Post on 23-Aug-2020
A New Paradigm to Achieve Optimal Serum LDL Cholesterol Levels
Experiences with Ezetimibe
A New Paradigm to Achieve Optimal Serum LDL Cholesterol Levels
Experiences with Ezetimibe
HAN, KI HOON MD
Asan Medical CenterUniversity of Ulsan
Seoul, Korea
Current Trend of Lipid Lowering ManagementCurrent Trend of Lipid Lowering Management
Set up individual goal of serum LDL cholesterol levels based on absolute global risk
LDL ; Lower, the better.
Human Being Has the Highest Serum Cholesterol Levels Human Being Has the Highest Serum Cholesterol Levels
300 (mg/dl)
250
200
150
100
50
0
300
250
200
150
100
50
0rat
sheep cow rabbit
Cat & dogpig lion baby
adults
fh
THREE-STEP
TITRATION
10 20 30 40 50 60
% Reduction in LDL Cholesterol0
-6% -6%
Simvastatin 10 mg 20 mg
40 mg
80 mg
-6%
Effect of Statin Therapy on LDL-C Levels: “The Rule of 6”
Why are patients not reaching Goals?Why are patients not reaching Goals?
Despite Evidence-based Medicine, Physicians Generally use Lower Doses of StatinsDespite Evidence-based Medicine, Physicians Generally use Lower Doses of Statins
In Spain:
typical simvastatin dose 17.5 mg/day
typical atorvastatin dose 13 mg/day
typical pravastatin dose 17 mg/day
New LDL Lowering Drug ; EzetimibeNew LDL Lowering Drug ; Ezetimibe
E-Z & Effective
Ezetimibe is a potent and specific inhibitor of dietary and biliary cholesterol absorption
F
OH
NO
OH
F
Structure of Ezetimibe (SCH 58235) Structure of Ezetimibe (SCH 58235)
The main route of metabolism for ezetimibe is glucuronidation
F
OH
NO
OH
F
F
O
NO
OH
F
O
HO
O
OHHO
SCH 60663 (Glucuronide)
Ezetimibe
Ezetimibe and its Metabolite (SCH 60663)Ezetimibe and its Metabolite (SCH 60663)
Overview of Cholesterol TransportOverview of Cholesterol Transport
Action of StatinsAction of Statins
Action of EzetimibeAction of Ezetimibe
Uptake of a fluorescent cholesterolanalog in hamster small intestine
Sparrow et al. J Lipid Res. 1999; 10:1747.
Ezetimibe Appears to Localize to the Site of Cholesterol AbsorptionEzetimibe Appears to Localize to the Site of Cholesterol Absorption
125 I-Gluc-Ezetimibe Delivered I.V. Localizes to the Intestinal Brush
Border in Bile-Duct Cannulated Rats
S. In
t. Ri
nse
S. In
t. W
allL.
Int.
Rins
eL.
Int.
Wall
Stom
ach
Live
rPa
ncre
asAd
rena
lKi
dney
Lung
Hear
tSp
leen
Test
e
Seru
m
0
60
50
40
30
20
10
% IV
dos
e
0.3 mg/kg, 3-hr post-dosing, n=4/group
Tissue
Localization of IV-Dosed 125I-Gluc-Ezetimibe (SCH 61209) in Normal RatsLocalization of IV-Dosed 125I-Gluc-Ezetimibe (SCH 61209) in Normal Rats
Steps of Cholesterol AbsorptionSteps of Cholesterol Absorption
EmulsificationTransfer from bile acid micelle to brush borderTransport to endoplasmic reticulumEsterification (ACAT)Incorporation into chylomicronsSecretion from basolateral surfaceMovement into lymph
SCH 48461 (10 mg/kg/d)
* p<0.05
0
25
50
75
100
(mg/
ml)
Control SCH48461
125
150
*
Cholesteryl Ester
0
1
2
3
4
(mg/
ml)
Control SCH48461
5
Free Cholesterol
0
15
20
25
30
(g/m
l)
Control SCH48461
35
40
10
5
Triglyceride
*
Depletion of Cholesterol from Postprandial Chylomicrons in Cynomolgus MonkeysDepletion of Cholesterol from Postprandial Chylomicrons in Cynomolgus Monkeys
van Heek et al. Eur J Pharmacol. 2001; 415:79.
