simvastatin increases hdl-c and apolipoprotein a-1 levels significantly more than atorvastatin john...

Simvastatin Increases HDL-C and Simvastatin Increases HDL-C and Apolipoprotein A-1 Levels Significantly Apolipoprotein A-1 Levels Significantly

More Than AtorvastatinMore Than Atorvastatin

John P. Kastelein, Evan A. Stein, Michael A. Davidson, John R. John P. Kastelein, Evan A. Stein, Michael A. Davidson, John R. Crouse, Leiv Ose, Minzhi Liu, Michael R. Melino, Laura O’Grady, Crouse, Leiv Ose, Minzhi Liu, Michael R. Melino, Laura O’Grady,

Michel Mercuri, Yale B. MitchelMichel Mercuri, Yale B. MitchelFor the Simvastatin Atorvastatin HDL Study Group; Academic Medical Center, For the Simvastatin Atorvastatin HDL Study Group; Academic Medical Center,

Amsterdam, The Netherlands Merck Research Laboratories, Rahway, New Jersey, USAAmsterdam, The Netherlands Merck Research Laboratories, Rahway, New Jersey, USA

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

Simvastatin/Atorvastatin HDL Study Simvastatin/Atorvastatin HDL Study BackgroundBackground

• HDL-C and apolipoprotein (apo) A-1 levels are inversely related to HDL-C and apolipoprotein (apo) A-1 levels are inversely related to the risk of coronary heart disease.the risk of coronary heart disease.

• Recently the VA-HIT study suggested that modest increases in Recently the VA-HIT study suggested that modest increases in HDL-C could have significant benefits on cardiovascular events. HDL-C could have significant benefits on cardiovascular events.

• Statins, in addition to lowering LDL-C and TG, increase HDL-C Statins, in addition to lowering LDL-C and TG, increase HDL-C levels.levels.

• However, recent data suggest that a differential effect of simvastatin However, recent data suggest that a differential effect of simvastatin and atorvastatin on HDL-C exists, in that at higher doses of both and atorvastatin on HDL-C exists, in that at higher doses of both drugs simvastatin raises HDL-C more than atorvastatin.drugs simvastatin raises HDL-C more than atorvastatin.


Simvastatin/Atorvastatin HDL Study Simvastatin/Atorvastatin HDL Study MethodsMethods

• This multicenter, double-blind, 36-week dose titration This multicenter, double-blind, 36-week dose titration study was designed to evaluate the effects of study was designed to evaluate the effects of simvastatin and atorvastatin on HDL-C and apo A-1 simvastatin and atorvastatin on HDL-C and apo A-1 levels.levels.

• Following a 4-week diet run-in period, 826 patients Following a 4-week diet run-in period, 826 patients (47% female) with LDL-C (47% female) with LDL-C >> 160 mg/dL and TG 160 mg/dL and TG << 350 350 mg/dL were randomized to simvastatin or atorvastatin mg/dL were randomized to simvastatin or atorvastatin for 36 weeks.for 36 weeks.


Simvastatin/Atorvastatin HDL StudySimvastatin/Atorvastatin HDL StudyDesignDesign

• TreatmentTreatment– Simvastatin 40 mg/day period 1 (6 weeks), and 80 mg/day periods 2 (6 Simvastatin 40 mg/day period 1 (6 weeks), and 80 mg/day periods 2 (6

weeks) and 3 (24 weeks)weeks) and 3 (24 weeks)– Atorvastatin 20 mg/day period 1 (6 weeks), 40 mg/day period 2 (6 weeks) Atorvastatin 20 mg/day period 1 (6 weeks), 40 mg/day period 2 (6 weeks)

and 80 mg/day period 3 (24 weeks)and 80 mg/day period 3 (24 weeks)• Primary lipid endpoint for week 6, 12 and 18/36 efficacy analysisPrimary lipid endpoint for week 6, 12 and 18/36 efficacy analysis

– HDL cholesterolHDL cholesterol• Key secondary lipid endpoint for week 6, 12 and 18/36 efficacy Key secondary lipid endpoint for week 6, 12 and 18/36 efficacy

analysisanalysis– Apolipoprotein A-1Apolipoprotein A-1


Study DesignStudy Design

Diet run-inDiet run-in

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

• Double Blind, randomized, 36-week dose titration studyDouble Blind, randomized, 36-week dose titration study• Patient eligibility: LDL-C Patient eligibility: LDL-C >> 160mg/dL and TG 160mg/dL and TG << 350mg/dL 350mg/dL• 826 patients (47% female)826 patients (47% female)• TreatmentTreatment

TreatmentTreatment

Simvastatin 40Simvastatin 40 Simvastatin 80Simvastatin 80 Simvastatin 80Simvastatin 80

Atorvastatin 20Atorvastatin 20 Atorvastatin 40Atorvastatin 40 Atorvastatin 80Atorvastatin 80

VisitVisitWeekWeek

11 22 33 4466

551212

661818

772424

883030

993636

ScreeningScreeningPeriod 1Period 16 weeks6 weeks

Period 2Period 26 weeks6 weeks

Period 3Period 324 weeks24 weeks

randomizationrandomization

• Primary lipid endpoint for week 6, 12 and 18/36 * Primary lipid endpoint for week 6, 12 and 18/36 * - HDL cholesterol- HDL cholesterol

