M1-糖尿病脂代谢紊乱及其与冠心病的关系糖尿病脂代谢紊乱及其与冠心病的关系血脂、脂蛋白和载脂蛋白FredericksonClas sificationofDyslipidemiasCausesofSecondaryDyslipidemiasWHY ?WHY?WHY?CHDpreventiontrialswithstatinsin diabeticsubjects4S:IncidenceofMCEbyglucosestatusReducti onofcoronaryevents普伐他汀与糖尿病发生的研究WHO?脂代谢紊乱的发生率糖尿病脂代谢紊乱 的特点WHO?成人治疗小组第三次指南JAMA,May16,2001-Vol285,No.19危险因素的分类主要 的、独立的危险因素生活习惯的危险因素正在出现的危险因素主要危险因素抽烟高血压(BP>140/90mmHg或进行降压药物 治疗)低HDL-C(<40mg/dL)早发冠心病家族史男性直系亲属<55岁患冠心病女性直系亲属<65岁患冠心病年龄( 男性?45岁;女性?55岁)生活习惯的危险因素肥胖(BMI?30)缺乏运动致动脉粥样硬化饮食正在出现的危险因素Lp( a)高半胱氨酸促凝和促炎症因子空腹血糖受损亚临床动脉粥样硬化ATPIII血脂和脂蛋白分层LDL-C TCHDL-CTG(mg/L)<100<200 <150(<200)理想100-129 接近理 想130-159200-239150-199(200~400)临界高值1 60-189>240>60200-499(>400)高 ?190 >500 非常高<40 低(< 35)分类TG TCLDL-C <1.7(150)<5.72(220)<3.64(1 40)<1.7(150) <5.2(200)<3.12(120)
<1.7(150)<4.68(180)<2.6(100)降脂目标(LDL-C <100mg/dl):临床试验证据他汀类临床试验治疗5年。LDL-C降低25-35%。除WOSCOPS外,平均LDL-C 均降至130mg/dl以下。CARE降至100mg/dl以下。急性冠心病事件和总死亡均显著减少。无非心血管事件(出血性中 风、癌症、意外事件)的增加。耐受性好。无严重不良反应。降脂目标(LDL-C<100mg/dl):血管造影证据Post-CAB G(1997)比较“积极”降脂(LDL-C至平均95mg/dl)与“适度”降脂(LDL-C至平均135mg/dl)对斑块的作用 ,发现前者斑块进展慢。AFCAPS中对低HDL-C(平均40mg/dl)和较高LDL-C(平均150mg/dl)的非冠心病患者研 究发现,治疗的绝对受益仅见于HDL-C<40mg/dl者。调脂治疗的指征和目标-TGPROCAM试验对4849名男性随访8 年,同一LDL-C或HDL-C水平的患者中,冠脉事件的发生率均随TG水平的升高而升高。以17个人群为基础的前瞻性研究的META分 析,TG升高明显增加人群的心血管危险。校正HDL-C和其它因素后,其危险性虽然减弱但依然存在。调脂治疗的指征和目标-TG关于 高TG血症的治疗目标问题仍缺乏足够的证据,有待进一步临床研究。WHO?LDLTreatmentGoalsAcc ordingtoCHDRisk2000ADArecommendationsbasedonLDL-Clevel sinadultswithdiabetes Medicalnutritiontx DrugtxWHEN ?NCEPguidelinesNCEP(AdultTreatmentPanelⅢ,ATPⅢ)WHEN ?急性冠脉综合症中早期应用Statins的益处冠心病患者早期调脂治疗的益处WHEN?糖尿病脂质紊乱患者更应积 极调脂治疗糖尿病脂质紊乱患者更应积极调脂治疗HOW?调脂药物的种类和作用机制调脂药物的种类和作用机制调脂药物的 种类和作用机制调脂药物的种类和作用机制Treatmentprioritiesfordiabeticdyslipidem iainadultsI. LowerLDL-ClevelStatinResin/fibrateII. Raise HDL-ClevelBehavioralinterventionsFibrates,statins,niacin Treatmentprioritiesfordiabeticdyslipidemiainadults(cont’ d)IV.CombinedhyperlipidemiaImprovedglycemiccontrolplushig h-dosestatinImprovedglycemiccontrolplusstatinplusfibric acidderivative(gemfibrozil,fenofibrate)Improvedglycemiccon trolplusresinplusfibricacidderivative(gemfibrozil,fenofib rate)Improvedglycemiccontrolplusstatinplusnicotinicacid (glycemiccontrolmustbemonitoredcarefully)其它调脂措施Backgrou ndType2(non-insulin-dependent)diabetesisassociatedwitham arkedincreaseintheriskofcoronaryheartdisease.Ithasbeen debatedwhetherpatientswithdiabeteswhohavenothadmyocardi alinfarctionsshouldbetreatedasaggressivelyforcardiovascul arriskfactorsaspatientswhohavehadmyocardialinfarctions. MethodsToaddressthisissue,wecomparedtheseven-yearinciden