糖尿病脂代谢紊乱的治疗与临床指南课件.ppt

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1、Clinical Trials and Guidelines for Lipid Management in the Diabetic PatientUKPDS DesignAimnTo determine whether intensified blood glucose control,with either sulphonylurea or insulin,reduces the risk of macrovascular or microvascular complications in type 2 diabetesPatientsn3867 newly diagnosed type

2、 2 diabetic patients who were asymptomatic after 3 months of diet;fasting glucose 6.1-15 mmol/L(110-270 mg/dl);treat for 10 yearsAdapted from UK Prospective Diabetes Study(UKPDS)Group.Lancet 1998;352:837-853;Turner R et al.Ann Intern Med 1996;124:136-145.UKPDS Group.Lancet 1998;352:837-853.UKPDS 10-

3、Year Follow-up Results:GlycemicGlycemic Control,Weight,and Plasma Insulin Control,Weight,and Plasma InsulinYears from Randomization0123456789 10 11 120123456789 10 11 12Years from RandomizationConventionalConventionalIntensiveIntensiveConventionalIntensiveIntensiveConventionalFasting plasma glucoseM

4、edian(mmol/L)Hemoglobin A1cWeightPlasma insulin111098760Median(%)987607.552.50-2.5Baseline=75 kgMean Change(kg)403020100-10-20Median Change(pmol/L)Baseline=89 pmol/LUKPDS:Proportion of Patients Taking Different UKPDS:Proportion of Patients Taking Different Therapies in the Conventional-Therapy Group

5、Therapies in the Conventional-Therapy GroupCourtesy of Dr.Amanda Adler%of patients10080604020Diet aloneDiet alone1357911Years from randomizationAdditionalAdditionalpharmacologicpharmacologictherapytherapyUKPDS:Causes of Death by Glucose Treatment GroupRate/1000Rate/1000patient-yearspatient-yearsMISt

6、rokeSudden deathPVDAll macrovascularRenal diseaseCancerOther specifiedUnknownTotalUKPDS Group.Lancet 1998;352:837-853.%Rate/1000Rate/1000patient-yearspatient-years%7.61.60.90.110.20.34.42.40.517.8CauseCause43951582251331008.01.31.60.311.20.24.42.70.218.74378260124141100ConventionalConventionalIntens

7、iveIntensiveUKPDS:Endpoints by Glucose Treatment GroupRate/1000Rate/1000Patient-YearsPatient-YearsAny diabetes-related*MIStrokePVD*MicrovascularUKPDS Group.Lancet 1998;352:837-853.Rate/1000Rate/1000Patient-YearsPatient-YearsP PCauseCause40.914.75.61.18.6 *Combined microvascular and macrovascular eve

8、nts*Amputation or death from PVD%Risk%RiskReductionReduction46.017.45.01.611.40.0290.0520.520.150.0099121625ConventionalConventionalIntensiveIntensiveUKPDS:Impact of Glucose-Lowering Agents on MI and StrokenSulphonylurea or exogenous insulin(n=2729)MI 16%reduction(P=0.052)Stroke 11%increase(P=0.52)n

9、Metformin in overweight subjects(n=342)MI 39%reduction(P=0.01)Stroke 41%reduction(P=0.13)Adapted from UK Prospective Diabetes Study(UKPDS)Group.Lancet 1998;352:837-853;UK Prospective Diabetes Study(UKPDS)Group.Lancet 1998;352:854-865.UKPDS Results:Intensive Blood Pressure ControlAny diabetes-related

10、 endpointDeaths related to diabetesMyocardial infarctionStrokeMicrovascular diseaseIntensive BloodIntensive BloodPressure ControlPressure Control24322144370.00460.019 NS0.0130.092Adapted from UK Prospective Diabetes Study Group.BMJ 1998;317:703-713.ReductionReduction(%)(%)P ValueP ValueComparison of

11、 Captopril vs.Atenolol in UKPDS Primary Any diabetes-related endpoint Death related to diabetes All-cause mortality Secondary Myocardial infarction Stroke Peripheral vascular disease Microvascular diseaseClinical EndpointClinical EndpointAdapted from UK Prospective Diabetes Study Group.BMJ 1998;317:

12、713-720.RR forRR forCaptoprilCaptoprilP ValueP Value 1.10(0.861.41)1.27(0.821.97)1.14(0.811.61)1.20(0.821.76)1.12(0.592.12)1.48(0.356.19)1.29(0.802.10)0.430.280.44 0.350.740.590.30Comparison of Glucose Lowering and Blood Pressure Lowering in UKPDSAny diabetes-related endpointMyocardial infarctionStr

13、okeMicrovascular disease121611 25Reduction Reduction%=Increase in riskAdapted from UK Prospective Diabetes Study(UKPDS)Group.Lancet 1998;352:837-853;UK Prospective Diabetes Study Group.BMJ 1998;317:703-713.P PValueValueReduction Reduction%P PValueValueIntensive BloodIntensive BloodGlucose Control(n=

