糖尿病合并高血脂

血脂異常合併

糖尿病或代謝症候群臺中榮民總醫院內分泌暨新陳代謝科主治醫師李奕德糖尿病and高血脂高血脂是心臟血管疾病的主因糖尿病的角色?USA2000:15M2025:21.9MJAPAN2000:6.9M2025:8.5MEUROPE2000:30.8M2025:38.5MAMERICAS(Ex-US)2000:20M2025:42MAFRICA2000:9.2M2025:21.5MASIA2000:71.8M2025:165.7MOCEANIA2000:0.8M2025:1.5MKingHetalDiabetesCare1998;21:1414-1431.Type2DiabetesPrevalenceIsProjectedtoReach300Millionby2025About155millionadultsworldwidediagnosedwithdiabetesin200083millionwomenand72millionmenType2DiabetesPrevalencewillreach300millionin2025PercentagePrevalenceofHyperglycemia

byAgeGroupinTaiwanAgeGroup<2030-3980+Definition:glucose>126ordrug.國民健康局.2003.20-2940-4950-5960-6970-79Incidencerate(%)IncreasedRiskofCVEvents

Over7yearsinType2DiabeticsMyocardialInfarctionStrokeCVDeathNondiabetic–MI(n=1,304)Diabetic+MI(169)Nondiabetic+MI(n=69)Diabetic–MI(n=890)P<0.001*P<0.001*P<0.001*-MI

+MI-MI

+MI-MI

+MI-MI

+MI-MI

+MI-MI

+MIHaffnerSMetalNEnglJMed1998;339:229-234.PrevalenceofhyperglycemiawithCo-morbiddiseasesHTNHyperlipidemiaCHDCVAP<0.001PercentageDefinition:glucose>126ordrug.國民健康局.2003.糖尿病的治療準則A1cBloodpressureCholesterol(lipid)DietcontrolExerciseFactorsreductionTherapeuticLifetherapyStamlerJetalDiabetesCare1993;16:434-444.心血管的死亡率/10,000人-年糖尿病

無糖尿病總膽固醇(mmol/L)020406080100120140<4.74.7–5.15.2–5.75.8–6.26.3–6.76.8–7.2>7.3160心血管死亡風險(MRFITstudy):

低膽固醇糖尿病患者比高膽固醇但無糖尿病的人高糖尿病合併血脂異常之特性三酸甘油酯(Triglyceride)過高高密度脂蛋白膽固醇(HDL)較低低密度脂蛋白(LDL)顆粒較小、密度較密糖尿病的apoB濃度更高DiabetesLDLparticles“Normal”LDL-Clevel,however:“Normal”LDL-ClevelNodiabetes

LDLparticlesNumberofLDLparticlesConcentrationofapoBLowerRiskHigherSmall,denseLDLwithmoreapoBAustinMA,EdwardsKLCurrOpinLipidol1996;7:167-171;AustinMAetalJAMA1988;260:1917-1921;SnidermanADetalDiabetesCare2002;25:579-582.apoBLDL-C根據UKPDS研究中﹕在第二型糖尿病中各種危險因子的重要性

VariableLow-DensityLipoproteinCholesterolHigh-DensityLipoproteinCholesterolHemoglobinA1cSystolicBloodPressureSmokingPValue<0.00010.00010.00220.00650.056CoronaryArteryDisease(n=280)PositioninModelFirstSecondThirdFourthFifth*Adjustedforageandsex.TurnerRCetal.BMJ1998;316:823-828.

