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1. Effects of High Doses of Simvastatin Effects of High Doses of Simvastatin
and Atorvastatin on High-Density and Atorvastatin on High-Density
Lipoprotein Cholesterol and Lipoprotein Cholesterol and
Apolipoprotein A-1Apolipoprotein A-1
John R. Crouse III, MD; Jiri Frohlich, MD; Leiv Ose, MD; Michele Mercuri, John R. Crouse III, MD; Jiri Frohlich, MD; Leiv Ose, MD; Michele Mercuri,
MD; PhD; Jonathan Tobert, MD, PhDMD; PhD; Jonathan Tobert, MD, PhD
Am J Cardiol 1999;83:1476-1477Am J Cardiol 1999;83:1476-1477

2. Study DesignStudy Design
•The main objective of the trial was to compare The main objective of the trial was to compare
simvastatin and atorvastatin at doses expected to simvastatin and atorvastatin at doses expected to
produce similar effects on lipids in a large clinical produce similar effects on lipids in a large clinical
trial (n=842)trial (n=842)
•Open-label, randomized, parallel, 12-week studyOpen-label, randomized, parallel, 12-week study
•Treatment arms:Treatment arms:
Simvastatin 40 mg (n=202) and 80 mg (n=215)Simvastatin 40 mg (n=202) and 80 mg (n=215)
Atorvastatin 20 mg (n=210) and 40 mg (n=215)Atorvastatin 20 mg (n=210) and 40 mg (n=215)
Am J Cardiol 1999;83:1476-1477Am J Cardiol 1999;83:1476-1477

3. MethodsMethods
• 842 patients (42% women) with high cholesterol were842 patients (42% women) with high cholesterol were
randomized at 49 centers in 19 countries to comparerandomized at 49 centers in 19 countries to compare
the 12 week efficacy of atorvastatin 20 mg or 40 mg, the 12 week efficacy of atorvastatin 20 mg or 40 mg,
to simvastatin 40 mg or 80 mg. to simvastatin 40 mg or 80 mg.
Am J Cardiol 1999;83:1476-1477Am J Cardiol 1999;83:1476-1477

4. Baseline Lipid ValuesBaseline Lipid Values
Lipid ParameterLipid Parameter Baseline Values*Baseline Values*
LDL-CLDL-C 212.7 mg/dL212.7 mg/dL
HDL-CHDL-C 46.4 mg/dL46.4 mg/dL
TriglyceridesTriglycerides 186 mg/dL186 mg/dL
ApoA-1ApoA-1 145.4 mg/dL145.4 mg/dL
Am J Cardiol 1999;83:1476-1477Am J Cardiol 1999;83:1476-1477
*There were negligible baseline differences between the treatment groups*There were negligible baseline differences between the treatment groups

5. Mean Percent Change in Plasma Lipids Produced Mean Percent Change in Plasma Lipids Produced
by Simvastatin and Atorvastatinby Simvastatin and Atorvastatin
Drug
(mg) N LDL-C TG HDL-C ApoA-1
Simvastatin 40mg202 -42.7% -23.0% 6.7%** 6.3%
Atorvastatin 20mg210 -45%* -23.3% 4.0% 5.0%
Simvastatin 80mg215 -49.2% -25.2% 6.6%** 5.9%***
Atorvastatin 40mg215 -51.1% -29.6% 3.0 -0.0
*p <0.05, **p <0.01, ***p <0.001 versus corresponding dose of *p <0.05, **p <0.01, ***p <0.001 versus corresponding dose of
simvastatin or atorvastatinsimvastatin or atorvastatin
Am J Cardiol 1999;83:1476-1477Am J Cardiol 1999;83:1476-1477

