代謝記憶與糖尿病微血管病變(英文版)

“TheMetabolicMemoryandPathogenesisofDiabeticMicrovascularComplications”AntonioCerielloCHN/DOX/0317/0011validuntilApril20182000151

million2013382million2035592

millionEstimatedglobalprevalenceofdiabetesInternationalDiabetesFederation.IDFDiabetesAtlas,1stand6thEditions.Diabetesisaglobaldisease2CHN/DOX/0317/0011validuntilApril2018DCCT/EDIC-Long-termMicrovascularRiskReduction

inType1Diabetes3DCCT/EDICResearchGroup.NEnglJMed.2000;342:381-389ComplicationRiskreductionwithintensivetherapy(%)aAfter6.5yrinDCCTbAfter4additionalyrinEDICcRetinopathy3-stepworsening6377Macularedema2672Proliferativeorseverenonproliferative4775Lasertherapy5177NephropathyMicroalbuminuria(≥40mg/24h)3953Clinicalgradeproteinuria(≥300mg/24h)5486CHN/DOX/0317/0011validuntilApril2018Inindividualswithtype1

diabetes,intensive

diabetes

treatmentyieldsdurablerenalbenefitsthatpersistforatleast18yearsafteritsapplication.DCCTINTandtheattendant6.5yearsoflowerHbA1chadlong-termsalutaryeffectsonthedevelopmentandprogressionofatherosclerosisandcardiovasculardiseaseduringthesubsequentfollow-upduringEDIC.Thepersistenteffectsofpriorintensivetherapyonneuropathymeasuresthrough14yearsofEDIClargelymirrorthoseobservedforother

diabetes

complications.IntensivecontroldelaystheonsetandslowstheprogressionofDR.Furthermore,theearlyeffectsofmetabolic

control

continuetoaccrueovermanyyearsdespitesubsequentcomparableglycemic

control

(metabolicmemory).

Afterameanof27years'follow-upofpatientswithtype1diabetes,6.5yearsofinitialintensivediabetestherapywasassociatedwithalowerall-causemortalityratewhencomparedwithconventionaltherapy.4Whereweare30yearslater--Lancet

Diabetes

Endocrinol2014;2:793-800--DiabetesCare2014;37:39-43--DiabetesCare2014;37:31-38--DiabetesCare2014;37:17-23--JAMA2015;313:45-53CHN/DOX/0317/0011validuntilApril2018Thebenefitsofearlytightcontrol:

UKPDS10-yearpost-trialfollow-up51.Holmanetal.NEnglJMed2008;359:1577–89;2.UKPDSStudyGroup.Lancet1998;352:837–53(*p<0.05;**p=0.052)-IntensivevsConventionalTreatmentIntensivevsConventionalTreatment10-yearPost-TrialFollowUp(Non-Interventional)20071(30years)1997(20years)TrialEnd1977-1991Randomisation12%*25%*16%**9%*24%*15%*AnydiabetesrelatedendpointMicrovasculardiseaseMyocardialinfarctionCHN/DOX/0317/0011validuntilApril2018Thebenefitsofearlytightcontrol:

UKPDS10-yearpost-trialfollow-up6R.R.Holmanetal.NEnglJMed2008;359:1577–89CHN/DOX/0317/0011validuntilApril2018ACCORD,ADVANCEandVADT:OutcomesACCORD1ADVANCE2VADT3Number10,25111,1401,791PrimaryCVD

endpoint10%(p=0.16)6%(p=0.37)*13%(p=0.12)Mortality

(overall)22%(p=0.04)7%(p=NS)6.5%(p=NS)CVmortality39%(p=0.02)12%(p=NS)25%(p=NS)*combinedmacroandmicro:

10%

,p=0.013 *microvascularendpoint:

