1、Clinical Trials and Guidelines for Lipid Management in the Diabetic PatientSteven Haffner, MDUKPDS DesignAimTo determine whether intensified blood glucose control, with either sulphonylurea or insulin, reduces the risk of macrovascular or microvascular complications in type 2 diabetesPatients3867 ne

2、wly diagnosed type 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

3、 1998;352:837-853.UKPDS 10-Year Follow-up Results:Glycemic Control, Weight, and Plasma InsulinYears from Randomization01234567891011120123456789101112Years from RandomizationConventionalConventionalIntensiveIntensiveConventionalIntensiveIntensiveConventionalFasting plasma glucoseMedian (mmol/L)Hemog

4、lobin 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 Therapies in the Conventional-Therapy GroupCourtesy of Dr. Amanda Adler% of patients10080604020Diet

5、 alone1357911Years from randomizationAdditionalpharmacologictherapyUKPDS: Causes of Death by Glucose Treatment GroupRate/1000patient-yearsMIStrokeSudden deathPVDAll macrovascularRenal diseaseCancerOther specifiedUnknownTotalUKPDS Group. Lancet 1998;352:837-853.%Rate/1000patient-years%7.61.60.90.110.

6、20.34.42.40.517.8Cause43951582251331008.01.31.60.311.20.24.42.70.218.74378260124141100ConventionalIntensiveUKPDS: Endpoints by Glucose Treatment GroupRate/1000Patient-YearsAny diabetes-related*MIStrokePVD*MicrovascularUKPDS Group. Lancet 1998;352:837-853.Rate/1000Patient-YearsPCause40.914.75.61.18.6

7、 *Combined microvascular and macrovascular events*Amputation or death from PVD% RiskReduction46.017.45.01.611.40.0290.0520.520.150.0099121625ConventionalIntensiveUKPDS: Impact of Glucose-Lowering Agents on MI and StrokeSulphonylurea or exogenous insulin (n=2729) MI 16% reduction (P = 0.052) Stroke 1

8、1% increase (P = 0.52)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

9、 Blood Pressure ControlAny diabetes-related endpointDeaths related to diabetesMyocardial infarctionStrokeMicrovascular diseaseIntensive BloodPressure Control24322144370.00460.019 NS0.0130.092Adapted from UK Prospective Diabetes Study Group. BMJ 1998;317:703-713.Reduction(%)P ValueComparison of Capto

10、pril 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 EndpointAdapted from UK Prospective Diabetes Study Group. BMJ 1998;317:713-720.RR forCaptopr

11、ilP 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 infarctionStrokeMicrovascular disease12161125Re

12、duction % = 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.PValueReduction %PValueIntensive BloodGlucose Control (n=2729)Intensive BloodPressure Control (n=758)0.0290.052NS0.0099242144370.00

13、46NS0.0130.092Treatment Strategies for Diabetic DyslipidemiaPrimary Strategy - Lower LDL cholesterolSecondary Strategy - Raise HDL cholesterol - Lower triglyceridesOther Approaches - Non-HDL cholesterol - ApoB - RemnantsAdapted from American Diabetes Association. Diabetes Care. 2000;23(suppl 1):S57-

14、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;16:716-730.CHD Prevention Trials with Statins in Diabetic Subjects: Subgroup AnalysesPrimary PreventionAFCAPS/TexCAPSSeco

15、ndary PreventionCARE4SLIPIDBaselineLDL-C,mg/dl(mmol/L)*Values for overall group Adapted from Downs JR et al. JAMA 1998;279:1615-1622; Goldberg RB et al. Circulation 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 Int

16、ervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med 1998;339:1349-1357.DrugNo.LDL-CLoweringLovastatinPravastatinSimvastatinPravastatin25%28%36%25%*150 (3.9)136 (3.6)186 (4.8)150* (3.9)239586202782StudyCHD Prevention Trials with Statins in Diabetic Subjects: Subgroup Ana