6. Simvastatin vs. Atorvastatin Simvastatin vs. Atorvastatin
Changes in LDL-C and TriglyceridesChanges in LDL-C and Triglycerides
-43
-23
-45
-23
-49
-25
-51
-30
-70
-60
-50
-40
-30
-20
-10
0
LDL-C Triglycerides (median change)
M
e
a
n
%
C
h
a
n
g
e
Simvastatin 40 mg (n=202)Atorvastatin 20 mg (n=210)
Simvastatin 80 mg (n=215)Atorvastatin 40 mg (n=215)
Crouse, JR, et al, Am J Cardiol, May 15 1999: 1476-77Crouse, JR, et al, Am J Cardiol, May 15 1999: 1476-77
P<0.05
P<0.01

7. Simvastatin vs. Atorvastatin Simvastatin vs. Atorvastatin
Changes in HDL and Apo-A1Changes in HDL and Apo-A1
6.7
6.3
4
5
6.6
5.9
3
0
-2
0
2
4
6
8
10
HDL Apo-A1
M
e
a
n
%
C
h
a
n
g
e
Simvastatin 40 mg (n=202)Atorvastatin 20 mg (n=210)
Simvastatin 80 mg (n=215)Atorvastatin 40 mg (n=215)
Crouse, JR, et al, Am J Cardiol, May 15 1999: 1476-77Crouse, JR, et al, Am J Cardiol, May 15 1999: 1476-77
P<0.01 P<0.01 P<0.001

8. HDL Cholesterol Subgroup AnalysesHDL Cholesterol Subgroup Analyses
0
2
4
6
8
10
% Change in
HDL-C
Men n=490 Women n=352
Simvastatin 40mgAtorvastatin 20mg
Simvastatin 80mgAtorvastatin 40mg
p=0.015p=0.015
p=0.002p=0.002
p=NSp=NS
p=0.011p=0.011
Crouse, JR, et al, Am J Cardiol, May 15 1999: 1476-77Crouse, JR, et al, Am J Cardiol, May 15 1999: 1476-77

9. HDL Cholesterol Subgroup Analyses HDL Cholesterol Subgroup Analyses
0
4
8
12
16
20
% Change in
HDL-C
HDL-C <35mg/dl n=113HDL-C>35mg/dl n=729
Simvastatin 40mg
Atorvastatin 20mg
Simvastatin 80mg
Atorvastatin 40mg
p=NSp=NS
p=0.002p=0.002
p=0.008p=0.008 p=0.017p=0.017
Crouse, JR, et al, Am J Cardiol, May 15 1999: 1476-77Crouse, JR, et al, Am J Cardiol, May 15 1999: 1476-77

10. HDL Cholesterol Subgroup Analyses HDL Cholesterol Subgroup Analyses
M
e
a
n
%

C
h
a
n
g
e
0
2
4
6
8
10
TG<200mg/dl n=561 TG>200mg/dl n=279
Simvastatin 40mg
Atorvastatin 20mg
Simvastatin 80mg
Atorvastatin 40mg
Presented at 1999 ACC meeting in New Orleans, La Presented at 1999 ACC meeting in New Orleans, La
P<0.005

11. 67%
70%
77% 77%
0%
20%
40%
60%
80%
100%
Drug: S 40 A20Drug: S 40 A20 S80 S80 A40 A40
n =n = 194 206 194 206 207 207 209 209
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Per Protocol AnalysisPer Protocol Analysis
Simvastatin & Atorvastatin Comparative StudySimvastatin & Atorvastatin Comparative Study
Percent to LDL-C GoalPercent to LDL-C Goal

12. Curves Study:Curves Study:
Effects of simvastatin and atorvastatin on HDL-CEffects of simvastatin and atorvastatin on HDL-C
6.8
5.5
5.25.1
9.6
4.8
-0.1
-3
0
3
6
9
12
10 mg n=143 20 mg n=100 40 mg n=122 80 mg n=11
Simvastatin
Atorvastatin
M
e
a
n

P
e
r
c
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n
t

C
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a
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g
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f
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Jones et al. Am J Cardiol 1998;81:582-7 Jones et al. Am J Cardiol 1998;81:582-7
pp<<0.050.05

