1、,Selecting Successful Lipid-Lowering TreatmentsJames M. McKenney, Pharm.D.,天馬行空官方博客： ；QQ:1318241189；QQ群：175569632,Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.,Treatment Categories, LDL-C Goals and Cutpoints,* 100129 mg/dL = after

2、TLC, consider statin, niacin, or fibrate therapy,Treatment of Hyperlipidemia,Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.,High LDL-C,Therapeutic Lifestyle Change,Drug Therapy,Therapy of Choice: Statin,Alternative: Resin or niacin,

3、Statins: Mechanism of Action,LDL receptormediated hepatic uptake of LDL and VLDL remnants,Serum VLDL remnants,Serum LDL-C,Cholesterol synthesis,LDL receptor (BE receptor) synthesis,Intracellular Cholesterol,Apo B,Apo E,Apo B,Systemic Circulation,Hepatocyte,Reduce hepatic cholesterol synthesis, lower

4、ing intracellular cholesterol, which stimulates upregulation of LDL receptor and increases the uptake of non-HDL particles from the systemic circulation.,Serum IDL,VLDL,The LDL-CLowering Efficacy of the Currently Available Statins,Physicians Desk Reference. 55th ed. Montvale, NJ: Medical Economics,

5、2001.,The Triglyceride-Lowering Effects of Statins,Stein EA et al. Am J Cardiol 1998;81:66B-69B.,*Nonfatal MI or CHD death; *ischemic events Downs JR et al. JAMA 1998;279:1615-1622. | Shepherd J et al. N Engl J Med 1999;333:1301-1307. | Scandinavian Simvastatin Study Group. Lancet 1994;344:1383-1389

6、. | 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 Statins,CHD Risk Reduction with Statin Therapy,La Rosa JC et al. JAMA 1999;28

7、2:2340-2346. | Crouse JR III et al. Arch Intern Med 1997;157:1305-1310. | Pedersen TR et al. Am J Cardiol 1998;81:333-335.,Endpoints,+20,35,30,25,0,5,10,15,20,Relative Risk Reduction (%),40,45,50,Major coronary events Coronary deaths Cardiovascular deaths Noncardiovascular events Total mortality Str

8、okes Intermittent claudication Angina,Potential Time Course of Statin Effects,* Time course established,Days,Years,LDL-C lowered*,Inflammationreduced,Vulnerableplaquesstabilized,Endothelialfunctionrestored,Ischemicepisodesreduced,Cardiaceventsreduced*,Statin Adverse Events,Common side effects Headac

9、he Myalgia Fatigue GI intolerance Flu-like symptoms Increase in liver enzymes Occurs in 0.5 to 2.5% of cases in dose-dependent manner Serious liver problems are exceedingly rare Manage by reducing statin dose or discontinue until levels return to normal Myopathy Occurs in 0.2 to 0.4% of patients Rar

10、e cases of rhabdomyolysis Reduce by Cautiously using statins in patients with impaired renal function Using the lowest effective dose Cautiously combining statins with fibrates Avoiding drug interactions Careful monitoring of symptoms Presence of muscle toxicity requires the discontinuation of the s

11、tatin,Bile Acid Resins: Mechanism of Action,Net Effect: LDL-C,LDL Receptors VLDL and LDL removal, Cholesterol 7- hydroxylase Conversion of cholesterol to BA BA Secretion,BA Excretion,Terminal Ileum,Bile Acid Enterohepatic Recirculation,Reabsorption of bile acids,Effect of Colesevelam on LDL-C,Davids

12、on MH et al. Expert Opin Investig Drugs 2000;9:2663-2671. Reprinted with permission from Ashley Publications.,Change in LDL-C,Placebo,3.8 g/d,4.5 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 BARs,Products availab

13、le: Cholestyramine (Questran), 416 g/d Colestipol (Colestid), 520 g/d Colesevelam (WelChol) 625 mg tablets, 67 tablets/d Reduce coronary events (LRC-CPPT) Adverse effects GI intolerance: constipation, bloating, abdominal pain, flatulence Lack systemic toxicity Drug interactions (colestipol and chole

14、styramine) Bind other negatively charged drugs Impede the absorption of drugs and/or fat-soluble vitamins Must give other drugs 1 hour before or 46 hours after,Nicotinic Acid: Mechanism of Action,Liver,Circulation,HDL,Serum VLDL results in reduced lipolysis to LDL,Serum LDL,VLDL,Decreases hepatic pr

15、oduction of VLDL and of apo B,VLDL secretion,Apo B,Hepatocyte,Systemic Circulation,Mobilization of FFA,TG synthesis,VLDL,Effect of Niacin on Lipoproteins,Adapted from Knopp RH. N Engl J Med 1999;341:498-511. 1999 Massachusetts Medical Society. All rights reserved.,0 1 g/d 2 g/d 3 g/d,Baseline,-15%,1

