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Update on the Metabolic SyndromeSteven Haffner,MDUpdate on the Metabolic SyndroExpert Panel on Detection,Evaluation,and Treatment of High Blood Cholesterol in Adults.JAMA 2001;285:2486-2497.Metabolic Syndrome Increases Risk for CHD Metabolic Syndrome Increases Risk for CHD and Type 2 Diabetesand Type 2 DiabetesCoronary Heart DiseaseType 2DiabetesHighLDL-CMetabolicSyndromeExpert Panel on Detection,EvaAtdischarge3 molaterAtdischargeHigh Risk of Impaired Glucose Tolerance and Type 2 High Risk of Impaired Glucose Tolerance and Type 2 Diabetes by OGTT in Post-MI Patients without Known Diabetes by OGTT in Post-MI Patients without Known DiabetesDiabetesIGTIGT%of Patients3 molaterNew DMNew DM35%35%40%40%31%31%25%25%n=181n=181Norhammar A et al.Lancet 2002;359:2140-2144.Atdischarge3 molaterAtdischConversion Status at Follow-upDiabetes(n=18)Normal(n=490)PBMI(kg/m2)28.2 1.127.2 0.2.472Centrality*1.38 0.091.16 0.2.472TG(mmol)1.83 0.121.26 0.10.006HDL-C(mmol)1.14 0.071.28 0.02.045SBP(mm Hg)116.8 3.0108.8 0.8.004Fasting glucose(mmol)5.28 0.15.00 0.02.032Fasting insulin(pmol)157 2781 5.006Increased Metabolic Syndrome in Prediabetic Subjects:Baseline Increased Metabolic Syndrome in Prediabetic Subjects:Baseline Risk Factors in Subjects with Normal Glucose Tolerance at Risk Factors in Subjects with Normal Glucose Tolerance at Baseline according to Conversion Status at Baseline according to Conversion Status at 8-Year Follow-up:8-Year Follow-up:San Antonio Heart Study San Antonio Heart StudyHaffner SM et al.JAMA 1990;263:2893-2898.*Ratio of subscapular to triceps skinfoldsConversion Status at Follow-upNondiabeticthroughout the studyPrior todiagnosis ofdiabetesElevated Risk of CVD Prior to Clinical Diagnosis of Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes:Type 2 Diabetes:Nurses Health StudyNurses Health StudyCopyright 2002 American Diabetes AssociationFrom Diabetes Care,Vol.25,2002;1129-1134Reprinted with permission from The American Diabetes Association.Relative Risk1 12.822.823.713.715.025.02After diagnosis ofdiabetesDiabetic atbaselineNondiabeticthroughout the stRisk of Major CHD Event Associated with Insulin Risk of Major CHD Event Associated with Insulin Quintiles in Nondiabetic Subjects:Quintiles in Nondiabetic Subjects:Helsinki Helsinki Policemen StudyPolicemen StudyYears5102001525Pyrl M et al.Circulation 1998;98:398-404.Log rank:Overall P=.001Q5 vs.Q1 P .001Q1Q2Q3Q4Q5Proportion without Major CHD Event0Risk of Major CHD Event AssociHOMA-IRQ1Q2Q3Q4Q5HDL-C(mg/dl)51.749.347.845.041.2LDL-C(mg/dl)115.7119.3125.0128.1124.8Cholesterol(mg/dl)188.0191.6197.9200.8199.0Triglyceride(mg/dl)105.7116.6129.7145.4187.2Systolic BP(mm Hg)114.9116.5118.3119.3123.0Diastolic BP(mm Hg)69.070.471.973.175.4CVD Risk Factors across HOMA-IR Quintiles:CVD Risk Factors across HOMA-IR Quintiles:San Antonio Heart Study(Phase II)San Antonio Heart Study(Phase II)All p(trend)102 cm(40 in)88 cm(35 in)TG150 mg/dlHDL-CMenWomen40 mg/dl50 mg/dlBlood pressure130/85 mm HgFasting glucose110 mg/dlATP III:The Metabolic SyndromeATP III:The Metabolic SyndromeDiagnosis is established when Diagnosis is established when 3 of these risk factors are 3 of these risk factors are presentpresentExpert Panel on Detection,Evaluation,and Treatment of High Blood Cholesterol in Adults.JAMA 2001;285:2486-2497.Risk FactorDefining