Slide 1EZT 2002-W-6022-SS
Ezetimibe Co-administered with Statins: Efficacy and Tolerability
Copyright © 2003 MSP Singapore Company, LLC. All rights reserved.
Slide 2EZT 2002-W-6022-SS
Ezetimibe Together with Statins Co-administration Studies
• Ezetimibe 10 mg co-administered with a statin in eight randomized phase III clinical trials
• Double-blind placebo-controlled studies– Co-administration at start of therapy (lovastatin, simvastatin,
pravastatin, atorvastatin)– Addition to current statin in patients with CHD or multiple
cardiovascular risk factors– Addition to therapy in patients not controlled by atorvastatin 10 mg or
simvastatin 20 mg• Double-blind study
– Addition to statin in patients with HoFH• Statins administered across the full range of recommended doses • Doses administered once daily
CHD = coronary heart disease; HoFH = homozygous familial hypercholesterolemia
Slide 3EZT 2002-W-6022-SS
Initial Co-administration Study 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*, lovastatin, and pravastatin• >2300 patients; 65 patients per group• Primary endpoint: % reduction from baseline in LDL-C
– Statin alone vs. ezetimibe + statin– Pairwise comparisons between treatment groups
Slide 4EZT 2002-W-6022-SS
Ezetimibe Co-administered with Statins: LDL-C Efficacy
*p<0.01 ezetimibe + pooled statin doses vs. pooled statin doses alone
Ezetimibe 10 mg +
pooledatorvastatin
(n=255)
Pooled
atorvastatin
(n=248)
Ezetimibe 10 mg +
pooledsimvastatin
(n=274)
Pooled
simvastatin
(n=263)
Ezetimibe 10 mg +
pooledlovastatin
(n=192)
Pooled
lovastatin
(n=220)
Ezetimibe 10 mg +
pooledpravastatin
(n=204)
Pooled
pravastatin
(n=205)
–50
–40
–30
–20
–10
0
–60
–56.3
–44.2
12.1%*
14.8%*–51.3
–36.5 15.0%*–40.4
–25.4
13.4%*–38.6
–25.2
Mea
n %
ch
ang
e in
cal
cula
ted
L
DL
-C f
rom
bas
elin
e at
12
wee
ks
Slide 5EZT 2002-W-6022-SS
Ezetimibe Co-administered with Simvastatin: LDL-C Efficacy
*p<0.01 combination therapy vs. statin alone
–46 –45
–27*
–36* –38*
Mea
n %
ch
ang
e in
cal
cula
ted
L
DL
-C f
rom
bas
elin
e at
12
wee
ks
10 mg
Ezetimibe 10 mg+
simvastatin 10 mg 80 mg40 mg20 mg
Simvastatin
–50
–40
–30
–20
–10
0
–60
Slide 6EZT 2002-W-6022-SS
Ezetimibe Co-administered with Atorvastatin: LDL-C Efficacy
*p<0.01 combination therapy vs. statin alone
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
L
DL
-C f
rom
bas
elin
e at
12
wee
ks
Slide 7EZT 2002-W-6022-SS
*p0.01 ezetimibe + pooled statin doses vs. pooled statin doses alone
Ezetimibe Co-administered with Statins: TG Efficacy
–30
–20
–10
0
–40
–33
–24
–29
–20
–25
–12
–21
–14
9%*
9%*
13%*7%*
Mea
n %
ch
ang
e in
TG
fro
m b
asel
ine
at 1
2 w
eeks
Ezetimibe 10 mg +
pooledatorvastatin
(n=255)
Pooled
atorvastatin
(n=248)
Ezetimibe 10 mg +
pooledsimvastatin
(n=274)
Pooled
simvastatin
(n=263)
Ezetimibe 10 mg +
pooledlovastatin
(n=192)
Pooled
lovastatin
(n=220)
Ezetimibe 10 mg +
pooledpravastatin
(n=204)
Pooled
pravastatin
(n=205)
Slide 8EZT 2002-W-6022-SS
*p0.05 ezetimibe + pooled statin doses vs. pooled statin doses alone
Ezetimibe Co-administered with Statins: HDL-C Efficacy
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
7
9
7
9
4
8
7
4
3%*
2%*
5%*
1%
Ezetimibe 10 mg +
pooledatorvastatin
(n=255)
Pooled
atorvastatin
(n=248)
Ezetimibe 10 mg +
pooledsimvastatin
(n=274)
Pooled
simvastatin
(n=263)
Ezetimibe 10 mg +
pooledlovastatin
(n=192)
Pooled
lovastatin
(n=220)
Ezetimibe 10 mg +
pooledpravastatin
(n=204)
Pooled
pravastatin
(n=205)
Slide 9EZT 2002-W-6022-SS
Ezetimibe Co-administered with Statins versus High-Dose Statins
Ezetimibe 10 mg once daily together with the lowest statin dose reduced plasma LDL-C as much as or more than the highest dose tested of statin alone.