14、2729)Glucose Control(n=2729)Intensive BloodIntensive BloodPressure Control(n=758)Pressure Control(n=758)0.0290.052NS0.0099242144370.0046NS0.0130.092Treatment Strategies for Diabetic DyslipidemianPrimary Strategy -Lower LDL cholesterolnSecondary Strategy -Raise HDL cholesterol -Lower triglyceridesnOt

15、her Approaches -Non-HDL cholesterol -ApoB -RemnantsAdapted from American Diabetes Association.Diabetes Care.2000;23(suppl 1):S57-S60;Chait A,Brunzell JD.Diabetes Mellitus.A Fundamental and Clinical Text.Philadelphia:Lippincott Raven,1996;772-779;European Diabetes Policy Group 1999.Diabet Med.1999;16

16、:716-730.CHD Prevention Trials with Statins in Diabetic Subjects:Subgroup AnalysesPrimary PreventionAFCAPS/TexCAPSSecondary PreventionCARE4SLIPIDBaselineBaselineLDL-C,LDL-C,mg/dlmg/dl(mmolmmol/L)/L)*Values for overall group Adapted from Downs JR et al.JAMA 1998;279:1615-1622;Goldberg RB et al.Circul

17、ation 1998;98:2513-2519;Pyrl K et al.Diabetes Care 1997;20:614-620;Haffner SM et al.Arch Intern Med 1999;159:2661-2667;The Long-Term Intervention with Pravastatin in Ischaemic Disease(LIPID)Study Group.N Engl J Med 1998;339:1349-1357.DrugDrugNo.No.LDL-CLDL-CLoweringLoweringLovastatinPravastatinSimva

18、statinPravastatin25%28%36%25%*150(3.9)136(3.6)186(4.8)150*(3.9)239586202782StudyStudyCHD Prevention Trials with Statins in Diabetic Subjects:Subgroup Analyses(contd)(contd)Primary PreventionAFCAPS/TexCAPSSecondary PreventionCARE4SLIPID4S-ExtendedCHD RiskCHD RiskReductionReduction(overall)(overall)Dr

19、ugDrugNo.No.LovastatinPravastatinSimvastatinPravastatinSimvastatin43%25%(p=0.05)55%(p=0.002)19%42%(p=0.001)37%23%32%25%32%239586202782483CHD RiskCHD RiskReductionReduction(diabetes)(diabetes)StudyStudyAdapted from Downs JR et al.JAMA 1998;279:1615-1622;Goldberg RB et al.Circulation 1998;98:2513-2519

20、;Pyrl K et al.Diabetes Care 1997;20:614-620;The Long-Term Intervention with Pravastatin in Ischaemic Disease(LIPID)Study Group.N Engl J Med 1998;339:1349-1357;Haffner SM et al.Arch Intern Med 1999;159:2661-2667.Adapted from Pyrl et al.Diabetes Care 1997;20:614-620.Diabetic vs.Nondiabetic Patients in

21、 4S00.20.40.81.4Relative Risk with 95%Confidence IntervalsTotal mortality0.61.01.2ReducedIncreasedCHD mortalitySimvastatin BetterPlacebo BetterMajor CHD eventCerebrovascular eventAny atherosclerotic eventP=0.001P=0.087P0.0001P=0.242P0.0001P=0.002P=0.097P=0.071P7 7 mmolmmol/L(126 mg/dl)/L(126 mg/dl)0

22、.00.20.40.81.4Relative RiskCHD mortality(P=0.26)Total mortality(P=0.34)Revascularizations(P=0.005)Major coronary events(P=0.001)0.61.01.20.720.790.520.58Adapted from Haffner SM et al.Arch Intern Med 1999;159:2661-26674S:Extended Diabetic Subgroup Analysis:Impaired Fasting Glucose(n=678;343 on Impair

23、ed Fasting Glucose(n=678;343 on SimvastatinSimvastatin)Fasting Glucose 6.0-6.9 Fasting Glucose 6.0-6.9 mmolmmol/L(110-125 mg/dl)/L(110-125 mg/dl)0.00.20.40.81.4Relative RiskCHD mortality(P=0.007)Total mortality(P=0.02)Revascularizations(P=0.01)Major coronary events(P=0.003)0.61.01.20.450.570.570.62S

24、imvastatinNormal fastingglucoseBed Days(per 100 Pts)4S:Effect of Statin Therapy on Hospital StayAdapted from Herman WH et al.Diabetes Care 1999;22:1771-1778.55%(p0.001)PlaceboSimvastatinImpaired fastingglucosePlaceboSimvastatinPlaceboDiabetesmellitus 38%(p=0.005)28%(p0.001)CARE:Major Coronary Events

25、 in Diabetic SubgroupsAdapted from Goldberg RB et al.Circulation 1998;98:2513-2519.4535302520151050Percent with EventNo Diabetes by HistoryNo Diabetes by HistoryDiabetes by HistoryDiabetes by HistoryFollow-up Time(years)Percent with Event4535302520151050Follow-up Time(years)01234650123465PlaceboPrav