LevelAbdom4049Prevalence of the NCEP Metabolic Syndrome:Prevalence of the NCEP Metabolic Syndrome:NNHANES III by AgeHANES III by AgeFord ES et al.JAMA 2002;287:356-359.Prevalence,%202070+70+Age,years20293030393950596060696970MenWomen24%24%23%23%8%8%6%6%44%44%44%44%4049Prevalence of the NCEP MePrevalence of the NCEP Metabolic Syndrome:Prevalence of the NCEP Metabolic Syndrome:NHANES III by Sex and Race/EthnicityNHANES III by Sex and Race/EthnicityPrevalence,%MenFord ES et al.JAMA 2002;287:356-359.WomenWhiteAfrican AmericanMexican AmericanOther25%25%16%16%28%28%21%21%23%23%26%26%36%36%20%20%Prevalence of the NCEP MetabolPrevalence of CHD by the Metabolic Syndrome and Prevalence of CHD by the Metabolic Syndrome and Diabetes in the NHANES Population Age 50+Diabetes in the NHANES Population Age 50+CHD Prevalence%of Population=No MS/No DMNo MS/No DM54.2%54.2%MS/No DMMS/No DM28.7%28.7%DM/No MSDM/No MS2.3%2.3%DM/MSDM/MS14.8%14.8%8.7%13.9%7.5%19.2%Alexander CM et al.Diabetes 2003;52:1210-1214.Prevalence of CHD by the MetabATP III Metabolic Syndrome:ATP III Metabolic Syndrome:Therapeutic ImplicationsTherapeutic ImplicationsnFocus on obesity(especially abdominal obesity)as the underlying cause of the metabolic syndromenTherefore,prevent development of obesity in the general populationnAlso,treat obesity in the clinical setting(NHLBI/NIDDK Obesity Education Initiative)ATP III Metabolic Syndrome:ThVariableOddsRatioLower 95%LimitUpper 95%LimitWaist circumference1.130.851.51Triglycerides1.120.711.77HDL cholesterol*1.741.182.58Blood pressure*1.871.372.56Impaired fasting glucose0.960.601.54Diabetes*1.551.072.25Metabolic syndrome0.940.541.68Different Components of the NCEP Metabolic Different Components of the NCEP Metabolic Syndrome Predict CHD:Syndrome Predict CHD:NHANESNHANES*Significant predictors of prevalent CHDSignificant predictors of prevalent CHDPrediction of CHD Prevalence using Multivariate Logistic Prediction of CHD Prevalence using Multivariate Logistic RegressionRegressionCopyright 2003 American Diabetes AssociationFrom Diabetes,Vol.52,2003;1210-1214Reprinted with permission from The American Diabetes Association.VariableOddsRatioLower 95%LiBMI per kg/m2HDL-C per mg/dl decreaseSBP per mm HgFPG per mg/dlDifferent Components of the NCEP Metabolic Different Components of the NCEP Metabolic Syndrome Predict Diabetes:Syndrome Predict Diabetes:San Antonio Heart StudySan Antonio Heart StudyStern MP et al.Ann Intern Med 2002;136:575-581.Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsRisk of Type 2 Diabetes per Unit Change in Risk Trait Levels8%8%2%2%4%4%7%7%BMI per kg/m2HDL-C per mg/dl dWHO.Definition,Diagnosis and Classification of Diabetes Mellitus and Its Complications:Report of a WHO Consultation.Geneva:WHO,1999.WHO Metabolic Syndrome Definition 1999:WHO Metabolic Syndrome Definition 1999:Based on Clinical CriteriaBased on Clinical CriterianInsulin resistance(type 2 diabetes,IFG,IGT)*nPlus any 2 of the following:nElevated BP(140/90 or drug Rx)nPlasma TG 150 mg/dlnHDL 35 mg/dl(men);30 and/or W/H 0.9(men),0.85(women)nUrinary albumin 20 mg/min;Alb/Cr 30 mg/g*Note that 1999 WHO uses hyperinsulinemic euglycemic clamp whereas 1998 WHO and EGIR use HOMA-IR.WHO.Definition,Diagnosis andMust Insulin Resistance be Present for a Patient Must Insulin Resistance be Present for a Patient to Have the Metabolic Syndrome?to Have the Metabolic Syndrome?nWHO 1999 clinical definitionnYesnATP III 2001 clinical definitionnNo,but it is usually presentnMultiple metabolic risk factors are sufficientnObesity can produce the metabolic syndrome without insulin resistanceWHO.Definition,Diagnosis and Classification of Diabetes Mellitus and Its Complications:Report of a WHO Consultation.Geneva:WHO,1999.