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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 Risk Category LDL-C Goal Consider Drug Therapy CHD or CHD risk equivalent 250 Lova 20 mg 1% 9% 32% Prava 10 mg 6% 11% 22% Simva 10 mg 1% 20% 28% *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;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 Trial Drug CHD Risk Reduction Primary Prevention AFCAPS/TexCAPS Lovastatin 40%* WOSCOPS Pravastatin 31%* Secondary Prevention 4S Simvastatin 34%* CARE Pravastatin 24%* LIPID Pravastatin 24%* Ischemia MIRACL Atorvastatin 26%* AVERT Atorvastatin 36%* CHD Risk Reduction with Statin Therapy La Rosa JC et al. JAMA 1999;282:2340-2346. | 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 3530250 5 101520 Relative Risk Reduction (%) 404550 Major coronary events Coronary deaths Cardiovascular deaths Noncardiovascular events Total mortality Strokes Intermittent claudication Angina Potential 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 n Common side effects n Headache Myalgia Fatigue n GI intolerance Flu-like symptoms n Increase in liver enzymes n Occurs in 0.5 to 2.5% of cases in dose-dependent manner n Serious liver problems are exceedingly rare n Manage by reducing statin dose or discontinue until levels return to normal n Myopathy n Occurs in 0.2 to 0.4% of patients n Rare cases of rhabdomyolysis n Reduce by n Cautiously using statins in patients with impaired renal function n Using the lowest effective dose n Cautiously combining statins with fibrates n Avoiding drug interactions n Careful monitoring of symptoms n Presence of muscle toxicity requires the discontinuation of the statin Bile Acid Resins: Mechanism of Action Net Effect: LDL-C Gall Bladder LDL Receptors VLDL and LDL removal Cholesterol 7- hydroxylase Conversion of cholesterol to BA BA Secretion Liver 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 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 0.10 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