選擇成功的降脂治療課件

1、Selecting Successful Lipid-Lowering TreatmentsJames M. McKenney, Pharm.D.Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.Treatment Categories, LDL-C Goals and CutpointsRisk CategoryLDL-C GoalConsider Drug TherapyCHD or CHD risk equiva

2、lent100 mg/dL 130 mg/dL*2 Risk Factors 10-yr risk 1020% 10-yr risk 10%130 mg/dL130 mg/dL130 mg/dL160 mg/dL2 Risk Factors160 mg/dL190 mg/dL* 100129 mg/dL = after TLC, consider statin, niacin, or fibrate therapyTreatment of HyperlipidemiaExpert Panel on Detection, Evaluation, and Treatment of High Blo

3、od Cholesterol in Adults. JAMA 2001;285:2486-2497.High LDL-CTherapeutic Lifestyle ChangeDrug TherapyTherapy of Choice: StatinAlternative: Resin or niacinStatins: Mechanism of ActionLDL receptormediated hepatic uptake of LDL and VLDL remnantsSerum VLDL remnantsSerum LDL-CCholesterol synthesisLDL rece

4、ptor (BE receptor) synthesisIntracellular CholesterolApo BApo EApo BSystemic CirculationHepatocyteReduce hepatic cholesterol synthesis, lowering intracellular cholesterol, which stimulates upregulation of LDL receptor and increases the uptake of non-HDL particles from the systemic circulation.LDLSer

5、um IDLVLDLRVLDLThe LDL-CLowering Efficacy of the Currently Available StatinsPhysicians Desk Reference. 55th ed. Montvale, NJ: Medical Economics, 2001.DailyDoseAtorvaFluvaLovaPravaSimva10 mg39%22%30%20 mg43%22%27%32%38%40 mg50%25%32%34%41%80 mg60%36%42% 47%The Triglyceride-Lowering Effects of Statins

6、Stein EA et al. Am J Cardiol 1998;81:66B-69B.Baseline TG (mg/dL)250 Lova 20 mg1%9%32% Prava 10 mg6%11%22% Simva 10 mg1%20%28%*Nonfatal MI or CHD death; *ischemic eventsDowns JR et al. JAMA 1998;279:1615-1622. | Shepherd J et al. N Engl J Med 1999;333:1301-1307. | Scandinavian Simvastatin Study Group

7、. Lancet 1994;344:1383-1389. | Sacks FM et al. N Engl J Med 1996;335:1001-1009. | LIPID Study Group. N Engl J Med 1998;339:1349-1357. | Schwartz GG et al. JAMA 2001;285:1711-1718. | Pitt B et al. N Engl J Med 1999;341:70-76.Endpoint Trials with the StatinsTrial DrugCHD Risk ReductionPrimary Preventi

8、on AFCAPS/TexCAPS Lovastatin40%* WOSCOPS Pravastatin31%*Secondary Prevention 4S Simvastatin34%* CARE Pravastatin24%* LIPID Pravastatin24%*Ischemia MIRACL Atorvastatin26%* AVERT Atorvastatin36%*Statin Adverse EventsCommon side effectsHeadache Myalgia FatigueGI intolerance Flu-like symptomsIncrease in

9、 liver enzymesOccurs in 0.5 to 2.5% of cases in dose-dependent mannerSerious liver problems are exceedingly rareManage by reducing statin dose or discontinue until levels return to normalMyopathyOccurs in 0.2 to 0.4% of patientsRare cases of rhabdomyolysisReduce byCautiously using statins in patient

10、s with impaired renal functionUsing the lowest effective doseCautiously combining statins with fibratesAvoiding drug interactionsCareful monitoring of symptomsPresence of muscle toxicity requires the discontinuation of the statinBile Acid Resins: Mechanism of ActionNet Effect: LDL-CGall Bladder LDL

11、Receptors VLDL and LDL removal Cholesterol 7- hydroxylase Conversion of cholesterol to BA BA SecretionLiver BA ExcretionTerminal IleumBile AcidEnterohepatic RecirculationReabsorption of bile acidsEffect of Colesevelam on LDL-CDavidson MH et al. Expert Opin Investig Drugs 2000;9:2663-2671.Reprinted w

12、ith permission from Ashley Publications.Change in LDL-CPlacebo3.8 g/d4.5 g/d(N=494 patients with baseline LDL-C of 130220 mg/dL and TG 300 mg/dL; after 24 weeks of therapy)0%15%18%Clinical Features of Nicotinic AcidProducts available (daily dose)Immediate-release, 24 g/dExtended-release (Niaspan), 1

