2型糖尿病患者嚴(yán)格血糖控制和心血管事件的預(yù)防

2型糖尿病患者嚴(yán)格血糖控制和

心血管事件的預(yù)防中山大學(xué)附屬第一醫(yī)院內(nèi)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(yán)峻的挑戰(zhàn)

“中國的糖尿病患者可能居世界之最”“經(jīng)濟(jì)的迅速發(fā)展，帶來了傳統(tǒng)生活方式的根本性變革，導(dǎo)致了中國2型糖尿病患者的劇增?！?/p>

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(diào)查結(jié)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(jié)果任一心血管事件,n=9,125NGTI-IFGIGTDM相對(duì)比例(%)PresentationofNovartisSatellitesymposiumduringESC2004,Munich,GermanyNAVIGATORGAMI:急性心梗患者中的糖代謝異常心肌梗死患者BartnikM,etal.JInternMed.2004Oct;256(4):288-97.中國心臟調(diào)查結(jié)果-匯總

（n=3513）中華內(nèi)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(yù)測因素BartnikM,etal.EurHeartJ.2004;25(22):1990-7.中位數(shù)隨訪時(shí)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(fēng)險(xiǎn)越來越多的2型糖尿病患者出現(xiàn)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(xué)上的關(guān)聯(lián)但是嚴(yán)格的血糖控制能否降低該風(fēng)險(xiǎn)?ACCORD,ADVANCE&VADT等大型研究就是針對(duì)上述問題而設(shè)計(jì)ACCORD:2型糖尿病強(qiáng)化降糖的效應(yīng)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(qiáng)化治療組(目標(biāo)A1c

<6.0%)

v標(biāo)準(zhǔn)治療組1/3有心血管病史或2個(gè)以上心血管危險(xiǎn)因素一級(jí)終點(diǎn):非致死性心?；蜃渲校恍难芩劳鯝CCORD:結(jié)果

ResultsofACCORD糖尿病心血管風(fēng)險(xiǎn)控制行動(dòng)(ACCORD)關(guān)于執(zhí)行過程的分析HbA1c降低過快(4

個(gè)月下降1.4%)頻發(fā)嚴(yán)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(yán)格的血糖控制目標(biāo)(HbA1c<6.0%)VADT:結(jié)果和分析平均隨訪5.6

年A1c6.9%A1c

在6個(gè)月內(nèi)降低2%

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

2型糖尿病強(qiáng)化降壓/降糖和血管事件結(jié)果2型糖尿病患者嚴(yán)格血糖控制和血管結(jié)局ADVANCE:析因設(shè)計(jì)

強(qiáng)化降糖組標(biāo)準(zhǔn)降糖組以達(dá)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(biāo)：HbA1c

<6.5%除達(dá)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(biāo)準(zhǔn)ADVANCE:血糖結(jié)果

ADVANCE:終點(diǎn)結(jié)果微血管和大血管復(fù)合終點(diǎn)結(jié)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(diǎn)ACCORDADVANCE

VADT基線:年齡(歲)

病程(年)

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

研究時(shí)間(yr)

胰島素(%)6.03.4776.55.0416.05.689結(jié)果:

HbA1c(%)

心血管死亡(%強(qiáng)化組v標(biāo)準(zhǔn)組)

嚴(yán)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(dòng)脈內(nèi)膜厚度DCCT/EDICStudy

累積的心血管事件數(shù)

歐洲糖尿病協(xié)會(huì)

減少2型糖尿病心血管風(fēng)險(xiǎn)

英國前瞻性糖尿病研究20年干預(yù)

研究結(jié)束后10年隨訪結(jié)果(1997-2007)

UKPDS結(jié)果Mean(95%CI)UKPDS結(jié)束10年后隨訪結(jié)果：HbA1c的變化磺脲類/胰島素

vs.

常規(guī)治療微血管疾病風(fēng)險(xiǎn)比強(qiáng)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(fēng)險(xiǎn)比(致死性或非致死性心?；蜮?強(qiáng)化治療(磺脲類/胰島素)vs.

常規(guī)治療HR(95%CI)全因死亡風(fēng)險(xiǎn)比強(qiáng)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(yīng)(LegacyEffect)

研究結(jié)束后隨訪8.5年結(jié)果綜合終點(diǎn) 1997 2007任何與糖尿病相關(guān)的終點(diǎn) 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(qiáng)化治療(磺脲類/胰島素)vs.

常規(guī)治療2型糖尿病強(qiáng)化組長期隨訪結(jié)果

UKPDS:延遲效應(yīng)實(shí)際意義:提示“血糖記憶”效應(yīng)需要盡早及嚴(yán)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(yù)對(duì)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