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 1987 Pravastatin 1991 Simvastatin 1991 Fluvastatin 1993 H3CH3C O HO O O O N F O OH O - Na + HO O O COON a OHOH H3CH3C O O HO O O H3CH3C Chemical Structures of Older Statins

TM © 1999 Professional Postgraduate Services ® Atorvastatin Cerivastatin F O OH ONa N CH 3 O O OH N NHC O F O - Ca + 2 H3CH3CCH 3 CH CH 2 CH Chemical Structures of Newer Statins

TM © 1999 Professional Postgraduate Services ® * Not FDA approved. AtorvastatinSimvastatinLovastatinPravastatinFluvastatinCerivastatinTCLDL-C — * *4255 Dose (mg) of agent% Reduction Comparative Efficacy of Available Statins Roberts WC. Am J Cardiol. 1997;80: Stein E et al. J Cardiovasc Pharmacol Therapeut. 1997;2:7-16.

TM © 1999 Professional Postgraduate Services ® Cerivastatin 0.1 mg bid Cerivastatin 0.2 mg qpm Placebo * Significantly different from placebo (P<0.05). † Significantly different from 0.1 mg bid (P<0.05). Stein E et al. J Cardiovasc Pharmacol Therapeut. 1997;2:7-16. Mean % + after 4 wk TCLDL-CHDL-CTGApoB * * * *†*† * * * *†*† Lipid Lowering With Cerivastatin in Primary Hypercholesterolemia

TM © 1999 Professional Postgraduate Services ® LDL-CTCLDL-C LovaTC Lova %+%+ Insull W et al. JACC. 1997;29(suppl A):46A. Dose (mg) Cerivastatin: TC and LDL-C Lowering in Patients With Primary Hypercholesterolemia

TM © 1999 Professional Postgraduate Services ® BaselineWeek 2Week 4Last DB visit Mean % +in LDL-C at 6 wk P<0.05. DB=double blind. Nawrocki JW et al. Arterioscler Thromb Vasc Biol. 1995;15: mg 20 mg 40 mg 80 mg Atorvastatin Dose-Response Relationship in Primary Hypercholesterolemia

TM © 1999 Professional Postgraduate Services ® * Significantly less than atorvastatin 10 mg (P<0.02). † Significantly less than atorvastatin 20 mg (P<0.01). ‡ Significantly greater than mg-equivalent dose of comparative agents (P  0.01). Jones P et al. Am J Cardiol. 1998;81: Atorvastatin Fluvastatin Lovastatin Pravastatin Simvastatin Dose range (mg) Mean % LDL-C reduction * * * * * * * † † † ‡ ‡ ‡ The CURVES Trial: A Comparison of LDL-C Lowering Among Statins

TM © 1999 Professional Postgraduate Services ® Mean % LDL-C reduction Atorvastatin (10 mg)* Simvastatin (10 mg)* Pravastatin (20 mg)* Lovastatin (20 mg)* Fluvastatin (20 mg)* † -28 † -24 † -29 † -17 † *Most commonly prescribed doses. Source: IMS NPA Plus™, December † Significantly less than atorvastatin 10 mg (P<0.01). Jones PH et al. Am J Cardiol. 1998;81: The CURVES Trial: Comparative LDL-C Reductions

TM © 1999 Professional Postgraduate Services ® Davidson M et al. Am J Cardiol. 1997;79: * -27* PlaceboAtorvastatin 10 mgLovastatin 20 mg % Patients reaching NCEP LDL-C target † *P<0.05 vs atorvastatin. † <160 mg/dL (<2RFs) 95% vs 86% 2RFs) 67% vs 42% <100 mg/dL (CHD) 18% vs 3% Mean % in LDL-C + Reaching NCEP Goals for LDL-C: Atorvastatin vs Lovastatin

TM © 1999 Professional Postgraduate Services ® Atorvastatin 10 mgPravastatin 20 mg Bertolini S et al. Atherosclerosis. 1997;130: * * *P<0.05 vs atorvastatin. % Patients reaching LDL-C target (<130 mg/dL) Mean % in LDL-C + Reaching NCEP Goals for LDL-C: Atorvastatin vs Pravastatin