*
*
Daily Dose of Ezetimibe (mg)0 5 10 20 40
From
Bas
elin
e to
End
poin
tM
ean
(±S
.E.M
.) P
erce
nt C
hang
e in
LD
L-C
-20%
-15%
-10%
-5%
0%
5%Placebo
Ezetimibe
Results from three Phase II Clinical Therapy Trials
Relationship Between Dose of Ezetimibe and % Change in Plasma LDL-CRelationship Between Dose of Ezetimibe and % Change in Plasma LDL-C
Placebo (n=88)EZ 5 mg (n=125)EZ 10 mg (n=123)
* p<0.05 vs placebo† p<0.05 vs 5 mg EZ
0
5
-5
-10
-15
-20
-15.7*
-18.5*†
-0.4 -1.3
-5.8 -4.9
-0.2
+2.9*+3.5*
Mea
n %
ch a
nge
from
ba s
eli n
e
LDL-C TG HDL-C
Lipka et al. J Am Coll Cardiol. 2000:35(suppl A):257A. Abstract.
Effects of Ezetimibe (EZ)on serum LDL-C, Triglyceride (TG), and HDL-C Effects of Ezetimibe (EZ)on serum LDL-C, Triglyceride (TG), and HDL-C
Results from three Phase II Clinical Therapy Trials
* p <0.01 vs. placebo
Mea
n %
Cha
nge
in L
DL
from
B
asel
ine
at W
eek
12
0
-5
-10
-15
-20
LDL-C TG
0.3
-17.4*
3.5
-4.2*
Placebo (n=409)EZ 10 mg (n=1234)
Effects of Ezetimibe (EZ)on serum LDL-C, Triglyceride (TG), and HDL-C Effects of Ezetimibe (EZ)on serum LDL-C, Triglyceride (TG), and HDL-C
HDL-C
-1.6
1.0*
Results from three Phase III Pooled Monotherapy Trials
Pooled Safety of Ezetimibe (EZ)Results from three Phase III Pooled Monotherapy Trials
Pooled Safety of Ezetimibe (EZ)Results from three Phase III Pooled Monotherapy Trials
No. of Patients (%) Placebo Ezetimibe( n=431 ) ( n=1288 )
Adverse events 285 (66) 802 (62)Gastrointestinal 93 (22) 230 (18)
DC 2° AE 11 (2.6) 51 (4)
Liver function tests (≥3 x ULN)ALT 2 (<1) 7 (<1) AST 3 (<1) 6 (<1) GGT 10 (2) 20 (2)Total bilirubin 0 0ALP 0 0
Creatine kinase (CK) elevations5-10 x ULN 0 8 (<1)≥10 x ULN 1 (<1) 3 (<1)
Ezetimibe Phase II / III Program:Summary of Monotherapy ResultsEzetimibe Phase II / III Program:Summary of Monotherapy Results
Efficacy of EZ 10 mg QD relative to placebo:
LDL-C decreased by ~18% TG decreased by ~7-8%HDL-C increased by ~2-3 %
LDL-C reduction occurred as early as 2 weeks
EZ had excellent safety and tolerability, with an AE profile indistinguishable from placebo
ONE-STEP COADMINISTRATION
THREE-STEP TITRATION
10 20 30 40 50 60
% Reduction in LDL-C0
StatinStatin 10 mg10 mg 20 20 mgmg
40 40 mgmg
80 80 mgmg
StatinStatin 10 mg10 mg ++ EzetimibeEzetimibe10 mg10 mg
One Step Move ; Ezetimibe on StatinOne Step Move ; Ezetimibe on Statin
Summary of Follow-up Add-on Study Summary of Follow-up Add-on Study
The addition of 10 mg EZ to statins resulted in
additional LDL-C reduction by 20 %
additional TG reduction by 10 %
additional CRP reduction by 10 %
70 % of subjects (who were not at optimal goal when randomized)achieved optimal LDL-C levels
Gagne et al. AJC 2002;90:1084Gagne et al. AJC 2002;90:1084--10911091
Co-administration of Ezetimibe and StatinCo-administration of Ezetimibe and Statin
Rosuva Atorva Simva / EZ Simva Lova / Prava TC LDL-C
5 10 20 22 27
10 20 40 27 34
10 20 40 80 32 41
20 40 10 / 10 80 37 48
40 80 42 55
Dose (mg) of agent % Reduction
Roberts WC. Am J Cardiol. 1997;80:106-107.Stein E et al. J Cardiovasc Pharmacol Therapeut. 1997;2:7-16.
Rule of 5s & 7s
EZ + Simvastatin Study: Efficacy on LDL-CEZ + Simvastatin Study: Efficacy on LDL-CM
ean
% C
hang
e
10 mg
EZ 10 mg+
Simva10 mg 80 mg40 mg20 mg
Simvastatin
* p<0.01 combination therapy versus statin alone
Davidson M et al. ACC 2002: Abstract.Davidson M et al. ACC 2002: Abstract.