|Expert Panel on Detection,Evaluation,and Treatment of High Blood Cholesterol in Adults.JAMA 2001;285:2486-2497.Must Insulin Resistance be PreWHO Metabolic Syndrome Definition 1999:WHO Metabolic Syndrome Definition 1999:Therapeutic ImplicationsTherapeutic ImplicationsnFocus on insulin resistance as the underlying cause of the metabolic syndromenMore emphasis on the genetic basis of the metabolic syndrome rather than obesitynLeads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndromeWHO Metabolic Syndrome DefinitTherapeutic Implications of Definition of Therapeutic Implications of Definition of Metabolic SyndromeMetabolic SyndromenIf focus is on obesity as underlying causenPrevent and treat obesitynIf focus is on insulin resistance as underlying causenTreat insulin resistancenIf focus is on metabolic risk factorsnTreat individual risk factorsTherapeutic Implications of DeCriteria for Comparing Different Definitions Criteria for Comparing Different Definitions of Metabolic Syndromeof Metabolic SyndromenRisk of:nCHDnDMnRelation to:nInsulin resistancenObesitynPrevalence in community could differ by racenHow simple is the definition?Criteria for Comparing DiffereIntensity of Therapy Should be Proportionate Intensity of Therapy Should be Proportionate to Level of Riskto Level of RisknWhat is the impact of the metabolic syndrome on health outcomes?nCardiovascular diseasenType 2 diabetesIntensity of Therapy Should beCardiovascular Disease Mortality Increased in the Cardiovascular Disease Mortality Increased in the Metabolic Syndrome:Metabolic Syndrome:Kuopio Ischaemic Heart Kuopio Ischaemic Heart Disease Risk Factor StudyDisease Risk Factor StudyLakka HM et al.JAMA 2002;288:2709-2716.Cumulative Hazard,%026812Follow-up,yYESYESMetabolic Syndrome:NONOCardiovascular Disease MortalityRR(95%CI),3.55(1.986.43)410Cardiovascular Disease MortaliNCEP MetSWHO MetSTotal PopulationAll Cause1.43(1.101.87)1.25(0.961.63)CVD2.55(1.753.72)1.64(1.132.37)Disease Free*All Cause1.11(0.741.67)0.87(0.571.33)CVD2.04(1.143.63)0.77(0.381.55)Cox Proportional Hazard Ratios(and 95%Confidence Cox Proportional Hazard Ratios(and 95%Confidence Intervals)Predicting All-Cause and Cardiovascular Intervals)Predicting All-Cause and Cardiovascular Mortality:Mortality:San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-upupHunt KJ et al.Diabetes 2003;52:A221-A222.*Those without diabetes,cardiovascular disease,or cancer.Adjusted for age,gender,and ethnic group.NCEP MetSWHO MetSTotal PopulatComparison of NCEP and 1999 WHO Metabolic Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Resistant Subjects:Syndrome to Identify Insulin-Resistant Subjects:IRASIRAS%in Lowest Quartile of SiHanley AJ et al.Diabetes 2003;52:2740-2747.NeitherNCEP OnlyWHO OnlyBothOverallHispanicsNon-Hispanic whitesAfrican AmericansComparison of NCEP and 1999 WHRelative RiskCRP Adds Prognostic Information at All Levels of Risk as CRP Adds Prognostic Information at All Levels of Risk as Defined by the Framingham Risk