13、2 g/dOTC products, sustained-release, 2 g/dBest agent to raise HDL-CReduces coronary events (Coronary Drug Project)Adverse effectsFlushing, itching, headache (immediate-release, Niaspan)Hepatotoxicity, GI (sustained-release)Activation of peptic ulcerHyperglycemia and reduced insulin sensitivityContr

14、aindicationsActive liver disease or unexplained LFT elevationsPeptic ulcer diseaseProgression of Drug Therapy for LDL-C LoweringExpert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.Visit 1Visit 2Visit 3F/U VisitsStart statin or bile acid r

15、esin or nicotinic acidConsider higher dose of the statin or add a bile acid resin or nicotinic acid6wksInitiate LDL-lowering drug therapy6wksq46moIf LDL goal not achieved, intensify LDL-lowering therapyIf LDL goal not achieved, drug therapy or refer to a lipid specialistMonitor response and adherenc

16、e to therapyIf LDL goal has been achieved, treat other lipid risk factorsSimvastatin Alone and with Colesevelam:Percent Change in LDL-CKnapp HH et al. Am J Med 2001;110:352-360.Reprinted with permission from Excerpta Medica Inc.Mean Percent ChangePlaceboSimvastatin 10 mgSimvastatin 20 mgColesevelam

17、2.3 g + Simvastatin 20 mgColesevelam 3.8 g + Simvastatin 10 mg(n=258 patients with baseline LDL-C 160220 mg/dL; treated for 6 weeks)4%* p0.05 vs placebo26%34%42%42%*Wolfe ML et al. Am J Cardiol 2001;87:476-479.The Effect of Adding Niaspan to a Stable Dose of a StatinPercent Change1 gram daily2 grams

18、 dailyLDL-CHDL-CTGLDL-CHDL-CTG27%23%30%-8%24%24%Targets for Therapy after LDL-C Goal in Patients with TG 200 mg/dLExpert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.Patient CategoryLDL-C target (mg/dL)Non-HDL-C target (mg/dL) No CHD, 2 R

19、F160190 No CHD, 2+ RF130160 CHD or CHD risk equivalent100130Treatment of Mixed HyperlipidemiaExpert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.High LDL-C and TGsTherapeutic Lifestyle ChangeDrug TherapyAchieve the LDL-C goal1STEPAchieve

20、the non-HDL-C goalIncrease LDL-C lowering orAdd a fibrate, niacin or fish oils2STEPChange in LDL-C and Non-HDL-C by Statins after 54 Weeks of TherapyBallantyne CM et al. Am J Cardiol 2001;88:265-269.Mean DoseAverage baseline LDL-C: 178 mg/dLAverage baseline non-HDL-C: 216 mg/dL24 mg62 mg52 mg31 mg23

21、 mgAtorvastatin(n=1,888)Fluvastatin(n=474)Lovastatin(n=472)Pravastatin(n=461)Simvastatin(n=462)42382926363228263632LDL-CNon-HDL-CPercent ChangePravastatin and Niacin Alone and TogetherDavignon J et al. Am J Cardiol 1994;73:339-345.LDL-C230 mg/dLPercent ChangeTG170 mg/dLHDL-C46 mg/dL16%33%42%11%14%35

22、%12%13%16%Niacin XL 0.51.0 g bidPravastatin 40 mg hsCombinationFish OilsIndications:Adjunctive therapy to dietHypertriglyceridemia (Type IV and V)With statins or other LDL-Clowering drugs in mixed hyperlipidemia Efficacy:Decrease TG 3040%LDL-C remains the same or increasesNo change in HDL-CSide Effe

23、cts:GI upset and a “fish burp”Intervention Trials:Lyon Heart Study (dietary), GISSI Prevenzione Trial, othersFibric Acid DerivativesIndications:Adjunctive therapy to dietHypertriglyceridemia (Type IV and V)Combined hyperlipidemia (Type IIb) with low HDL-C who do not respond to nicotinic acidMechanis

24、m of Action:Increase peripheral lipolysis and decrease hepatic TG productionEfficacy:Decrease TG 2550%LDL-C decreases, remains the same, or increasesIncrease HDL-C 1525% in hypertriglyceridemiaSide Effects:GI upset (8%), cholelithiasis, myositis, abn LFTsContraindications:Hepatic or renal dysfunctionPre-existing gallbladder diseaseIntervention Trials:HHS, VA-HIT, BIP, LOCAT, BECAIT, DAISEffects of Fenofibrate on Plasma LipidsHypercholesterolemia (%)Mixed HPL (%)Fenon=92Plbn=88 Feno n=24 Plb n=22Total Cholesterol17.50.415.8+4.6LDL-C20.3+0.46.10.5HDL-C +11.11.2+15.33.5