HDL的藥物治療優(yōu)選課件

1、NCEP ATP-II Cutpoints for TG and HDL-CParametermg/dLNormal TG 1,000Low HDL-C 35High (protective) HDL-C 60Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 1993;269:30153023NCEP ATP-II Cutpoints for TG aEffects of Lipid-Modifying Drugs on HDL-C LevelsNiaci

2、n 1535%Fibrates 1015%Estrogens 1015%Statins 510%Belalcazar LM et al. Progr Cardiovasc Dis 1998;41:151174Effects of Lipid-Modifying DruDrug Effects on HDL: NiacinLiverBBTGCMR/IDLC-IICM/VLDLLPLA-ICECEFCFCLCATA-IABC1MacrophageMature HDLNascent HDLLDLRHLIntestineNIACINNIACIN*Inhibits uptake of apoA-I bu

3、t not CEDrug Effects on HDL: NiacinLivExtended-Release Niacin for Treatment of Dyslipidemia*Significant difference (P 0.001) between dosage groups.1. Morgan JM et al. Am J Cardiol 1998;82(12A):29U34U2. Capuzzi DM et al. Am J Cardiol 1998;82(12A):74U81U Copyright 1998, with permission from Excerpta M

4、edica Inc.% change from baselineBaseline (mg/dL):-617-1523-28-2028-40-30-20-10010203040TG(156)LDL-C(197)HDL-C(44)TG(137)LDL-C(206)HDL-C(42)TG(174)LDL-C(195)HDL-C(45)1,000 mg/d* (1)(12 wk; n = 35)2,000 mg/d* (1)(12 wk; n = 31) 3,000 mg/d (2)(96 wk; n = 225)-21-28Extended-Release Niacin for TFibrate C

5、hemical StructuresClCOOCH3CH3CCOOCHCH3CH3ClFenofibrateClofibrateOCCOOC2H5CH3CH3CCOOHCH3CH3CH2OCH2CH2CH2CH3CH3GemfibrozilFibrate Chemical StructuresClCDrug Effects on HDL: FibratesLiverBBTGCMR/IDLC-IICM/VLDLLPLA-ICECEFCFCLCATA-IABC1MacrophageMature HDLNascent HDLLDLRHLFIBRATES+FIBRATESIntestineDrug E

6、ffects on HDL: FibratesLFenofibrate for Treatment of Types IV and V Hyperlipoproteinemia*Mean percentage changes, not percentage changes in means.Goldberg AC et al. Clin Ther 1989;11:6983. 14.519.6-46.245.022.9-54.5-60-50-40-30-20-1001020304050Group A(TG = 350499 mg/dL)Group B(TG = 5001,500 mg/dL)%

7、change from baseline*LDL-C(128.4)HDL-C(33.7)LDL-C(103.1)HDL-C(29.6)Mean baseline(mg/dL):Total-TG(432.0)Total-TG(725.6)Fenofibrate for Treatment of TTrials of Agents That Increase HDL-C in Patients With Isolated Low HDL-CRandomized, Placebo-Controlled Studies1. Vega GL, Grundy SM. JAMA 1989;262:31483

8、1532. Miller M et al. Am J Med 1993;94:7123. Lavie CJ et al. Am J Cardiol 1992;69:108310854. King JM et al. Am J Med 1994;97:3233315. Miller M et al. Arterioscler Thromb Vasc Biol 1995;15:215121569927311205101520253035Vega (1)(n = 22)Miller (2)(n = 14)Lavie (3)(n = 19)King (4)(n = 15)Miller (5)(n =

9、39)GemfibrozilNiacinPhenytoin% increase in HDL-CTrial:Trials of Agents That IncreaseDrug Effects on HDL: EstrogensLiverBBTGCMR/IDLC-IICM/VLDLLPLA-ICECEFCFCLCATA-IABC1MacrophageMature HDLNascent HDLLDLRHLESTROGENS+ESTROGENSIntestineDrug Effects on HDL: EstrogensEstrogen Versus Estrogen/Progestin in P