ScoreDefined by the Framingham Risk Score3.0Ridker PM et al.N Engl J Med 2002;347:1557-1565.10+592401Copyright 2002 Massachusetts Medical Society.All rights reserved.Adapted with permission.Relative RiskCRP Adds PrognostPartial Spearman Correlation Analysis of Inflammation Markers Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Adjusted for Age,Sex,Clinic,Ethnicity,and with Variables of IRS Adjusted for Age,Sex,Clinic,Ethnicity,and Smoking Status:Smoking Status:IRASIRASCRPWBCFibrinogenBMI0.400.170.22Waist0.430.180.27Systolic BP0.200.08*0.11Fasting glucose0.180.130.07*Fasting insulin0.330.240.18Si0.370.240.18Festa A et al.Circulation 2000;102:4247.*P0.05,P0.005,P0.0001CRP=C-reactive protein;IRS=insulin-resistance syndrome;WBC=white blood cell count.Partial Spearman Correlation A0Mean Value of Log CRPMean Values of CRP by Number of Metabolic Disorders Mean Values of CRP by Number of Metabolic Disorders(Dyslipidemia,Upper Body Adiposity,Insulin Resistance,(Dyslipidemia,Upper Body Adiposity,Insulin Resistance,Hypertension):Hypertension):IRASIRASFesta A et al.Circulation 2000;102:4247.Number of Metabolic Disorders12340Mean Value of Log CRPMean ValFibrinogenCRPPAI-1Five-Year Incidence of Type 2 Diabetes Stratified Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Proteins:by Quartiles of Inflammatory Proteins:IRASIRASIncidence,%1stFesta A et al.Diabetes 2002;51:1131-1137.2nd3rd4thQuartiles:P=0.06P=0.06P=0.001P=0.001P=0.001P=0.001FibrinogenCRPPAI-1Five-Year InThe Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRPHaffner SM et al.Circulation 2002;106:679-684.Rosiglitazone8 mg/d8 mg/dRosiglitazone4 mg/d4 mg/dChange from Baseline to Week 26,%Difference=26.8 Difference=26.8(95%CI:39.7,21.8)(95%CI:39.7,21.8)PlaceboDifference=21.8(95%CI:34.7,5.6)Difference=21.8(95%CI:34.7,5.6)n=95n=124n=134The Effect of Rosiglitazone onThe Effect of Rosiglitazone on IL-6Haffner SM et al.Circulation 2002;106:679-684.Rosiglitazone8 mg/d8 mg/dRosiglitazone4 mg/d4 mg/dDifference=1.9 Difference=1.9(95%CI:11.3,9.3)(95%CI:11.3,9.3)PlaceboDifference=0.0(95%CI:9.0,10.0)Difference=0.0(95%CI:9.0,10.0)Change from Baseline to Week 26,%n=91n=120n=132The Effect of Rosiglitazone onhs-CRP(mg/L)Reduction of CRP Levels with Statin Therapy(n=22)Jialal I et al.Circulation 2001;103:1933-1935.*AtorvastatinAtorvastatin(10 mg/d)(10 mg/d)SimvastatinSimvastatin(20 mg/d)(20 mg/d)PravastatinPravastatin(40 mg/d)(40 mg/d)BaselineBaseline*p0.025 vs.Baselinep0.025 vs.Baselinehs-CRP(mg/L)Reduction of CRP nInsulin resistance is related to increased PAI-1,fibrinogen,and CRP levels cross-sectionallynIncreased levels of PAI-1,CRP,and fibrinogen(weak)predict the development of type 2 diabetes.In some analyses,these associations are independent of obesity and insulin resistancenRosiglitazone,a TZD,decreases levels of PAI-1,CRP,and MMP-9SummaryInsulin resistance is related Does Lipid and Blood Pressure Therapy Work Does Lipid and Blood Pressure Therapy Work in Subjects with the Metabolic Syndrome?in Subjects with the Metabolic Syndrome?nDiabetic subjectsnBlood pressure:YESnStatin therapy:YESnNondiabetic subjectsnLittle data availableDoes Lipid and Blood Pressure StudyStudyDrugDrugNo.No.CHD Risk CHD Risk Reduction Reduction OverallOverallCHD Risk CHD Risk Reduction in Reduction in DiabeticsDiabeticsPrimary PreventionPrimary PreventionAFCAPS/TexCAPSLovastatin15537%43%(NS)HPSSimvastatin291224%33%(p=.0003)Secondary PreventionSecondary PreventionCARE Pravastatin58623%25%(p=.05)4SSimvastatin20232%55%(p=.002)LIPIDPravastatin78225%19%4S ReanalysisSimvastatin48332%42%(p=.001)HPSSimvastatin198124%15%CHD Prevention Trials with Statins in Diabetic Subjects:Subgroup AnalysesDowns JR et al.JAMA 1998;279:1615-1622.