Slide 1 Downloaded from Ezetimibe Factorial Coadministration Studies.

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Ezetimibe Factorial Coadministration Studies

Slide 2


Rationale for Coadministration of Ezetimibe and Statins• Cholesterol homeostasis depends on the balance between cholesterol biosynthesis and

cholesterol absorption

• Statins primarily affect hepatic production of cholesterol by blocking HMG CoA reductase– Reduces hepatic stores– Leads to up-regulation of LDL receptors and removal of cholesterol

from circulation– Enterohepatic recirculation of cholesterol into the bile with transport

to the intestine

• Ezetimibe inhibits intestinal absorption of cholesterol– Reduces amount of cholesterol delivered to the liver– Leads to up-regulation of LDL receptors, facilitating removal

of cholesterol from circulation

• Dual inhibition of cholesterol absorption and synthesis by coadministration of ezetimibe and statins provides greater LDL-C lowering efficacy than inhibition of either pathway alone

Slide 3



• Four multicenter, randomized, double-blind, placebo-controlled trials

• Entry criteria – LDL-C 145–250 mg/dl (3.75–6.50 mmol/L)– Triglycerides 350 mg/dl (4.00 mmol/L)

• Design– 2- to 12-week screening phase: washout of lipid-modifying

therapy, NCEP Step I diet– 4-week prerandomization phase: placebo run-in,

NCEP Step I diet– 12-week double-blind phase: treatment with ezetimibe alone,

statin alone, or coadministration of ezetimibe with a statin

Adapted from Ballantyne CM et al Circulation 2003;107:2409–2415; Davidson MH et al J Am Coll Cardiol 2002;40:2125–2134; Melani L et al Eur Heart J 2003;24:717–728,1381; Kerzner B et al Am J Cardiol 2003;91:418–424.

Slide 4


Ezetimibe Coadministration Studies: Factorial Design

*Only atorvastatin and simvastatin were given in an 80 mg dose.


Placebo

Ezetimibe 10 mg

Statin Statin Statin Statin Placebo 10 mg 20 mg 40 mg 80 mg*

• Statins: atorvastatin,* simvastatin,* pravastatin, and lovastatin• >2300 patients; ~65 patients per group• Primary endpoint: % reduction from baseline in LDL-C

– Pooled statin alone vs. pooled ezetimibe + statin– Pairwise comparisons between treatment groups

Slide 5


Ezetimibe Coadministered with Atorvastatin

Slide 6


Ezetimibe Coadministered with Atorvastatin: Pooled Results for LDL-C

*p<0.01 coadministration therapy vs. statin alone

Adapted from Ballantyne CM et al Circulation 2003;107:2409–2415.

–50

–40

–30

–20

–10

0

Mea

n %

ch

ang

e in

cal

cula

ted

L

DL

-C f

rom

bas

elin

e at

12

wee

ks

Atorvastatin (10–80 mg)

(n=248)

4.69 mmol/L

Ezetimibe + atorvastatin (10–80 mg)

(n=255)

4.70 mmol/L Baseline LDL-C

–56.3

–44.2

–12.1%*

Pooled doses

–60

Slide 7


Ezetimibe Coadministered with Atorvastatin: LDL-C Lowering Efficacy


10 mg

Ezetimibe 10 mg+

atorvastatin 10 mg 80 mg40 mg20 mg

Atorvastatin

–50

–40

–30

–20

–10

0

–60

–54

–45–42

–37

–53

Mea

n %

ch

ang

e in

cal

cula

ted

LD

L-C

fro

m b

asel

ine

at 1

2 w

eeks

p<0.01 p<0.01 p<0.01

Slide 8


Ezetimibe Coadministered with Atorvastatin: LDL-C Lowering Efficacy

*p<0.01 coadministration vs. statin alone


Mea

n %

ch

ang

e in

cal

cula

ted

L

DL

-C f

rom

bas

elin

e at

12

wee

ks

–50

–40

–30

–20

–10

0

–70

Ezetimibe+

atorvastatin10 mg(n=65)

Atorvastatin10 mg(n=60)