14%

,p=0.01571.NEnglJMed2008;358:2545-59;2.NEnglJMed2008;358:2560-72;3.NEnglJMed2009;360:129-39;123CHN/DOX/0317/0011validuntilApril2018Earlyversuslateglycemicintervention81.UKPDSGroup.Lancet1998;352:837.;2.ADVANCECollaborativeGroup.NEnglJMed2008;358:2560.;3.ACCORDStudyGroup.NEnglJMed2008;358:2545.;4.Duckworthetal.NEnglJMed2009;360:129(n=3,867)(n=11,140)(n=10,251)(n=1,791)Durationofdiabetes(years)0*81011.5MeanbaselineHbA1c(%)7.17.58.39.4MeanbaselineFPG(mmol/L)8.08.59.711.4Meanage(years)53666260Microvascular

?=Macrovascular

=

=Diseaseprogression1234*NewlydiagnosedpatientswithnoprevioushistoryofCVD;FPG:fastingplasmaglucoseCHN/DOX/0317/0011validuntilApril2018TheMetabolicMemory9HolmanRetal.NEnglJMed.2008;359:1577-89ConventionaltherapySulfonylurea-insulinP=0.006DeathfromAnyCauseNo.atRiskConventionaltherapy1138106693966527028Sulfonylurea-insulin272925732276167568083DelPratoS,Diabetologia2009;52:1219–1226BeforeenteringVADTintensivetreatmentarmAfterenteringVADTintensivetreatmentarmGenerationofa“badglycaemiclegacy”DrivesriskofcomplicationsCHN/DOX/0317/0011validuntilApril2018Ongoingandrecentlycompletedcardiovascularoutcomestrialswithindiabetesenrolling>130,000patients1020132014201520162017201820192020GLP-1DPP-4TECOS

(Sitagliptin,DPP-4i)

n=14,671;follow-up~3yrs

Q12015-RESULTSCARMELINA

(Linagliptin,DPP-4i)

n=8,300;duration~4yrs

completionQ12018CAROLINA

(Linagliptin,DPP-4ivsSU)

n=6,000;duration~8yrs

completionQ32018SAVORTIMI-53

(Saxagliptin,DPP-4i)

n=16,492;follow-up~2yrsQ22013-RESULTSEXAMINE

(Alogliptin,DPP-4i)n=5,380;follow-up~1.5yrs

Q32013-RESULTSALECARDIO

(Aleglitazar,PPAR-αγ)n=7,226;follow-up2.0yrs

Termin.Q32013RESULTSLEADER

(Liraglutide,GLP-1)

n=9,340;duration3.5-5yrs

completionQ42015ELIXA

(Lixisenatide,GLP-1)

n=6,068;follow-up~2yrs

Q12015–RESULTSEMPA-REGOUTCOME*

(Empagliflozin,SGLT2i)

n=7,097;durationupto5yrsQ22015–RESULTSSUSTAIN6

(Semaglutide,GLP-1)

n=3,297;duration~2.8yrs

completionQ12016EXSCEL

(ExenatideQW,QWGLP-1)

n=14,000;duration~7.5yrs

completionQ12018OMNEON

(Omarigliptin,QWDPP-4i)

n=4,000;duration~3yrs

completionQ42017CANVAS

(Canagliflozin,SGLT2i)

n=4,407;duration4+yrs

completionQ22017CANVAS-R

(Canagliflozin,SGLT2i)

n=5,865;duration~3yrs

completionQ12017DEVOTE(Insulindegludec,basalinsulin)

n=7,637;durationupto5yrs

completionH22016FREEDOM-CVO

(ITCA650,GLP-1inDUROS)

n=4,000;duration~2yrs

completionQ32018CREDENCE(cardio-renal)