|HPS Collaborative Group.Lancet 2003;361:2005-2016.|Goldberg RB et al.Circulation 1998;98:2513-2519.|Pyrl K et al.Diabetes Care 1997;20:614-620.|LIPID Study Group.N Engl J Med 1998;339:1349-1357.|Haffner SM et al.Arch Intern Med 1999;159:2661-2667.StudyDrugNo.CHD Risk ReductioCompleted Clinical Trials with Antihypertensive Agents in DiabetesTrialDiabetic/TotalResultsSHEP583/4736BeneficialGISSI-32790/18,131BeneficialSyst-Eur492/4695BeneficialHOT1501/18,790BeneficialUKPDS1148BeneficialCAPPP572/10,985BeneficialCurb JD et al.JAMA 1996;276:1886-1892.|Zuanetti G et al.Circulation 1997;96:4239-4245.|Staessen JA et al.Am J Cardiol 1998;82:20R22R.|Hansson L et al.Lancet 1998;351:1755-1762.|UKPDS Group.BMJ 1998;317:703-713.|Hansson L et al.Lancet 1999;353:611-616.Completed Clinical Trials withIsolated Isolated LDL-C LDL-CRR=0.86(0.591.26)RR=0.86(0.591.26)221“Metabolic Syndrome”in 4SEvent Rate,%Ballantyne CM et al.Circulation 2001;104:3046-3051.SimvastatinPlacebo23726128418.020.319.036.9Lipid TriadLipid TriadRR=0.48(0.33RR=0.48(0.33 0.69)0.69)Isolated LDL-CRR=0.86(0.59Glycosylatedhemoglobin 6.5%Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects(Type 2 Diabetes with Microalbuminuria):(Type 2 Diabetes with Microalbuminuria):Steno-2Steno-2Patients Reaching Intensive-Treatment Goals at Mean 7.8 y,(%)Gde P et al.N Engl J Med 2003;348:383-393.Intensive TherapyCholesterol175 mg/dlTriglycerides150 mg/dlSystolic BP130 mm HgDiastolic BP80 mm HgConventional TherapyP=0.06P0.001P=0.19P=0.001P=0.21Copyright 2003 Massachusetts Medical Society.All rights reserved.Glycosylatedhemoglobin 6.5%Composite Endpoint of Death from CV Causes,Nonfatal MI,Composite Endpoint of Death from CV Causes,Nonfatal MI,CABG,PCI,Nonfatal Stroke,Amputation,or Surgery for PAD:CABG,PCI,Nonfatal Stroke,Amputation,or Surgery for PAD:STENO-2STENO-2Primary Composite Endpoint(%)Months of Follow-upGde P et al.N Engl J Med 2003;348:383-393.02448609636847212Conventional Conventional TherapyTherapyIntensive Intensive TherapyTherapyP=0.007P=0.007Hazard ratio=0.47(95%Hazard ratio=0.47(95%CI,0.240.73;P=0.008)CI,0.240.73;P=0.008)Copyright 2003 Massachusetts Medical Society.All rights reserved.Composite Endpoint of Death frSummary:Metabolic SyndromeSummary:Metabolic SyndromenThe metabolic syndrome predicts the development of both diabetes and CHD nInsulin resistance and obesity characterize most individuals subjects with the metabolic syndrome,although not required features of the NCEP metabolic syndromenInitial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activitynConventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome,although no recommendations have so far suggested intensification of risk factor managementnNo consensus exists on whether insulin sensitizers should be used in nondiabetic individuals with the metabolic syndromeSummary:Metabolic SyndromeTh谢谢您的聆听与观看THANK YOU FOR YOUR GUIDANCE.感谢阅读！为了方便学习和使用，本文档的内容可以在下载后随意修改，调整和打印。欢迎下载！汇报人：XXX日期：20XX年XX月XX日谢谢您的聆听与观看THANK YOU FOR YOUR GU
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