ceofmyocardialinfarction(fatalandnonfatal)among1373nondi abeticsubjectswiththeincidenceamong1059diabeticsubjects, allfromaFinnishpopulation-basedstudy.ResultsTheseven-year incidenceratesofmyocardialinfarctioninnondiabeticsubjects withandwithoutpriormyocardialinfarctionatbaselinewere1 8.8percentand3.5percent,respectively(P<0.001).Theseven-ye arincidenceratesofmyocardialinfarctionindiabeticsubjects withandwithoutpriormyocardialinfarctionatbaselinewere45 .0percentand20.2percent,respectively(P<0.001).EBT,anon invasivediagnosisofCADbeforeclinicalpresentationasymptomat icdiabeticpersonshavethesameatherogenicburdenofthosepat ientswithCADwithoutdiabetes.ThehighprevalenceofCCinas ymptomaticpersonswithdiabetessupportstheneedforaggressive managementofdiabetesandassociatedriskfactors.EBT:electr onbeamtomographyCC:coronarycalciumAmHeartJ141(4):637- 644,2001?表4我国高脂血症防治的目标水平[mmol/L(mg/dl)]1.无冠心病危险因子,无动脉粥样 硬化疾病2.有冠心病危险因子,无动脉粥样硬化疾病3.有动脉粥样硬化疾病或冠心病注:1.为冠心病低危人群; 2.为中危人群;3.为高危人群,属于冠心病二级预防调脂治疗的指征和目标-HDL糖尿病脂代谢紊乱的特 点调脂治疗的目标(TreattoGoals)糖尿病冠心病需要更积极、严格的目标吗?PatientCategoryI nitiationLevelLDLGoalDietarytherapyPrimarypreventionNoCH D,<2RF>=160mg/dL(4.1mmol/L)<160mg/dL(4.1mmol/L)NoCHD ,>=2RF>=130mg/dL(3.4mmol/L)<130mg/dL(3.4mmol/L)Second aryPreventionCHD>100mg/dL(2.6mmol/L)=<100mg/dL(2.6mmol/ L)DrugtherapyPrimaryPreventionNoCHD,<2RF>=190mg/dL(4.9 mmol/L)<160mg/dL(4.1mmol/L)NoCHD,>=2RF>=160mg/dL(4.1 mmol/L)<130mg/dL(3.4mmol/L)SecondaryPreventionCHD>=130 mg/dL(3.4mmol/L)=<100mg/dL(2.6mmol/L)Valuesrepresentmg /dL.?Someauthoritiesrecommenddruginitiationbetween100an d130mg/dL.AmericanDiabetesAssociation.DiabetesCare.2000 ;23(suppl1):S1–S116. Initiation LDL-C Initiation LDL-CStatus l evel goal level goalWithCHD,PVD,orCVD >100 ?100 >100 ?100WithoutCHD,PVD,andCVD >100 ?100 ?130? ?100NC EP急性冠脉综合症中早期应用Statins的益处糖尿病脂质紊乱患者即刻应用调脂药物?Forsecondary prevention,NCEPguidelinessuggestthatdrugtherapybeconsider edifthegoaloftherapyhasnotbeenreachedafter6to12week sofdietarytherapy.突出多种危险因素(主要的独立危险因素和生活习惯危险因素,正在出现的危险因素) 糖尿病与冠心病危险因素等同多重代谢性危险因素(代谢综合症)血脂目标:LDL-c<100mg/dl(理想) HDL-c<40mg/dl(原35mg/dl)低T G分类界限JAMA,May16,2001,285(19),2486-2497NCEP急性冠脉综合症中早期应用Sta tins的益处糖尿病脂质紊乱患者即刻应用调脂药物?他汀类抗炎、抗AS、抗血栓作用一些回顾性研究证据(PRISM- PLUS,RISK-HIA….)和MIRACL的结果提示早期治疗是有益的提高达标率,饮食控制对大部分患者来说是不够的提高依从 性NCEP急性冠脉综合症中早期应用Statins的益处糖尿病脂质紊乱患者即刻应用调脂药物?diabetics ubjectswithoutclinicalCADwouldhaveacceleratedCADsimilart othatofnondiabeticsubjectswithsymptomaticCAD.diabeticsu bjectsevenwithoutCADhadextensiveatherosclerosisinthecaro tidartery.AmJCardiol2000Jun15;85(12):1395-400糖尿病患者的脂代谢紊乱有 高血糖的原因,也有遗传异质性的原因糖尿病冠心病对健康危害更大调脂药有除调脂以外的其它作用饮食治疗、运动治疗、烟酒等生活方式干 预调脂药物的选择种类、机制、应用、副作用胆酸螯合树脂类:阻止胆酸或胆固醇从肠道吸收,促进胆固醇降解,适用 于高胆固醇血症,对高甘油三酯血症无效。