26、astatinPravastatinPlaceboRelative risk=0.75P=0.05Relative risk=0.77P0.001%Risk ReductionAFCAPS/TexCAPS:Subgroup AnalysisDowns JR et al.JAMA 1998;279:1615-1622.MenWomenOlderSmokersHTNDiabetes-37-46-31-58-38-42LovastatinLovastatin Reduced the Risk of Acute MCE Reduced the Risk of Acute MCECARE:Major C

27、oronary Events in Diabetic SubgroupsAdapted from Goldberg RB et al.Circulation 1998;98:2513-2519.454035302520151050Percent with EventNo Diabetes by HistoryNo Diabetes by HistoryDiabetes by HistoryDiabetes by HistoryFollow-up Time(years)Percent with EventFollow-up Time(years)01234650123465PlaceboPrav

28、astatinPravastatinPlaceboRelative risk=0.75P=0.05Relative risk=0.77P0.001454035302520151050Per-Patient%of GraftsPOST-CABG:Effect of Aggressive Lipid Lowering on Progression in a Diabetic Subgroup Hoogwerf BJ et al.Diabetes.1999;48:1289-1294.AggressiveRxModerateRxAggressiveRxModerateRxDiabetes(n=116)

29、No Diabetes(n=1235)99%CI99%CI(0.20-1.19)(0.20-1.19)99%CI99%CI(0.46-0.79)(0.46-0.79)51%51%40%40%CHD Prevention Trials with Fibrates in Diabetic Subjects:Subgroup AnalysesPrimary PreventionHelsinkiHeart StudySecondary PreventionVA-HITBaselineBaselineLDL-C,LDL-C,mg/dlmg/dl(mmolmmol/L)/L)No.No.LDL-CLDL-

30、CLoweringLoweringAdapted from Koskinen P et al.Diabetes Care 1992;15:820-825;Rubins HB et al.N Engl J Med 1999;341:410-418.DrugDrugDoseDoseStudyStudyCHDCHDReductionReductionGemfibrozil(1200 mg/d)Gemfibrozil(1200 mg/d)135627203(5.2)112(2.9)68%NS24%p=0.056%Primary CHD*Prevention in Type 2 Diabetic Pat

31、ients:The Helsinki Heart Study5-Year Incidence of CHD(%)Type 2(n=135)*Myocardial infarction or cardiac deathAdapted from Koskinen P et al.Diabetes Care 1992;15:820-825.Others(n=3946)Type 2 on Placebo(n=76)Type 2 onGemfibrozil(n=59)P65,n 10,000)Diabetics(n 6,000)Stroke(n 3,000)Hypertension(n 8,000)No

32、ncoronary vascular disease(n 7,000)Low to average blood cholesterol(n 8,000)nFPI 1996,fully enrolled,results 2001 Medical Research Council.August 1994Endpoint Studies:Treating to New Targets Endpoint Studies:Treating to New Targets(TNT):(TNT):Study DesignSite SelectionSite SelectionNovember 1997Nove

33、mber 1997InvestigatorInvestigatorMeetingMeetingMarch 1998March 1998RecruitmentRecruitmentCompleteCompleteJune 1999June 1999Study EndStudy EndDec 2004Dec 2004AtorvastatinAtorvastatin10 mg10 mgLDLLDL75 mg/75 mg/dLdLLDLLDL100 mg/100 mg/dLdL5 Years5 YearsAtorvastatinAtorvastatin80 mg80 mg10,000 CAD Pati

34、entsStudy of the Effectiveness of Additional Study of the Effectiveness of Additional Reductions in Cholesterol and Reductions in Cholesterol and HomocysteineHomocysteine with with SimvastatinSimvastatin and Folic Acid/Vitamin B and Folic Acid/Vitamin B1212 (SEARCH):(SEARCH):Study DesignStudy Design

35、nPrimary objective:To determine whether the greater cholesterol reductions achieved with simvastatin 80 mg produce greater CHD reductions in post-MI patients than achieved with simvastatin 20 mgnSecondary preventionn2x2 factorial design:simvastatin 20 or 80 mg;2 mg folic acid/1 mg Vitamin B12nN=12,0

36、00nFPI 12/97,results 2003CerivastatinCerivastatin Arm ArmFenofibrateFenofibrate Arm ArmCerivastatinCerivastatinFenofibrateFenofibrate(n=1,250)(n=1,250)PlaceboPlaceboFenofibrateFenofibrate(n=1,250)(n=1,250)CerivastatinCerivastatinPlaceboPlacebo(n=1,250)(n=1,250)PlaceboPlaceboPlaceboPlacebo(n=1,250)(n

37、=1,250)2,5002,500activeactivefenofibratefenofibrate2,5002,500placeboplacebofenofibratefenofibraten=2,500 activen=2,500 activecerivastatincerivastatinn=2,500 placebon=2,500 placebocerivastatincerivastatin5,000 pts5,000 ptsin totalin totalLipids in Diabetes Study(LDS):Two-by-Two Factorial RandomizationConclusionsnCHD risk is extremely high in diabetic subjectsnBenefits of risk-factor modification in intervention trials also apply to subgroups with diabetesnResults of strict glycemic control on macrovascular disease are inconclusive