(Canagliflozin,SGLT2i)

n=3,700;duration~5.5yrs

completionQ12019REWIND

(Dulaglutide,QWGLP-1)

n=9,622;duration~6.5yrs

completionQ22019DECLARE-TIMI-58

(Dapagliflozin,SGLT2i)n=17,150;duration~6yrs

completionQ22019NCT01986881

(Ertugliflozin,SGLT2i)

n=3,900;duration~6.3yrs

completionQ22021HARMONYOUTCOMES

(Albiglutide,GLP-1)

n=9,400;duration~4yrscompletionbyQ22019OngoingSource:ClinicalT(30June2015).‘Completiondate’istheestimatedcompletiondatefortheprimaryoutcomesmeasure.*AlsoknownasC-SCADE-8.SGLT2iCHN/DOX/0317/0011validuntilApril2018Timetofirsteyeevent:Photocoagulationortreatmentwithintravitrealagents,vitreoushaemorrhage,orblindnessThecumulativeincidenceswereestimatedwiththeuseoftheKaplan–Meiermethod,andtheHRswiththeuseoftheCoxproportional-hazardregressionmodel.Thedataanalysesaretruncatedat54monthsbecauselessthan10%ofthepatientshadanobservationtimebeyond54months.11Presentedat52ndEASDAnnualMeeting,14September2016,Munich,GermanyHR:1.1595%CI(0.87-1.52)LiraglutidePlaceboPatientsatriskLiraglutide466846244566450944424366429742311689473Placebo467246364565448944174339426441881681454CI:confidenceinterval;HR:hazardratioCHN/DOX/0317/0011validuntilApril2018DiabeticretinopathycomplicationsSupplementaryFigure5A.KaplanMeierplotfortimefromrandomisationtofirstEAC-confirmeddiabeticretinopathycomplicationusing‘in-trial’datafromsubjectsinthefullanalysisset.HRisfromaproportionalhazardmodel.HR,1.76(95%CI,1.11;2.78)Events:50semaglutide;29placeboP=0.02NumberofpatientsatriskSemaglutide16481622161215951570154815351525Placebo16491636161716051576155815391530109Semaglutide,3.0%Placebo,1.8%12Marsoetal.NEJM[inpress]CHN/DOX/0317/0011validuntilApril2018PathogenesisofDiabeticComplications,TheMetabolicMemoryandTheroleofoxidativestressCHN/DOX/0317/0011validuntilApril2018Pathwaysofhyperglycaemia-inducedvasculardamageNADPH,nicotinamideadeninedinucleotidephosphatehydrogen;GFAT,glutaminefructosephosphateamidotransferase14Brownlee.Nature2001;414:813–20PolyolpathwayHexosaminepathwayProteinkinaseCpathwayAGEpathwayNADPHNADP+NAD+NADH

Sorbitol

FructoseGlnGlu

Glucosamine-6-P

UDP-GlcNAcGFATNADHNAD+

α-Glycerol-P

PKC

DHAP

DAG

Methylglyoxal

AGEs

Glucose

Glucose-6-P

Fructose-6-P

Glyceraldehyde-3-P1-3-Diphosphoglycerate

GAPDHNAD+NADHO2CHN/DOX/0317/0011validuntilApril201815CerielloA,DiabetesCare2003MitochondriaPKCNAD(P)HoxidaseNF-kBiNOSeNOSNONitrotyrosineDNAdamageGAPDHNAD+AdhesionmoleculesProinflammatoryCytokinesVEGFPARPEndothelialdysfunctionPolyolPathwayAGEFormationHexosamineFluxHyperglycemiaO2-O2-PeroxynitriteDiabeticComplicationsCHN/DOX/0317/0011validuntilApril2018The“MetabolicMemory:theroleofoxidativestress16I.ContinuousnormalorhighglucoseII.Persistenceofhighglucosestress21days14days7dayshighglucosenormalglucosenormalglucoseorhighglucoseIhnatMetal,Diabetologia2007CHN/DOX/0317/0011validuntilApril2018EffectsofhighglucoseforthreeweeksorfortwoweeksplusoneweekofnormalglucoseinHUVECs17*****Fibronectin**phospho-PKC-α/βII***p47phox****3-NY****PAR**BaxDensitometry(%5mM)CHN/DOX/0317/0011validuntilApril2018“Epidemiologicalandprospectivedatasupportalong-terminfluenceofearlymetaboliccontrolonclinicaloutcomes”“...earlyglycaemicenvironmentisrememberedinthetargetorgans

(i.e.,eye,kidney,heart,extremities)”“Theconceptofametabolicmemoryisofdiabeticvascularstressespersistingafterglucosenormalization”AntonioCeriello,MichaelA.IhnatandJessicaE.ThorpeThe"MetabolicMemory":IsMoreThanJustTightGlucoseControlNecessarytoPreventDiabeticComplications?Definingmetabolicmemory18JClin.Endocrinol.Metab.200994:410-415CHN/DOX/0317/0011validuntilApril2018Theviciouscircleofthe“MetabolicMemory”19A.Cerielloetal.JClinEndocrinolMetab,2009;94:410-5

GlucoseAGEInhibitorsAGEformationRAGEInhibitorsRAGEAntioxidantsrespiratorychainproteinDeleteriousCycleleadingto“metabolicmemory”respiratorychainproteinalterationmtDNA(glycated)

ROS

respiratorychainactivity

ROSrespiratorychainactivity

VascularstresssignalingDiabeticComplicationsCardioDisordersRetinopathyNephropathyLossofLimbCHN/DOX/0317/0011validuntilApril201820CalciumDobesilatemodeofactionCHN/DOX/0317/0011validuntilApril2018Doxium?reducesmicrovascularleakagebyactingatmultiplelevelsDoxium?has3keyeffects

limitingmicrovascularleakagebytargetingkeymechanismsoftheendothelialdysfunction:Oxidativestress

(scavengesROS)Inflammatorymediators

(inhibitsactivation

ofinflammatorymediators)Angiogenesis(VEGF)(knownasTHEleakagefactor)Vascularleakage

(endothelialdysfunction)Pro-inflammatorycytokinesOxidativestressVEGFPKCNeurodegeneration?EndothelinEye/kidney21PKC,proteinkinaseC;ROS,reactiveoxygenspecies;VEGF,vascularendothelialgrowthfactorCHN/DOX/0317/0011validuntilApril2018DiabeticretinopathyDoxium?-ClinicaldataCHN/DOX/0317/0011validuntilApril2018Diabeticretinopathy23Ribeiroetal.2006Ribeiro–2006-StudyoverviewMulticenter,multinational,doubleblindplacebocontrolledtrialPopulation:299screened,197eligibleadults(40-75)withtype2diabetesandearlyDR*enrolledin8EUcountriesStudytreatmentCaD2g/dayvsplacebofor24monthsPrimaryefficacyendpointschangeinPVPR*(measuredevery6monthsbyfluoresceinleakage)SecondaryefficacyendpointsRetinographicassessmentsbyfundusphotographyaccordingtoWisconsinGrading[1],angiographicassessmentsaccordingtoETDRSGrading[2],visualacuityandintra-ocularpressure*<level47ETDRSgrading&PVPR20-50x10-6/min,plasmafluoresceinFundusparametersinvestigated:haemorrhages,microaneurysmsandDRlevel.mild/moderatenonproliferativediabeticretinopathy(NPDR)*PosteriorVitreousPenetrationRatio24RibeiroML,etal.DX-RetinopathyStudyGroup.Effectofcalciumdobesilateonprogressionofearlydiabeticretinopathy:arandomiseddouble-blindstudy.GraefesArchClinExpOphthalmol2006;244:1591-600.CHN/DOX/0317/0011validuntilApril2018*PVPR=posteriorvitreouspenetrationratio