Mea
n %
ch
ang
e in
LD
L-C
fr
om
bas
elin
e
–40
–20
0
–60
Atorvastatin80 mg(n=62)
–54
Ezetimibe 10 mg +
atorvastatin 10 mg (n=65)
–53
Simvastatin80 mg(n=66)
–45
Ezetimibe 10 mg +
simvastatin 10 mg(n=67)
–46
Lovastatin40 mg(n=73)
–30
Ezetimibe 10 mg +
lovastatin 10 mg(n=64)
–34
Pravastatin40 mg(n=69)
–31
Ezetimibe 10 mg +
pravastatin 10 mg(n=71)
–34
Slide 10EZT 2002-W-6022-SS
Ezetimibe Co-administered with Statins: Easier Control of LDL-C
• One-step co-administration of ezetimibe equivalent to three-step statin titration
Adapted from Stein E Eur Heart J Suppl 2001;3(suppl E):E11-E16.
0 60
Three-step titration
One-step co-administrationStatin 10 mg
Statin 10 mg
+ Ezetimibe10 mg
5040302010
20mg
40mg
80mg
% reduction in LDL-C
Slide 11EZT 2002-W-6022-SS
Ezetimibe Co-administration with Ongoing Statin Study Objectives
Adapted from Gagné C et al Am J Cardiol 2002;90:1084-1091.
Assess efficacy and safety profile of ezetimibe 10 mg/day co-administered with ongoing statin monotherapy in patientsneeding further LDL-C lowering
• Primary endpoint– LDL-C–lowering efficacy of co-administering ezetimibe
10 mg/day vs. placebo with a statin
• Secondary endpoints– TG-lowering and HDL-C–increasing efficacy– Patients achieving target LDL-C values with ezetimibe
vs. placebo– Tolerability
Slide 12EZT 2002-W-6022-SS
Ezetimibe Co-administration with Ongoing Statin Study Design
*21 patients in the placebo group and 23 patients in the ezetimibe group were enrolled while taking nonmarketed doses of statins.
Adapted from Gagné C et al Am J Cardiol 2002;90:1084-1091.
ScreeningScreeningCo-administration phaseCo-administration phase
(ezetimibe or placebo with statin)*(ezetimibe or placebo with statin)*
SimvastatinSimvastatin(n=240)(n=240)
AtorvastatinAtorvastatin(n=308)(n=308)
Other statinsOther statins(n=221)(n=221)
RandomizeRandomize
Ezetimibe 10 mgEzetimibe 10 mg(n=114)(n=114)
Placebo (n=112)Placebo (n=112)
Patients taking statin who require further LDL-C lowering
Ezetimibe 10 mgEzetimibe 10 mg(n=136)(n=136)
Placebo (n=152)Placebo (n=152)
Ezetimibe 10 mgEzetimibe 10 mg(n=106)(n=106)
Placebo (n=105)Placebo (n=105)
Slide 13EZT 2002-W-6022-SS
Ezetimibe Co-administered with Ongoing Statin Therapy: Effect on Lipid Levels
*p<0.001 vs. statin + placebo **p<0.05 vs. statin + placebo***median % change
Adapted from Gagné C et al Am J Cardiol 2002;90:1084-1091.
–25*
–14*
–4 –3
1 3**
–30
–25
–20
–15
–10
–5
0
5
Mea
n %
ch
ang
e fr
om
M
ean
% c
han
ge
fro
m
bas
elin
e at
8 w
eeks
bas
elin
e at
8 w
eeks
–11%
–21%
Statin and placebo (n=390)
Statin and ezetimibe (n=379)
LDL-C
HDL-C
TG***
Slide 14EZT 2002-W-6022-SS
Ezetimibe Co-administered with Ongoing Statin Therapy: Better LDL-C Goal Attainment
*p<0.001 vs. statin monotherapy **p<0.01 vs. statin monotherapy
NCEP ATP = National Cholesterol Education Program Adult Treatment Panel
Adapted from Gagné C et al Am J Cardiol 2002;90:1084-1091.
Statin monotherapy (n=388)
Ezetimibe + statin (n=375)
% o
f p
atie
nts
at
LD
L-C
g
oal
at
8 w
eeks
All patients Patients not above goal at baseline
20
40
60
0
80
100
76*
27
72*
19
NCEP ATP II Goal Attainment
Slide 15EZT 2002-W-6022-SS
Ezetimibe Co-administered with Ongoing Statin Therapy: Consistent LDL-C Reductions Across Patient Subgroups
BMI = body mass index
Adapted from Gagné C et al Am J Cardiol 2002;90:1084-1091.