CHD罹病風險增加%

LDL-C

1mmol/L 57HDL-C

0.1mmol/L –15

收縮壓

10mmHg 15HbA1c

濃度

1% 11

抽菸也是增加CHD罹病風險的重要因子TurnerRCetalBMJ1998;316:823-828.這些數據證明，糖尿病患者有必要降低其LDL-C濃度，以降低CHD的罹病風險。在UKPDS研究中LDL-C是預測糖尿病患者CHD罹病風險時最有力的指標ThePyramidofRecentTrials

RelativeSizeoftheVariousSegmentsofthePopulation4SCAREWOSCOPSAFCAPS/TexCAPSLIPIDVeryhighcholesterolwithCHDorMIModeratelyhighcholesterolinhighriskCHDorMINormalcholesterolwithCHDorMIHighcholesterolwithoutCHDorMINohistoryofCHDorMI過去對心臟血管疾病的大型介入性（治療性）降血脂臨床試驗的結果對糖尿病患一樣有效嗎？糖尿病合併高血脂症的藥物治療效果StudyDrugNo.BaselineLDL-C,mg/dl(mmol/L)LDL-CLoweringPrimaryPreventionAFCAPS/TexCAPSLovastatin155150(3.9)25%HPSSimvastatin3985127(3.3)30%SecondaryPreventionCAREPravastatin586136(3.6)28%

4SSimvastatin202186(4.8)36%

LIPIDPravastatin782150(3.9)25%Statins在大型心血管保護研究中﹕

針對整個族群的分析(降LDL效果)DownsJRetal.JAMA1998;279:1615-1622HPSInvestigators.PresentedatAHA,2001GoldbergRBetal.Circulation1998;98:2513-2519PyoralaKetal.DiabetesCare1997;20:614-620HaffnerSMetal.ArchInternMed1999;159:2661-2667LIPIDStudyGroup.NEnglJMed1998;339:1349-1357.StudyDrugNo.CHDRisk

Reduction

(overall)CHDRiskReduction(diabetics)PrimaryPreventionAFCAPS/TexCAPSLovastatin15537%43%HPSSimvastatin398524%26%SecondaryPreventionCARE

Pravastatin58623%25%4SSimvastatin20232%55%LIPIDPravastatin78225%19%Statins在大型心血管保護研究中﹕

針對糖尿病次族群的分析(降LDL效果)DownsJRetal.JAMA1998;279:1615-1622HPSInvestigators.PresentedatAHA,2001GoldbergRBetal.Circulation1998;98:2513-2519PyoralaKetal.DiabetesCare1997;20:614-620HaffnerSMetal.ArchInternMed1999;159:2661-2667LIPIDStudyGroup.NEnglJMed1998;339:1349-1357.結果對心臟血管疾病而言，由過去的大型介入性（治療性）臨床試驗事後分析(posthocanalysis)得知，糖尿病患只要接受積極降低血脂治療（尤其是statins藥物），便可得到與非糖尿病患一樣（甚至更多）的好處。CARDSStudyPatientpopulation:Enrolledat132sitesintheUKandIrelandType2diabeteswithnopreviousMIorCHD≥1otherCHDriskfactorplusLDL-C≤4.14mmol/L

(160mg/dL)andTG≤6.78mmol/L(600mg/dL)Aged40-75yearsColhounHM,etal.DiabetMed.2002;19:201-211.2,838patientsAtorvastatin10mg/dayPlaceboAtleast4years6-weekplacebolead-in

Pre-randomizationPlaceboRecruitmentandFollowUp1,398(99.1%)Completefollowup1,421(99.5%)Completefollowup1,410Allocatedplacebo4,053Screened3,249(80%)Enteredbaseline1,428Allocatedatorvastatin10mgdaily2,838(70%)Randomized

Meanfollow-upof3.7yearsinbothgroupsColhounHM,etal.DiabetMed.2002;19:201-211.TCandLDL-CLevelsPlaceboAtorvastatinEffectofAtorvastatinonthePrimaryEndPoint:MajorCVEventsIncludingStrokeRelativeRiskReduction37%YearsPlacebo127eventsAtorvastatin83eventsCumulativehazard(%)051015012344.75P=0.001ColhounHM,BetteridgeDJ,DurringtonPN,etal.Lancet.2004;364:685-696.CARDSSummarystatinprovidedbenefitsintype2diabeteswithnohistoryofCVDandwithnormaltomildly-elevatedcholesterollevels37%reductioninmajorCVDevents(P=0.001)48%reductioninstroke(P=0.016)27%reductioninall-causemortality(P=0.059)ColhounHM,etal.DiabetMed.2002;19:201-211.AdultTreatmentPanelIII(ATPIII)GuidelinesNationalCholesterolEducationProgram治療的主要目標LDLcholesterolLDL的升高是心臟血管疾病的主因降低LDL可減少心臟血管疾病的風險ATPIII治療的主要目標著重在