Ezetimibe+



Ezetimibe+



Ezetimibe+



–53*

–37

–54*

–42

–61*

–54–56*

–45

–60

Slide 9


Ezetimibe Coadministered with Atorvastatin: Pooled Results for LDL-C, TG, and HDL-C

* Calculated LDL-C

** Median % changes shown

***p<0.01 coadministration vs. statin alone


–56*

7***

–44

4

–24

–33*

Mea

n %

ch

ang

e fr

om

bas

elin

e at

12

wee

ks

LDL-C* HDL-CTG**

–60

–50

–40

–30

10

0

20

–20

–10

Atorvastatin (n=248)Ezetimibe + atorvastatin (n=255)

Slide 10


Ezetimibe Coadministered with Simvastatin

Slide 11


Ezetimibe Coadministered with Simvastatin: Pooled Results for LDL-C

–60

–40

–30

–20

–10

0

Mea

n %

ch

ang

e in

cal

cula

ted

L

DL

-C f

rom

bas

elin

e at

12

wee

ks

Simvastatin (10–80 mg)

(n=263)

4.66 mmol/L

Ezetimibe + simvastatin (10–80 mg)

(n=274)


–51.3

–36.5

–14.8%*

Pooled doses


Adapted from Davidson MH et al J Am Coll Cardiol 2002;40:2125–2134.

–50

Slide 12


Ezetimibe Coadministered with Simvastatin: LDL-C Lowering Efficacy


–46 –45

–27

–37 –38

Mea

n %

ch

ang

e in

cal

cula

ted

LD

L-C

fro

m b

asel

ine

at 1

2 w

eeks

10 mg

Ezetimibe 10 mg+

simvastatin 10 mg 80 mg40 mg20 mg

Simvastatin

–50

–40

–30

–20

–10

0

–60

p<0.01 p<0.01 p<0.01

Slide 13


Ezetimibe Coadministered with Simvastatin: LDL-C Lowering Efficacy



Mea

n %

ch

ang

e in

cal

cula

ted

L

DL

-C f

rom

bas

elin

e at

12

wee

ks

–50

–40

–30

–20

–10

0

–60

Ezetimibe+

simvastatin10 mg(n=67)

Simvastatin10 mg(n=70)

Ezetimibe+



Ezetimibe+



Ezetimibe+



–46*

–27

–46*

–37

–58*

–45

–56*

–38

Slide 14


Ezetimibe Coadministered with Simvastatin: Pooled Results for LDL-C, TG, and HDL-C

* Calculated LDL-C **p<0.01 coadministration vs. statin alone *** p=0.03 coadministration vs. statin alone


–51*

9***

–37

7

–17–24**

Mea

n %

ch

ang

e fr

om

b

asel

ine

at 1

2 w

eeks

Simvastatin (n=263)Ezetimibe + simvastatin (n=274)–60

–50

–40

–30

10

0

20

–20

–10

LDL-C* HDL-CTG

Slide 15


Ezetimibe Coadministered with Simvastatin: Effect on CRP

*p<0.01 coadministration vs. statin alone **p<0.05 coadministration vs. statin alone***p=0.09 coadministration vs. statin alone

CRP=C-reactive protein

Adapted from Sager P et al Am J Cardiol 2003;92:1414–1418.

Med

ian

% c

han

ge

fro

m b

asel

ine

at 1

2 w

eeks

(n=227)(n=232)10 mg(n=57)

(n=62)

20 mg(n=54)

20 mg(n=55)

–35*

–18

–27**

–12

–40**

–24

–31***

–13

–20

–10

0

10

20

–40

–30

(n=54)

10 mg(n=57)

40 mg(n=60)

80 mg(n=54)

80 mg(n=60)

40 mg(n=62)

SimvastatinPlaceboEzetimibeEzetimibe + simvastatin

–36**

–29

112

Pooled Individual Dose Groups

Slide 16


Ezetimibe Coadministered with Pravastatin

Slide 17


Ezetimibe Coadministered with Pravastatin: Pooled Results for LDL-C

–45

–20

–15

–10

–5

0

Mea

n %

ch

ang

e in

cal

cula

ted

L

DL

-C f

rom

bas

elin

e at

12

wee

ks

Pravastatin (10–40 mg)

(n=205)

4.6 mmol/L

Ezetimibe + pravastatin (10–40 mg)

(n=204)


–38.6

–25.2

–13.4%*

Pooled doses


Adapted from Melani L et al Eur Heart J 2003;24:717–728,1381.