烟酸类:抑制cAMP的形成,降低甘油三酯酶活性,肝脏VLDL合成减少,进而减少IDL和LD L,并抑制肝细胞利用辅酶A合成胆固醇。阿西莫司(Acipimox):烟酸衍生物羟甲基戊二酸单酰辅酶A(HMG- CoA)还原酶抑制剂:又称他汀类药。HMG-CoA还原酶是胆固醇生物合成限速酶。该类药物通过对HMG-CoA还原酶的特异竞争性抑 制作用,使HMG-CoA不能转变为甲基二羟戊酸,阻断胆固醇的合成。可使LDL受体表达增加。可降低VLDL、TG、LDL-c、TC, 升高HDL-c。氯贝丁酯类(Clofibrate):又称贝丁酸类或纤维酸类。通过抑制腺苷酸环化酶,使脂肪细胞内cAMP减少,抑 制脂肪组织水解,使血中非酯化脂肪酸含量减少,肝脏VLDL合成和分泌减少。增强LPL活性,加速TG和VLDL的分解。故可降低TG、 VLDL、LDL-c、TC,升高HDL-c。其它:亚油酸及其复方制剂,如含红花油制剂(含多双键不饱和脂肪酸),含20碳5烯酸的鱼 油制剂,有不同程度的减低胆固醇和甘油三酯作用。中药:三楂、首乌、桑寄生、毛冬青、决明子、灵芝、海藻、昆布、泽泻、虎杖等Amer icanDiabetesAssociation.DiabetesCare.2000;23(suppl1):S1–S 116.ADApositionstatementIII.LowerTriglyceridelevelGly cemiccontrolBehavioralinterventionsFibratesStatins aremoderatelyeffectiveathighdoseNiacincanworsen glycemiccontrolindiabetes.Thecombinationofstatinswith nicotinicacidandespeciallywithgemfibrozilorfenofibratemay carryanincreasedriskofmyositis.AmericanDiabetes Association.DiabetesCare.2000;23(suppl1):S1–S116.ADAposit ionstatement外科治疗:回肠末端切除术、门腔静脉分流吻合术,肝移植术血浆净化疗法:免疫吸附法,肝素沉淀法(去除高浓 度的脂蛋白,再输入新的血浆或代用品基因治疗HOW?调脂药物的选择糖尿病冠心病患者的综合措施(Improv edglycemiccontrolAggressivetreatmentofcardiovascularris kfactors:dyslipidemia,hypertension,smokingcessation,etc) 个体化原则内分泌科糖尿病中心中山医科大学附属第一医院廖志红黄知敏WHYWHO-----GOALSWH ENHOW血脂是血浆中的中性脂肪(甘油三酯和胆固醇)和类脂(磷脂、糖脂、固醇、类固醇)的总称脂蛋白是由蛋白质、胆固醇、甘油三 酯和磷脂组成的球形大分子复合体载脂蛋白是脂蛋白的蛋白质部分,它与脂质结合,在血浆中运转脂质TypicalLipidRang e,mg/dLPhenotypeLipoproteininExcessCholesterolTriglyceride ICM300to5005,000to6,000IIALDL250to800<250IIBLDL, VLDL240to350250to500IIIb-VLDL,IDL300to450300to1,00 0IVVLDL200to240300to700VCM,VLDL200to1,000500to6, 000表型分类法有助于高脂血症的诊断和治疗,但是较繁琐。简易分型法将高脂血症分为高胆固醇血症、高甘油三酯血症和混合型高脂血症 HypercholesterolemiaHypertriglyceridemiaCombinedHyperlipidemi aCommondisordersHypothyroidismDiabetesHypothyroidismNephrot icsyndromeObesityNephroticsyndromeObstructiveliverdisease AlcoholChronicrenalfailureChronicrenalfailureUncommondiso rdersPregnancyMyocardialinfarctionAcromegalyAnorexianervosa AcuteinfectionLiverdiseaseConnectivetissuediseasesNephrot icsyndromePregnancyBulimiaMedicationsThiazidediureticsb-bl ockersThiazidediureticsRetinoidsRetinoidsGlucocorticoidsGlu cocorticoidsOralestrogensRetinoidsCyclosporineProgestinsAnd rogens糖尿病冠心病的危害性糖尿病冠心病的临床特点脂代谢紊乱在糖尿病冠心病中的地位糖尿病患者调脂治疗的 益处大血管病变,微血管病变,其它方面MortalityinpeoplewithdiabetesCause sofdeathGeissLS,etal.In:DiabetesinAmerica.2nded.1 995;chap11.0%ofdeaths Ischemic Other Strictly