LDL.高危險群CHDHistoryofCHDCHDriskequivalentsOtherclinicalformsofatheroscleroticdiseaseperipheralarterialdiseaseabdominalaorticaneurysmsymptomaticcarotidarterydiseaseDiabetes(糖尿病)Multipleriskfactorswitha10-yearriskforCHD>20%ATPIIIRiskCategoryCHDandCHDriskequivalentsMultiple(2+)riskfactors0-1oneriskfactorLDLGoal(mg/dL)

<100

<130 <160ThreeCategoriesofRiskthatModify

LDL-CholesterolGoalsATPIIINCEPATPIIIdefinition:>3ofthefollowingcriteriaRiskfactorsDefininglevelAbdominalobesity:Waistcircumference>102cm,Men>88cm,WomenTriglycerides

>150mg/dLHDL-cholesterol<40mg/dL,Men

<50mg/dL,WomenBloodpressure

>130/85mmHgFastingglucose

>110mg/dLPrevalenceoftheMetabolicSyndrome

Age-SpecificPrevalenceoftheMetabolicSyndromeAmong8814USAdultsAgedatLeast20Years,NationalHealthandNutritionExaminationSurveyIII,1988-1994HarrisMI,etal.,DiabetesCare1998;21:518FordES,etal.,JAMA.2002Jan16;287(3):356-9.PrevalenceoftheMetabolicSyndrome

FordES,etal.,JAMA.2002Jan16;287(3):356-9.DifferenceinAsianWHOExpertconsultation.Lancet2004;363:157-163國內成人肥胖定義身體質量指數(BMI)(kg/m2)

腰圍(cm)

體重過輕BMI＜18.5正常範圍18.5≦BMI＜24異常範圍過重：24≦BMI＜27輕度肥胖：27≦BMI＜30中度肥胖：30≦BMI＜35重度肥胖：BMI≧35男性：≧90公分女性：≧80公分肥胖的判定MetabolicSyndrome,carotidatherosclerosisandLDLsizeLDLsizeinmetabolicsyndromeHultheJetal.,Arterioscler

Thromb

Vasc

Biol2000;20:2140.GemfibrozilforinsulinresistanceRubinsHBetal.,ArchInternMed.2002;162:2597代謝症候群(metabolicsyndrome)第二個治療目標LDL控制之後的目標標準腹部肥胖Men(腹圍)>102cm(90cm)Women(腹圍)>88cm(80cm)HightriglycemiaTG>150mg/dlLowHDLcholesterolMen<40mg/dlWomen<50mg/dl血壓高>130/>85mmHg空腹血糖高Plasmaglucose>110mg/dlATPIIITriglycerides高可能原因肥胖(obesity)不運動(physicalinactivity)抽煙(cigarettesmoking)酗酒(excessalcoholintake)高碳水化合物飲食high-carbohydratediets(>60%ofenergyintake)疾病糖尿病Diabetes慢性腎衰竭Chronicrenalfailure腎病症侯群nephroticsyndrome藥物

corticosteroids,estrogens,retinoids,higherdosesofB-adrenergicblockingagents基因familialcombinedhyperlipidemia,familialhypertriglyceridemiafamilialdysbetalipoproteinemia

ATPIIITriglycerides嚴重度TriglycerideslevelNormal <150mg/dLBorderlinehigh 150–199mg/dLHigh 200–499mg/dLVeryhigh 500mg/dLNon-HDLCholesterolVLDL+LDL=Totalcholesterol–HDLTarget:LDL+30mg/dlATPIII治療triglycerides過高治療的主要目標著重在

