Simvastatin Increases HDL-C and HDLApolipoprotein A-1 Levels Significantly AMore Than Atorvastatin

John P. Kastelein, Evan A. Stein, Michael A. Davidson, John R. Crouse, Leiv Ose, Minzhi Liu, Michael R. Melino, Laura OGrady, Michel Mercuri, Yale B. Mitchel
For the Simvastatin Atorvastatin HDL Study Group; Academic Medical Center, Amsterdam, The Netherlands Merck Research Laboratories, Rahway, New Jersey, USA JACC February 2000 Volume 35 Number 2 (supplement A): 315A ACC 2000, Anaheim, CA

Simvastatin/Atorvastatin HDL Study Background

HDL-C and apolipoprotein (apo) A-1 levels are inversely related to HDLAthe risk of coronary heart disease. Recently the VA-HIT study suggested that modest increases in VAHDLHDL-C could have significant benefits on cardiovascular events. Statins, in addition to lowering LDL-C and TG, increase HDL-C LDLHDLlevels. However, recent data suggest that a differential effect of simvastatin and atorvastatin on HDL-C exists, in that at higher doses of both HDLdrugs simvastatin raises HDL-C more than atorvastatin. HDLJACC February 2000 Volume 35 Number 2 (supplement A): 315A ACC 2000, Anaheim, CA

Simvastatin/Atorvastatin HDL Study Methods

This multicenter, double-blind, 36-week dose titration double36study was designed to evaluate the effects of simvastatin and atorvastatin on HDL-C and apo A-1 HDLAlevels. Following a 4-week diet run-in period, 826 patients 4run(47% female) with LDL-C > 160 mg/dL and TG < 350 LDLmg/dL were randomized to simvastatin or atorvastatin for 36 weeks.
JACC February 2000 Volume 35 Number 2 (supplement A): 315A ACC 2000, Anaheim, CA

Simvastatin/Atorvastatin HDL Study Design

Treatment
Simvastatin 40 mg/day period 1 (6 weeks), and 80 mg/day periods 2 (6 weeks) and 3 (24 weeks) Atorvastatin 20 mg/day period 1 (6 weeks), 40 mg/day period 2 (6 weeks) and 80 mg/day period 3 (24 weeks)

Primary lipid endpoint for week 6, 12 and 18/36 efficacy analysis

HDL cholesterol

Key secondary lipid endpoint for week 6, 12 and 18/36 efficacy analysis
Apolipoprotein A-1 AJACC February 2000 Volume 35 Number 2 (supplement A): 315A ACC 2000, Anaheim, CA

Study Design
Double Blind, randomized, 36-week dose titration study 36 Patient eligibility: LDL-C > 160mg/dL and TG < 350mg/dL LDL 826 patients (47% female) Treatment
Diet run-in runSimvastatin 40

Treatment
Simvastatin 80 Atorvastatin 40 Period 2 6 weeks Simvastatin 80 Atorvastatin 80 Period 3 24 weeks

Screening

Atorvastatin 20 Period 1 6 weeks

Visit 1 Week

3
randomization

4 6

5 12

6 18

7 24

8 30

9 36

Primary lipid endpoint for week 6, 12 and 18/36 * Key secondary lipid endpoint for week 6, 12, and 18/36* *Avg. of weeks 18, 24, 30 and 36

- HDL cholesterol - Apolipoprotein A-1 A-

Kastelein et al, JACC Vol 35: 2: Suppl. A, pg 315 Abstract 1009-173 1009-

Simvastatin/Atorvastatin HDL Study Demographic Characteristics

Simvastatin (n=414) Gender [No. (%)] Females Males Mean Age, yrs
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Atorvastatin (n=412)

Total (n=826)

177 (42.8%) 237 (57.2%)

213 (51.7%) 199 (48.3%)

390 (47.2) 436 (52.8%) 55

Simvastatin/Atorvastatin HDL Study Baseline Lipid Levels

Baseline Lipid, mg/dL HDLHDL-C Apolipoprotein A-1 ALDLLDL-C Total cholesterol Triglycerides (median)
ACC 2000, Anaheim, CA

Simvastatin N=414 50.2 150.3 209.1 294.7 165.5

Atorvastatin N=412 51.4 153.6 205.8 292.3 165.5

Simvastatin/Atorvastatin HDL Study Changes in HDL-C and Apo A-1 at Week 6/12 HDLA10 8 6.7 Mean % Change 6 4 2.6 2 0 5.5 * 9*