-46 -45
-27*
-36* -38*
-60
-50
-40
-30
-20
-10
0
EZ + Statin Studies: Efficacy on TGPooled ResultsEZ + Statin Studies: Efficacy on TGPooled Results
* * p<0.01 combination therapy versusp<0.01 combination therapy versus statinstatin alonealone
AtorvastatinAtorvastatinPravastatinPravastatinSimvastatinSimvastatinLovastatinLovastatin
Med
ian
% C
hang
eM
edia
n %
Cha
nge
**
**
**
**
Davidson M et al. ACC 2002: Abstract.Davidson M et al. ACC 2002: Abstract.BallantyneBallantyne C et al. ACC 2002: Abstract.C et al. ACC 2002: Abstract.MelaniMelani L et al. WCC 2002: Abstract.L et al. WCC 2002: Abstract.LipkaLipka L et al. WCC 2002: Abstract.L et al. WCC 2002: Abstract.
-24
-14
-20
-12
-33
-21
-29
-25
-40
-30
-20
-10
0
StatinsStatins onlyonly+ EZ 10 mg/d+ EZ 10 mg/d
AtorvastatinPravastatinSimvastatinLovastatin
4
7 7
4
9* 9**8
7*
0
2
4
6
8
10
Mea
n %
Cha
nge
* p<0.01 combination therapy versus statin alone** p=0.03 combination therapy versus statin alone
Ezetrol + Statin Studies: Efficacy on HDL-CPooled ResultsEzetrol + Statin Studies: Efficacy on HDL-CPooled Results
Davidson M et al. ACC 2002: Abstract.Davidson M et al. ACC 2002: Abstract.BallantyneBallantyne C et al. ACC 2002: Abstract.C et al. ACC 2002: Abstract.MelaniMelani L et al. WCC 2002: Abstract.L et al. WCC 2002: Abstract.LipkaLipka L et al. WCC 2002: Abstract.L et al. WCC 2002: Abstract.
StatinsStatins onlyonly+ EZ 10 mg/d+ EZ 10 mg/d
Ezetimibe in KOREANSEzetimibe in KOREANS
Wk - 4 0 4 8 12 14
Eze10mg + Simva10mg (n = 55 pts)
Simva10mg (n = 55 pts)
Placebo run-in & diet
Figure 2. Plot of LS Mean Percent Change from Baseline in LDL-Cover Time: Modified Intention-to-Treat Approach
-60
-50
-40
-30
-20
-10
0Baseline Week 4 Week 8 Week 12
Week
Per
cent
Cha
nge
from
Bas
elin
e in
LD
L-C
SimvastatinEzetimibe + Simvastatin
Ezetimibe in KOREANS (2)Ezetimibe in KOREANS (2)
Number of Patients Treated With Ezetimibe(as of March 2002)Number of Patients Treated With Ezetimibe(as of March 2002)
Total patients exposed to Ezetimibe: over 5700
Total patients exposed for ≥6 months: over 2100
Total patients exposed for ≥12 months: over 1600
Total patients exposed for ≥18 months: 980
Ongoing exposure: up to 27 months
Ongoing exposure to ezetimibe + statins: up to 23 months
Ezetimibe Mechanism of ActionEzetimibe Mechanism of Action
Ezetimibe is a highly potent and specific inhibitor of dietary and biliary cholesterol absorption
Ezetimibe prevents cholesterol uptake at the level of the intestinal wall and is localized on the brush border membraneOnset of action is rapid, <90 minutesEzetimibe may act on a cholesterol transporter (subject of ongoing research)
Ezetimibe:Dosage and AdministrationEzetimibe:Dosage and Administration
Recommended dose of ezetimibe is 10 mg once dailyEzetimibe can be administered at any time of the day, with or without foodEzetimibe may be administered concurrently with a statinfor incremental effect
For convenience, the daily dose of ezetimibe may be taken at the same time as the statin, according to the dosing recommendations for the statin
No important drug interaction with commonly used drugs
ConclusionConclusion
The co-administration of Ezetimibe and any statin enables dual inhibition to address both liver-synthesized and intestinally-absorbed cholesterolEzetimibe reduced LDL-C by an additional 19% to 23% when co-administered with a statin Co-administration of Ezetimibe with 10 mg of any statinprovides an LDL reduction equal to 80 mg of that statinFor patients on a statin and not at goal when Ezetimibe is added to their therapy, 72% reach goalThe safety profile of co-administration therapy with Ezetimibe is similar to that of the statin aloneEzetimibe has a safety and tolerability profile similar to placebo