1、 2003 Thomson Professional Postgraduate ServicesLIPID:Reduction in Nonfatal MI and CHD Death Risk Stratified by Diabetic Status-19-25302520151050With diabetesWithout diabetes(n=782)(n=8,232)LIPID Study Group.N Engl J Med.1998;339:1349-1357.%TM 1999 Professional Postgraduate Services 2003 Thomson Pro
2、fessional Postgraduate ServicesTM 1999 Professional Postgraduate Services0123CHD mortality(per 1,000)Fontbonne AM et al.Diabetes Care.1991;14:461-469.2930-5051-7273-114 115Quintiles(pmol)of fasting plasma insulinP0.01CHD Mortality and Hyperinsulinemia:Paris Prospective Study(n=943)2003 Thomson Profe
3、ssional Postgraduate ServicesTM 1999 Professional Postgraduate Services010203040506012345%Macrovasculardisease P0.0010102030405060708012345%Macrovasculardisease P0.05010203040506012345%CHDP4 hr/wk0.0011225Fiber intake 15 g/1,000 kcal0.0011126Saturated-fat intake 10%energy0.0012647Fat intake 5%of sub
4、jectsP value*ControlsInterventionGoals 2002 Thomson Professional Postgraduate Services 2003 Thomson Professional Postgraduate ServicesFinnish Diabetes Prevention Study:Reduction in Risk for Diabetes*Tuomilehto J et al.N Engl J Med.2001;344:1343-1350.11%23%0510152025InterventionControl(n=265)(n=257)2
5、002 Thomson Professional Postgraduate Services 2003 Thomson Professional Postgraduate ServicesBMI=body mass index.DPP Research Group.N Engl J Med.2002;346:393-403.Diabetes Prevention Program:Study Design Entry Criteria age 25 years BMI 24 kg/m2 (22 kg/m2 in Asians)fasting plasma glucose 95-125 mg/dL
6、 postglucose challenge 140-199 mg/dL Intervention standard lifestyle recommendations+placebo twice daily standard lifestyle recommendations+metformin titrated to 850 mg twice daily intensive lifestyle modification(low-calorie/low-fat diet,moderate physical activity 150 min/wk)troglitazone(later with
7、drawn)Outcome type 2 diabetes over average follow-up of 2.8 years 2002 Thomson Professional Postgraduate Services 2003 Thomson Professional Postgraduate ServicesTM 2000 Professional Postgraduate ServicesDAIS:Impact of Aggressive Therapy on Atherosclerosis in Patients With Type 2 DiabetesStudy popula
8、tion N=418(305 men,113 women)Type 2 diabetes 1 minimal lesion on angiography Mild elevations of LDL-C or TG+TC:HDL-C 4Treatment 8 weeks on Step I diet Randomized,blinded to micronized fenofibrate(200 mg/d)and placeboPrimary end point Progression or regression of CAD on quantitative angiographyDAIS=D
9、iabetes Atherosclerosis Intervention Study.Steiner G et al.Am J Cardiol.1999;84:1004-1010.2003 Thomson Professional Postgraduate Services 2003 Thomson Professional Postgraduate ServicesGarber AJ.Clin Cornerstone.2003;5:22-37.Garber AJ.Med Clin North Am.1998;82:931-948.National Diabetes Data Group.Di
10、abetes in America.2nd ed.NIH;1995.Atherosclerosis in DiabetesAccelerated atherosclerosis is multifactorial and begins years/decades prior to diagnosis of type 2 diabetes 50%of patients with newly diagnosed type 2 diabetes have CHDRisk for atherosclerotic events is 2-to 4-fold greater in diabetics th
11、an in nondiabeticsAtherosclerosis accounts for 65%of all diabetic mortality 40%due to ischemic heart disease 15%due to other heart disease 10%due to cerebrovascular disease 2003 Thomson Professional Postgraduate ServicesTM 1999 Professional Postgraduate ServicesFramingham Heart Study 30-Year Follow-
12、Up:CVD Events in Patients With Diabetes(Ages 35-64)10920119638193*300246810Age-adjusted annual rate/1,000MenWomenTotal CVDCHDCardiac failureIntermittent claudicationStrokeRiskratioP0.001 for all values except*P0.05.Wilson PWF,Kannel WB.In:Hyperglycemia,Diabetes and Vascular Disease.Ruderman N et al,
13、eds.Oxford;1992.2003 Thomson Professional Postgraduate ServicesTM 1999 Professional Postgraduate Services05101520DiabetesNondiabetesMortality Rates for Ischemic Heart Diseasein Patients With and Without Diabetes*Men,cohort 1Men,cohort 2Women,cohort 1Women,cohort 2Men,cohort 1Men,cohort 2Women,cohort