16、2.5%,25%,-30%,HDL-C with Niaspan,TG with Niaspan,TG with crystalline niacin,LDL-C with Niaspan,LDL-C with crystalline niacin,35%,HDL-C with crystalline niacin,Clinical Features of Nicotinic Acid,Products available (daily dose) Immediate-release, 24 g/d Extended-release (Niaspan), 12 g/d OTC products

17、, sustained-release, 2 g/d Best agent to raise HDL-C Reduces coronary events (Coronary Drug Project) Adverse effects Flushing, itching, headache (immediate-release, Niaspan) Hepatotoxicity, GI (sustained-release) Activation of peptic ulcer Hyperglycemia and reduced insulin sensitivity Contraindicati

18、ons Active liver disease or unexplained LFT elevations Peptic ulcer disease,Progression of Drug Therapy for LDL-C Lowering,Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.,Visit 1,Visit 2,Visit 3,F/U Visits,Start statin or bile acid r

19、esin or nicotinic acid,Consider higher dose of the statin or add a bile acid resin or nicotinic acid,6wks,Initiate LDL-lowering drug therapy,6wks,q46mo,If LDL goal not achieved, intensify LDL-lowering therapy,If LDL goal not achieved, drug therapy or refer to a lipid specialist,Monitor response and

20、adherence to therapy,If LDL goal has been achieved, treat other lipid risk factors,Simvastatin Alone and with Colesevelam:Percent Change in LDL-C,Knapp HH et al. Am J Med 2001;110:352-360. Reprinted with permission from Excerpta Medica Inc.,Mean Percent Change,Placebo Simvastatin 10 mg Simvastatin 2

21、0 mg Colesevelam 2.3 g + Simvastatin 20 mg Colesevelam 3.8 g + Simvastatin 10 mg,(n=258 patients with baseline LDL-C 160220 mg/dL; treated for 6 weeks),4%,* p0.05 vs placebo,26%,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 Stati

22、n,Percent Change,1 gram daily,2 grams daily,LDL-C,HDL-C,TG,LDL-C,HDL-C,TG,27%,23%,30%,-8%,24%,24%,Brown BG et al. Am J Cardiol 1997;80:111-115.,Triple-Drug Regimen,Lovastatin40 mg/d,Niaspan 2 g/d,Colestipol 20 g/d,+,+,Targets for Therapy after LDL-C Goal in Patients with TG 200 mg/dL,Expert Panel on

23、 Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.,Treatment of Mixed Hyperlipidemia,Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.,High LDL-C and TGs,Therapeutic Lifestyle Change,Dru

24、g Therapy,Achieve the LDL-C goal,1,STEP,Achieve the non-HDL-C goalIncrease LDL-C lowering or Add a fibrate, niacin or fish oils,2,STEP,Change in LDL-C and Non-HDL-C by Statins after 54 Weeks of Therapy,Ballantyne CM et al. Am J Cardiol 2001;88:265-269.,Mean Dose,Average baseline LDL-C: 178 mg/dLAver

25、age baseline non-HDL-C: 216 mg/dL,24 mg,62 mg,52 mg,31 mg,23 mg,Atorvastatin(n=1,888),Fluvastatin(n=474),Lovastatin(n=472),Pravastatin(n=461),Simvastatin(n=462),42,38,29,26,36,32,28,26,36,32,LDL-C,Non-HDL-C,Percent Change,Pravastatin and Niacin Alone and Together,Davignon J et al. Am J Cardiol 1994;

26、73:339-345.,LDL-C 230 mg/dL,Percent Change,TG 170 mg/dL,HDL-C 46 mg/dL,16%,33%,42%,11%,14%,35%,12%,13%,16%,Niacin XL 0.51.0 g bid Pravastatin 40 mg hs Combination,Fish Oils,Fibric Acid Derivatives,Effects of Fenofibrate on Plasma Lipids,Double-Blind, Multicenter, 24-Week Study in Patients with Prima

27、ry Hypercholesterolemia or Mixed Hyperlipidemia (HPL),p0.10,Brown WV et al. Arteriosclerosis 1986;6:670-678. 1999 Lippincott Williams 317:1237-1245. | Manninen V et al. Circulation 1992;85:37-45. | BIP Study Group. Circulation 2000;102:21-27. | Rubins HB et al. N Engl J Med 1999;341:410-418.,* Post

28、hoc analysis of subgroup with TG 200 mg/dL and HDL-C 42 mg/dL. * Post hoc analysis of subgroup with TG 200 mg/dL and HDL-C 35 mg/dL. * Difference between placebo and Rx for primary endpoint was statistically significant (p 0.05).,% CHD Death/Nonfatal MI,Rx Placebo,2.7,4.1*,2.7,8.0,13.6,15.0,13.0,22.3