Slide 1 Downloaded from www.ezetrol.ae Ezetimibe Factorial Coadministration Studies
Slide 2
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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
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Ezetimibe Factorial Coadministration Studies
• 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
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Ezetimibe Coadministration Studies: Factorial Design
*Only atorvastatin and simvastatin were given in an 80 mg dose.
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.
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 6
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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
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Ezetimibe Coadministered with Atorvastatin: LDL-C Lowering Efficacy
Adapted from Ballantyne CM et al Circulation 2003;107:2409–2415.
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
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Ezetimibe Coadministered with Atorvastatin: LDL-C Lowering Efficacy
*p<0.01 coadministration vs. statin alone
Adapted from Ballantyne CM et al Circulation 2003;107:2409–2415.
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+
atorvastatin20 mg(n=62)
Atorvastatin20 mg(n=60)
Ezetimibe+
atorvastatin80 mg(n=63)
Atorvastatin80 mg(n=62)
Ezetimibe+
atorvastatin40 mg(n=65)
Atorvastatin40 mg(n=66)
–53*
–37
–54*
–42
–61*
–54–56*
–45
–60
Slide 9
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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
Adapted from Ballantyne CM et al Circulation 2003;107:2409–2415.
–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 11
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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)
4.60 mmol/L Baseline LDL-C
–51.3
–36.5
–14.8%*
Pooled doses
*p<0.01 coadministration vs. statin alone
Adapted from Davidson MH et al J Am Coll Cardiol 2002;40:2125–2134.
–50
Slide 12
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Ezetimibe Coadministered with Simvastatin: LDL-C Lowering Efficacy
Adapted from Davidson MH et al J Am Coll Cardiol 2002;40:2125–2134.
–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
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Ezetimibe Coadministered with Simvastatin: LDL-C Lowering Efficacy
*p<0.01 coadministration vs. statin alone
Adapted from Davidson MH et al J Am Coll Cardiol 2002;40:2125–2134.
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+
simvastatin20 mg(n=69)
Simvastatin20 mg(n=61)
Ezetimibe+
simvastatin80 mg(n=65)
Simvastatin80 mg(n=67)
Ezetimibe+
simvastatin40 mg(n=73)
Simvastatin40 mg(n=65)
–46*
–27
–46*
–37
–58*
–45
–56*
–38
Slide 14
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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
Adapted from Davidson MH et al J Am Coll Cardiol 2002;40:2125–2134.
–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
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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 17
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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)
4.6 mmol/L Baseline LDL-C
–38.6
–25.2
–13.4%*
Pooled doses
*p<0.01 coadministration vs. statin alone
Adapted from Melani L et al Eur Heart J 2003;24:717–728,1381.
–25
–35
–30
–40
Slide 18
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Ezetimibe Coadministered with Pravastatin: LDL-C Lowering Efficacy
Adapted from Melani L et al Eur Heart J 2003;24:717–728,1381.
–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
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Ezetimibe Coadministered with Pravastatin: LDL-C Lowering Efficacy
*p<0.01 coadministration vs. statin alone
Adapted from Melani L et al Eur Heart J 2003;24:717–728,1381.
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+
pravastatin20 mg(n=66)
Pravastatin20 mg(n=69)
Ezetimibe+
pravastatin40 mg(n=67)
Pravastatin40 mg(n=70)
–34*
–21
–40*
–23
–42*
–31
–50
Slide 20
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Ezetimibe Coadministered with Pravastatin: Pooled Results for LDL-C, TG, and HDL-C
*p<0.01 coadministration vs. statin alone
Adapted from Davidson MH et al J Am Coll Cardiol 2002;40:2125–2134.
–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 22
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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
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*p<0.01 ezetimibe + pooled statin doses vs. pooled statin doses alone
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.
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
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*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
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*Median change; **p<0.01 ezetimibe + pooled statin doses vs. pooled statin doses alone
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.
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
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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.
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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
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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
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 29
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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 31
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Ezetimibe Factorial Coadministration Studies
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
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