《肾眼同治-代谢记忆与糖尿病微血管病变（英文版）》经典培训课件

“THEMETABOLICMEMORYANDPATHOGENESISOFDIABETICMICROVASCULARCOMPLICATIONS”ANTONIOCERIELLOINSTITUTDINVESTIGACIONSBIOMDIQUESAUGUSTPIISUNYERIDIBAPSBARCELONA,SPAINANDIRCCSMULTIMEDICAMILAN,ITALYCHN/DOX/0317/0011VALIDUNTILAPRIL20182000151MILLION2013382MILLION2035592MILLIONESTIMATEDGLOBALPREVALENCEOFDIABETESINTERNATIONALDIABETESFEDERATIONIDFDIABETESATLAS,1STAND6THEDITIONSDIABETESISAGLOBALDISEASE2CHN/DOX/0317/0011VALIDUNTILAPRIL2018DCCT/EDICLONGTERMMICROVASCULARRISKREDUCTIONINTYPE1DIABETES3DCCT/EDICRESEARCHGROUPNENGLJMED2000342381389COMPLICATIONRISKREDUCTIONWITHINTENSIVETHERAPYAAFTER65YRINDCCTBAFTER4ADDITIONALYRINEDICCRETINOPATHY3STEPWORSENING6377MACULAREDEMA2672PROLIFERATIVEORSEVERENONPROLIFERATIVE4775LASERTHERAPY5177NEPHROPATHYMICROALBUMINURIA40MG/24H3953CLINICALGRADEPROTEINURIA300MG/24H5486CHN/DOX/0317/0011VALIDUNTILAPRIL2018ININDIVIDUALSWITHTYPE1DIABETES,INTENSIVEDIABETESTREATMENTYIELDSDURABLERENALBENEFITSTHATPERSISTFORATLEAST18YEARSAFTERITSAPPLICATIONDCCTINTANDTHEATTENDANT65YEARSOFLOWERHBA1CHADLONGTERMSALUTARYEFFECTSONTHEDEVELOPMENTANDPROGRESSIONOFATHEROSCLEROSISANDCARDIOVASCULARDISEASEDURINGTHESUBSEQUENTFOLLOWUPDURINGEDICTHEPERSISTENTEFFECTSOFPRIORINTENSIVETHERAPYONNEUROPATHYMEASURESTHROUGH14YEARSOFEDICLARGELYMIRRORTHOSEOBSERVEDFOROTHERDIABETESCOMPLICATIONSINTENSIVECONTROLDELAYSTHEONSETANDSLOWSTHEPROGRESSIONOFDRFURTHERMORE,THEEARLYEFFECTSOFMETABOLICCONTROLCONTINUETOACCRUEOVERMANYYEARSDESPITESUBSEQUENTCOMPARABLEGLYCEMICCONTROLMETABOLICMEMORYAFTERAMEANOF27YEARSFOLLOWUPOFPATIENTSWITHTYPE1DIABETES,65YEARSOFINITIALINTENSIVEDIABETESTHERAPYWASASSOCIATEDWITHALOWERALLCAUSEMORTALITYRATEWHENCOMPAREDWITHCONVENTIONALTHERAPY4WHEREWEARE30YEARSLATERLANCETDIABETESENDOCRINOL20142793800DIABETESCARE2014373943DIABETESCARE2014373138DIABETESCARE2014371723JAMA20153134553CHN/DOX/0317/0011VALIDUNTILAPRIL2018THEBENEFITSOFEARLYTIGHTCONTROLUKPDS10YEARPOSTTRIALFOLLOWUP51HOLMANETALNENGLJMED20083591577892UKPDSSTUDYGROUPLANCET199835283753P130,000PATIENTS1020132014201520162017201820192020GLP1DPP4TECOSSITAGLIPTIN,DPP4IN14,671FOLLOWUP3YRSQ12015RESULTSCARMELINALINAGLIPTIN,DPP4IN8,300DURATION4YRSCOMPLETIONQ12018CAROLINALINAGLIPTIN,DPP4IVSSUN6,000DURATION8YRSCOMPLETIONQ32018SAVORTIMI53SAXAGLIPTIN,DPP4IN16,492FOLLOWUP2YRSQ22013RESULTSEXAMINEALOGLIPTIN,DPP4IN5,380FOLLOWUP15YRSQ32013RESULTSALECARDIOALEGLITAZAR,PPARN7,226FOLLOWUP20YRSTERMINQ32013RESULTSLEADERLIRAGLUTIDE,GLP1N9,340DURATION355YRSCOMPLETIONQ42015ELIXALIXISENATIDE,GLP1N6,068FOLLOWUP2YRSQ12015RESULTSEMPAREGOUTCOMEEMPAGLIFLOZIN,SGLT2IN7,097DURATIONUPTO5YRSQ22015RESULTSSUSTAIN6SEMAGLUTIDE,GLP1N3,297DURATION28YRSCOMPLETIONQ12016EXSCELEXENATIDEQW,QWGLP1N14,000DURATION75YRSCOMPLETIONQ12018OMNEONOMARIGLIPTIN,QWDPP4IN4,000DURATION3YRSCOMPLETIONQ42017CANVASCANAGLIFLOZIN,SGLT2IN4,407DURATION4YRSCOMPLETIONQ22017CANVASRCANAGLIFLOZIN,SGLT2IN5,865DURATION3YRSCOMPLETIONQ12017DEVOTEINSULINDEGLUDEC,BASALINSULINN7,637DURATIONUPTO5YRSCOMPLETIONH22016FREEDOMCVOITCA650,GLP1INDUROSN4,000DURATION2YRSCOMPLETIONQ32018CREDENCECARDIORENALCANAGLIFLOZIN,SGLT2IN3,700DURATION55YRSCOMPLETIONQ12019REWINDDULAGLUTIDE,QWGLP1N9,622DURATION65YRSCOMPLETIONQ22019DECLARETIMI58DAPAGLIFLOZIN,SGLT2IN17,150DURATION6YRSCOMPLETIONQ22019NCT01986881ERTUGLIFLOZIN,SGLT2IN3,900DURATION63YRSCOMPLETIONQ22021HARMONYOUTCOMESALBIGLUTIDE,GLP1N9,400DURATION4YRSCOMPLETIONBYQ22019ONGOINGSOURCECLINICALTRIALSGOV30JUNE2015COMPLETIONDATEISTHEESTIMATEDCOMPLETIONDATEFORTHEPRIMARYOUTCOMESMEASUREALSOKNOWNASCSCADE8SGLT2ICHN/DOX/0317/0011VALIDUNTILAPRIL2018TIMETOFIRSTEYEEVENTPHOTOCOAGULATIONORTREATMENTWITHINTRAVITREALAGENTS,VITREOUSHAEMORRHAGE,ORBLINDNESSTHECUMULATIVEINCIDENCESWEREESTIMATEDWITHTHEUSEOFTHEKAPLANMEIERMETHOD,ANDTHEHRSWITHTHEUSEOFTHECOXPROPORTIONALHAZARDREGRESSIONMODELTHEDATAANALYSESARETRUNCATEDAT54MONTHSBECAUSELESSTHAN10OFTHEPATIENTSHADANOBSERVATIONTIMEBEYOND54MONTHS11PRESENTEDAT52NDEASDANNUALMEETING,14SEPTEMBER2016,MUNICH,GERMANY0246810061218243036424854PATIENTSWITHANEVENTTIMESINCERANDOMISATIONMONTHSHR11595CI087152LIRAGLUTIDEPLACEBOPATIENTSATRISKLIRAGLUTIDE466846244566450944424366429742311689473PLACEBO467246364565448944174339426441881681454CICONFIDENCEINTERVALHRHAZARDRATIOCHN/DOX/0317/0011VALIDUNTILAPRIL2018DIABETICRETINOPATHYCOMPLICATIONSSUPPLEMENTARYFIGURE5AKAPLANMEIERPLOTFORTIMEFROMRANDOMISATIONTOFIRSTEACCONFIRMEDDIABETICRETINOPATHYCOMPLICATIONUSINGINTRIALDATAFROMSUBJECTSINTHEFULLANALYSISSETHRISFROMAPROPORTIONALHAZARDMODEL02468081624324048566472808896104PATIENTSWITHANEVENTWEEKSSINCERANDOMISATIONHR,17695CI,111278EVENTS50SEMAGLUTIDE29PLACEBOP002NUMBEROFPATIENTSATRISKSEMAGLUTIDE16481622161215951570154815351525PLACEBO16491636161716051576155815391530109SEMAGLUTIDE,30PLACEBO,1812MARSOETALNEJMINPRESSCHN/DOX/0317/0011VALIDUNTILAPRIL2018PATHOGENESISOFDIABETICCOMPLICATIONS,THEMETABOLICMEMORYANDTHEROLEOFOXIDATIVESTRESSCHN/DOX/0317/0011VALIDUNTILAPRIL2018PATHWAYSOFHYPERGLYCAEMIAINDUCEDVASCULARDAMAGENADPH,NICOTINAMIDEADENINEDINUCLEOTIDEPHOSPHATEHYDROGENGFAT,GLUTAMINEFRUCTOSEPHOSPHATEAMIDOTRANSFERASE14BROWNLEENATURE200141481320POLYOLPATHWAYHEXOSAMINEPATHWAYPROTEINKINASECPATHWAYAGEPATHWAYNADPHNADPNADNADHSORBITOLFRUCTOSEGLNGLUGLUCOSAMINE6PUDPGLCNACGFATNADHNADGLYCEROLPPKCDHAPDAGMETHYLGLYOXALAGESGLUCOSEGLUCOSE6PFRUCTOSE6PGLYCERALDEHYDE3P13DIPHOSPHOGLYCERATEGAPDHNADNADHO2CHN/DOX/0317/0011VALIDUNTILAPRIL201815CERIELLOA,DIABETESCARE2003MITOCHONDRIAPKCNADPHOXIDASENFKBINOSENOSNONITROTYROSINEDNADAMAGEGAPDHNADADHESIONMOLECULESPROINFLAMMATORYCYTOKINESVEGFPARPENDOTHELIALDYSFUNCTIONPOLYOLPATHWAYAGEFORMATIONHEXOSAMINEFLUXHYPERGLYCEMIAO2O2PEROXYNITRITEDIABETICCOMPLICATIONSCHN/DOX/0317/0011VALIDUNTILAPRIL2018THE“METABOLICMEMORYTHEROLEOFOXIDATIVESTRESS16ICONTINUOUSNORMALORHIGHGLUCOSEIIPERSISTENCEOFHIGHGLUCOSESTRESS21DAYS14DAYS7DAYSHIGHGLUCOSENORMALGLUCOSENORMALGLUCOSEORHIGHGLUCOSEIHNATMETAL,DIABETOLOGIA2007CHN/DOX/0317/0011VALIDUNTILAPRIL2018EFFECTSOFHIGHGLUCOSEFORTHREEWEEKSORFORTWOWEEKSPLUSONEWEEKOFNORMALGLUCOSEINHUVECS170100200300400NHHNDENSITOMETRYNFIBRONECTIN0100200300400NHHNDENSITOMETRYNPHOSPHOPKC/II0100200300400NHHNDENSITOMETRYNP47PHOX0100200300400NHHNDENSITOMETRYN3NY0100200300400NHHNDENSITOMETRYNPAR0100200300400NHHNBAXDENSITOMETRY5MMCHN/DOX/0317/0011VALIDUNTILAPRIL2018“EPIDEMIOLOGICALANDPROSPECTIVEDATASUPPORTALONGTERMINFLUENCEOFEARLYMETABOLICCONTROLONCLINICALOUTCOMES”“EARLYGLYCAEMICENVIRONMENTISREMEMBEREDINTHETARGETORGANSIE,EYE,KIDNEY,HEART,EXTREMITIES”“THECONCEPTOFAMETABOLICMEMORYISOFDIABETICVASCULARSTRESSESPERSISTINGAFTERGLUCOSENORMALIZATION”ANTONIOCERIELLO,MICHAELAIHNATANDJESSICAETHORPETHE“METABOLICMEMORY“ISMORETHANJUSTTIGHTGLUCOSECONTROLNECESSARYTOPREVENTDIABETICCOMPLICATIONSDEFININGMETABOLICMEMORY18JCLINENDOCRINOLMETAB200994410415CHN/DOX/0317/0011VALIDUNTILAPRIL2018THEVICIOUSCIRCLEOFTHE“METABOLICMEMORY”19ACERIELLOETALJCLINENDOCRINOLMETAB,2009944105GLUCOSEAGEINHIBITORSAGEFORMATIONRAGEINHIBITORSRAGEANTIOXIDANTSRESPIRATORYCHAINPROTEINDELETERIOUSCYCLELEADINGTO“METABOLICMEMORY”RESPIRATORYCHAINPROTEINALTERATIONMTDNAGLYCATEDROSRESPIRATORYCHAINACTIVITYROSRESPIRATORYCHAINACTIVITYVASCULARSTRESSSIGNALINGDIABETICCOMPLICATIONSCARDIODISORDERSRETINOPATHYNEPHROPATHYLOSSOFLIMBCHN/DOX/0317/0011VALIDUNTILAPRIL201820CALCIUMDOBESILATEMODEOFACTIONCHN/DOX/0317/0011VALIDUNTILAPRIL2018DOXIUMREDUCESMICROVASCULARLEAKAGEBYACTINGATMULTIPLELEVELSDOXIUMHAS3KEYEFFECTSLIMITINGMICROVASCULARLEAKAGEBYTARGETINGKEYMECHANISMSOFTHEENDOTHELIALDYSFUNCTIONOXIDATIVESTRESSSCAVENGESROSINFLAMMATORYMEDIATORSINHIBITSACTIVATIONOFINFLAMMATORYMEDIATORSANGIOGENESISVEGFKNOWNASTHELEAKAGEFACTORVASCULARLEAKAGEENDOTHELIALDYSFUNCTIONPROINFLAMMATORYCYTOKINESOXIDATIVESTRESSVEGFPKCNEURODEGENERATIONENDOTHELINEYE/KIDNEY21PKC,PROTEINKINASECROS,REACTIVEOXYGENSPECIESVEGF,VASCULARENDOTHELIALGROWTHFACTORCHN/DOX/0317/0011VALIDUNTILAPRIL2018DIABETICRETINOPATHYDOXIUMCLINICALDATACHN/DOX/0317/0011VALIDUNTILAPRIL2018DIABETICRETINOPATHY23RIBEIROETAL2006RIBEIRO2006STUDYOVERVIEWMULTICENTER,MULTINATIONAL,DOUBLEBLINDPLACEBOCONTROLLEDTRIALPOPULATION299SCREENED,197ELIGIBLEADULTS4075WITHTYPE2DIABETESANDEARLYDRENROLLEDIN8EUCOUNTRIESSTUDYTREATMENTCAD2G/DAYVSPLACEBOFOR24MONTHSPRIMARYEFFICACYENDPOINTSCHANGEINPVPRMEASUREDEVERY6MONTHSBYFLUORESCEINLEAKAGESECONDARYEFFICACYENDPOINTSRETINOGRAPHICASSESSMENTSBYFUNDUSPHOTOGRAPHYACCORDINGTOWISCONSINGRADING1,ANGIOGRAPHICASSESSMENTSACCORDINGTOETDRSGRADING2,VISUALACUITYANDINTRAOCULARPRESSURELEVEL47ETDRSGRADING2441591600CHN/DOX/0317/0011VALIDUNTILAPRIL2018PVPRPOSTERIORVITREOUSPENETRATIONRATIOMEASUREOFLEAKAGEVIAFLUORESCEINANGIOGRAPHYPOSTERIORVITREOUSPENETRATIONRATIOPVPR25RIBEIROML,ETALDXRETINOPATHYSTUDYGROUPEFFECTOFCALCIUMDOBESILATEONPROGRESSIONOFEARLYDIABETICRETINOPATHYARANDOMISEDDOUBLEBLINDSTUDYGRAEFESARCHCLINEXPOPHTHALMOL20062441591600CHN/DOX/0317/0011VALIDUNTILAPRIL2018RIBERIO2006STUDYMETHODOLOGYLEAKAGEWASMEASUREDEVERY6MONTHSWITHFLUOROTRONMASTEROCUMETRICS,MOUNTAINVIEW,CALIF,USASCANSTAKENBEFOREINTRAVENOUSADMINISTRATIONOFFLUORESCEIN14MG/KGAND60MINAFTERINJECTIONBLOODSAMPLESWERECOLLECTEDAFTER10,15AND50MINTOMEASUREPLASMAFLUORESCEINCONCENTRATION26RIBEIROML,ETALDXRETINOPATHYSTUDYGROUPEFFECTOFCALCIUMDOBESILATEONPROGRESSIONOFEARLYDIABETICRETINOPATHYARANDOMISEDDOUBLEBLINDSTUDYGRAEFESARCHCLINEXPOPHTHALMOL20062441591600CHN/DOX/0317/0011VALIDUNTILAPRIL2018PROGRESSIONOFMEANPVPROVER24MONTHPROGRESSIONOFPVPRWASSIGNIFICANTLYGREATERINPLACEBOGROUPFROMBASELINETOTHE24MONTHVALUEP0002FROMBASELINETOTHELAVP0006642024606121824DELTAPVPRTIMEMONTHS6PLATREATMENTCADTREATMENT13273P0002NS27PROGRESSIONOFPVPRMEANSEMDURINGTHESTUDY,P0002ATM24DATAOBTAINEDBYROBUSTREGRESSIONCAD,CALCIUMDOBESILATEPLA,PLACEBOLAV,LASTAVAILABLEVISITRIBEIROML,ETALDXRETINOPATHYSTUDYGROUPEFFECTOFCALCIUMDOBESILATEONPROGRESSIONOFEARLYDIABETICRETINOPATHYARANDOMISEDDOUBLEBLINDSTUDYGRAEFESARCHCLINEXPOPHTHALMOL20062441591600CHN/DOX/0317/0011VALIDUNTILAPRIL2018PVPRIMPROVEMENTREGARDLESSGLUCOSECONTROL1050510606121824DELTAPVPRTIMEMONTHS1050510606121824DELTAPVPRTIMEMONTHSCADPLA1050510606121824DELTAPVPRTIMEMONTHSHBA1C77HBA1C9HBA1C928CAD,N27PLA,N16P0043AT24MONTHSCAD,N38PLA,N46P005AT24MONTHSCAD,N21PLA,N20P0044BYANCOVA19EVOLUTIONOFPVPRMEANSEMACCORDINGTOHBA1CLEVELDATAOBTAINEDBYROBUSTREGRESSI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1977311011734709061039096EBLEITE1990420821132053019147TOTAL95CI139731000062042090TOTALEVENTS4032HETEROGENEITYTAU2000CHI2019DF2P091P0TESTFOROVERALLEFFECTZ253P001ACOMPARISONOFTHEEFFECTIVENESSOFCALCIUMDOBESILATEONMICROANEURYSMIMPROVEMENTSTUDYORSUBGROUPYEARCADPLACEBOWEIGHTRISKRATIOEVENTSTOTALEVENTSTOTALMH,RANDOM,95CIHWLARSEN1977418618378067023197ISBENARROCH1977111011334622028014058TOTAL95CI119521000039017088TOTALEVENTS1519HETEROGENEITYTAU2015CHI2167DF1P020I240TESTFOROVERALLEFFECTZ226P002ACOMPARISONOFTHEEFFECTIVENESSOFCALCIUMDOBESILATEONFUNDUSHEMORRHAGEIMPROVEMENTIMPROVEMENTOFEARLYRETINOPATHYZHANG201536ZHANG,XLIU,WWU,SJIN,JWANG,NCALCUMDOBESILATEFORDIABETICRETINOPATHYASYSTEMATICREVIEWANDMETAANALYSISSCICHINALIFESCI,2015,58,1011070205125FAVOURSPLACEBOFAVOURSCAD0205125FAVOURSPLACEBOFAVOURSCADCHN/DOX/0317/0011VALIDUNTILAPRIL2018DIABETICRENALRETINALSYNDROME1980MORETHAN90OFUREMICT1DMWILLHAVESOMEDEGREEOFRETINOPATHY11987NEPHROPATHYISPRESENTIN3550OFTHEDIABETICSWITHSYMPTOMATICRETINOPATHY21999CLASSICKIMMELSTIELWILSONKWPATHOLOGYISASSOCIATEDWITHPROLIFERATIVEDIABETICRETINOPATHY32001DIABETICPATIENTSWITHMODERATEORSEVEREGLOMERULOSCLEROSISCOULDHAVERETINOPATHYINMORESIGNIFICANTFORMTHANTHOSEWITHMILDKIDNEYDISEASE4371FRIEDMAN,EAANDLESPERANCE,FA1980DIABETICRENALRETINALSYNDROMETHEPROGNOSISIMPROVESJAMAINTERNALMEDICINE,140,114911502COWAN,CL1987DIABETICRENALRETINALSYNDROMEDOESTIGHTCONTROLHELPTRANSPLANTATIONPROCEEDINGS,19,86893SESSA,A,BATTINI,G,MERONI,M,AGNELI,F,GIORDANO,FANDTARELLI,LT1999RENALRETINALDIABETICSYNDROMENEPHRON,83,2852864IZZEDINE,H,FONGORO,S,PAJOT,O,BEAUFILS,HANDDERAY,G2001RETINOPATHY,HEMATURIAANDDIABETICNEPHROPATHYNEPHRON,88,382383CHN/DOX/0317/0011VALIDUNTILAPRIL2018COMMONPATHOGENESISBETWEENDR468083TOTALPATIENTS42CONTROL21CALCIUMDOBESILATE21CHN/DOX/0317/0011VALIDUNTILAPRIL201802040608010004812UAERMG/24HWEEKSP005VSTHESAMEGROUPBEFORETREATMENT,P005VSTHECONTROLGROUPINTHESAMEPERIODRESULT41DONGJ,LIANGCG,ZHANGXQ,ETALCALCIUMDOBESILATEINTHETREATMENTOFEARLYDIABETICNEPHROPATHYJSHANDONGUNIV2008468083CONTROLGROUPCALCIUMDOBESILATEGROUPCHN/DOX/0317/0011VALIDUNTILAPRIL2018DONG,JING,XIAOQIANZHANG,ANDCUIGELIANGTHERAPEUTICEFFECTCOMPARISONBETWEENCALCIUMDOBESILATEANDPERINDOPRILINTREATMENTOFEARLYDIABETICNEPHROPATHYCHINESEGENERALPRACTICE14200800612321236DOXIUMVSACEINHIBITORSCOMPARISONOFTHERAPEUTICEFFECTSOFCALCIUMDOBESILATEANDPERINDOPRILINTREATMENTOFEARLYDIABETICNEPHROPATHYCHN/DOX/0317/0011VALIDUNTILAPRIL2018DOXIUMVSPERINDOPRILDKD106WITHOUTHTCONTROL33CASESCAD37CASESPERINDOPRIL36CASES43DONG,JING,XIAOQIANZHANG,ANDCUIGELIANGTHERAPEUTICEFFECTCOMPARISONBETWEENCALCIUMDOBESILATEANDPERINDOPRILINTREATMENTOFEARLYDIABETICNEPHROPATHYCHINESEGENERALPRACTICE14200800612321236CHN/DOX/0317/0011VALIDUNTILAPRIL2018RESULT44DONG,JING,XIAOQIANZHANG,ANDCUIGELIANGTHERAPEUTICEFFECTCOMPARISONBETWEENCALCIUMDOBESILATEANDPERINDOPRILINTREATMENTOFEARLYDIABETICNEPHROPATHYCHINESEGENERALPRACTICE14200800612321236020406080100WEEK0WEEK4WEEK8W