MeasureofleakageviafluoresceinangiographyPosteriorVitreousPenetrationRatio*[PVPR]25RibeiroML,etal.DX-RetinopathyStudyGroup.Effectofcalciumdobesilateonprogressionofearlydiabeticretinopathy:arandomiseddouble-blindstudy.GraefesArchClinExpOphthalmol2006;244:1591-600.CHN/DOX/0317/0011validuntilApril2018Riberio–2006-StudymethodologyLeakagewasmeasuredevery6monthswithFluorotronMaster(OcuMetrics,MountainView,Calif.,USA)Scanstakenbeforeintravenousadministrationoffluorescein(14mg/kg)and60minafterinjectionBloodsampleswerecollectedafter10,15and50mintomeasureplasmafluoresceinconcentration26RibeiroML,etal.DX-RetinopathyStudyGroup.Effectofcalciumdobesilateonprogressionofearlydiabeticretinopathy:arandomiseddouble-blindstudy.GraefesArchClinExpOphthalmol2006;244:1591-600.CHN/DOX/0317/0011validuntilApril2018ProgressionofmeanPVPRover24-monthProgressionofPVPRwassignificantlygreaterinplacebogroup:frombaselinetothe24-monthvalue(p=0.002)frombaselinetotheLAV(p=0.006)-6PLATreatmentCaDTreatment-13.2%+7.3%(P=0.002)NS27ProgressionofPVPR(mean±SEM)duringthestudy,P=0.002atM24;dataobtainedbyrobustregression.CaD,calciumdobesilate;PLA,placebo;LAV,LastAvailableVisitRibeiroML,etal.DX-RetinopathyStudyGroup.Effectofcalciumdobesilateonprogressionofearlydiabeticretinopathy:arandomiseddouble-blindstudy.GraefesArchClinExpOphthalmol2006;244:1591-600.CHN/DOX/0317/0011validuntilApril2018PVPRimprovementregardlessglucosecontrolHbA1c<7%7%≤HbA1c<9%HbA1c≥9%28CaD,N=27;PLA,N=16P=0.043at24monthsCaD,N=38;PLA,N=46P=0.05at24monthsCaD,N=21;PLA,N=20P=0.044byANCOVA[19]EvolutionofPVPR(mean±SEM)accordingtoHbA1clevel(dataobtainedbyrobustregression).CaD,calciumdobesilate;PLA,placebo;n,numberofpatientsatbaselineTreatmentRibeiroML,etal.DX-RetinopathyStudyGroup.Effectofcalciumdobesilateonprogressionofearlydiabeticretinopathy:arandomiseddouble-blindstudy.GraefesArchClinExpOphthalmol2006;244:1591-600.CHN/DOX/0317/0011validuntilApril2018ConcomitantmedicationsConcomitanttreatmenthadafavorableinfluenceonPVPRintheplacebogroup,withoutaffectingtheefficacyofCaD29CaD,N=57;PLA,N=59P=0.002at24monthsAnti-hypertensiveandlipid-loweringagents=NOCaD,N=29;PLA,N=23NSat24monthsAnti-hypertensiveand/orlipid-loweringagents=YES(p=0.011)Baselinevs24months:(p=0.223)TreatmentRibeiroML,etal.DX-RetinopathyStudyGroup.Effectofcalciumdobesilateonprogressionofearlydiabeticretinopathy:arandomiseddouble-blindstudy.GraefesArchClinExpOphthalmol2006;244:1591-600.CHN/DOX/0317/0011validuntilApril2018FundusanalysisofworsteyebasedonDRlevelReductioninnumberofhemorrhagesImprovement/reductionofDRlevelDRlevelimprovedinsignificantlymorepatientsintheactivetreatmentgroupthanintheplacebogroup(P<0.001)30Evolutionoffundusparametersfrombaselinetothelastvisit.MO:baseline;LAV:lastavailablevisitP=0.029atLAVP<0.001atLAVDoxiumPlaceboDoxiumPlaceboRibeiroML,etal.DX-RetinopathyStudyGroup.Effectofcalciumdobesilateonprogressionofearlydiabeticretinopathy:arandomiseddouble-blindstudy.GraefesArchClinExpOphthalmol2006;244:1591-600.CHN/DOX/0317/0011validuntilApril2018ReductioninmicroaneurysmsNumberofmicroaneurysmswasimprovedinsignificantlymorepatientswiththeactivetreatmentcomparedtoplaceboatthelastvisit(P=0.038)Byrankingmicroaneurysmsbyclasses,differenceofprogressionbetweengroupsappearsevenmoreevidentandalsogivesasignificantresultinfavorofCaD(P=0.013).CaDdecreasesnumberofmicroaneurysmappearance31TreatmentMicroaneurysms(classes)p=0.013atLAVRibeiroML,etal.DX-RetinopathyStudyGroup.Effectofcalciumdobesilateonprogressionofearlydiabeticretinopathy:arandomiseddouble-blindstudy.GraefesArchClinExpOphthalmol2006;244:1591-600.CHN/DOX/0317/0011validuntilApril2018Clinicalefficacy-SummaryCaDexhibitedasignificantlybetteractivitythanplaceboonpreventionofBRBleakage(permeability)progressionCaDshowedabeneficialeffectincontrolling:hemorrhagesmicroaneurysmglobalevolutionofDRIndependentlyofdiabetescontrolandtheuseofanti-hypertensiveandlipid-loweringagentsCaDwaswelltolerated32CHN/DOX/0317/0011validuntilApril2018Randomised,doubleblind,placebo-controlledstudiesindiabeticretinopathyAuthor/JournalTitlePatientsDosemg/dayResultsBinkhorstPGCurrTherResClinExp,1976CaDversusplacebointhetreatmentofdiabeticretinotpathyN=32750cross-overstudy,6-months:reductioninhemorrhageleakageareaSalama-BennarochOphthalmologica,1977AssessmentofCaDindiabeticretinopathy:adoubleblindclinicalinvestigationN=6875024months:reductionofmicroaneurysms,numberandsizeofleakagespotsVojnikovicBOphthalmRes,1984Hyperviscosityofthewholeblood,plasmaandaqueoushumordecreasedbyCaDinDRorglaucoma:adoubleblindcontrolledstudyN=5015003months:reductionbloodviscosity