–25

–35

–30

–40

Slide 18


Ezetimibe Coadministered with Pravastatin: LDL-C Lowering Efficacy


–34–31

Mea

n %

ch

ang

e in

cal

cula

ted

LD

L-C

fro

m b

asel

ine

at 1

2 w

eeks

–21

10 mg

Ezetimibe 10 mg+

pravastatin 10 mg 40 mg

–23

20 mg

Pravastatin

–50

–40

–30

–20

–10

0

–60

p<0.01 p<0.01

Slide 19


Ezetimibe Coadministered with Pravastatin: LDL-C Lowering Efficacy



Mea

n %

ch

ang

e in

cal

cula

ted

L

DL

-C f

rom

bas

elin

e at

12

wee

ks

–40

–30

–20

–10

0

–60

Ezetimibe+

pravastatin10 mg(n=71)

Pravastatin10 mg(n=66)

Ezetimibe+



Ezetimibe+



–34*

–21

–40*

–23

–42*

–31

–50

Slide 20


Ezetimibe Coadministered with Pravastatin: Pooled Results for LDL-C, TG, and HDL-C



–39*

8

–25

7

–8

–18*

Mea

n %

ch

ang

e fr

om

b

asel

ine

at 1

2 w

eeks

Pravastatin (n=205)Ezetimibe + pravastatin (n=204)–40

–30

0

10

–20

–10

CalculatedLDL-C HDL-CTG

Slide 21


Ezetimibe Coadministered with Statins

Slide 22


Ezetimibe Coadministered with Statins: Efficient Control of LDL-C

• One-step coadministration of ezetimibe similar to doubling the statin dose 3 times

Adapted from Stein E Eur Heart J Suppl 2001;3(suppl E):E11-E16.

0 60

The “rule of 6”

One-step coadministrationStatin 10 mg

Statin 10 mg

+ Ezetimibe10 mg

50

+6%

302010

20mg

40mg

80mg

% Reduction in LDL-C

+6% +6%

+25%

40

Slide 23


*p<0.01 ezetimibe + pooled statin doses vs. pooled statin doses alone


Ezetimibe Coadministered with Statins: Results for LDL-C

Mea

n %

ch

ang

e in

cal

cula

ted

L

DL

-C f

rom

bas

elin

e at

12

wee

ks

–60

–50

–40

–20

0

Ezetimibe10 mg +

atorvastatin(n=255)

Atorvastatin(n=248)

Ezetimibe10 mg +

simvastatin(n=274)

Simvastatin(n=263)

Ezetimibe10 mg +

lovastatin(n=192)

Lovastatin(n=220)

Ezetimibe10 mg +

pravastatin(n=204)

Pravastatin(n=205)

–56*

–44

–51*

–37–40*

–25

–39*

–25

–30

–10

Slide 24


*p<0.01 ezetimibe + pooled statin doses vs. pooled statin doses alone; **p=0.03 ezetimibe + pooled statin doses vs. pooled statin doses aloneAdapted from Ballantyne CM et al Circulation 2003;107:2409–2415; Davidson MH et al J Am Coll Cardiol 2002;40:2125–2134; Melani L et al Eur Heart J 2003;24:717–728,1381; Kerzner B et al Am J Cardiol 2003;91:418–424.

