2型糖尿病患者嚴格血糖控制和心血管事件的預防

2型糖尿病患者嚴格血糖控制和

心血管事件的預防中山大學附屬第一醫(yī)院內分泌科肖海鵬ChallengeTohavepatientsbelieveinyourguidanceforthemanagementoftheirdiabetesmellitus.NationalGeographics(2004)AugustPrevalenceofobesityincreased61%

between1991and2000Morethan60%ofUS

adultsareoverweightOnly43%ofobese

personsadvisedtoloseweightduringcheckupsBMIandweightgain

majorriskfactors

fordiabetesPrevalence(%)DiabetesMeanbodyweightkgYearMokdadetal.DiabetesCare.2000;23:1278.Mokdadetal.JAMA.1999;282:1519.Mokdadetal.JAMA.2001;286:1195.PrevalenceofDiabetesandObesityGlobalprevalenceofdiabetes*246millionpeoplewithdiabetesworldwide =roughly6%oftheadultpopulationIn2007,thefivecountrieswiththelargestnumbersofpeoplewithdiabetesare:India,China,UnitedStates,Russia,GermanyBy2025,thelargestincreasesindiabetesprevalencewilloccurinlow-andmiddle-incomecountriesEachyearanadditional7millionpeopleworldwidedevelopdiabetes*DiabetesAtlas,3rdedition,InternationalDiabetesFederation,2006中國的2型糖尿病管理面臨嚴峻的挑戰(zhàn)

“中國的糖尿病患者可能居世界之最”“經濟的迅速發(fā)展，帶來了傳統生活方式的根本性變革，導致了中國2型糖尿病患者的劇增。”

潘長玉301醫(yī)院DiabetescomplicationsEachyear3.8milliondeathsworldwideareattributabletodiabetesDiabetesisassociatedwithcomplicationssuchas:DiabeticneuropathyRenalfailureBlindnessMacrovasculardiseaseMacrovascularcomplicationsareamajorcauseofdeathinpeoplewithdiabetes心血管疾病在糖尿病者中的比率新診斷的2型糖尿病患者 ～25%總糖尿病人群 ～50%占糖尿病死亡原因 ～65-75%AmHeartJ1999;138:5330歐洲心臟調查結果n=2107n=2854TheEuroHeartSurveyondiabetesandtheheart，EuropeanHeartJournal(2004)25,1880–189043,509

例高危人群中

9,125例合并心血管疾病OGTT結果任一心血管事件,n=9,125NGTI-IFGIGTDM相對比例(%)PresentationofNovartisSatellitesymposiumduringESC2004,Munich,GermanyNAVIGATORGAMI:急性心?；颊咧械奶谴x異常心肌梗死患者BartnikM,etal.JInternMed.2004Oct;256(4):288-97.中國心臟調查結果-匯總

（n=3513）中華內分泌代謝雜志2006,22:7Riskofcardiovasculardisease(CVD)

inrelationtoHbA1c–TheARICStudyRelativeriskofCVDn=1626(p

0.001)5.25.25.75.76.56.58.28.2HbA1cAjustedforage,gender,race,smoking,BMI,visceralobesity,physicalactivity,BPanddyslipidemia.Adaptedfrom:Selvin,E.etcoll.Arch.Int.Med.165:1910-1916,2005GAMI:新診斷高血糖

是心肌梗死后“無心血管事件存活”的預測因素BartnikM,etal.EurHeartJ.2004;25(22):1990-7.中位數隨訪時間:34月Diabetespatientsrequiringglucose-loweringtherapyandnon-diabeticswithapriormyocardialinfarctioncarrythesamecardiovascularrisk:Apopulationstudyof3.3millionpeopleCirculation117:1945-54,2008All3.3mioDanesolderthan30yearswerefollowedfrom1997to2002bynationwideregistersMedicationtreateddiabetespatientsandnondiabeticswithandwithoutapriormyocardialinfarctionwerecomparedAtbaseline71,801Daneshadmedicationtreateddiabetesand79,575hadapriormyocardialinfarctionRelativeriskforCVDmortalitywas2.42inmenwithdiabetesmellituswithoutapriormyocardialinfarctionand2.44innondiabeticmenwithapriormyocardialinfarction(P=0.60)