TM © 1999 Professional Postgraduate Services ® Dart A et al. Am J Cardiol. 1997;80: *P<0.05 vs atorvastatin. Mean % in LDL-C * % Patients reaching LDL-C target (<130 mg/dL) Atorvastatin 10 mgSimvastatin 10 mg Reaching NCEP Goals for LDL-C: Atorvastatin vs Simvastatin

TM © 1999 Professional Postgraduate Services ® Bakker-Arkema RG et al. JAMA. 1996;275: Mean % + in lipids at 4 wk *P<0.05 vs placebo. † P<0.05 vs 5-mg dose. % Lipid levels at 4 wk Placebo Atorvastatin 5 mg Atorvastatin 20 mg Atorvastatin 80 mg * Baseline TG=603 mg/dL Baseline LDL-C=119 mg/dL Baseline HDL-C=32 mg/dL TGLDL-CHDL-C * * *†*† *†*† * Impact of Atorvastatin on Lipids in Patients With Hypertriglyceridemia

TM © 1999 Professional Postgraduate Services ® Marais AD et al. 12th DALM Symposium; November 7-10, Atorvastatin Simvastatin % Reduction in LDL-C Receptor negative (N=2) Baseline LDL-C: 498 mg/dL (12.9 mmol/L) Receptor defective (N=6) Baseline LDL-C: 521 mg/dL (13.5 mmol/L) Impact of Statin Therapy on LDL-C in Patients With Homozygous FH

TM © 1999 Professional Postgraduate Services ® Marais AD et al. Arterioscler Thromb Vasc Biol. 1997;17: % +% + % Change in lipids at 6 wk -45* -57* * TCLDL-CHDL-CTG † *P< † P<0.01. Impact of Statin Therapy on LDL-C in Patients With Heterozygous FH

TM © 1999 Professional Postgraduate Services ® PEPI Writing Group. JAMA. 1995;273: Impact of Estrogen and Progestin on Cholesterol Concentrations Placebo CEE only CEE + MP (cyc) CEE + MPA (cyc) CEE + MPA (con)

TM © 1999 Professional Postgraduate Services ® * -43* -7* -31* Placebo Atorvastatin 10 mg Placebo + estradiol 1 mg Atorvastatin 10 mg + estradiol 1 mg Heinonen TM et al. 66th Congress, European Atherosclerosis Society. July 13-17, Mean % + at 12 wk *P<0.05 vs placebo. % Lipid levels at 12 wk TCLDL-CHDL-CTG Impact of Atorvastatin on Lipids in Postmenopausal Women

TM © 1999 Professional Postgraduate Services ® E+PSimvastatin %+%+ *P < HRT=hormone replacement therapy; E=estrogen; P=medroxyprogesterone. Darling GM et al. N Engl J Med. 1997;337: * -36* TCLDL-C HDL-C TG Lp(a) Effects of HRT and Simvastatin Compared in Hypercholesterolemic Postmenopausal Women

TM © 1999 Professional Postgraduate Services ® HERS: Combined HRT Does Not Decrease All-Cause Mortality Log rank P=0.56 *0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate. Hulley S et al. JAMA. 1998;280: Incidence (%) Follow-up, yr (No. at risk) (2,763) 1 (2,720) 2 (2,666) 3 (2,595) 4 (1,590) 5 (130) Estrogen-Progestin* Placebo

TM © 1999 Professional Postgraduate Services ® HERS: Primary CHD Events Data from Blumenthal RS, Post WS. Mediguide to Heart Diseases. 1999;2:1-7. Events/1,000 women-years Follow-up, yr (No. at risk) (4-5) Placebo HRT (2,763)(2,720)(2,666)(1,590®130) ­52% ¯25%

TM © 1999 Professional Postgraduate Services ® HERS: HDL-C Distribution in a Cohort With CHD LowNormalHigh Postmenopausal women* (%) HDL-C (mg/dL) <3535–59  60 *Mean age 67 years Bittner V et al. Am Heart J. 2000;139:

TM © 1999 Professional Postgraduate Services ® Log rank P=0.91. *Combined incidence of nonfatal MI and CHD death. † mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate. Hulley S et al. JAMA. 1998;280: HERS: Combined HRT Does Not Reduce Primary CHD End Points* Estrogen-Progestin* Placebo 0 (2,763) 1 (2,631) 2 (2,506) 3 (2,392) 4 (1,435) 5 (113) Incidence (%) Follow-up, yr (No. at risk)

