Atorvastatin: Effective Therapy for

a Broad Range of Dyslipidemias

dr Novian Wibowo SpS

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

6-12
months

>190 mg/dL
>4.9 mmol/L

<160 mg/dL
<4.1 mmol/L

No CHD and
>2 CHD risk
factors

3-6
months

>160 mg/dL
>4.1 mmol/L

<130 mg/dL
<3.4 mmol/L

Established
CHD

6-12
weeks

>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

Epidemiologic

Observational

Size of cohort

5127 (original)

361,662

Conclusions

1% in cholesterol =
2% in CHD risk

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

Helsinki Heart Study

Study type

Prospective
comparative

Prospective
comparative

Treatment

Cholestyramine

Gemfibrozil

Effect on lipids

TC 9%
LDL-C 13%

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

Impact on CHD risk

19% in risk of
nonfatal MI or fatal
CHD

34% in risk of fatal and

nonfatal MI or cardiac death

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
35% in LDL-C
10% in TG

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:

20% in Total-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.

5%

in HDL-C

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
28% in LDL-C
14% in TG

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

% LDL-C Reduction

60

Chemical Structure of Atorvastatin

CH3

CH3
O
NHC

OH

CH
CH2
N

CH2

CH

OH

CH2

CH

O
CH2

Ca 2+

Cholesterol Biosynthesis Pathway

HMG-CoA
reductase

Acetyl
CoA

HMGCoA

Mevalonate

Ras
protein

Dolichol

Squalene
synthase

Farnesyl
pyrophosphate

Farnesyltransferase
Farnesylated
proteins

Squalene

Cholesterol

E,E,E-Geranylgeranyl
pyrophosphate
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

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

7.6

-10
-20
%

-30
41

-40

-50

44

-60

50

61

-70
Placebo

10 mg

20 mg

*P<0.05 vs placebo.
Nawrocki JW et al. Arterioscler Thromb Vasc Biol. 1995;15:678-682.

40 mg

80 mg

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
4

0
%

-10
-20

13

12

Placebo
Atorvastatin 5 mg
Atorvastatin 20 mg
Atorvastatin 80 mg

17

26

-30
-40

32

33

46

-50
TG

41

LDL-C

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

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

HDL-C

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

* 7 7

-10
%

19

-20

17

17

VLDL-C

TG

20

Placebo
Atorvastatin 10 mg
Lovastatin 20 mg

27

27

28

-30
36

-40
Total-C

LDL-C

Apo B

*P0.05 vs atorvastatin.
Bakker-Arkema RG et al. Atherosclerosis. 1996, and data on file, Parke-Davis (981-08).

HDL-C

Atorvastatin vs Pravastatin
Mean Percent Change in Lipids at 16 Weeks
10
6

0
9
-10

16

17

%
-20
-30

17
*

24

25

Atorvastatin 10 mg
Pravastatin 20 mg

27

*
35

-40
Total-C

LDL-C

Apo B

TG

*P0.05.
Egros F et al. Atherosclerosis. 1996, and data on file, Parke-Davis (981-09).

HDL-C

Atorvastatin vs Simvastatin
Mean Percent Change in Lipids at 16 Weeks
10
7

0
Atorvastatin 10 mg

-10

15

%
-20

23
-23

24
29

-30

30
37

-40
Total-C

Simvastatin 10 mg

LDL-C

34

30

*
Apo B

TG

*P0.05.
Bracs P et al. Atherosclerosis. 1996, and data on file, Parke-Davis (981-37).

HDL-C

Mean Percent Reduction in LDL-C in Fredrickson

Type II Patients in Five Clinical Trials
0

981-13

981-04

981-43

981-04

981-07

44

45

981-04

981-44

981-04

-10
-20
%
Reduction
in LDL-C

-30
-40

39

35
41

50

-50

57
61

-60
-70

10 mg

20 mg
40 mg
Atorvastatin Dose

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

80 mg

Atorvastatin: LDL-C Reduction

vs Other Statins
0
Pravastatin

-20
-30
%
Change
in LDL-C

Fluvastatin
-40

Lovastatin

Simvastatin

-50
-60

Atorvastatin

-70
0

10

20

40
Dose (mg/d)

Adapted from Black DM. Intl Congress Series No. 1066. 1995:307-310.

60

80

Atorvastatin in Heterozygous FH Patients

Percent Change in Lipids at 6 Weeks
40

*
25

20

-20
34
-40

45
57

-60

Total-C

*P<0.001; P<0.01.
Marais AD et al. Atherosclerosis. 1994;109:316.

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

Receptor Defective (N=6)

Baseline LDL-C: 521 mg/dL
(13.5 mmol/L)

-5
-10
Percent
Reduction
in LDL-C

-15
-20

17
22

-25
-30
-35

Atorvastatin
Simvastatin

Marais AD et al. 12th DALM Symposium; Nov 7-10, 1995; Houston, Tex.

35

Atorvastatin in Postmenopausal Women

Mean Percent Change in Lipids at 12 Weeks
30
20
*

10

0
% -10

7
7

2
5

-40
-50

31

30

Total-C

*P<0.05 vs estradiol.
Heinonen T et al. Atherosclerosis. 1996.

43

TG

*
LDL-C

11

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

-20
-30

16

46

HDL-C

Atorvastatin vs Simvastatin in NIDDM

Effects on Lipids at 4 Weeks
10
8

0
%
Change

-10

15

-20
-30

24
30

-40
Total-C

30

27

Atorvastatin
Simvastatin

39

LDL-C

TG

*P<0.01.
Best JD et al. Atherosclerosis. 1994;109:312, and data on file, Parke-Davis (981-13).

HDL-C

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

Atorvastatin 80 mg/d

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

Month

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).

18

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