17、lyses (contd)Primary PreventionAFCAPS/TexCAPSSecondary PreventionCARE4SLIPID4S-ExtendedCHD RiskReduction(overall)DrugNo.LovastatinPravastatinSimvastatinPravastatinSimvastatin43%25% (p=0.05)55% (p=0.002)19%42% (p=0.001)37%23%32%25%32%239586202782483CHD RiskReduction(diabetes)StudyAdapted from Downs J

18、R et al. JAMA 1998;279:1615-1622; Goldberg RB et al. Circulation 1998;98:2513-2519; 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

19、.Adapted from Pyrl et al. Diabetes Care 1997;20:614-620.Diabetic vs. Nondiabetic Patients in 4S00.20.40.81.4Relative Risk with 95% Confidence IntervalsTotal mortality0.61.01.2ReducedIncreasedCHD mortalitySimvastatin BetterPlacebo BetterMajor CHD eventCerebrovascular eventAny atherosclerotic eventP=0

20、.001P=0.087P0.0001P=0.242P0.0001P=0.002P=0.097P=0.071P7 mmol/L (126 mg/dl)0.00.20.40.81.4Relative 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:

21、 Extended Diabetic Subgroup Analysis:Impaired Fasting Glucose (n=678; 343 on Simvastatin) Fasting Glucose 6.0-6.9 mmol/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)0.61.01.20.450.570.570.62Simvas

22、tatinNormal 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 fastingglucosePlaceboSimvastatinPlaceboDiabetesmellitus38%(p=0.005)28%(p0.001)CARE: Major Coronary Events i

23、n Diabetic SubgroupsAdapted from Goldberg RB et al. Circulation 1998;98:2513-2519.4535302520151050Percent with EventNo Diabetes by HistoryDiabetes by HistoryFollow-up Time (years)Percent with Event4535302520151050Follow-up Time (years)01234650123465PlaceboPravastatinPravastatinPlaceboRelative risk =

24、 0.75P=0.05Relative risk = 0.77P0.001% Risk ReductionAFCAPS/TexCAPS: Subgroup AnalysisDowns JR et al. JAMA 1998;279:1615-1622.MenWomenOlderSmokersHTNDiabetes-37-46-31-58-38-42Lovastatin Reduced the Risk of Acute MCECARE: Major Coronary Events in Diabetic SubgroupsAdapted from Goldberg RB et al. Circ

25、ulation 1998;98:2513-2519.454035302520151050Percent with EventNo Diabetes by HistoryDiabetes by HistoryFollow-up Time (years)Percent with EventFollow-up Time (years)01234650123465PlaceboPravastatinPravastatinPlaceboRelative risk = 0.75P=0.05Relative risk = 0.77P0.001454035302520151050Per-Patient % o

26、f 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)No Diabetes (n=1235)99% CI(0.20-1.19)99% CI(0.46-0.79)51% 40% CHD Prevention Trials with Fibrates in

27、 Diabetic Subjects: Subgroup AnalysesPrimary PreventionHelsinkiHeart StudySecondary PreventionVA-HITBaselineLDL-C,mg/dl(mmol/L)No.LDL-CLoweringAdapted from Koskinen P et al. Diabetes Care 1992;15:820-825; Rubins HB et al. N Engl J Med 1999;341:410-418.DrugDoseStudyCHDReductionGemfibrozil(1200 mg/d)G

28、emfibrozil(1200 mg/d)135627203(5.2)112(2.9)68%NS24%p=0.056%Primary CHD* Prevention in Type 2 Diabetic Patients: 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

29、Placebo(n=76)Type 2 onGemfibrozil(n=59)P65, n 10,000) Diabetics (n 6,000) Stroke (n 3,000) Hypertension (n 8,000) Noncoronary vascular disease (n 7,000) Low to average blood cholesterol (n 8,000)FPI 1996, fully enrolled, results 2001 Medical Research Council. August 1994Endpoint Studies: Treating to New Targets (TNT): Study DesignSite SelectionNovember 1997InvestigatorMeetingMarch 1998RecruitmentCompleteJune 1999Study EndDec 2004Atorvastatin10 mgLDL75 mg/dLLDL100 mg/dL5 YearsAtorvastatin80 mg10,000 CAD PatientsStudy of the Effectiveness of Addi