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1、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 and Type 2 DiabetesCoronary Heart DiseaseType 2DiabetesHighLDL-C

2、MetabolicSyndromeExpert Panel on Detection, EvaAtdischarge3 molaterAtdischargeHigh Risk of Impaired Glucose Tolerance and Type 2 Diabetes by OGTT in Post-MI Patients without Known DiabetesIGT% of Patients3 molaterNew DM35%40%31%25%n = 181Norhammar A et al. Lancet 2002;359:2140-2144.Atdischarge3 mola

3、terAtdischConversion 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

4、2781 5.006Increased Metabolic Syndrome in Prediabetic Subjects: Baseline Risk Factors in Subjects with Normal Glucose Tolerance at Baseline according to Conversion Status at 8-Year Follow-up: San Antonio Heart StudyHaffner SM et al. JAMA 1990;263:2893-2898.* Ratio of subscapular to triceps skinfolds

5、Conversion Status at Follow-upNondiabeticthroughout the studyPrior todiagnosis ofdiabetesElevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes: Nurses Health StudyCopyright 2002 American Diabetes AssociationFrom Diabetes Care, Vol. 25, 2002; 1129-1134Reprinted with permission from The

6、American Diabetes Association.Relative Risk12.823.715.02After diagnosis ofdiabetesDiabetic atbaselineNondiabeticthroughout the stRisk of Major CHD Event Associated with Insulin Quintiles in Nondiabetic Subjects: Helsinki Policemen StudyYears5102001525Pyrl M et al. Circulation 1998;98:398-404.Log ran

7、k: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 (m

8、m Hg)114.9116.5118.3119.3123.0Diastolic BP (mm Hg)69.070.471.973.175.4CVD Risk Factors across HOMA-IR Quintiles: 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

9、SyndromeDiagnosis is established when 3 of these risk factors are presentExpert 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: NHANES III by AgeFord ES et al. JAMA

10、 2002;287:356-359.Prevalence, %2070+Age, years202930395059606970MenWomen24%23%8%6%44%44%4049Prevalence of the NCEP MePrevalence of the NCEP Metabolic Syndrome: NHANES III by Sex and Race/EthnicityPrevalence, %MenFord ES et al. JAMA 2002;287:356-359.WomenWhiteAfrican AmericanMexican AmericanOther25%1

11、6%28%21%23%26%36%20%Prevalence of the NCEP MetabolPrevalence of CHD by the Metabolic Syndrome and Diabetes in the NHANES Population Age 50+CHD Prevalence% of Population =No MS/No DM54.2%MS/No DM28.7%DM/No MS2.3%DM/MS14.8%8.7%13.9%7.5%19.2%Alexander CM et al. Diabetes 2003;52:1210-1214.Prevalence of

12、CHD by the MetabATP III Metabolic Syndrome:Therapeutic ImplicationsFocus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndromeTherefore, prevent development of obesity in the general populationAlso, treat obesity in the clinical setting (NHLBI/NIDDK Obesity Educ

13、ation 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 C

14、omponents of the NCEP Metabolic Syndrome Predict CHD: NHANES*Significant predictors of prevalent CHDPrediction of CHD Prevalence using Multivariate Logistic RegressionCopyright 2003 American Diabetes AssociationFrom Diabetes, Vol. 52, 2003; 1210-1214Reprinted with permission from The American Diabet

15、es Association.VariableOddsRatioLower 95%LiBMI per kg/m2HDL-C per mg/dl decreaseSBP per mm HgFPG per mg/dlDifferent Components of the NCEP Metabolic Syndrome Predict Diabetes: San Antonio Heart StudyStern MP et al. Ann Intern Med 2002;136:575-581.Risk of Type 2 Diabetes per Unit Change in Risk Trait

16、 Levels8%2%4%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: Based on Clinical CriteriaInsulin resistance (type 2 diabetes, IFG, IGT)*Plus

17、 any 2 of the following:Elevated BP (140/90 or drug Rx)Plasma TG 150 mg/dlHDL 35 mg/dl (men); 30 and/or W/H 0.9 (men), 0.85 (women)Urinary 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 and

18、Must Insulin Resistance be Present for a Patient to Have the Metabolic Syndrome?WHO 1999 clinical definitionYesATP III 2001 clinical definitionNo, but it is usually presentMultiple metabolic risk factors are sufficientObesity can produce the metabolic syndrome without insulin resistanceWHO. Definiti

19、on, 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 Defin

20、ition 1999: Therapeutic ImplicationsFocus on insulin resistance as the underlying cause of the metabolic syndromeMore emphasis on the genetic basis of the metabolic syndrome rather than obesityLeads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabol

21、ic syndromeWHO Metabolic Syndrome DefinitTherapeutic Implications of Definition of Metabolic SyndromeIf focus is on obesity as underlying causePrevent and treat obesityIf focus is on insulin resistance as underlying causeTreat insulin resistanceIf focus is on metabolic risk factorsTreat individual r

22、isk factorsTherapeutic Implications of DeCriteria for Comparing Different Definitions of Metabolic SyndromeRisk of:CHDDMRelation to:Insulin resistanceObesityPrevalence in community could differ by raceHow simple is the definition?Criteria for Comparing DiffereIntensity of Therapy Should be Proportio

23、nate to Level of RiskWhat is the impact of the metabolic syndrome on health outcomes?Cardiovascular diseaseType 2 diabetesIntensity of Therapy Should beCardiovascular Disease Mortality Increased in the Metabolic Syndrome: Kuopio Ischaemic Heart Disease Risk Factor StudyLakka HM et al. JAMA 2002;288:

24、2709-2716.Cumulative Hazard, %026812Follow-up, yYESMetabolic Syndrome:NOCardiovascular 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.

25、741.67)0.87 (0.571.33)CVD2.04 (1.143.63)0.77 (0.381.55)Cox Proportional Hazard Ratios (and 95% Confidence Intervals) Predicting All-Cause and Cardiovascular Mortality: San Antonio Heart Study 14-Year Follow-upHunt KJ et al. Diabetes 2003;52:A221-A222.* Those without diabetes, cardiovascular disease,

26、 or cancer.Adjusted for age, gender, and ethnic group.NCEP MetSWHO MetSTotal PopulatComparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Resistant Subjects: IRAS% in Lowest Quartile of SiHanley AJ et al. Diabetes 2003;52:2740-2747.NeitherNCEP OnlyWHO OnlyBothOverallHispanicsNon-His

27、panic whitesAfrican AmericansComparison of NCEP and 1999 WHRelative RiskCRP Adds Prognostic Information at All Levels of Risk as Defined 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

28、 with permission.Relative RiskCRP Adds PrognostPartial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Adjusted for Age, Sex, Clinic, Ethnicity, and Smoking Status: IRASCRPWBCFibrinogenBMI0.400.170.22Waist0.430.180.27Systolic BP0.200.08*0.11Fasting glucose7*Fas

29、ting 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 (Dyslipide

30、mia, Upper Body Adiposity, Insulin Resistance, Hypertension): IRASFesta A et al. Circulation 2000;102:4247.Number of Metabolic Disorders12340Mean Value of Log CRPMean ValFibrinogenCRPPAI-1Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Proteins: IRASIncidence, %1stFest

31、a A et al. Diabetes 2002;51:1131-1137.2nd3rd4thQuartiles:P=0.06P=0.001P=0.001FibrinogenCRPPAI-1Five-Year InThe Effect of Rosiglitazone on CRPHaffner SM et al. Circulation 2002;106:679-684.Rosiglitazone8 mg/dRosiglitazone4 mg/dChange from Baseline to Week 26, %Difference = 26.8 (95% CI: 39.7, 21.8)Pl

32、aceboDifference = 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/dRosiglitazone4 mg/dDifference = 1.9 (95% CI: 11.3, 9.3)PlaceboDifference = 0.0 (95% CI: 9.0, 10.0)Change from Bas

33、eline 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.*Atorvastatin(10 mg/d)Simvastatin(20 mg/d)Pravastatin(40 mg/d)Baseline* p0.025 vs. Baselinehs-CRP (mg/L)Reduction of CRP Insuli

34、n resistance is related to increased PAI-1, fibrinogen, and CRP levels cross-sectionallyIncreased 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 resistanceRosiglitazone, a TZD, decrea

35、ses levels of PAI-1, CRP, and MMP-9SummaryInsulin resistance is related Does Lipid and Blood Pressure Therapy Work in Subjects with the Metabolic Syndrome?Diabetic subjectsBlood pressure: YESStatin therapy: YESNondiabetic subjectsLittle data availableDoes Lipid and Blood Pressure StudyDrugNo.CHD Ris

36、k Reduction OverallCHD Risk Reduction in DiabeticsPrimary PreventionAFCAPS/TexCAPSLovastatin15537%43% (NS)HPSSimvastatin291224%33% (p=.0003)Secondary PreventionCARE Pravastatin58623%25% (p=.05)4SSimvastatin20232%55% (p=.002)LIPIDPravastatin78225%19%4S ReanalysisSimvastatin48332%42% (p=.001)HPSSimvas

37、tatin198124%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 Gro

38、up. 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,

39、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.

40、Lancet 1999;353:611-616.Completed Clinical Trials withIsolated LDL-CRR=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 TriadRR=0.48 (0.330.69)Isolated LDL-CRR=0.86 (0.59Glycosylatedhemoglobi

41、n 6.5%Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with Microalbuminuria): Steno-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 Mas