Ezetimibe Coadministered with Statins:Results for HDL-C

Ezetimibe10 mg +

atorvastatin(n=255)

Atorvastatin(n=248)

Ezetimibe10 mg +

simvastatin(n=274)

Simvastatin(n=263)

Ezetimibe10 mg +

lovastatin(n=192)

Lovastatin(n=220)

Ezetimibe10 mg +

pravastatin(n=204)

Pravastatin(n=205)

Mea

n %

ch

ang

e in

HD

L-C

fro

m b

asel

ine

at 1

2 w

eeks

2

4

6

8

10

0

4

7*

9**

7

9*

4

8

7

Slide 25


*Median change; **p<0.01 ezetimibe + pooled statin doses vs. pooled statin doses alone


Ezetimibe Coadministered with Statins: Results for TG

Mea

n %

ch

ang

e in

TG

fro

m b

asel

ine

at 1

2 w

eeks

–35

–30

–25

–20

–10

0

Ezetimibe10 mg +

atorvastatin(n=255)

Atorvastatin(n=248)

Ezetimibe10 mg +

simvastatin(n=274)

Simvastatin(n=263)

Ezetimibe10 mg +

lovastatin(n=192)

Lovastatin(n=220)

Ezetimibe10 mg +

pravastatin(n=204)

Pravastatin(n=205)

–33*,**

–25* –24**

–17

–22**

–11

–18**

–8

–15

–5

Slide 26


Ezetimibe Coadministered with Statins: Tolerability and Safety Profile

• Tolerability profile of ezetimibe + statin similar to that of statin alone• Tolerability profile of ezetimibe monotherapy similar to that of placebo

• No increased risk of hematologic or blood chemistry abnormalities over statin alone

• No clinically significant ezetimibe–statin pharmacokinetic interactions

Ezetimibe Placebo Ezetimibe Statin + statin(n=259) (n=262) (n=936) (n=925)

Treatment-related AE (%) 18.1 15.6 16.9 19.5

Discontinuation due to 3.9 2.7 2.5 3.7treatment-related AE (%)

Serious treatment-related AE (%) 0 0.4 0.1 1.1

AE=adverse event

Adapted from Kosoglou T et al. Presented at the European Atherosclerosis Society Meeting, 2004; Summary of Product Characteristics, EZETROLTM, MSP; Data from Registration File, MSP.

Slide 27


Ezetimibe Coadministered with Statins: Pooled Safety Data

*All asymptomatic and reversible with drug continuation or discontinuation

ULN=upper limit of normal; ALT=alanine aminotransferase; AST=aspartate aminotransferase; GGT=gamma-glutamyl transpeptidase; CPK=creatine phosphokinase

Adapted from Data from Registration File, MSP.

Ezetimibe Ezetimibe

Placebo 10 mg Statin + statin (n=259) (n=262) (n=936) (n=925)

Liver function tests (3 ULN)*ALT, %—total 0 0 0.4 1.3ALT, %—normal baseline 0 0 0.3 0.4

AST, % 0 0 0.3 0.5GGT, % 1 3.5 3 3.6

CPK (10 ULN), % 0 0 <1 0Myalgia, % 5 5 4 4.5

Slide 28


Ezetimibe Coadministered with Statins: Summary

• Coadministration of ezetimibe and a statin for dual inhibition of cholesterol absorption and synthesis provides greater LDL-C lowering than a statin alone– Coadministration of ezetimibe with each statin dose provided

significantly greater reductions in LDL-C than the corresponding statin dose alone (p<0.01)

• Coadministration of ezetimibe and a statin also improves HDL-C and TG– 7%–9% increase in HDL-C– 18%–33% reduction in TG

• Coadministration of ezetimibe and a statin is well tolerated– Safety profile comparable to statin therapy alone


Slide 29


Ezetimibe: Dosage and Administration

• Recommended ezetimibe dosage: 10 mg once daily, coadministered with a statin or as monotherapy– No dosage adjustment required in children and

adolescents 10 years or in the elderly

• May be taken at any time of day, with or without food

• May be taken at same time as statin

Adapted from Summary of Product Characteristics, EZETROLTM, MSP.

Slide 30


References

• Please see notes page

Slide 31



Before prescribing, please consult the manufacturers’ prescribing information.

MSP does not recommend the use of any productin any different manner than as described

in the prescribing information.

Copyright © 2004 MSP Singapore Company, LLC.All rights reserved. 6-05 EZT 2004-W-6159-SS Printed in USA

VISIT US ON THE WORLD WIDE WEB AT http://www.ezetrol.com

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