TM © 1999 Professional Postgraduate Services ® HERS: Primary CHD Events Data from Hulley S et al. JAMA. 1998;280: Placebo HRT 123(4-5) Yr Events/1,000 women-years P for time trend=0.009

TM © 1999 Professional Postgraduate Services ® CRP (mg/dL) Box plots show 10th, 25th, 50th, 75th, and 90th percentile cutpoints of CRP distribution for each study group. CRP=C-reactive protein. Ridker PM et al. Circulation. 1999;100: HRT Effects on C-Reactive Protein Levels MenWomenWomenWomenWomen (n=291)no HRTany HRTestrogen estrogen plus (n=311)(n=182) alone progestin (n=99) (n=83) P=0.001P=0.003P=0.03

TM © 1999 Professional Postgraduate Services ® HRT Effects on C-Reactive Protein Levels: PEPI Trial Subgroup Cushman M et al. Circulation. 1999;100: CRP (mg/L) Time (mo) P= CRP = C-reactive protein

TM © 1999 Professional Postgraduate Services ® Delmas PD et al. N Engl J Med. 1997;337: %+%+ Raloxifene: Effects on Lipids in Postmenopausal Women

TM © 1999 Professional Postgraduate Services ® Patients recommended for angioplasty CAD  1 lesion  50% stenosis LDL-C  115 mg/dL (  3.0 mmol/L) TG  500 mg/dL (  5.6 mmol/L); LVEF  40% Bruce protocol treadmill test or 20-W/min bicycle exercise test  4 min Atorvastatin 80 mg/d + usual medical therapy (n=164) Angioplasty + usual care, including lipid lowering (n=177) 18 months Occurrence of ischemic events (death from cardiac causes, nonfatal MI, CVA, CABG, angioplasty, worsening angina verified by objective evidence resulting in hospitalization, resuscitation after cardiac arrest) Time to first ischemic event Change in lipid parameters Safety Pitt B et al. N Engl J Med. 1999;341: AVERT: Study Design and Inclusion Criteria

TM © 1999 Professional Postgraduate Services ® Pitt B et al. N Engl J Med. 1999;341: McCormick LS et al. Am J Cardiol. 1997;80: AVERT: Major Exclusion Criteria Left main disease or 3-vessel disease Unstable angina MI within previous 14 days Known ejection fraction <40% or NYHA Class III or IV heart failure Previous CABG, unless grafts were patent and patient did not have 3-vessel disease CABG recommended based on current angiogram Percutaneous revascularization in previous 6 months Known hypersensitivity to HMG-CoA reductase inhibitors AST/ALT >2 x ULN CPK >3 x ULN or unexplained elevations

TM © 1999 Professional Postgraduate Services ® Pitt B et al. N Engl J Med. 1999;341: McCormick LS et al. Am J Cardiol. 1997;80: AVERT: Overview of Study Procedures Treatment phase Patients randomized to atorvastatin –discontinued other lipid-lowering medication and immediately began atorvastatin 80 mg/d Patients randomized to angioplasty/usual care (UC) –underwent angioplasty followed by “usual care” usual care may or may not have included lipid-lowering therapy (eg, diet, behavior modification, or medication) angioplasty may or may not have included stenting usual care was determined by investigator or patient’s primary physician

TM © 1999 Professional Postgraduate Services ® Pitt B et al. N Engl J Med. 1999;341: –angioplasty (other than the original procedure in angioplasty/usual care group) –worsening angina verified by objective evidence resulting in hospitalization CVA=cerebrovascular accident. AVERT: Primary Efficacy Assessment Incidence of an ischemic event in each treatment group Ischemic event was defined as occurrence of one of the following: –cardiac death –resuscitation after cardiac arrest –nonfatal MI –CVA –CABG

TM © 1999 Professional Postgraduate Services ® Pitt B et al. N Engl J Med. 1999;341: McCormick LS et al. Am J Cardiol. 1997;80: AVERT: Secondary Efficacy Assessments Time from randomization to ischemic event Percent change from baseline in TC, LDL-C, HDL-C, TG, apo A1, apo B, and Lp(a) All-cause mortality Change from baseline in angina class Worsening angina with objective evidence Change in quality of life Economic assessment