14、 1Women,cohort 2Gu K et al.JAMA.1999;281:1291-1297.*In national sample of adults in NHANES I(1971-75).-16.6%(P=0.46)+10.7%(P=0.76)-43.8%(P0.001)-20.4%(P=0.12)17.014.26.87.67.44.22.41.9 2003 Thomson Professional Postgraduate ServicesTM 1999 Professional Postgraduate ServicesKannel WB.Am Heart J.1985;
15、110:1100-1107.Abbott RD et al.JAMA.1988;260:3456-3460.Women,Diabetes,and CHD Diabetic women are at high risk for CHD Diabetes eliminates relative cardioprotective effect of being premenopausal risk of recurrent MI in diabetic women is three times that of nondiabetic women Age-adjusted mean time to r
16、ecurrent MI or fatal CHD event is 5.1 yr for diabetic women vs 8.1 yr for nondiabetic women 2003 Thomson Professional Postgraduate ServicesTM 1999 Professional Postgraduate Services7.43.310.53.4051015Type 2(n=135)Others(n=3,946)Type 2 on placebo(n=76)Type 2 on gemfibrozil(n=59)5-Yr incidenceof CHD(%
17、)*Myocardial infarction or cardiac death.NS=not significant.Koskinen P et al.Diabetes Care.1992;15:820-825.P0.02P=NSPrimary CHD*Prevention in Patients With Type 2 Diabetes:The Helsinki Heart Study 2003 Thomson Professional Postgraduate ServicesTM 1999 Professional Postgraduate ServicesHaffner SM et
18、al.N Engl J Med.1998;339:229-234.012345678020406080100Nondiabetic subjects without prior MI(n=1,304)Diabetic subjects without prior MI(n=890)Nondiabetic subjects with prior MI(n=69)Diabetic subjects with prior MI(n=169)Survival(%)YearRisk Similar in Patients With Type 2 Diabetes and No Prior MI vs N
19、ondiabetic Subjects With Prior MI 2003 Thomson Professional Postgraduate ServicesTM 1999 Professional Postgraduate ServicesSecondary Prevention:CHD Risk Reduction in the 4S Subgroup of Patients With DiabetesPyrl K et al.Diabetes Care.1997;20:614-620.Total mortality2321672415CHD mortality172991712Maj
20、or CHD event5784074424Any CHD event8716675641CABG or PTCA3632382015Cerebrovascular event9070125Any atherosclerotic event9617506146NondiabeticDiabeticPS00.20.40.60.81.01.21.4RR with 95%CIsNo.patientsSimvastatinPlacebowith eventsbetterbetter 2003 Thomson Professional Postgraduate ServicesTM 1999 Profe
21、ssional Postgraduate Services0.600.700.800.901.004S:Total Mortality Reduction in a Subgroup of Patients With DiabetesPyrl K et al.Diabetes Care.1997;20:614-620.0.001.002.003.004.005.000123456Proportion aliveYr since randomization-P=0.08-P=0.001Diabetic,simvastatinDiabetic,placeboNondiabetic,simvasta
22、tinNondiabetic,placebo29%43%2003 Thomson Professional Postgraduate ServicesTM 1999 Professional Postgraduate Services4S:Major CHD Event Reduction in a Subgroup of Patients With DiabetesPyrl K et al.Diabetes Care.1997;20:614-620.0.500.600.700.800.901.000.001.002.003.004.005.000123456Proportionwithout
23、major CHD eventYr since randomization-P=0.002-P=0.0001Diabetic,simvastatinDiabetic,placeboNondiabetic,simvastatinNondiabetic,placebo32%55%2003 Thomson Professional Postgraduate ServicesTM 1999 Professional Postgraduate ServicesWESDR:Hyperglycemia and the Risk forVascular Complications in Older-Onset
24、 DiabetesPDR=proliferative diabetic retinopathy.Klein R.Diabetes Care.1995;18:258-268.Incidence of retinopathyProgression of retinopathyProgression to PDRVisual lossProteinuriaAmputationIschemic heart death0.511.522.5Risk ratio and 95%Cl 2003 Thomson Professional Postgraduate ServicesTM 1999 Profess
25、ional Postgraduate ServicesWESDR:Hyperglycemia and the Risk forCause-Specific CVD MortalityKlein R.Diabetes Care.1995;18:258-268.0.91.01.11.21.31.41.5Hazard ratio and 95%CIYounger-Ischemiconsetheart diseaseOlder-Ischemiconsetheart diseaseOtherheart diseaseStroke 2003 Thomson Professional Postgraduat