andameliorationofvisualacuityVinazzer

HVASA,1987InfluenceofCaD

(Doxium?)onbloodviscosityandcoagulationparametersinDRN=2015003months:

reductionbloodviscosityandameliorationofvisualacuityVojinikovicBOphtalmicRes,

1991Hyperviscosityofthewholeblood,plasmaandaqueoushumordecreasedbyCaDinDRorglaucoma:adoubleblindcontrolledstudyn=7915006months:IOP,visualfielddefects,surfaceareaofretinalhemorrhages

andwholebloodandplasmaviscosity

weresignificantlyreduced(p<0.001)LeiteEBIntOphthalmol,1990EffectofCaDinbloodretinalbarrierinearlyDRN=47200012-months:PVPR*(Photofluorometrypenetrationratio)-stabilizationofBRBRibeiroMArchClin

Exp

Ophthalmol,2006Effectofcalciumdobesilateonprogressionofearlydiabeticretinopathy*:arandomizeddouble-blindstudyN=137200024months:significantdecreaseofPVPR*andnumberofhemorrhages,microaneurysm

andDRlevelregardlessofglucose,bloodpressureandlipidcontrolHaritoglou

Lancet,2009EffectofCaDonoccurrenceofdiabeticmacularedema(CALDIRETstudy)N=6351500Upto5years:Nodifferencevsplacebotopreventclinicalsignificantmacularedema(CSME),significantdifferencesinhigherrisksubgroups33CHN/DOX/0317/0011validuntilApril2018ZHANGetal.2015CaDinDR:Meta-analysis34Zhang,X.;Liu,W.;Wu,S.;Jin,J.;Wang,N.Calcum-dobesilatefordiabeticretinopathy:asystematicreviewandmeta-analysis.Sci.ChinaLifeSci.,2015,58,101-107.CHN/DOX/0317/0011validuntilApril2018“CalciumDobesilatewassignificantlyassociatedwithimprovingretinalmicro-aneurysms,hemorrhages,exudates,aswellasreductionofwholebloodandplasmaviscosity”CaDinDR:Meta-analysis(Zhang2015)35DB,doubleblinding;RCT,randomizedclinicaltrial;estimatedeffectsofcalciumdobesilateonstudycharacteristics,independentcomparisonsonly(n=8).StudyStudytypeRandomizationBlindingLosttofollowupJadadscoreLarsenetal.RCT1214Vojnikovicetal.RCT1214Leiteetat.RCT2215Benarrochetal.RCT1214Vojnikovicetal.RCT1214Benarrochetal.RCT1203Ribeiroetal.RCT1214Javadzadehetal.RCT2204Zhang,X.;Liu,W.;Wu,S.;Jin,J.;Wang,N.Calcum-dobesilatefordiabeticretinopathy:asystematicreviewandmeta-analysis.Sci.ChinaLifeSci.,2015,58,101-107.CHN/DOX/0317/0011validuntilApril2018StudyorSubgroupYearCaDplaceboWeightRiskRatioEventsTotalEventsTotalM-H,Random,95%CIHWLarsen197751871815.8%0.71(0.28-1.84)ISBenarroch197731101173470.9%0.61(0.39-0.96)EBLeite199042082113.2%0.53(0.19-1.47)Total(95%CI)13973100.0%0.62(0.42-0.90)Totalevents4032Heterogeneity:Tau2=0.00;Chi2=0.19;df=2(P=0.91);P=0%Testforoveralleffect:Z=2.53(P=0.01)Acomparisonoftheeffectivenessofcalciumdobesilateonmicroaneurysmimprovement.StudyorSubgroupYearCaDplaceboWeightRiskRatioEventsTotalEventsTotalM-H,Random,95%CIHWLarsen197741861837.8%0.67(0.23-1.97)ISBenarroch197711101133462.2%0.28(0.14-0.58)Total(95%CI)11952100.0%0.39(0.17-0.88)Totalevents1519Heterogeneity:Tau2=0.15;Chi2=1.67;df=1(P=0.20);I2=40%Testforoveralleffect:Z=2.26(P=0.02)Acomparisonoftheeffectivenessofcalciumdobesilateonfundushemorrhageimprovement.ImprovementofEarlyRetinopathy(Zhang2015)36Zhang,X.;Liu,W.;Wu,S.;Jin,J.;Wang,N.Calcum-dobesilatefordiabeticretinopathy:asystematicreviewandmeta-analysis.Sci.ChinaLifeSci.,2015,58,101-107.0.20.5125FavoursplaceboFavoursCaD0.20.5125FavoursplaceboFavoursCaDCHN/DOX/0317/0011validuntilApril2018DiabeticRenal-RetinalSyndrome1980:Morethan90%ofuremicT1DMwillhavesomedegreeofretinopathy11987:Nephropathyispresentin35%-50%ofthediabeticswithsymptomaticretinopathy21999:ClassicKimmelstiel-Wilson(KW)pathologyisassociatedwithProliferativeDiabeticRetinopathy3

2001:Diabeticpatientswithmoderateorsevereglomerulosclerosiscouldhaveretinopathyinmoresignificantformthanthosewithmildkidneydisease4371.Friedman,E.A.andL’Esperance,F.A.(1980)DiabeticRenal-RetinalSyndrome:ThePrognosisImproves.JAMAInternalMedicine,140,1149-11502.Cowan,C.L.(1987)DiabeticRenal-RetinalSyndrome:DoesTightControlHelp?TransplantationProceedings,19,86-893.Sessa,A.,Battini,G.,Meroni,M.,Agneli,F.,Giordano,F.andTarelli,L.T.(1999)Renal-RetinalDiabeticSyndrome.Nephron,83,285-2864.Izzedine,H.,Fongoro,S.,Pajot,O.,Beaufils,H.andDeray,G.(2001)Retinopathy,HematuriaandDiabeticNephropathy.Nephron,88,382-383CHN/DOX/0317/0011validuntilApril2018CommonPathogenesisbetweenDR&DKD38RobinsonR.etal.Updateonanimalmodelsofdiabeticretinopathy:frommolecularapproachestomiceandhighermammals.DiseaseModels&Mechanisms5,444-456(2012)doi:10.1242/dmm.009597HyperglycemiaOxidativestressInflammationPKCactivationAGEsPolyolpathwayActivationofcytokinesandgrowthfactorsDysfunctionofvascularandneuronalcellsNeuraldysfunctionVascularpermeabilityRetinalhypoxiaNeovascularistionVisionlossDiabeticretinopathyMetabolicfactorsHyperglycemiaAGEROSEndothelialdysfunctionNOSdysregulationVEGFPDGFMonBloodICAM-1ChemokinesCSF-1MCP-1MIFUrineGFRlossProteinuriaPodocytelossOxidativestressCellp38αJNKPKC-βNF-κBTranscriptionfactorsApoptosisProfibroticcytokinesTGF-βCTGFHemodynamicalterationsEndothelinUrotensinIIAngiotensinIIkidneyInflammatorycytokinesIL-1TNF-αIL-6IL-18CellsignalingFibroblastactivationInflammatoryinfiltrateMacMacMacCHN/DOX/0317/0011validuntilApril2018Doxium?

