Atorvastatin: Effective Therapy for a Broad Range of Dyslipidemias

1
Atorvastatin Effective Therapy fora Broad Range
of Dyslipidemias
2
NCEP Guidelines for LDL Cholesterol
NCEP. Circulation. 1994891329-1445.
3
Major Studies Showing Relationship Between
Cholesterol Levels and CHD Risk
(Pre-Statin Studies)

• Study type
• Size of cohort
• Conclusions

Epidemiologic 5127 (original) 1 ? in cholesterol
2 ? in CHD risk
Observational 361,662 Continuous,
gradedassociation betweencholesterol level and
CHDrisk starting at 180 mg/dL
Castelli WP. Can J Cardiol. 19884(suppl
A)5A-10A. Neaton JD, Wentworth D. Arch Intern
Med. 199215256-64.
4
Major Studies Showing a Beneficial Effect of
Lipid-Lowering Therapy on CHD Risk
(Pre-Statin Studies)
Lipid Research Clinics Program. JAMA.
1984251351-364. Frick MH et al. N Engl J Med.
19873171237-1245.
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

P0.0003 Plt0.00001.
Scandinavian Simvastatin Survival Study Group.
Lancet. 19943441383-1389.
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

Plt0.001 P0.042 P0.051.
Shepherd J et al. N Engl J Med.
19953331301-1307.
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

P0.002 P0.007 P0.0001.
Braunwald E, Pfeffer MA, Sacks FM. Presented at
the 45th ACC March 26, 1996 Orlando Fla.
8
Benefits of Hypolipidemic Treatment
0
20
LRC-CPPT
Reduction inRisk ofCardiac End Points
WOSCOPS
40
4S
?
70
10
13
26
35
60
LDL-C Reduction
9
Chemical Structure of Atorvastatin
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.
1995115173-180.Krause BR. Newton RS.
Atherosclerosis. 1995117237-244.
12
Atorvastatin Clinical Development
13
Atorvastatin Dose-Response Study
Mean Percent Change in LDL-C at 6 Weeks
7.6

41
44
50



61

Placebo
10 mg
20 mg
40 mg
80 mg
Plt0.05 vs placebo.
Nawrocki JW et al. Arterioscler Thromb Vasc Biol.
199515678-682.
14
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. 1996275128-133,
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
0
1
9
-10
Placebo Atorvastatin 5 mg Atorvastatin 20
mg Atorvastatin 80 mg
17


-20
26
32
-30
33


41
-40
46


-50
TG
LDL-C
HDL-C
Plt0.05 vs placebo Plt0.05 vs 5-mg dose.
Bakker-Arkema RG et al. JAMA. 1996275128-133.
16
Atorvastatin vs Lovastatin
Mean Percent Change in Lipids at 16 Weeks





7
7

1
1
4
4
1
3
5
6


Placebo Atorvastatin 10 mg Lovastatin 20 mg
17
17
19
20


27
27
28

36
VLDL-C
TG
LDL-C
Total-C
HDL-C
Apo B
P0.05 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
Atorvastatin 10 mg Pravastatin 20 mg




HDL-C
Total-C
LDL-C
Apo B
TG
P0.05.
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
7
7
Atorvastatin 10 mg Simvastatin 10 mg
15
23
-23
24

29
30
30
34

37


HDL-C
Total-C
Apo B
LDL-C
TG
P0.05.
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
981-04
981-04
981-07
981-04
981-13
981-43
981-04
981-44
Reduction in LDL-C
35
39
41
45
44
50
57
61
40 mg
20 mg
10 mg
80 mg
Atorvastatin Dose
Black DM. Intl Congress Series No. 1066.
1995307-310, and data on file, Parke-Davis.
20
Atorvastatin LDL-C Reduction vs Other Statins
Adapted from Black DM. Intl Congress Series No.
1066. 1995307-310.
21
Atorvastatin in Heterozygous FH Patients
Percent Change in Lipids at 6 Weeks

25




34
45
57
Total-C
LDL-C
HDL-C
TG
Plt0.001 Plt0.01.
Marais AD et al. Atherosclerosis. 1994109316.
22
Atorvastatin Efficacy in Homozygous FH
Receptor Negative (N2) Baseline LDL-C 498 mg/dL
(12.9 mmol/L)
Receptor Defective (N6) Baseline LDL-C 521
mg/dL(13.5 mmol/L)
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

16
11
4
9
2
1
7
5
7
9
3
Placebo Atorvastatin 10 mg Placebo Estradiol 1
mg Atorvastatin 10 mg Estradiol 1 mg

30
31

43
46

LDL-C
Total-C
HDL-C
TG
Plt0.05 vs estradiol.
Heinonen T et al. Atherosclerosis. 1996.
24
Atorvastatin vs Simvastatin in NIDDM
Effects on Lipids at 4 Weeks
Plt0.01.
Best JD et al. Atherosclerosis. 1994109312, and
data on file, Parke-Davis (981-13).
25
Atorvastatin Medical Therapy vs Recanalization
(AVERT)
Patient Population (N320)
RecanalizationProcedure
Usual Care

• LDL-C 130 mg/dL (3.4 mmol/L)
• TG 400 mg/dL (4.5 mmol/L)
• Asymptomatic tomoderately symptomatic
• 1 lesion 50-90stenosis

Titrate to LDL-C 100 mg/dL 2.6 mmol/L
Atorvastatin 80 mg/d
0
18
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).
26
Atorvastatin Safety Summary

• Administered to gt3000 participants in clinical
  trials worldwide
• 3 serious adverse events possibly attributable to
  atorvastatin have been reported
• ALT elevations gt3x ULN lt1 overall
• No incidence of myopathy
• lt2 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 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