TM © 1999 Professional Postgraduate Services ® Atorvastatin (n=164)Angioplasty/UC (n=177) Age (yr), mean5958 Gender Male130 (79%) 157 (89%) Female34 (21%)20 (11%) Mean ejection fraction61%61% Nature of CHD Single vessel94 (57%)99 (56%) Double vessel70 (43%)78 (44%) Mean % stenosis80%81% Mean no. of risk factors Prior MI73 (45%)70 (40%) Patients with target lesion LAD70 (43%)53 (30%) LCX59 (36%)63 (36%) RCA59 (36%)64 (36%) CCS Angina Class Asymptomatic29 (18%)27 (15%) Class I74 (45%)70 (40%) Class II60 (37%)77 (44%) Class III1 (1%)2 (1%) Class IV0 (0%)1 (1%) Pitt B et al. N Engl J Med. 1999;341: AVERT: Baseline Patient Characteristics

TM © 1999 Professional Postgraduate Services ® Number (%) of patients experiencing an ischemic event AtorvastatinAngioplasty/UC n=164n=177%  Any Ischemic event22 (13) 37 (21) -36* Death1 (0.6)1 (0.6) Resuscitated cardiac arrest0 (0.0)0 (0.0) Nonfatal MI4 (2.4)5 (2.8) CVA0 (0.0)0 (0.0) CABG2 (1.2)9 (5.1) Revascularization18 (11.0)21 (11.9) Worsening angina with objective evidence & hospitalization11 (6.7)25 (14.1) *P=0.048 vs an adjusted significance level of Pitt B et al. N Engl J Med. 1999;341: AVERT: Ischemic Events

TM © 1999 Professional Postgraduate Services ® *P=0.048 vs an adjusted significance level of atorvastatin vs angioplasty/UC. Data from Pitt B et al. N Engl J Med. 1999;341: AtorvastatinAngioplasty/UC % of patients with an ischemic event 13% 21% -36% difference * (P=0.048) n=22 of 164n=37 of 177 AVERT: Ischemic Events

TM © 1999 Professional Postgraduate Services ® P=0.03 Cumulative incidence (%) Time since randomization (months) Pitt B et al. N Engl J Med. 1999;341: Atorvastatin (n=164) Angioplasty/UC (n=177) AVERT: Time to First Ischemic Event

TM © 1999 Professional Postgraduate Services ® * Significantly different from angioplasty/UC (P<0.05). † Baseline values represented patients at randomization without a washout period from existing lipid-lowering therapy. Note: 73% of angioplasty/UC-treated patients were on lipid-lowering medication. Pitt B et al. N Engl J Med. 1999;341: mg/dL (mmol/L) Atorvastatin end of study Angioplasty/UC baseline † Angioplasty/UC end of study Atorvastatin baseline † 10%  LDL-CTCTGHDL-C 18%  31%  * 46%  * 10%  11%  * 8%  11%  (6.5) (2.6) (3.9) (5.2) (1.3) AVERT: Summary of Lipid Parameters

TM © 1999 Professional Postgraduate Services ® months>6-18 months Atorvastatin Angioplasty/UC 24% difference 46% difference % of patients with an ischemic event 7% 6% 10% 11% Pitt B et al. N Engl J Med. 1999;341: AVERT: Incidence of First Ischemic Event by Time

TM © 1999 Professional Postgraduate Services ® Pitt B et al. N Engl J Med. 1999;341: AVERT: Safety Evaluation Elevations in AST or ALT (consecutive elevations >3 x ULN) –4 (2.4%) atorvastatin-treated patients –none in angioplasty/UC-treated patients Elevations in CPK (>10 x ULN) –none in either treatment group There were no clinically significant differences in adverse event rates between the two treatment groups –in this study, eight patients discontinued atorvastatin treatment due to an adverse event, seven of which remained in the study

TM © 1999 Professional Postgraduate Services ® Reduces ischemic events by 36% Delays the time to first event Is safe Can delay or prevent the need for percutaneous revascularization Pitt B et al. N Engl J Med. 1999;341: Aggressive lipid lowering with atorvastatin in stable CAD patients: AVERT: Conclusions

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