*p<0.001 between treatment groups

S 40/80 A 20/40 HDLHDL-C

S 40/80 A 20/40 Apo A-1 A-

JACC February 2000 Volume 35 Number 2 (supplement A): 315A ACC 2000, Anaheim, CA

Simvastatin/Atorvastatin HDL Study

Change in HDL-C for Each Treatment Period HDL15
Simvastatin Atorvastatin 8.4

*p<0.001
9.7 7.6 6.5 3.1

Mean % Change

10

7.2

1.3% 3.2%* 4.4%* Bars represent difference between treatment groups

6 40 mg 20 mg 12 80 mg 40 mg 18/36 80 mg 80 mg

-5
Week Simvastatin Atorvastatin

ACC 2000, Anaheim, CA

Simvastatin/Atorvastatin HDL Study

Change in Apo A-1 for Each Treatment Period A15
Simvastatin Atorvastatin

*p<0.001

Mean % Change

10 5 0 -5

1.6%

4.5%*

6.0%*

Bars represent difference between treatment groups

-10
Week Simvastatin Atorvastatin

6 40 mg 20 mg

12 80 mg 40 mg

18/36 80 mg 80 mg

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Larger Increases in HDL-C with Simvastatin Were Seen HDLin Patients with Both Low and High HDL-C Levels HDL8
Mean % Difference Between Treatment Groups

Low HDL-C Stratum HDL(M: < 40 mg/dL; F: < 50 mg/dL)

High HDL-C Stratum HDL(M: > 40 mg/dL; F: > 50 mg/dL)

6 4.7

5.7

6 4.1

4 2.7 2 0.7

0 6
Simvastatin 40 mg Atorvastatin 20 mg

0 12
80 mg 40 mg

18/36
80 mg 80 mg

6
40 mg 20 mg

12
80 mg 40 mg

18/36
80 mg 80 mg

ACC 2000, Anaheim, CA

Simvastatin/Atorvastatin HDL Study

Change in LDL-C for Each Treatment Period LDL0

Bars represent difference between treatment groups 3.7%*

Simvastatin Atorvastatin -42.5 -49.1 -48.4 -54 18/36 80 mg 80 mg -46.2 -51.7

Mean % Change

-10 -20 -30 -40 -50

2.6%*

5.6%* *p<0.001

-60 Week Simvastatin Atorvastatin

6 40 mg 20 mg

12 80 mg 40 mg

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Simvastatin/Atorvastatin HDL Study

Change in TG for Each Treatment Period
0

Bars represent difference between treatment groups 1.3%* 5.7%*

-26 -23.6 Simvastatin Atorvastatin -31.7 -31.4

Mean % Change

-10 -20 -30 -40 -50 -22.3

7.8%*
-23.6

*p<0.001

-60 Week Simvastatin Atorvastatin

6 40 mg 20 mg

12 80 mg 40 mg

18/36 80 mg 80 mg

ACC 2000, Anaheim, CA

Number of Patients with Clinically Relevant Elevations in ALT and CK During the Third Treatment Period
S 80 mg n/m* (%) Consecutive ALT > 3X ULN Female Male CK > 10X ULN Female Male 2/384 1/162 1/222 3/384 0/162 3/222 (0.5) (0.6) (0.5) (0.8) (0.0) (1.4) 15/392** (3.8) 12/202 3/190 2/392 0/202 2/190 (5.9) (1.6) (0.5) (0.0) (1.1) A 80 mg n/m* (%)

Note: There were no clinically significant events during ACC 2000, Anaheim, CA the first two treatment periods *Number of patients with elevated tests/patients tested **2 patients with aesthenia, fatigue Simvastatin 80 mg vs atorvastatin 80 mg, p<0.004

Simvastatin/Atorvastatin HDL Study ~ Summary

At clinically equipotent doses for lowering LDL-C, simvastatin increased HDL-C and apo LDLHDLA-1 more than atorvastatin:
Differences between the drugs in increasing HDL-C were larger at higher doses. HDL 80 mg simvastatin increased HDL-C by 7.6% (compared to 3.1% with atorvastatin 80 mg) and HDLraised apo A-1 2.5% (compared to a 3.5% decrease with atorvastatin). A-

These data on HDL and apo A-1 confirm previously reported results of another large Acomparative multicenter trial. Both drugs produced comparable and substantial reductions in LDL-C. LDL Differences between atorvastatin and simvastatin were statistically significant but small in comparison to the magnitude of LDL-C reduction. LDL-

Both drugs produced substantial reductions in TGs, with atorvastatin showing slightly larger reductions than simvastatin. At the 80 mg dose more patients treated with atorvastatin were discontinued due to clinically significant increases in ALT (3.8% of total participants or 5.9% of women) compared to simvastatin (0.5% and 0.6%, respectively).
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Simvastatin/Atorvastatin HDL Study ~ Conclusions

Simvastatin increased HDL-C and apo A-1 consistently more than HDLAatorvastatin Both agents were well tolerated at doses that led to approximately 50% reductions in LDL-C (atorvastatin 40 mg and simvastatin 80 mg). LDL LDL-C reduction achieved with 80 mg atorvastatin during the final 24 LDLweek period was 2.3% greater than that achieved with 40 mg atorvastatin. However, at the highest dose of atorvastatin (80 mg), the benefit of the small additional percent LDL-C reduction may be offset by: LDL higher risk of clinically significant and consecutive increases in ALT necessitating withdrawal from study reduction in apo A-1 A modest effect on HDL-C HDL-

Benefits need to be weighed against the risk for the increased incidence of liver adverse effects with 80 mg atorvastatin ACC 2000, Anaheim, CA