13. Simvastatin and Atorvastatin - Effects on HDLSimvastatin and Atorvastatin - Effects on HDL
9
10
11
9
7
8
0
3
6
9
12
15
Week 12 Week 24 Week 54
M
e
a
n
%
I
n
c
r
e
a
s
e
i
n
H
D
L
f
r
o
m

b
a
s
e
l
i
n
e
Simvastatin (n=76)
Atorvastatin (n=78)
Alan Brown, et al, J Am Coll Cardiol 1998;32:665-72Alan Brown, et al, J Am Coll Cardiol 1998;32:665-72
Baseline HDL, 41 mg/dL in both groups
Simvastatin
10 mg
Simvastatin
10 - 20 mg
Simvastatin
10 - 40 mg +/- colestipol
Atorvastatin
10 mg
Atorvastatin
10 - 20 mg
Atorvastatin
10 - 80 mg +/- colestipol

14. SummarySummary
•Both simvastatin and atorvastatin provided substantial reductions in Both simvastatin and atorvastatin provided substantial reductions in
LDL-C and TG.LDL-C and TG.
•The differences in effects on LDL-C and TG were small relative to the The differences in effects on LDL-C and TG were small relative to the
substantial reductions produced by all 4 treatment groups.substantial reductions produced by all 4 treatment groups.
•Both doses of simvastatin produced approximately twice the increase Both doses of simvastatin produced approximately twice the increase
in HDL-C observed with atorvastatin, and apoA-I (the principal in HDL-C observed with atorvastatin, and apoA-I (the principal
protein of HDL-C) did not increase at all in the atorvastatin 40 mg protein of HDL-C) did not increase at all in the atorvastatin 40 mg
group.group.
•The greater effect of simvastatin on HDL-C was apparent in men and The greater effect of simvastatin on HDL-C was apparent in men and
women, especially by comparison with atorvastatin 40 mg, and was women, especially by comparison with atorvastatin 40 mg, and was
particularly significant at the higher dose comparison in patients with particularly significant at the higher dose comparison in patients with
baseline HDL-C (baseline HDL-C (<< 35mg/dl), the level below which it is considered a 35mg/dl), the level below which it is considered a
major risk factor for CAD.major risk factor for CAD.
Am J Cardiol 1999;83:1476-1477Am J Cardiol 1999;83:1476-1477

15. SummarySummary
•Differential effects on HDL-C have not been Differential effects on HDL-C have not been
previously recognized, however in CURVES, previously recognized, however in CURVES,
simvastatin 40 mg increased HDL-C twice as much as simvastatin 40 mg increased HDL-C twice as much as
atorvastatin 40 mg (9.6% vs 4.8%, p<0.05). atorvastatin 40 mg (9.6% vs 4.8%, p<0.05).
•The mechanism underlying the different effects on The mechanism underlying the different effects on
HDL-C is unknown, but may be related to the 20 HDL-C is unknown, but may be related to the 20
hour half-life of atorvastatin (vs the 2 hour half-life of hour half-life of atorvastatin (vs the 2 hour half-life of
simvastatin), leading to a more prolonged inhibition simvastatin), leading to a more prolonged inhibition
of cholesterol biosynthesis by atorvastatin.of cholesterol biosynthesis by atorvastatin.
Am J Cardiol 1999;83:1476-1477Am J Cardiol 1999;83:1476-1477

16. ConclusionsConclusions
•There is no data to suggest that differences in HDL-C There is no data to suggest that differences in HDL-C
metabolism between atorvastatin and simvastatin will metabolism between atorvastatin and simvastatin will
lead to different effects on clinical outcomes.lead to different effects on clinical outcomes.
•Although there is a strong inverse relationship between Although there is a strong inverse relationship between
HDL-C and CAD, it has not yet been firmly established HDL-C and CAD, it has not yet been firmly established
that increasing HDL-C reduces coronary risk.that increasing HDL-C reduces coronary risk.
•However, the present data indicate that differences in However, the present data indicate that differences in
metabolic effects of simvastatin and atorvastatin do, in metabolic effects of simvastatin and atorvastatin do, in
fact, exist.fact, exist.
Am J Cardiol 1999;83:1476-1477Am J Cardiol 1999;83:1476-1477