Atorvastatin: Effective Therapy for a Broad Range of Dyslipidemias

NCEP Guidelines for LDL Cholesterol

For individuals with:

Trial of dietary therapy and counselling:

Initiate drug therapy if LDL-C remains:

LDL-C Goal:

No CHD and <2 CHD risk factors

No CHD and >2 CHD risk factors Established CHD

6-12 months
3-6 months 6-12 weeks

>190 mg/dL >4.9 mmol/L

>160 mg/dL >4.1 mmol/L >130 mg/dL >3.4 mmol/L

<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 Study type Treatment Prospective comparative Cholestyramine Helsinki Heart Study Prospective comparative Gemfibrozil

Effect on lipids

TC 9% LDL-C 13%

TC 9% LDL-C 8% HDL-C 10% TG 34%

34% in risk of fatal and nonfatal MI or cardiac death

Impact on CHD risk

19% in risk of nonfatal MI or fatal CHD

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: in Total-C 35% in LDL-C 10% in TG
25%

8% in HDL-C

*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: in Total-C 26% in LDL-C 12% in TG
20%

5% in HDL-C

*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:

in Total-C 28% in LDL-C 14% in TG

20%

5% in HDL-C

*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%

% Reduction in Risk of Cardiac End Points

20%

LRC-CPPT WOSCOPS

40%

4S

? 70% 10 13 26 35 60 % LDL-C Reduction

Chemical Structure of Atorvastatin

CH3 O CH3

CH
CH2 N CH2

OH CH CH2

OH CH CH2

Ca 2+

NHC

Cholesterol Biosynthesis Pathway

HMG-CoA reductase

Squalene synthase

Dolichol

Acetyl CoA

HMGCoA

Mevalonate

Farnesyl pyrophosphate

Squalene

Cholesterol

Ras protein

Farnesyltransferase

E,E,E-Geranylgeranyl pyrophosphate Geranylgeranylated proteins Ubiquinones

Farnesylated proteins

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:
Guinea pigs:

VLDL production
LDL production

Auerbach BJ et al. Atherosclerosis. 1995;115:173-180. Krause BR. Newton RS. Atherosclerosis. 1995;117:237-244.

Atorvastatin Clinical Development

N=154 Phase I

No. of 6 Studies

N=380 Phase II N=3150 Phase III

25

500

1000

1500
No. of Subjects

2000

2500

3000

Atorvastatin Dose-Response Study

Mean Percent Change in LDL-C at 6 Weeks
10

0
-10 -20 % -30 -40 -50 -60 -70

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: Mean baseline TG: 119 mg/dL (3.1 mmol/L) 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 0
9
1 17 26 32 4

*
13

12

-10 % -20 -30 -40 -50 TG

*P<0.05 vs placebo; P<0.05 vs 5-mg dose.

*
33

Placebo Atorvastatin 5 mg Atorvastatin 20 mg Atorvastatin 80 mg

41

*
46

* * LDL-C

* HDL-C

Bakker-Arkema RG et al. JAMA. 1996;275:128-133.

Atorvastatin vs Lovastatin
Mean Percent Change in Lipids at 16 Weeks
10
1

*
3

*
4 5

*
4 6

* 7 7
1

0 -10 %
19

*
17

17 20

-20
27

Placebo Atorvastatin 10 mg Lovastatin 20 mg

*
27 28

* *
36

-30 -40 Total-C

LDL-C

Apo B

VLDL-C

TG

HDL-C

*P0.05 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
10
6 0 9 -10 % -20 25 * -30 35 17 24 27 * 16 17 * Atorvastatin 10 mg Pravastatin 20 mg

*
-40 Total-C LDL-C Apo B TG HDL-C

*P0.05. 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
10
7 7

0 -10 % -20
29
24 30 34 37 30 23 -23

Atorvastatin 10 mg
15

Simvastatin 10 mg

-30 -40

* Total-C LDL-C

* Apo B TG HDL-C

*P0.05. 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
0 -10 -20 % Reduction in LDL-C
98113 98104 98143 98104 98107 98104 98144 98104

-30
39 -40 -50 -60 -70 10 mg 41

35 44 45 50 57 61

20 mg 40 mg Atorvastatin Dose

80 mg

Black DM. Intl Congress Series No. 1066. 1995:307-310, and data on file, Parke-Davis.

Atorvastatin: LDL-C Reduction vs Other Statins

0 Pravastatin

-20 -30 % Change -40 in LDL-C -50 -60 -70 0

Fluvastatin Simvastatin Lovastatin

Atorvastatin

10

20

40 Dose (mg/d)

60

80

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 0 % -20 34 -40 -60 Total-C
*P<0.001; P<0.01. Marais AD et al. Atherosclerosis. 1994;109:316.

*
25

45 57 LDL-C TG HDL-C

Atorvastatin Efficacy in Homozygous FH

Receptor Negative (N=2) Baseline LDL-C: 498 mg/dL (12.9 mmol/L)
0 -5 -10 Percent Reduction in LDL-C 3

Receptor Defective (N=6) Baseline LDL-C: 521 mg/dL (13.5 mmol/L)

-15
-20 -25 -30 -35 22

17

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
30 20 10
1

*
9 7 7 5 9 2 4 11

16

0 % -10 -20 -30 -40 -50 Total-C TG

31 30

*
43
46

Placebo Atorvastatin 10 mg Placebo + Estradiol 1 mg Atorvastatin 10 mg + Estradiol 1 mg * 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
10

8
0

% Change

-10 -20 -30 24

15 Atorvastatin Simvastatin

30

30
39

27

*
-40
Total-C

LDL-C

TG

HDL-C

*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 400 mg/dL (4.5 mmol/L) Asymptomatic to moderately symptomatic 1 lesion 50%-90% stenosis

Recanalization Procedure

Usual Care Titrate to LDL-C 100 mg/dL 2.6 mmol/L Month 18

Atorvastatin 80 mg/d 0

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