• Key secondary lipid endpoint for week 6, 12, and 18/36* Key secondary lipid endpoint for week 6, 12, and 18/36* - Apolipoprotein A-1- Apolipoprotein A-1

**Avg. of weeks 18, 24, 30 and 36Avg. of weeks 18, 24, 30 and 36

Simvastatin/Atorvastatin HDL StudySimvastatin/Atorvastatin HDL StudyDemographic CharacteristicsDemographic Characteristics

Simvastatin Atorvastatin Total (n=414) (n=412) (n=826)

Gender [No. (%)]

Females 177 (42.8%) 213 (51.7%) 390 (47.2)

Males 237 (57.2%) 199 (48.3%) 436 (52.8%)

Mean Age, yrs 55

ACC 2000, Anaheim, CAACC 2000, Anaheim, CA

Simvastatin/Atorvastatin HDL StudySimvastatin/Atorvastatin HDL StudyBaseline Lipid LevelsBaseline Lipid Levels

SimvastatinSimvastatin AtorvastatinAtorvastatinBaseline Lipid, mg/dLBaseline Lipid, mg/dL N=414N=414 N=412N=412

HDL-CHDL-C 50.250.2 51.451.4

Apolipoprotein A-1Apolipoprotein A-1 150.3150.3 153.6153.6

LDL-CLDL-C 209.1209.1 205.8205.8

Total cholesterolTotal cholesterol 294.7294.7 292.3292.3

Triglycerides (median)Triglycerides (median) 165.5165.5 165.5165.5


Simvastatin/Atorvastatin HDL StudySimvastatin/Atorvastatin HDL StudyChanges in HDL-C and Apo A-1 at Week 6/12Changes in HDL-C and Apo A-1 at Week 6/12

9

5.5

6.7

2.6

0

2

4

6

8

10

Mea

n %

Cha

nge

S 40/80 A 20/40S 40/80 A 20/40 HDL-CHDL-C

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

**

**

*p<0.001 between treatment groups*p<0.001 between treatment groups


Simvastatin/Atorvastatin HDL StudySimvastatin/Atorvastatin HDL StudyChange in HDL-C for Each Treatment PeriodChange in HDL-C for Each Treatment Period

7.6

9.78.4

3.16.57.2

-5

0

5

10

15

6 12 18/36

Simvastatin

Atorvastatin

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

WeekWeekSimvastatinSimvastatin 40 mg40 mg 80 mg 80 mg 80 mg 80 mgAtorvastatinAtorvastatin 20 mg20 mg 40 mg 40 mg 80 mg 80 mg


Me

an

% C

han

ge

Me

an

% C

han

ge

*p<0.001*p<0.001

Simvastatin/Atorvastatin HDL StudySimvastatin/Atorvastatin HDL StudyChange in Apo A-1 for Each Treatment PeriodChange in Apo A-1 for Each Treatment Period

-10

-5

0

5

10

15

6 12 18/36

Simvastatin

Atorvastatin

1.6% 4.5%* 6.0%*

Bars represent difference between treatment groups



Me

an

% C

han

ge

Me

an

% C

han

ge

*p<0.001*p<0.001

Larger Increases in HDL-C with Simvastatin Were Seen Larger Increases in HDL-C with Simvastatin Were Seen in Patients with Both Low and High HDL-C Levelsin Patients with Both Low and High HDL-C Levels

3

4.7

5.7

0

2

4

6

8

6 12 18/36

Simvastatin 40 mg 80 mgSimvastatin 40 mg 80 mg 80 mg80 mgAtorvastatin 20 mg 40 mg Atorvastatin 20 mg 40 mg 80 mg80 mg

Mea

n %

Diff

ere

nce

Bet

we

en

Mea

n %

Diff

ere

nce

Bet

we

en

Tre

atm

ent G

roup

sT

reat

men

t Gro

ups

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

0.7

2.7

4.1

0

2

4

6

8

6 12 18/36

40 mg 80 mg40 mg 80 mg 80 mg80 mg 20 mg 40 mg 20 mg 40 mg 80 mg80 mg

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


Simvastatin/Atorvastatin HDL StudySimvastatin/Atorvastatin HDL StudyChange in LDL-C for Each Treatment PeriodChange in LDL-C for Each Treatment Period

-48.4-49.1

-42.5

-54-51.7

-46.2

-60

-50

-40

-30

-20

-10

0

6 12 18/36

Simvastatin

Atorvastatin

3.7%* 2.6%* 5.6%*




Me

an

% C

han

ge

Me

an

% C

han

ge

*p<0.001*p<0.001

Simvastatin/Atorvastatin HDL StudySimvastatin/Atorvastatin HDL StudyChange in TG for Each Treatment PeriodChange in TG for Each Treatment Period

