TM © 1999 Professional Postgraduate Services ® Perspectives on Lipid-Lowering Therapy With HMG-CoA Reductase Inhibitors

TM © 1999 Professional Postgraduate Services ® Acetyl CoA HMG- CoA Mevalonate Farnesyl pyrophosphate Squalene Cholesterol Squalene synthase Dolichol HMG-CoA reductase Ras protein Farnesyl- transferase Farnesylated proteins E,E,E-Geranylgeranyl pyrophosphate Geranylgeranylated proteins Ubiquinones Cholesterol Biosynthetic Pathway

TM © 1999 Professional Postgraduate Services ® AgentsLDL-CHDL-CVLDL-C Bile acid sequestrants  clearance(modest  )  secretion Niacin  synthesis  clearance  synthesis Fibric acid derivatives(modest  )  synthesis  clearance HMG-CoA reductase  clearance(modest  )  clearance inhibitors (statins)  synthesis* * with atorvastatin Metabolic Effects of Lipid-Lowering Agents on Lipoproteins Adapted from Levy et al. Circulation. 1993;87:III45-III53.

TM © 1999 Professional Postgraduate Services ® Lovastatin Study Groups I through IV. Arch Intern Med. 1993;153: Second Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP II). September 1993; NIH Publication Safety Summary for HMG-CoA Reductase Inhibitors Excellent patient acceptance Few drug-drug interactions Few side effects –most common are gastrointestinal: mild to moderate –at high doses, elevated ALT/AST in 1% to 2% –myopathy reported in 0.1% (CK >10 x ULN) Only rare cases of toxicity No increases in total or non-CHD mortality

TM © 1999 Professional Postgraduate Services ® C=control; T=treatment; A=aggressive; M=moderate. Yusuf S, Anand S. Circulation. 1996;93: Post-treatment TC (mg/dL) 5-yr CV events (%) CARE-T Post-CABG-A 4S-T CARE-C Post-CABG-M 4S-C Risk of CHD Events and Level of Cholesterol

TM © 1999 Professional Postgraduate Services ® PI=placebo; Rx=treatment Shepherd J et al. N Engl J Med. 1995;333: S Study Group. Lancet. 1995;345: Sacks FM et al. N Engl J Med. 1996;335: Downs JR et al. JAMA. 1998;279: Tonkin A. Presented at AHA Scientific Sessions, Mean LDL-C level at follow-up (mg/dL) Relation Between CHD Events and LDL-C in Recent Statin Trials % with CHD event CARE-Rx LIPID-Rx 4S-Rx CARE-PI LIPID-PI 4S-PI 2° Prevention 1° Prevention WOSCOPS-PI WOSCOPS-Rx AFCAPS/TexCAPS-Rx AFCAPS/TexCAPS-PI