheroleofpotassiumbindersinpatientswithdiabetesandCKD?Topic6:CardiovascularriskreductionamongpeoplewithdiabetesandCKDPatientswithdiabetesandCKDareathighriskofcardiovascularevents,includingcoronaryheartdisease,stroke,peripheralvasculardisease,heartfailure,andarrhythmia.Inadditiontoglycemiccontrolandlifestyleinterventions,bloodpressurelowering,lipidlowering,andantiplateletmedicationsarecommonlyusedtoreducecardiovascularrisk.BloodpressureloweringalsoaffectsCKDprogression.Itisnotclearwhetherdiabetesaltersoptimalbloodpressuretargets.RASinhibitorsarerecommendedforbloodpressureloweringamongpatientswithalbuminuria,butit’snotclearforexactlywhichpatientsRASinhibitorsshouldberecommendedoverotherantihypertensivemedications.QuestionssurroundingbloodpressuremanagementinCKDpatientswithdiabeteswillbeaddressedbytheupcomingKDIGOBloodPressureguidelineupdatingWorkGroup.Recentclinicaltrialshavealsodemonstratedcardiovascularbenefittointensifyinglipid-loweringtherapybeyondtypicalstatintherapy,targetinglowLDLcholesterolconcentrationsoraddingadditionalagentstostatintherapy.TheextenttowhichthisapproachmaybeusefulforpatientswithDKDisnotclear.

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Relevantkeyquestions:WhatistheoptimaltreatmentforCVDriskreductioninCKDG3a-G5Dpatientswithdiabetes?WhatistheoptimallipidinterventionstrategyinCKDG3a-5Dpatientswithdiabetes?Whatisknownabouttherisk-benefitratioofanti-plateletagentsandanticoagulantsinpatientswithCKDanddiabetes?Aretherenewagentsindevelopment(e.g.,CETPinhibitors,PCSK9inhibitors,mineralocorticoid-receptorantagonists)thatmightbeparticularlypromisingforpeoplewithdiabetesandCKD?

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References1. IDFAtlas2017.http://www.diabetesatlas.org/IDF_Diabetes_Atlas_8e_interactive_EN/

(AccessedMarch12,2018)

2. AmericanDiabetesA.10.MicrovascularComplicationsandFootCare:StandardsofMedicalCareinDiabetes-2018.DiabetesCare2018;41:S105-S18.

3. VillarE,ChangSH,McDonaldSP.Incidences,treatments,outcomes,andsexeffectonsurvivalinpatientswithend-stagerenaldiseasebydiabetesstatusinAustraliaandNewZealand(19912005).DiabetesCare2007;30:3070-6.

4. USRDS2013AnnualDataReport:AtlasofChronicKidneyDiseaseandEndStageRenalDiseaseintheUnitedStates2013.athttp://www.usrds.org/2013/pdf/v2_ch12_13.pdf.)

5. NinomiyaT,PerkovicV,deGalanBE,etal.Albuminuriaandkidneyfunctionindependentlypredictcardiovascularandrenaloutcomesindiabetes.JAmSocNephrol2009;20:1813-21.

6. ToyamaT,FuruichiK,NinomiyaT,etal.TheimpactsofalbuminuriaandloweGFRontheriskofcardiovasculardeath,all-causemortality,andrenaleventsindiabeticpatients:meta-analysis.PloSone2013;8:e71810.

7. GaedeP,Lund-AndersenH,ParvingHH,PedersenO.Effectofamultifactorialinterventiononmortalityintype2diabetes.NEnglJMed2008;358:580-91.

8. GreggEW,LiY,WangJ,etal.Changesindiabetes-relatedcomplicationsintheUnitedStates,1990-2010.NEnglJMed2014;370:1514-23.

9. BrennerBM,CooperME,deZeeuwD,etal.Effectsoflosartanonrenalandcardiovascularoutcomesinpatientswithtype2diabetesandnephropathy.NEnglJMed2001;345:861-9.

10. LewisE,HunsickerL,BainR,RhodeR.Theeffectofangiotensin-converting-enzymeinhibitionondiabeticnephropathy.NEnglJMed1993;329:1456-62.

11. LewisEJ,HunsickerLG,ClarkeWR,etal.Renoprotectiveeffectoftheangiotensin-receptorantagonistirbesartaninpatientswithnephropathyduetotype2diabetes.NEnglJMed2001;345:851-60.

12. MarsoSP,DanielsGH,Brown-FrandsenK,etal.LiraglutideandCardiovascularOutcomesinType2Diabetes.NEnglJMed2016;375:311-22.

13. ZinmanB,WannerC,LachinJM,etal.Empagliflozin,CardiovascularOutcomes,andMortalityinType2Diabetes.NEnglJMed2015;373:2117-28.

14. MannJFE,OrstedDD,Brown-FrandsenK,etal.LiraglutideandRenalOutcomesinType2Diabetes.NEnglJMed2017;377:839-48.

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15. WannerC,InzucchiSE,LachinJM,etal.EmpagliflozinandProgressionofKidneyDiseaseinType2Diabetes.NEnglJMed2016;375:323-34.

16. WannerC,InzucchiSE,ZinmanB.EmpagliflozinandProgressionofKidneyDiseaseinType2Diabetes.NEnglJMed2016;375:1801-2.

17. NealB,PerkovicV,MahaffeyKW,etal.CanagliflozinandCardiovascularandRenalEventsinType2Diabetes.NEnglJMed2017;377:644-57.

18. RuospoM,SaglimbeneVM,PalmerSC,etal.Glucosetargetsforpreventingdiabetickidneydiseaseanditsprogression.CochraneDatabaseofSystematicReviews2017,Issue6.Art.No:CD010137.DOI:10.1002/14651858.CD010137.pub2.