Atorvastatin: Effective Therapy for a Broad Range of Dyslipidemias

NCEP Guidelines for LDL Cholesterol For individuals with: No CHD and <2 CHD risk factors No CHD and >2 CHD risk factors Established CHD Trial of dietary therapy and counselling: 6-12 months 3-6 months 6-12 weeks Initiate drug therapy if LDL-C remains: >190 mg/dL >4.9 mmol/L >160 mg/dL >4.1 mmol/L >130 mg/dL >3.4 mmol/L LDL-C Goal: <160 mg/dL <4.1 mmol/L <130 mg/dL <3.4 mmol/L <100 mg/dL <2.6 mmol/L NCEP. Circulation. 1994;89:1329-1445.

Major Studies Showing Relationship Between Cholesterol Levels and CHD Risk (Pre-Statin Studies) Framingham Heart Study MRFIT Screenees Study type Size of cohort Conclusions Epidemiologic 5127 (original) 1%  in cholesterol = 2%  in CHD risk Observational 361,662 Continuous, graded association between cholesterol level and CHD risk starting at 180 mg/dL Castelli WP. Can J Cardiol. 1988;4(suppl A):5A-10A. Neaton JD, Wentworth D. Arch Intern Med. 1992;152:56-64.

Major Studies Showing a Beneficial Effect of Lipid-Lowering Therapy on CHD Risk (Pre-Statin Studies) LRC-CPPT Prospective comparative Gemfibrozil TC  9% LDL-C  8% HDL-C  10% TG  34% 34%  in risk of fatal and nonfatal MI or cardiac death Helsinki Heart Study Cholestyramine TC  9% LDL-C  13% 19%  in risk of nonfatal MI or fatal CHD Study type Treatment Effect on lipids Impact on CHD risk Lipid Research Clinics Program. JAMA. 1984;251:351-364. Frick MH et al. N Engl J Med. 1987;317:1237-1245.

4S Results 30%  in risk of total (all-cause) mortality* 34%  in risk of major coronary events† 42%  in risk of definite and suspected CHD death Changes in lipids: 25%  in Total-C — 8% in HDL-C 35%  in LDL-C 10%  in TG *P=0.0003; †P<0.00001. Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383-1389.

WOSCOPS Results 31%  in risk of nonfatal MI or CHD death* 33%  in risk of definite and suspected CHD death† 22%  in risk of all-cause mortality‡ Changes in lipids: 20%  in Total-C — 5%  in HDL-C 26%  in LDL-C 12%  in TG *P<0.001; †P=0.042; ‡P=0.051. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.

CARE: Preliminary Results 24%  in risk of fatal CHD or nonfatal MI* 25%  in risk of fatal or nonfatal MI† 27%  in need for coronary revascularization‡ Changes in lipids: 20%  in Total-C — 5%  in HDL-C 28%  in LDL-C 14%  in TG *P=0.002; †P=0.007; ‡P=0.0001. Braunwald E, Pfeffer MA, Sacks FM. Presented at the 45th ACC; March 26, 1996; Orlando Fla.

Benefits of Hypolipidemic Treatment 0% 20% LRC-CPPT % Reduction in Risk of Cardiac End Points WOSCOPS 40% 4S ? 70% 10 13 26 35 60 % LDL-C Reduction

Chemical Structure of Atorvastatin – 2+ NHC O CH CH3 F CH2 OH • Ca 2

Cholesterol Biosynthesis Pathway HMG-CoA reductase Squalene synthase Dolichol Acetyl CoA HMG- CoA Farnesyl pyrophosphate Mevalonate Squalene Cholesterol Ras protein Farnesyl- transferase E,E,E-Geranylgeranyl pyrophosphate Farnesylated proteins Geranylgeranylated proteins Ubiquinones

Mechanism of Action of Atorvastatin Conclusions Based on Animal Studies Atorvastatin inhibits hepatic production of major apo B-containing lipoproteins as shown in these animal models – EH rabbits: LDL production EHT rats: VLDL production Guinea pigs: LDL production Auerbach BJ et al. Atherosclerosis. 1995;115:173-180. Krause BR. Newton RS. Atherosclerosis. 1995;117:237-244.

Atorvastatin Clinical Development 500 1000 1500 2000 2500 3000 25 6 No. of Studies N=3150 Phase III N=380 Phase II N=154 Phase I No. of Subjects

Atorvastatin Dose-Response Study Mean Percent Change in LDL-C at 6 Weeks 10 -70 -60 -50 -40 -30 -20 -10 7.6 % 41 44 * 50 * * 61 * Placebo 10 mg 20 mg 40 mg 80 mg *P<0.05 vs placebo. Nawrocki JW et al. Arterioscler Thromb Vasc Biol. 1995;15:678-682.

Atorvastatin in Hypertriglyceridemia Design and Baseline Lipids 56 hypertriglyceridemic patients, 26-74 y/o 4-week, randomized, double-blind, placebo-controlled, parallel Atorvastatin 5, 20, 80 mg Mean baseline LDL-C: 119 mg/dL (3.1 mmol/L) Mean baseline TG: 603 mg/dL (6.8 mmol/L) Mean baseline HDL-C: 32 mg/dL (0.8 mmol/L) Bakker-Arkema RG et al. JAMA. 1996;275:128-133, and data on file, Parke-Davis (981-38).