ShowsactivitiesinDKD39CHN/DOX/0317/0011validuntilApril201842patientswithearlyDiabeticKidneyDiseasewithouthypertensionwererandomizedintothetreatmentandcontrolgroupsCalciumDobesilate(500mgx3perday)for12weeks40DongJ,LiangCG,ZhangXQ,etal.CalciumDobesilateinthetreatmentofearlydiabeticnephropathy.JShandongUniv2008;46:80–83.TotalPatients42Control21CalciumDobesilate21CHN/DOX/0317/0011validuntilApril2018*P<0.05vsthesamegroupbeforetreatment,#P<0.05vsthecontrolgroupinthesameperiod*#*#*#Result41DongJ,LiangCG,ZhangXQ,etal.CalciumDobesilateinthetreatmentofearlydiabeticnephropathy.JShandongUniv2008;46:80–83.ControlgroupCalciumDobesilategroupCHN/DOX/0317/0011validuntilApril2018DONG,Jing,Xiao-qianZHANG,andCui-geLIANG.TherapeuticEffectComparisonbetweenCalciumDobesilateandPerindoprilinTreatmentofEarlyDiabeticNephropathy.ChineseGeneralPractice14(2008):006;1232-1236

Doxium?

vs.ACEInhibitorsComparisonofTherapeuticEffectsofCalciumDobesilateandPerindoprilinTreatmentofEarlyDiabeticNephropathyCHN/DOX/0317/0011validuntilApril2018Doxium?

vs.PerindoprilDKD

(106withoutHT)Control(33cases)CaD(37cases)Perindopril(36cases)43DONG,Jing,Xiao-qianZHANG,andCui-geLIANG.TherapeuticEffectComparisonbetweenCalciumDobesilateandPerindoprilinTreatmentofEarlyDiabeticNephropathy.ChineseGeneralPractice14(2008):006;1232-1236CHN/DOX/0317/0011validuntilApril2018Result44DONG,Jing,Xiao-qianZHANG,andCui-geLIANG.TherapeuticEffectComparisonbetweenCalciumDobesilateandPerindoprilinTreatmentofEarlyDiabeticNephropathy.ChineseGeneralPractice14(2008):006;1232-1236***After12weeks,thelevelsofUAEdecreasedsignificantlyinBandCgroupswhencomparingtocontrolgroup(P<0.05)ThereisnodifferencebetweenCalciumDobesilateandPerindoprilgroupCHN/DOX/0317/0011validuntilApril2018ThelevelofTXB2

decreasedwhilethelevelof6-keto-PGF1α

increasedinCalciumDobesilategroup,butthechangeisnotobviousinPerindoprilgroupDoxium?actsondifferentpathways45DONG,Jing,Xiao-qianZHANG,andCui-geLIANG.TherapeuticEffectComparisonbetweenCalciumDobesilateandPerindoprilinTreatmentofEarlyDiabeticNephropathy.ChineseGeneralPractice14(2008):006;1232-1236GroupTXB2(ng/L)6-keto-PGF1α

(ng/L)GroupA(Control)Beforetreatment173.2±47.811.50±3.3Aftertreatment174.1±38.511.6±2.8GroupC(Perindopril)Beforetreatment175.2±37.811.5±3.1Aftertreatment171.2±36.011.4±3.2GroupB(CalciumDobesilate)Beforetreatment171.3±43