1、,Selecting Successful Lipid-Lowering Treatments James 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 Cutpoints,* 100129 mg/dL = after TLC, consider statin, niacin, or fibra
2、te 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,Statins: Mechanism of Action,LDL recep
3、tormediated 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, lowering intracellular cholesterol, which s
4、timulates 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, 2001.,The Triglyceride-Lowering Effect
5、s 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. | Sacks FM et al. N Engl J Med 1996;
6、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;282:2340-2346. | Crouse JR III et al. Ar
7、ch 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 eventsCoronary deathsCardiovascular deathsNoncardiovascular eventsTotal mortalityStrokesIntermittent claudicationAngina,Potenti
8、al Time Course of Statin Effects,* Time course established,Days,Years,LDL-C lowered*,Inflammation reduced,Vulnerable plaques stabilized,Endothelial function restored,Ischemic episodes reduced,Cardiac events reduced*,Statin Adverse Events,Common side effects Headache Myalgia Fatigue GI intolerance Fl
9、u-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 Rare cases of rhabdomyolysis Reduce by
10、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 statin,Bile Acid Resins: Mechanism of
11、 Action,Net Effect: LDL-C,LDL ReceptorsVLDL and LDL removal, Cholesterol 7- hydroxylaseConversion of cholesterol to BABA Secretion,BA Excretion,Terminal Ileum,Bile Acid Enterohepatic Recirculation,Reabsorption of bile acids,Effect of Colesevelam on LDL-C,Davidson MH et al. Expert Opin Investig Drugs
12、 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 available: Cholestyramine (Questran), 416 g/d
13、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 cholestyramine) Bind other negatively charge
14、d 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 production of VLDL and of apo B,VLDL secr
15、etion,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%,12.5%,25%,-30%,HDL-C with Niaspan,TG wit
16、h 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, sustained-release, 2 g/d Best agent t
17、o 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 Contraindications Active liver disease or unexplained
18、 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 resin or nicotinic acid,Consider higher
19、dose of the statin or add a bile acid resin or nicotinic acid,6 wks,Initiate LDL-lowering drug therapy,6 wks,q 46 mo,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 adherence to therapy,If LDL goal ha
20、s 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 20 mg Colesevelam 2.3 g + Simvastat
21、in 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 Statin,Percent Change,1 gram daily,2 gr
22、ams 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,Lovastatin 40 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 Detection, Evaluation, and Treat
23、ment 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,Drug Therapy,Achieve the LDL-C goal,
24、1,STEP,Achieve the non-HDL-C goal Increase 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/dL Average baseline non-HDL-C: 216 mg/
25、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;73:339-345.,LDL-C 230 mg/d
26、L,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 Primary Hypercholesterolemia or
27、 Mixed Hyperlipidemia (HPL),p0.10,Brown WV et al. Arteriosclerosis 1986;6:670-678. 1999 Lippincott Williams & Wilkins. ,Trials of Fibrates: Effects on Cardiac Events,Frick MH et al. N Engl J Med 1987;317:1237-1245. | Manninen V et al. Circulation 1992;85:37-45. | BIP Study Group. Circulation 2000;10
28、2:21-27. | Rubins HB et al. N Engl J Med 1999;341:410-418.,* Post 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).,% CH
29、D Death/Nonfatal MI,Rx Placebo,2.7,4.1*,2.7,8.0,13.6,15.0,13.0,22.3,17.3,21.7*,66%,34%,9%,42%,22%,PRIMARY PREVENTION,SECONDARY PREVENTION,HHS,HHS (Post Hoc)*,BIP,BIP (Post Hoc)*,VA-HIT,Deaths,2.2,2.1,10.4,9.9,15.7,17.4,Da Col PG et al. Curr Ther Res Clin Exp 1973;53:473-482. | Ellen RL et al. Am J C
30、ardiol 1998;81:60B-65B.,Statin + Fibrate,Simva + Gemfibrozil,50%,39%,16%,22%,41%,28%,Prava/Simva + Fenofibrate,230,332,38,191,166,LDL-C,TG,HDL-C,LDL-C,TG,HDL-C,Percent Change,34,Steps to Minimize the Risk of Muscle Toxicity with FibrateStatin Combination Therapy,Use statin alone for non-HDL-C goals
31、Use fish oils or niacin rather than fibrates Keep the doses of the statin and fibrate low Dose the fibrate in the AM and the statin in the PM Avoid (or cautiously use) combo in renal impairment Assure no interactions Teach the patient to recognize muscle symptoms Discontinue therapy if muscle symptoms are present and CK is 10 times the upper limit of normal,Guidelines that arent implemented dont work,