LDL但當TG>500mg/dl治療的目標﹕先預防急性胰臟炎低脂肪飲食Verylowfatdiets(15%ofcaloricintake)使用降Triglyceride藥物(fibrateornicotinicacid)ATPIIIHDLCholesterol過低-原因-Triglycerides過高肥胖(obesity)不運動(physicalinactivity)糖尿病(type2diabetes)抽煙(cigarettesmoking)高碳水化合物飲食high-carbohydratediets(>60%ofenergyintake)

藥物beta-blockers,anabolicsteroids,progestationalagentsATPIIIHDLCholesterol過低-治療-治療的主要目標著重在

LDL增加運動及控制體重仍依上述原則TG>500ReducetriglyceridesbeforeLDLlowering

TG:200–499Non-HDLcholesterolissecondarytargetoftherapyTG<200considernicotinicacidorfibratesinpersonwithCHDorCHDriskATPIIITherapeuticLifertherapy

-DietcontrolandExcerciseTheOslodiet-heartstudy的11-year追蹤報告：至少三十年前就證實有效地預防心血管疾病 (LerenP,1970)

FinnishDiabetesPreventionStudySubjects522patients,40-65y,CaucasiansIGTon2occasionsInterventions1.

Intensifieddietandexerciselifestyle5%reductioninbodyweightReductionindietaryfat<30%,saturatedfat<10%Increaseindietaryfiber,fruitsandvegetablesIncreaseactivity2. UsualcareNEnglJMed344:1343-1349,2001生活型態與糖尿病

FinnishDPS:DevelopmentofdiabetesintheinterventionandcontrolgroupsRiskreduction:58%Meanfollow-up:3.2yearsNEnglJMed344:1343-1349,2001生活型態與糖尿病USDiabetesPreventionProgramSubjects3234patients,>25y,45%minoritiesIGTwithfastingplasmaglucose>5.6mmol/LInterventions1. Intensifieddietandexerciselifestyle7%reductioninbodyweightincreasecalorieexpenditure700kcalperweek2. Metformin1700mgperday3. PlacebotabletDiabetesCare23:1619-1629USDPP:EffectondiabetesincidenceMetformin:31%decreaseinincidentdiabetesLifestyle:58%decreaseinincidentdiabetesReleasedearly(08/08/01)afterameanfollow-upof3yearsDiabetesCare23:1619-1629TherapeuticLifestyleChanges

NutrientCompositionofTLCDietNutrient

RecommendedIntakeSaturatedfat Lessthan7%oftotalcaloriesPolyunsaturatedfat Upto10%oftotalcaloriesMonounsaturatedfat Upto20%oftotalcaloriesTotalfat 25–35%oftotalcaloriesCarbohydrate 50–60%oftotalcaloriesFiber 20–30gramsperdayProtein Approximately15%oftotalcaloriesCholesterol Lessthan200mg/dayTotalcalories Balanceenergyintakeandexpenditure tomaintaindesirablebodyweight/

preventweightgainATPIII回顧三十年前，發表運動者比長期辦公者對insulin反應較好Bjorntorpetal.Metabolism1970;19:631-638.數天的不運動即造成insulin反應差。Rudermanetal.Diabetes1979;28:89-92.單一次的運動即可改善insulin作用，而且甚至可達兩天之久。Mikinesetal.AmJPhysiol1988;254:E248-E259

若運動後給醣類飲食後，insulinsensitivity只維持了15小時Bogardusetal.JClinInvest1983;72:1605-1610.

但運動當時的catacholamine升高也可能阻礙insulin作用。Kjæretal.JAppl

Physiol1986;61:1693-1700.

Insulin增加血糖的吸收及利用與insulinreceptor作用經由一些protein下傳訊息Ex:insulinreceptorsubstrate(IRS)其中可經由GLUT4(glucosetransporter)移至細胞膜上，以利glucose的傳送運動增加insulinsensitivity的機轉運動後，肌肉會比以前