Cancer Stroke Infection Other heart heart diabetes- disease disease related 5040302010Type2diabetesandCHD:7-yearincidenceoffatal /nonfatalMI(EastWestStudy)MI=myocardialinfarction.Thes epatientshadnopriorMIatbaseline.HaffnerSM,etal.NEng lJMed.1998;339:229–234.051015202530354045507-year incidencerateofMI NopriorMI MI NopriorMI MI Nondiabe tic Diabetic n=1373 n=1059P<0.001P<0.0014%19%20%45 %Type2diabetesandCHD:7-yearincidenceoffatal/nonfatalMI (EastWestStudy)糖尿病合并冠心病的临床特点较高的合并动脉粥样硬化的比例;发病率高且发病年龄提前,女性的保护 作用消失;无痛性心梗发生率高;心梗并发症(心衰、心律失常、心源性休克等)发生率高;更容易合并感染;住院时间长,住院病死率高 。Across-sectionalaxialimagefroma56-year-olddiabeticpatie ntwithextensivecalcificationoftheleftanteriordescendinga rtery(LAD)anddiagonalbranch.AmHeartJ141(4):637-644 ,2001糖尿病冠心病的危害性糖尿病冠心病的临床特点脂代谢紊乱在糖尿病冠心病中的地位糖尿病患者调脂治疗 的益处大血管病变,微血管病变,其它方面糖尿病冠心病的危害性糖尿病冠心病的临床特点脂代谢紊乱在糖 尿病冠心病中的地位糖尿病患者调脂治疗的益处大血管病变,微血管病变,其它方面1°PreventionAF CAPS/TexCAPS Lovastatin 155 -37% -43%2°PreventionCARE Pra vastatin 586 -23% -25%4S Simvastatin 202 -32% -55%LIPID Pr avastatin 782 -25% -19%4Sreanalysis Simvastatin 483 -32% -42% CHDrisk CHDrisk reduction reductionStudy Drug n (ov erall) (diabetes)AdaptedfromDownsJR,etal.JAMA.1998;279: 1615–1622;Py?r?l?K,etal.DiabetesCare.1997;20:614–620;Go ldbergRB,etal.Circulation.1998;98:2513–2519;TheLong-Term InterventionwithPravastatinDisease(LIPID)StudyGroup.NEn glJMed.1998;339:1349–1357;HaffnerSM,etal.ArchInternMe d.1999;159:2661–2667.SubgroupanalysesMCE=majorcoronaryev ents.HaffnerSM,etal.ArchInternMed.1999;159:2661–2667.2 6.230.437.518.619.523.505101520253035404550NFGI FGDM-32%RRRP<.001-38%RRRP=.003-42%RRRP=.001Patie nts(%)PBO SIMVACardiovascularEventsincludedCHDdeath,n onfatalMI,CABG,orPTCA.GoldbergRB,etal.Circulation.199 8;98:2513–2519.CAREStudyPlacebo PravastatinEventrate(%)01 020304012345Follow-uptime(yrs)Relativerisk=0.77P=<0.001Nodiabetes(n=3573)06Diabetes(n=586)Relativerisk=0.75P=0.05Follow-uptime(yrs)1234506普伐他汀治疗可以将患糖尿病的危险性降低30%。(Circulation,Jan23,2001)尚在进行普伐他汀对老年人危险性的前瞻性研究(PROSPER)糖尿病脂代谢紊乱的特点调脂治疗的目标(TreattoGoals)糖尿病冠心病需要更积极、严格的目标吗?<0.00184.4%72.8%LDL-c>3.4<0.00111.7%24.8%HDL-c<0.9<0.00113.1%29.2%TG>2.3p非糖尿病2型糖尿病Mmol/LTG,VLDL-TG↑HDL-c↓颗粒细小(较少HDL2,TG高)LDL-c正常或轻度↑小而密LDL↑(更易氧化,更大的动脉壁亲和力)ApoBLp(a)糖尿病脂代谢紊乱的特点调脂治疗的目标(TreattoGoals)糖尿病冠心病需要更积极、严格的目标吗?美国国家胆固醇教育计划ATPIII的新内容血脂和脂蛋白分类的修改LDL-C<100mg/dL--理想HDL-C<40mg/dL绝对的危险因素从原先的35mg/dL提高高甘油三酯分类界限更加注意中度水平的升高? HDL胆固醇?60mg/dL计算为一个“负”危险因素;它可除去总危险因素其中一个HDL及LDL胆固醇水平与冠心病的关系FraminghamHeartStudyMenaged50-7085mg65mg45mg25mgHDL-C |
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