1. Atorvastatin: Effective Therapy for a Broad Range of Dyslipidemias

2. 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:

3. 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.

4. 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:
Frick MH et al. N Engl J Med. 1987;317:

5. 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<
Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:

6. 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:

7. 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=
Braunwald E, Pfeffer MA, Sacks FM. Presented at the 45th ACC; March 26, 1996; Orlando Fla.

8. Benefits of Hypolipidemic Treatment0%
20%
LRC-CPPT
% Reduction in Risk of Cardiac End Points
WOSCOPS
40% 4S ?
70% 10 13 26 35 60
% LDL-C Reduction

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

10. 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

11. 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: Krause BR. Newton RS. Atherosclerosis. 1995;117:

12. 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

13. 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 ;15:

14. Atorvastatin in Hypertriglyceridemia
Design and Baseline Lipids
56 hypertriglyceridemic patients, 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: mg/dL (0.8 mmol/L)
Bakker-Arkema RG et al. JAMA. 1996;275: , and data on file, Parke-Davis (981-38).

15. 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:

16. 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 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).

17. 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).

18. 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).

19. 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 : , and data on file, Parke-Davis.

20. 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 :

21. 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.

22. 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.

23. 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

24. 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).

25. 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).

26. 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.

27. Atorvastatin: Conclusions
Atorvastatin has a positive dose-response relationship over the range of 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