HazardRatioDiabetes,Glucose,andCVDiseaseDMisanestablishedriskfactorforCVDInDM,higherglucoselevels/A1cpredicthigherCVriskStrattonIM,etal.BMJ2000;321:405–41212%riseper1%riseinA1CP<.035Fatal&NonfatalStrokeHazardRatio14%riseper1%riseinA1CP<.00011010.5

Fatal&NonfatalMI1043%riseper1%riseinA1CP<.00011010.5Amputation/DeathfromPVD6578916%riseper1%riseinA1CP<.021HeartFailure6578910

0.88(0.79,0.99)

Anydiabetes-relatedendpoint

0.84(0.71,1.00)

Myocardialinfarction

1.11(0.81,1.51)

Stroke

0.75(0.60,0.93)

MicrovasculardiseaseRelativerisk(95%CI)Relativerisk0.10.52.010FavorsmoreintensiveFavorslessintensiveUKProspectiveDiabetesStudyBloodglucoseandvascularriskindiabetes---UKPDS高血糖和心血管風險越來越多的2型糖尿病患者出現心血管并發(fā)癥UKPDS表明高血糖和心血管疾病之間存在流行病學上的關聯但是嚴格的血糖控制能否降低該風險?ACCORD,ADVANCE&VADT等大型研究就是針對上述問題而設計ACCORD:2型糖尿病強化降糖的效應研究多中心研究(77研究中心)美國/加拿大10,251例患者(平均年齡62.2歲)強化治療組(目標A1c

<6.0%)

v標準治療組1/3有心血管病史或2個以上心血管危險因素一級終點:非致死性心?；蜃渲?；心血管死亡ACCORD:結果

ResultsofACCORD糖尿病心血管風險控制行動(ACCORD)關于執(zhí)行過程的分析HbA1c降低過快(4

個月下降1.4%)頻發(fā)嚴重低血糖(16.2%)TZD(92%)

&胰島素(77%)

用量過多平均體重增加

3.5Kg

(4人中有1人增加>10Kg

)過于嚴格的血糖控制目標(HbA1c<6.0%)VADT:結果和分析平均隨訪5.6

年A1c6.9%A1c

在6個月內降低2%

心血管終點和死亡率上沒有顯著性差異體重增加9Kg嚴重低血糖發(fā)生率21.2%ADVANCE協作組研究

2型糖尿病強化降壓/降糖和血管事件結果2型糖尿病患者嚴格血糖控制和血管結局ADVANCE:析因設計

強化降糖組標準降糖組以達美康緩釋片（格列齊特緩釋片）為起始治療不限制其他藥物的使用（磺脲類除外）目標：HbA1c

<6.5%除達美康緩釋片以外的其他磺脲類藥物為起始治療

不限制其他藥物的使用（磺脲類除外）依照各地指南標準ADVANCE:血糖結果

ADVANCE:終點結果微血管和大血管復合終點結果主要大血管事件全因死亡微血管事件

ADA2008AnualMeetinginSanFrancisco

NopositivetrialeffectofIntensive

glucoseloweringonmacrovascularcomplicationsintype2diabetes,atleastinthetypesofpatientsstudied

ACCORDADVANCEVADT比較:ACCORD,ADVANCE&VADT研究特點ACCORDADVANCE

VADT基線:年齡(歲)

病程(年)

心血管疾病(%)62103566832601141干預:目標HbA1c(%)

研究時間(yr)

胰島素(%)6.03.4776.55.0416.05.689結果:

HbA1c(%)

心血管死亡(%強化組v標準組)

嚴重低血糖(%)

6.42.6v1.8*16.26.54.5v5.22.76.94.5v3.721.2

HazardRatiosforthePrimaryOutcomeandDeathfromAnyCauseinPrespecifiedSubgroupsHazardRatiosforthePrimaryOutcomeandDeathfromAnyCauseinPrespecifiedSubgroupsNEnglJMed,2003;348:2294-303DCCT－EDIC：早期代謝控制的益處

——頸動脈內膜厚度DCCT/EDICStudy

累積的心血管事件數

歐洲糖尿病協會

減少2型糖尿病心血管風險

英國前瞻性糖尿病研究20年干預

研究結束后10年隨訪結果(1997-2007)

UKPDS結果Mean(95%CI)UKPDS結束10年后隨訪結果：HbA1c的變化磺脲類/胰島素

vs.

