1、Slide SourceLipidsOnlinewww.lipidsonline.orgSlide SourceLipidsOnlinewww.lipidsonline.orgnNeed for combination lipid-altering drug therapynEzetimibe and statinsnBile acid sequestrants and statinsnPPAR agonists and statinsnFish oils and statinsnNiacin and statinsSlide SourceLipidsOnlinewww.lipidsonlin
2、e.orgCHD or CHD Risk Equivalents(10-year risk 20%)1002+Risk Factors(10-year risk 20%)13001 Risk Factor160NCEP ATP=National Cholesterol Education Program Adult Treatment Panel.LDL-C=low-density lipoprotein cholesterol.Expert Panel on Detection,Evaluation,and Treatment of High Blood Cholesterol in Adu
3、lts.JAMA 2001;285:2486-2497.Slide SourceLipidsOnlinewww.lipidsonline.orgCHDAll PatientsHigh RiskPatients Achieving Goal(%)70%Adapted from Pearson TA et al.Arch Intern Med 2000;160;459-467.Low RiskDrug therapy included statins(fluvastatin,lovastatin,pravastatin,simvastatin),gemfibrozil,bile acid sequ
4、estrants,niacin,psyllium fiber,and combination drug therapy.1,3524,1371,92486140%18%39%n=0%20%40%60%80%100%Slide SourceLipidsOnlinewww.lipidsonline.org10/20/40/80 mg211 mg/dl*10/20/40 mg219 mg/dl*-60%-50%-40%-30%-20%-10%0%Mean%Change from BaselineAdapted from Jones P et al.Am J Cardiol 1998;81:582-5
5、87.*Mean baseline LDL-C.At the time of this study,the maximum dose for simvastatin was 40 mg.10 mg20 mg40 mg80 mg38%46%51%54%28%35%41%Slide SourceLipidsOnlinewww.lipidsonline.orgHealthier artery with decreased plaqueHDLHDLLiverSR-B1LDL/apo BEReceptorBays H et al.Expert Opin Pharmacother 2003;4:779-7
6、90.CEFreecholesterolexcretion(esterification)Arterial lumenAtherosclerotic plaque/foam cellsOvaryIntestineMuscleSkinAdrenalCMAtherosclerotic plaqueArtery with increased plaqueLDLLDLSlide SourceLipidsOnlinewww.lipidsonline.orgBays H et al.Expert Opin Pharmacother 2003;4:779-790.Cholesteryl esters Fre
7、echolesterolexcretion(esterification)Slide SourceLipidsOnlinewww.lipidsonline.orgnEzetimibe selectively inhibits intestinal cholesterol absorptionn intestinal delivery of cholesterol to the livern expression of hepatic LDL receptorsn cholesterol content of atherogenic particlesnEzetimibe and its act
8、ive glucuronide metabolite circulate enterohepaticallynDelivers agent back to the site of actionnLimits systemic exposureBays H.Expert Opin Investig Drugs 2002;11:1587-1604.Catapano AL.Eur Heart J Suppl 2001;3:E6-E10.Photo courtesy of Harry R.Davis,PhDSlide SourceLipidsOnlinewww.lipidsonline.orgMean
9、%Change in LDL-C from Baseline at Week 12Bays HE et al.Clin Ther 2001;23:1209-1230.*p0.05 vs placebo.-30-20-10010Slide SourceLipidsOnlinewww.lipidsonline.orgGagn C et.al.Am J Cardiol 2002;90:1084-1091.*40%on atorvastatin(weighted mean baseline dose 34 mg);31%simvastatin(37 mg),and 29%others combined
10、(pravastatin 29 mg,fluvastatin 35 mg,lovastatin 26 mg,and cerivastatin 0.4 mg)Week 608RANDOMIZATIONSlide SourceLipidsOnlinewww.lipidsonline.org-30-25-20-15-10-505%Reduction from Baseline at Week 8Gagn C et al.Am J Cardiol 2002;90:1084-1091.Slide SourceLipidsOnlinewww.lipidsonline.orgStatin+Ezetimibe
11、(n=305)Statin+Placebo(n=322)Patients at NCEP II Goal*(%)72%Gagn C et al.Am J Cardiol 2002;90:1084-1091.19%Mean LDL-C139 mg/dl133 mg/dl138 mg/dl102 mg/dlStatin monotherapyStatin+placebo or ezetimibe*p NnReducing VLDL particles:N=AnShifting LDL to larger particle size:N AnConverting LDL pattern B to A
12、:N AnIncreasing HDL particles:N AnIncreasing HDL particle size:N A*McKenney JM et al.Am J Cardiol 2001;88:270-274.Bays H.Am J Cardiol 2002;90:30K-43K.In a study*of immediate-release niacin 3000 mg vs.atorvastatin 10 mg:Slide SourceLipidsOnlinewww.lipidsonline.orgPercent Change from BaselineWeek 8Wee
13、k 12Niacin ER/L1000/40 mgA 10 mgNiacin ER/L1000/40 mg S 20 mgLDL-C39%*38%42%*35%HDL-C+20%*+3%+19%*+8%Triglyceride30%*20%36%*15%Lipoprotein(a)16%*+5%20%*1%Bays H et al.Am J Cardiol 2003;91:667-672.Slide SourceLipidsOnlinewww.lipidsonline.orgLDL Particles Pattern B Pattern Intermediate Pattern A IVb I
14、Va IIIb IIIa IIb IIa IHDL Particles 3c 3b 3a 2a 2b VLDL Particles VLDL subclass distribution not normally measured by this commercial methodNuclear magnetic resonanceLDL Particles Pattern B Pattern A L1 L2 L3HDL Particles H1 H2 H3 H4 H5VLDL Particles V1 V2 V3 V4 V5 V6Short,single vertical spin densi
15、ty-gradient ultracentrifugation(Vertical Auto Profile/VAP)LDL Particles Pattern B Pattern A/B Pattern A LDL 4 LDL 3 LDL 2 LDL1HDL Particles HDL3(d,c,b,a)HDL2(a,b,c)VLDL Particles VLDL 3b VLDL 3a VLDL 1+2Bays HE et al.Prev Cardiol 2003;6:179-188.Slide SourceLipidsOnlinewww.lipidsonline.org6.02.07.01.
16、89.92.62.1024681027.49.527.72.441.816.75.201020304050Bays HE et al.Prev Cardiol 2003;6:179-188.Week 8 Week 12 Week 16 Week 8 Week 12 Week 16 Slide SourceLipidsOnlinewww.lipidsonline.org-15.8-4.4-18.02.5-13.6-4.54.3-25-20-15-10-505Week 8 Week 12 Week 16-55-15-55-16-81-10-25-100-80-60-40-200Week 8 Wee
17、k 12 Week 16 Bays HE et al.Prev Cardiol 2003;6:179-188.Slide SourceLipidsOnlinewww.lipidsonline.orgGroupBLWk 4Wk 8Wk 12Wk 161000/4028283028272000/402526262727Simva2931313233Atorva2832343437Bays H et al.Am J Cardiol 2003;91;667-672.Slide SourceLipidsOnlinewww.lipidsonline.orgPlaceboS+N+AVS+N051015202
18、5Brown BG et al.N Engl J Med 2001;345:1583-1592.AV21.42.6*14.3*P.05vs Placebo23.7Slide SourceLipidsOnlinewww.lipidsonline.orgnNeed for combination lipid-altering drug therapynEzetimibe and statinsnBile acid sequestrants and statinsnPPAR agonists and statinsnFish oils and statinsnNiacin and statinsSlide SourceLipidsOnlinewww.lipidsonline.org