-23.6-26

-22.3

-31.4-31.7

-23.6

-60

-50

-40

-30

-20

-10

0

6 12 18/36

Simvastatin

Atorvastatin

1.3%* 5.7%* 7.8%*




Me

an

% C

han

ge

Me

an

% C

han

ge

*p<0.001*p<0.001

Number of Patients with Clinically Relevant Elevations Number of Patients with Clinically Relevant Elevations in ALT and CK During the Third Treatment Periodin ALT and CK During the Third Treatment Period

S 80 mgS 80 mg A 80 mgA 80 mg n/m*n/m* (%)(%) n/m* n/m* (%)(%)

ConsecutiveConsecutive

ALT > 3X ULNALT > 3X ULN 2/384 2/384 (0.5)(0.5) 15/392** 15/392** (3.8) (3.8)

FemaleFemale 1/162 1/162 (0.6)(0.6) 12/202 12/202 (5.9)(5.9)

MaleMale 1/222 1/222 (0.5)(0.5) 3/190 3/190 (1.6)(1.6)

CK > 10X ULNCK > 10X ULN 3/384 3/384 (0.8)(0.8) 2/392 2/392 (0.5)(0.5)

FemaleFemale 0/162 0/162 (0.0)(0.0) 0/202 0/202 (0.0)(0.0)

MaleMale 3/222 3/222 (1.4)(1.4) 2/190 2/190 (1.1) (1.1)

ACC 2000, Anaheim, CAACC 2000, Anaheim, CANote: There were no clinically significant events duringNote: There were no clinically significant events duringthe first two treatment periodsthe first two treatment periods*Number of patients with elevated tests/patients tested*Number of patients with elevated tests/patients tested**2 patients with aesthenia, fatigue**2 patients with aesthenia, fatigue Simvastatin 80 mg vs atorvastatin 80 mg, p<0.004Simvastatin 80 mg vs atorvastatin 80 mg, p<0.004

Simvastatin/Atorvastatin HDL Study ~ SummarySimvastatin/Atorvastatin HDL Study ~ Summary• At clinically equipotent doses for lowering LDL-C, simvastatin increased HDL-C and apo A-1 more than At clinically equipotent doses for lowering LDL-C, simvastatin increased HDL-C and apo A-1 more than

atorvastatin:atorvastatin:– Differences between the drugs in increasing HDL-C were larger at higher doses.Differences between the drugs in increasing HDL-C were larger at higher doses.– 80 mg simvastatin increased HDL-C by 7.6% (compared to 3.1% with atorvastatin 80 mg) and raised apo A-1 80 mg simvastatin increased HDL-C by 7.6% (compared to 3.1% with atorvastatin 80 mg) and raised apo A-1

2.5% (compared to a 3.5% decrease with atorvastatin).2.5% (compared to a 3.5% decrease with atorvastatin).• These data on HDL and apo A-1 confirm previously reported results of another large comparative These data on HDL and apo A-1 confirm previously reported results of another large comparative

multicenter trial.multicenter trial.• Both drugs produced comparable and substantial reductions in LDL-C.Both drugs produced comparable and substantial reductions in LDL-C.

– Differences between atorvastatin and simvastatin were statistically significant but small in comparison to the Differences between atorvastatin and simvastatin were statistically significant but small in comparison to the magnitude of LDL-C reduction.magnitude of LDL-C reduction.

• Both drugs produced substantial reductions in TGs, with atorvastatin showing slightly larger reductions Both drugs produced substantial reductions in TGs, with atorvastatin showing slightly larger reductions than simvastatin.than simvastatin.

• At the 80 mg dose more patients treated with atorvastatin were discontinued due to clinically significant 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%, increases in ALT (3.8% of total participants or 5.9% of women) compared to simvastatin (0.5% and 0.6%, respectively). respectively).


Simvastatin/Atorvastatin HDL Study ~ ConclusionsSimvastatin/Atorvastatin HDL Study ~ Conclusions• Simvastatin increased HDL-C and apo A-1 consistently more than atorvastatinSimvastatin increased HDL-C and apo A-1 consistently more than atorvastatin• Both agents were well tolerated at doses that led to approximately 50% reductions in Both agents were well tolerated at doses that led to approximately 50% reductions in

LDL-C (atorvastatin 40 mg and simvastatin 80 mg).LDL-C (atorvastatin 40 mg and simvastatin 80 mg).• LDL-C reduction achieved with 80 mg atorvastatin during the final 24 week period was LDL-C reduction achieved with 80 mg atorvastatin during the final 24 week period was

2.3% greater than that achieved with 40 mg atorvastatin.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 However, at the highest dose of atorvastatin (80 mg), the benefit of the small additional

percent LDL-C reduction may be offset by:percent LDL-C reduction may be offset by:– higher risk of clinically significant and consecutive increases in ALT necessitating withdrawal from studyhigher risk of clinically significant and consecutive increases in ALT necessitating withdrawal from study– reduction in apo A-1reduction in apo A-1– modest effect on HDL-Cmodest effect on HDL-C

• Benefits need to be weighed against the risk for the increased incidence of liver adverse Benefits need to be weighed against the risk for the increased incidence of liver adverse effects with 80 mg atorvastatineffects with 80 mg atorvastatin


simvastatin increases hdl-c and apolipoprotein a-1 levels significantly more than atorvastatin john...

Documents