26、e ServicesTM 2001,Professional Postgraduate ServicesWOSCOPS:Development of Type 2 DiabetesKaplan-Meier plots of time to development of type 2 diabetes according to treatment assignment.Freeman DJ et al.Circulation.2001;103:357-362.%diabeticYears in study00.511.522.533.544.555.56543210PlaceboPravasta
27、tin 40 mg/d 2003 Thomson Professional Postgraduate Services 2003 Thomson Professional Postgraduate ServicesSteno-2:Effect of Therapies on Selected Risk FactorsGaede P et al.N Engl J Med.2003;348:383-393.05678910110123456780110120130140150160170012345678065707580859095012345678SBP(mm Hg)HbA1c(%)Follo
28、w-up(yr)Conventional therapyIntensive therapyIntensive therapyConventional therapyConventional therapyIntensive therapyDBP(mm Hg)05010015020025030035001234567805075100125150175200012345678050100150200250300350012345678TG(mg/dL)LDL-C(mg/dL)TC(mg/dL)Follow-up(yr)Conventional therapyIntensive therapyIn
29、tensive therapyConventional therapyIntensive therapyConventional therapy 2003 Thomson Professional Postgraduate Services 2003 Thomson Professional Postgraduate ServicesSteno-2:Primary Composite End Point or Surgery for PADGaede P et al.N Engl J Med.2003;348:383-393.No.at RiskConventional tx 80 72 70
30、 63 59 50 44 41 13Intensive tx80 78 74 71 66 63 61 59 19Follow-up(mo)0 12 24 36 48 60 72 84 966050403020100Conventional therapyIntensive therapyP=0.007%PAD=peripheral artery disease.(log-rank test)2003 Thomson Professional Postgraduate Services%HPS Substudy:First Major Vascular Event in Patients Wit
31、h DiabetesFollow-up(years)PlaceboSimvastatinBenefit/1,000-11334475158P0.00010123456051015202530 2003 Thomson Professional Postgraduate ServicesHPS Substudy:First Major Coronary Event and Stroke by Prior Diabetes StatusSimvastatin(10,269)Placebo(10,267)Rate ratio(95%CI)Statin betterPlacebo betterVasc
32、ular event&diabetes statusMajor coronary eventWith diabetes279(9.4%)377(12.6%)No diabetes619(8.5%)835(11.5%)All patients898(8.7%)1,212(11.8%)27%reduction(P0.0001)StrokeWith diabetes149(5.0%)193(6.5%)No diabetes295(4.0%)392(5.4%)All patients444(4.3%)585(5.7%)25%reduction(P0.0001)0.40.60.81.01.21.4Any
33、 majorvascular event(including revascularizations)2,033(19.8%)2,585(25.2%)24%reduction(P0.0001)2003 Thomson Professional Postgraduate ServicesRisk reductions:HPS Diabetes Substudy:Absolute Effects on 5-Year Rates of First Major Vascular Event40Proportion(%)ProportionalAbsolute/1,000P value32.9%440.0
34、00324.5%620.000118.4%660.002Diabetesalone(n=2,912)Occlusive arterial disease alone(n=14,335)Both(n=3,051)9%13%20%25%31%36%SSSPPP302010 0S=simvastatinP=placebo 2003 Thomson Professional Postgraduate ServicesGould AL et al.Circulation.1998;97:946-952.Clinical Benefits of Cholesterol Reduction A recent
35、 meta-analysis of 38 trials demonstrated that for every 10%reduction in TC CHD mortality decreased by 15%(P0.001)total mortality decreased by 11%(P0.001)Decreases were similar for all treatment modalities Cholesterol reduction did not increase non-CHD mortalityTM 1999 Professional Postgraduate Servi
36、ces 2003 Thomson Professional Postgraduate ServicesLp(a)in Atherogenesis:Another Culprit?Identical to LDL particle except for addition of apo(a)Plasma concentration predictive of atherosclerotic disease in many epidemiologic studies,although not all Accumulates in atherosclerotic plaque Binds apo B-
37、containing lipoproteins and proteoglycans Taken up by foam cell precursors May interfere with thrombolysisMaher VMG et al.JAMA.1995;274:1771-1774.Stein JH,Rosenson RS.Arch Intern Med.1997;157:1170-1176.TM 1999 Professional Postgraduate Services 2003 Thomson Professional Postgraduate ServicesLp(a):An
38、 Independent CHD Risk Factor in Men of the Framingham Offspring CohortRR=relative risk;HT=hypertension;GI=glucose intolerance.Bostom AG et al.JAMA.1996;276:544-548.1.91.81.81.22.73.6RR0.1110250.20.5Lp(a)TCHDL-CHTGISmokingTM 1999 Professional Postgraduate Services 2003 Thomson Professional Postgradua