10、ostmenopausal WomenEffect on LipidsCEE = conjugated equine estrogen; MPA = medroxyprogesterone acetate; cyc = cyclic administration (days 1 through 12 of each month); con = administered daily for 1 month; MP = micronized progesteroneWriting Group for PEPI Trial. JAMA 1995;273:199208-2.9-2.0-3.2-10.3

11、9.013.9-12.92.413.5-11.61.911.1-10.96.513.7-20-15-10-505101520LDL-CHDL-CTGPlaceboCEECEE + MPA (cyc)CEE + MPA (con)CEE + MP (cyc)(143.3) (140.6) (137.0) (141.7) (135.7)% change from baseline(61.4) (61.9) (64.8) (62.7) (62.6)(99.0) (98.7) (94.3) (102.7) (97.5)Baseline (mg/dL):Estrogen Versus Estrogen/

12、ProgeStatin Chemical Structures*OHCH3CH3H3CH3COHOSimvastatinH3CHOOOHCH3HH3CHOOHHOPravastatinCOONaHHH3COOHCH3HH3CH3CHOLovastatinHH3CHNO*Na+CH3CH3FluvastatinCerivastatinNHCNNHCCH3OCH2CH3Naphthalene sub-class (hydronaphthalene ring in common)Fluorophenyl sub-class (fluorophenyl ring in common)*The clin

13、ical impact of these differences is not known.Lennernas H et al. Clin Pharmacokinet 1997;32:403423.AtorvastatinOCH3CH3OHOHOOOOOOHOHCH3CH3FFOFOHOHOCH3FOHOHO*Na+OCH3CH3NO* Ca+O*NStatin Chemical Structures*OHCDrug Effects on HDL: StatinsLiverBBTGCMR/IDLC-IICM/VLDLLPLA-ICECEFCFCLCATA-IABC1MacrophageMatu

14、re HDLNascent HDLLDLRHL+STATINSIntestineSTATINSSTATINS+?Drug Effects on HDL: StatinsLiSimvastatin in Mixed HyperlipidemiaBaseline CharacteristicsMean age (range):53 y (2170 y)Sex (M/F):68/62 (N = 130)Baseline lipids:LDL-C (mean)156 mg/dLHDL-C (mean)39 mg/dLTG (median)389 mg/dLType-2 diabetes mellitu

15、s:n = 21 (16%)Stein E et al. Am J Cardiol 2000;86:406-411 Simvastatin in Mixed HyperlipiSimvastatin in Mixed HyperlipidemiaChanges in LipidsPlaceboSimvastatin 40 mgSimvastatin 80 mg*Mean; mediann = 119121 per treatment groupP 0.05 for between-treatment comparisonsStein E et al. Am J Cardiol 2000;86:

16、406-41123-4-2913-28-3616-33-50-40-30-20-1001020LDL-C*HDL-C*TG% changeSimvastatin in Mixed HyperlipiSimvastatin in Mixed HyperlipidemiaChanges in ApolipoproteinsPlaceboSimvastatin 40 mgSimvastatin 80 mgn = 120123 per treatment groupaS40 vs placebo: P 0.001; bS80 vs placebo: P 0.001; cS40 vs S80: P 0.