常規(guī)治療微血管疾病風險比強化治療(磺脲類/胰島素)vs.

常規(guī)治療(腎衰竭，玻璃體積血，光凝固法)HR(95%CI)心梗風險比(致死性或非致死性心梗或猝死)強化治療(磺脲類/胰島素)vs.

常規(guī)治療HR(95%CI)全因死亡風險比強化治療(磺脲類/胰島素)vs.

常規(guī)治療HR(95%CI)早期血糖控制所帶來的延續(xù)效應(LegacyEffect)

研究結束后隨訪8.5年結果綜合終點 1997 2007任何與糖尿病相關的終點 RRR:

12% 9%

P: 0.029 0.040

微血管疾病 RRR:

25% 24%

P:

0.0099 0.001心梗 RRR: 16% 15%

P:

0.052 0.014全因死亡 RRR: 6% 13%

P:

0.44 0.007

1RuryR.Holmanetal,NEnglJMed.2008;359(15):1618-20RRR=RelativeRiskReduction,P=LogRank強化治療(磺脲類/胰島素)vs.

常規(guī)治療2型糖尿病強化組長期隨訪結果

UKPDS:延遲效應實際意義:提示“血糖記憶”效應需要盡早及嚴格血糖控制可能獲得長期的心血管獲益Steno-2PostTrial

aim1Toexaminewhetheranintensifiedmultifactorialinterventionsimilartocurrentguidelineshasanimpactonmortalityinpatientswithtype2diabetesandmicroalbuminuria2Toexaminewhetherriskreductionsalreadyachievedforbothmacro-andmicrovasculardiseasewithintensifiedmultifactorialinterventionweresustainedinaclinicalsettingoutsidethestructuredframeworkofaclinicaltrialSTENO-2PercentageofPatientsWhoReachedtheIntensive-TreatmentGoalsataMeanof7.8YearsGlycosylatedHemoglobin<6.5%Patients(%)02030405060701080Cholesterol<175mg/dlTriglycerides<150mg/dlSystolicBP<130mmHgDiastolicBP<80mmHgP=0.06P<0.001P=0.19P=0.001P=0.21Intensive

therapyConventional

therapyG?dePetal.NEJM.2003;348:383–393.STENO-2CompositeEndPointofDeathfromCVCauses,NonfatalMI,CABG,PCI,NonfatalStroke,Amputation,orSurgeryforPeripheralAtheroscleroticArteryDiseaseG?dePetal.NEJM.2003;348:383–393.PrimaryCompositeEndPoint(%)003612966048847224603040201050IntensivetherapyConventionalTherapyMonthsofFollow-upP=0.007Hazardratio=0.47(95percentc.i.,0.24to0.73;P=0.008)Steno-2研究:2型糖尿病多因素干預對死亡率的影響NumbersatriskConventionalIntensiveSteno-2PostTrial:Mortality8080807877756972636551624357HR=0.54(0.32-0.89),P=0.0153039Yearsoffollow-upPercentageofpatientsdying(%)GaedePetal.NEJM358:580-591,2008ImplicationsofthesefindingsforclinicalcareTreatmenttoA1Ctargetsbeloworaround7%intheyearssoonafterthediagnosisofdiabetesisassociatedwithlong-termreductioninriskofmacrovasculardiasease.Untilmoreevidencebecomesavailable,thegeneralgoalof<7%appearsreasonable.(ADA,B-level)ImplicationsofthesefindingsforclinicalcareForselectedindividuals,includingthosewithshortd