39、te Services2004 PPSLp(a)=lipoprotein(a);CHD=coronary heart disease.No.of events/1,000 person-yearsQuintile(mg/dL)CHDStrokeDeathWomenMenWomenMenWomenMen1(0.1-1.2)19.8736.1511.386.3322.9233.472(1.3-3.0)17.0533.0111.4412.2618.6937.003(3.1-5.5)18.2141.5810.3413.4325.3834.964(5.6-8.1)20.3142.419.2312.182
40、0.5336.975(8.2-47.5)22.2245.3913.4118.9923.0657.31Total19.6039.3011.0612.4422.1438.01Adapted from Ariyo AA et al.N Engl J Med.2003;349:2108-2115.Lp(a):Vascular Events by Sex and Quintileat Baseline(Cardiovascular Health Study)2003 Thomson Professional Postgraduate ServicesAFCAPS/TexCAPS:RR of Acute
41、Coronary EventsLDL-C and Homocysteine*Median LDL-C=149 mg/dL;median Hcy=11.27 mmol/L.Calculated on 5 patient-years at risk to prevent one event.RR=relative risk;Hcy=homocysteine;CI=confidence interval.Data from Ridker PM et al.Circulation.2002;105:1776-1779.RR with 95%CINo.Patients with EventsLPLDL-
42、C median,Hcy median(n=1,375)1723LDL-C median(n=1,384)2228LDL-C median,Hcy median,Hcy median(n=1,380)2550 0.0 0.5 1.0 1.5Lovastatin(L)betterPlacebo(P)betterNo.Neededto Treat10413011526 2002 Thomson Professional Postgraduate Services 2003 Thomson Professional Postgraduate ServicesAFCAPS/TexCAPS:RR of
43、Acute Coronary EventsTC:HDL-C Ratio and CRP Level*Median TC:HDL-C ratio=5.96;median CRP=0.16 mg/dL.Calculated on 5 patient-years at risk to prevent one event.RR=relative risk;CRP=C-reactive protein;CI=confidence interval.Adapted from Ridker PM et al.N Engl J Med.2001;344:1959-1965.RR with 95%CINo.Pa
44、tients with EventsLPTC:HDL-Cmedian,CRPmedian(n=1,525)1920TC:HDL-Cmedian(n=1,346)1735TC:HDL-Cmedian,CRPmedian,CRPmedian(n=1,528)34420.00.51.01.52.02.5Lovastatin(L)betterPlacebo(P)betterNo.Neededto Treat983433562TM 2001,Professional Postgraduate Services 2003 Thomson Professional Postgraduate Services
45、NonHDL-CNo.of Deaths(mg/dL)(Subjects)16060(790)160 to 19056(653)190 to 22053(506)22065(432)LDL-C(mg/dL)13060(794)130 to 16068(694)160 to 19057(532)19049(361)LRC Follow-up Study:CVD Mortality by NonHDL-C and LDL-C in MenLRC=Lipid Research Clinics;RR=relative risk;CI=confidence interval.Adapted from C
46、ui Y et al.Arch Intern Med.2001;161:1413-1419.00.250.50 0.75 1.001.25 1.50 1.75 2.002.25 2.50 2.75 3.00RR with 95%CITM 2001,Professional Postgraduate Services 2003 Thomson Professional Postgraduate ServicesNonHDL-CNo.of Deaths(mg/dL)(Subjects)16028(898)160 to 19027(465)190 to 22021(337)22037(333)LDL
47、-C(mg/dL)13029(707)130 to 16026(535)160 to 19025(427)19033(364)LRC Follow-up Study:CVD Mortality by NonHDL-C and LDL-C in WomenLRC=Lipid Research Clinics;RR=relative risk;CI=confidence interval.Adapted from Cui Y et al.Arch Intern Med.2001;161:1413-1419.00.501.001.502.002.503.003.504.00RR with 95%CI
48、TM 2001,Professional Postgraduate Services 2003 Thomson Professional Postgraduate ServicesACCESS:Change in LDL-C,NonHDL-C in All Patients at 54 WeeksACCESS=Atorvastatin Comparative Cholesterol Efficacy and Safety Study.Data from Ballantyne CM et al.Am J Cardiol.2001;88:265-269.-42-29-36-28-36-38-26-
49、32-26-32-50-40-30-20-1001020LDL-CNonHDL-C%D DAtorvastatinFluvastatinLovastatinPravastatinSimvastatin(n=1,888)(n=474)(n=472)(n=461)(n=462)TM 2001,Professional Postgraduate Services 2003 Thomson Professional Postgraduate ServicesAge-Adjusted Total Cholesterol Levels in NHANES III vs NHANES 1999-2000Fo
50、rd ES et al.Circulation.2003;107:2185-2189.PopulationNHANES III19881994(mg/dL)NHANES19992000(mg/dL)PAll adults2052030.159Men2042030.605Women2062040.130 2003 Thomson Professional Postgraduate Services 2003 Thomson Professional Postgraduate ServicesElevated TC Effects on Risk of CHD Death in Younger M