Placebo + statinPlacebo + statin
Ezetimibe 10 mg + statinEzetimibe 10 mg + statin
Difference between treatmentsDifference between treatments
Mean difference in % LDL-C Mean difference in % LDL-C reduction between treatmentsreduction between treatments
% LDL-C reduction by treatment group% LDL-C reduction by treatment group
Non-CaucasianNon-Caucasian
CaucasianCaucasian
65 years65 years
<65 years<65 years
WomenWomen
MenMen
2 4 6 8 10 12 14 16 18 20 22 24 26 28 302 4 6 8 10 12 14 16 18 20 22 24 26 28 30 10 15 20 25 3010 15 20 25 30
• Similar consistency observed for NCEP ATP II risk grades and BMI subcategories
Slide 16EZT 2002-W-6022-SS
Ezetimibe Co-administered with Statins: Consistency of Study Results
Ezetimibe plus statin resulted in 20 to 22% lower LDL-C than statin alone
Mea
n L
DL
-C (
mm
ol/
L)
at s
tud
y en
d
0.5
1.5
2.5
3.0
3.5
0
1.0
2.0
Statin alone
Statin + ezetimibe
Atorvastatin
2.1
2.7 22%
Simvastatin
2.3
2.9 21%
Pravastatin
2.8
3.5 20%
Lovastatin
2.8
3.5 20%
Ongoing statins
2.7
3.421%
0.5
1.5
2.5
3.0
3.5
0
1.0
2.0
Slide 17EZT 2002-W-6022-SS
Ezetimibe Co-administration with a Statin for Treatment of HoFH
*p=0.007 vs. statin alone**p=0.0001 vs. statin alone
Adapted from Gagné C et al Circulation 2002;105:2469-2475.
% L
DL
-C r
edu
ctio
n
at 1
2 w
eeks
–20
–10
0
–30
Statin80 mg(n=17)
Ezetimibe + statin
40 or 80 mg(n=33)
–20.7%*
–6.7%
–27.5%**
–7.0%
Statin80 mg(n=17)
Ezetimibe + statin 80 mg(n=17)
Slide 18EZT 2002-W-6022-SS
Data from Controlled Clinical Trials:Ezetimibe Tolerability and Safety Profile in Co-administration
• 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
Slide 19EZT 2002-W-6022-SS
Ezetimibe Initial Co-administration with Statin Studies: Pooled Safety Data
*From placebo-controlled monotherapy studies**All asymptomatic and reversible with drug continuation or discontinuationGI = gastrointestinal; ULN = upper limit of normal; ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT = gamma-glutanyl transpepsidase; CK = creatine kinase
Adapted from Melani L et al. Presented at American Diabetes Association Meeting, San Francisco, CA, July 14–18, 2002 .
Ezetimibe Ezetimibe Statin + statin
Placebo* 10 mg (pooled) (pooled) (n=259) (n=262) (n=936) (n=925)
Adverse events, no. (%) 166 (64.1) 177 (67.6) 606 (64.7) 593 (64.1)
GI disorders, no. (%) 47 (18.1) 54 (20.6) 171 (18.3) 155 (16.8)
Liver function tests (3 ULN)**ALT, no. (%)—total 0 (0) 0 (0) 4 (0.4) 12 (1.3)AST, no. (%) 0 (0) 0 (0) 3 (0.3) 5 (0.5)GGT, no. (%) 3 (1.2) 9 (3.5) 26 (2.8) 33 (3.6)
CK (10 ULN), no. (%) 0 (0) 0 (0) 4 (0.4) 1 (0.1)Myalgia, no. (%) 12 (4.6) 13 (5.0) 38 (4.1) 42 (4.5)
Slide 20EZT 2002-W-6022-SS
Initial Co-administration of Ezetimibe with Statins: Summary
• Phase III trials of ezetimibe + statin show– Additive effects of ezetimibe + atorvastatin, simvastatin,
pravastatin, or lovastatin on LDL-C reduction– LDL-C–lowering efficacy of ezetimibe + lowest-dose
statin comparable to maximum dose of every statin tested
– Beneficial effects on HDL-C and TG– Good tolerability
Slide 21EZT 2002-W-6022-SS
Ezetimibe Co-administration with Ongoing Statin Therapy: Summary
• Significant additional efficacy – LDL-C lowered 21% more than placebo (p<0.001)– HDL-C raised 2% more than placebo (p<0.05)– TG lowered 11% more than placebo (p<0.001)
• Significantly better NCEP ATP II goal attainment among patients not at goal when randomized (p<0.001)– 72% (vs. 19%, statin + placebo)
Adapted from Gagné C et al Am J Cardiol 2002;90:1084-1091.
Slide 22EZT 2002-W-6022-SS
Ezetimibe: Dosage and Administration
• Recommended dose of ezetimibe is 10 mg once daily, co-administered with a statin or alone, to be used as per approved product information
• Ezetimibe may be taken at any time of day, with or without food
• Ezetimibe is not recommended for patients with moderate or severe hepatic insufficiency
• Ezetimibe co-administration with fibrates has not been studied and is not recommended
• No important interactions with commonly used drugs (cholestyramine lowered mean AUC of ezetimibe by 55%)
AUC = area under the plasma concentration-time curve
Slide 23EZT 2002-W-6022-SS
Before prescribing, please consult full
manufacturer’s prescribing information.