17、05; dS40 vs placebo: P 0.005 Stein E et al. Am J Cardiol 2000;86:406-4114435-23889-31111211-35-30-25-20-15-10-5051015ApoBa,b,cApoA-Ib,dLpA-Ib,dLpA-I:A-IIb,dMean % changeSimvastatin in Mixed HyperlipiSimvastatin Versus Atorvastatin inPrimary HypercholesterolemiaStudy DesignOpen-label, randomized, par

18、allel, 12-week study842 patients (42% female)Treatments:Simvastatin 40 mg and 80 mgAtorvastatin 20 mg and 40 mgLDL-C inclusion criteria:CHD: 130 mg/dLNo CHD plus 2 risk factors: 160 mg/dLNo CHD plus 2 risk factors: 190 mg/dLTG 350 mg/dLCrouse JR III et al. Am J Cardiol 1999;83:14761477Simvastatin Ve

19、rsus AtorvastatiSimvastatin Versus Atorvastatin inPrimary HypercholesterolemiaChanges in LipidsSimvastatin 40 mg (n = 202)Atorvastatin 20 mg (n = 210)Simvastatin 80 mg (n = 215)Atorvastatin 40 mg (n = 215)*Mean; medianCrouse JR III et al. Am J Cardiol 1999;83:14761477-60-50-40-30-20-100P = 0.04P = 0

20、.10NSP 0.01LDL-C*TG% change-42.7-45.0-49.2-51.1-23.0-23.3-25.2-29.6Simvastatin Versus AtorvastatiSimvastatin Versus Atorvastatin inPrimary HypercholesterolemiaSimvastatin 40 mgAtorvastatin 20 mgSimvastatin 80 mg Atorvastatin 40 mgMean % changeP 0.01P 0.001NS*N = 842; N = 113Crouse JR III et al. Am J

21、 Cardiol 1999;83:14761477024681012141618HDL-CApoA-IHDL-C 35 mg/dLP 0.001NSP = 0.002All patients*Subgroup analysis6.74.06.63.06.35.05.90Simvastatin Versus AtorvastatiSimvastatin Atorvastatin HDL StudyKastelein JJP et al. Am J Cardiol 2000;86:221-223. Copyright 2000, with permission from Excerpta Medi

22、ca Inc.% Change from BaselineWeeks612612Apo A-IHDL-C8.57.39.76.45.64.05.71.0*p0.001; *p=0.04*Simvastatin 40 mgAtorvastatin 20 mgSimvastatin 80 mgAtorvastatin 40 mgSimvastatin Atorvastatin HDL SEffects of n-3 Fatty Acids on HDL-Cin Normo- and Hypertriglyceridemic SubjectsTG 177 mg/dLTG 177 mg/dL02468

23、101214Placebon-3 fatty acidsP 0.008NSHarris WS. Lipids 1996;31:243252HDL-C net change (%) from baselineEffects of n-3 Fatty Acids on Combination TherapyStatin Plus Niacin1. Guyton JR, Capuzzi DM. Am J Cardiol 1998;82:82U84U2. Jacobson TA et al. Am J Cardiol 1994;74:149154-3931-36-4028-30-50-40-30-20

24、-10010203040LDL-CHDL-CTGLDL-CHDL-CTGSimvastatin + Niacin (1)Fluvastatin + Niacin (2)Mean % change from baselineCombination TherapyStatin PluCombination TherapyStatin Plus Fibrate1. Wierzbicki AS et al. QJM 1997;90:6316342. Wiklund O et al. Am J Med 1993;94:1320Mean % change from baseline-4120-17-371

25、7-42-50-40-30-20-100102030LDL-CHDL-CTGLDL-CHDL-CTGSimvastatin + Fenofibrate (1)Pravastatin + Gemfibrozil (2)Combination TherapyStatin PluCombination TherapyNiacin + Statin + ColestipolBrown BG et al. Am J Cardiol 1997;80:111115-60.413-32.4-54.421.7-38.7-5.52.13.6-70-60-50-40-30-20-100102030LDL-C(215

26、)HDL-C(46)TG(191)Baseline(mg/dL):Controlled-release niacin + lovastatin + colestipol (8 mos)Regular niacin + lovastatin + colestipol (8 mos)No therapy (6 wks)Change in lipid levels (%)Combination TherapyNiacin + SCombination TherapyAdding Niacin or a Fibrate to a StatinPros Better TG and HDL-C May LDL-C more (niacin o