2型糖尿病患者严格血糖控制和心血管事件的预防

2型糖尿病患者严格血糖控制和

心血管事件的预防中山大学附属第一医院内分泌科肖海鹏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中国的2型糖尿病管理面临严峻的挑战

“中国的糖尿病患者可能居世界之最”“经济的迅速发展，带来了传统生活方式的根本性变革，导致了中国2型糖尿病患者的剧增。”

潘长玉301医院DiabetescomplicationsEachyear3.8milliondeathsworldwideareattributabletodiabetesDiabetesisassociatedwithcomplicationssuchas:DiabeticneuropathyRenalfailureBlindnessMacrovasculardiseaseMacrovascularcomplicationsareamajorcauseofdeathinpeoplewithdiabetes心血管疾病在糖尿病者中的比率新诊断的2型糖尿病患者 ～25%总糖尿病人群 ～50%占糖尿病死亡原因 ～65-75%AmHeartJ1999;138:5330欧洲心脏调查结果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结果任一心血管事件,n=9,125NGTI-IFGIGTDM相对比例(%)PresentationofNovartisSatellitesymposiumduringESC2004,Munich,GermanyNAVIGATORGAMI:急性心梗患者中的糖代谢异常心肌梗死患者BartnikM,etal.JInternMed.2004Oct;256(4):288-97.中国心脏调查结果-汇总

（n=3513）中华内分泌代谢杂志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:新诊断高血糖

是心肌梗死后“无心血管事件存活”的预测因素BartnikM,etal.EurHeartJ.2004;25(22):1990-7.中位数随访时间: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高血糖和心血管风险越来越多的2型糖尿病患者出现心血管并发症UKPDS表明高血糖和心血管疾病之间存在流行病学上的关联但是严格的血糖控制能否降低该风险?ACCORD,ADVANCE&VADT等大型研究就是针对上述问题而设计ACCORD:2型糖尿病强化降糖的效应研究多中心研究(77研究中心)美国/加拿大10,251例患者(平均年龄62.2岁)强化治疗组(目标A1c

<6.0%)

v标准治疗组1/3有心血管病史或2个以上心血管危险因素一级终点:非致死性心梗或卒中；心血管死亡ACCORD:结果

ResultsofACCORD糖尿病心血管风险控制行动(ACCORD)关于执行过程的分析HbA1c降低过快(4

个月下降1.4%)频发严重低血糖(16.2%)TZD(92%)

&胰岛素(77%)

用量过多平均体重增加

3.5Kg

(4人中有1人增加>10Kg

)过于严格的血糖控制目标(HbA1c<6.0%)VADT:结果和分析平均随访5.6

年A1c6.9%A1c

在6个月内降低2%

心血管终点和死亡率上没有显著性差异体重增加9Kg严重低血糖发生率21.2%ADVANCE协作组研究

2型糖尿病强化降压/降糖和血管事件结果2型糖尿病患者严格血糖控制和血管结局ADVANCE:析因设计

强化降糖组标准降糖组以达美康缓释片（格列齐特缓释片）为起始治疗不限制其他药物的使用（磺脲类除外）目标：HbA1c

<6.5%除达美康缓释片以外的其他磺脲类药物为起始治疗

不限制其他药物的使用（磺脲类除外）依照各地指南标准ADVANCE:血糖结果

ADVANCE:终点结果微血管和大血管复合终点结果主要大血管事件全因死亡微血管事件

ADA2008AnualMeetinginSanFrancisco

NopositivetrialeffectofIntensive

glucoseloweringonmacrovascularcomplicationsintype2diabetes,atleastinthetypesofpatientsstudied

ACCORDADVANCEVADT比较:ACCORD,ADVANCE&VADT研究特点ACCORDADVANCE

VADT基线:年龄(岁)

病程(年)

心血管疾病(%)62103566832601141干预:目标HbA1c(%)

研究时间(yr)

胰岛素(%)6.03.4776.55.0416.05.689结果:

HbA1c(%)

心血管死亡(%强化组v标准组)

严重低血糖(%)

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

HazardRatiosforthePrimaryOutcomeandDeathfromAnyCauseinPrespecifiedSubgroupsHazardRatiosforthePrimaryOutcomeandDeathfromAnyCauseinPrespecifiedSubgroupsNEnglJMed,2003;348:2294-303DCCT－EDIC：早期代谢控制的益处

——颈动脉内膜厚度DCCT/EDICStudy

累积的心血管事件数

欧洲糖尿病协会

减少2型糖尿病心血管风险

英国前瞻性糖尿病研究20年干预

研究结束后10年随访结果(1997-2007)

UKPDS结果Mean(95%CI)UKPDS结束10年后随访结果：HbA1c的变化磺脲类/胰岛素

vs.

常规治疗微血管疾病风险比强化治疗(磺脲类/胰岛素)vs.

常规治疗(肾衰竭，玻璃体积血，光凝固法)HR(95%CI)心梗风险比(致死性或非致死性心梗或猝死)强化治疗(磺脲类/胰岛素)vs.

常规治疗HR(95%CI)全因死亡风险比强化治疗(磺脲类/胰岛素)vs.

常规治疗HR(95%CI)早期血糖控制所带来的延续效应(LegacyEffect)

研究结束后随访8.5年结果综合终点 1997 2007任何与糖尿病相关的终点 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强化治疗(磺脲类/胰岛素)vs.

常规治疗2型糖尿病强化组长期随访结果

UKPDS:延迟效应实际意义:提示“血糖记忆”效应需要尽早及严格血糖控制可能获得长期的心血管获益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

therapyGædePetal.NEJM.2003;348:383–393.STENO-2CompositeEndPointofDeathfromCVCauses,NonfatalMI,CABG,PCI,NonfatalStroke,Amputation,orSurgeryforPeripheralAtheroscleroticArteryDiseaseGædePetal.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型糖尿病多因素干预对死亡率的影响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