Atorvastatin in Hypertriglyceridemia Mean Percent Change in Lipids at 4 Weeks 20 * 10 13 12 9 4 9 1 -10 Placebo Atorvastatin 5 mg Atorvastatin 20 mg Atorvastatin 80 mg 17 % -20 * 26 -30 32 33 * *† 41 -40 46 *† -50 * TG LDL-C HDL-C *P<0.05 vs placebo; †P<0.05 vs 5-mg dose. Bakker-Arkema RG et al. JAMA. 1996;275:128-133.

Atorvastatin vs Lovastatin Mean Percent Change in Lipids at 16 Weeks -40 -30 -20 -10 10 % * * * * * * 7 7 1 1 4 4 3 1 5 6 * * Placebo Atorvastatin 10 mg Lovastatin 20 mg 17 17 19 20 * * 27 27 28 * 36 Total-C LDL-C Apo B VLDL-C TG HDL-C *PŠ0.05 vs atorvastatin. Bakker-Arkema RG et al. Atherosclerosis. 1996, and data on file, Parke-Davis (981-08).

Atorvastatin vs Pravastatin Mean Percent Change in Lipids at 16 Weeks -40 -30 -20 -10 10 % 8 6 25 17 35 24 27 16 9 Atorvastatin 10 mg Pravastatin 20 mg * * * * Total-C LDL-C Apo B TG HDL-C *PŠ0.05. Egros F et al. Atherosclerosis. 1996, and data on file, Parke-Davis (981-09).

Atorvastatin vs Simvastatin Mean Percent Change in Lipids at 16 Weeks -40 -30 -20 -10 10 % 7 7 Atorvastatin 10 mg Simvastatin 10 mg 15 23 24 -23 29 * 30 30 34 * 37 * * Total-C LDL-C Apo B TG HDL-C *PŠ0.05. Bracs P et al. Atherosclerosis. 1996, and data on file, Parke-Davis (981-37).

Mean Percent Reduction in LDL-C in Fredrickson Type II Patients in Five Clinical Trials 981-13 981-04 981-43 981-04 981-07 981-04 981-44 981-04 -10 -20 -30 -40 -50 -60 -70 % Reduction in LDL-C 35 39 41 44 45 50 57 61 10 mg 20 mg 40 mg 80 mg Atorvastatin Dose Black DM. Intl Congress Series No. 1066. 1995:307-310, and data on file, Parke-Davis.

Atorvastatin: LDL-C Reduction vs Other Statins Lovastatin -20 -30 -40 -50 -60 -70 10 20 40 60 80 % Change in LDL-C Dose (mg/d) Pravastatin Fluvastatin Simvastatin Atorvastatin Adapted from Black DM. Intl Congress Series No. 1066. 1995:307-310.

Atorvastatin in Heterozygous FH Patients Percent Change in Lipids at 6 Weeks 40 20 -20 -40 -60 * 25 * * † % 34 45 57 Total-C LDL-C TG HDL-C *P<0.001; †P<0.01. Marais AD et al. Atherosclerosis. 1994;109:316.

Atorvastatin Efficacy in Homozygous FH 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) -35 -30 -25 -20 -15 -10 -5 3 Percent Reduction in LDL-C 17 22 Atorvastatin Simvastatin 35 Marais AD et al. 12th DALM Symposium; Nov 7-10, 1995; Houston, Tex.

Atorvastatin in Postmenopausal Women Mean Percent Change in Lipids at 12 Weeks -50 -40 -30 -20 -10 10 20 % 30 * 16 11 9 4 1 2 7 7 5 3 9 Placebo Atorvastatin 10 mg Placebo + Estradiol 1 mg Atorvastatin 10 mg + Estradiol 1 mg * 31 30 * 43 46 * Total-C TG LDL-C HDL-C *P<0.05 vs estradiol. Heinonen T et al. Atherosclerosis. 1996.

Atorvastatin vs Simvastatin in NIDDM Effects on Lipids at 4 Weeks HDL-C 8 TG 15 27 Total-C 24 30 * LDL-C 39 % Change 10 -10 -20 -30 -40 Atorvastatin Simvastatin *P<0.01. Best JD et al. Atherosclerosis. 1994;109:312, and data on file, Parke-Davis (981-13).

Atorvastatin Medical Therapy vs Recanalization (AVERT) Patient Population (N=320): LDL-C 130 mg/dL (3.4 mmol/L) TG Š400 mg/dL (4.5 mmol/L) Asymptomatic to moderately symptomatic 1 lesion 50%-90% stenosis Recanalization Procedure + Usual Care Titrate to LDL-C Š100 mg/dL Š2.6 mmol/L Atorvastatin 80 mg/d Month 18 Efficacy Parameters Primary: incidence rate of ischemic events, time to ischemic event Secondary: all-cause mortality, lipid profile, angina classification, QOL Economic assessment of outcomes McCormick L et al. Atherosclerosis. 1996, and data on file, Parke-Davis (981-68).

Atorvastatin Safety Summary Administered to >3000 participants in clinical trials worldwide 3 serious adverse events possibly attributable to atorvastatin have been reported ALT elevations >3x ULN: <1% overall No incidence of myopathy <2% withdrawn due to associated adverse events Data on file, Parke-Davis.

Atorvastatin: Conclusions Atorvastatin has a positive dose-response relationship over the range of 10-80 mg LDL-C reductions from 40% to 60% Effective in the broadest range of patients, including hypercholesterolemia, mixed dyslipidemia, hypertriglyceridemia, and homozygous FH Safe and well tolerated in studies up to 2 years