Pathway of Exogenous Cholesterol Metabolism

1
Pathway of Exogenous Cholesterol Metabolism
BILIARY TRACT
INTESTINAL LUMEN
Plaque formation
Bile acids
Free cholesterol
Remnants
DIET
Unstirred water layer
BLOOD
Cholesterol
CE
Micelles
Chylomicrons
LYMPH
2
Complementary Mechanisms of Action Lead to
Broader Lipid Control
VLDL
LDL
IDL
Statins
synthesis
BILIARY SECRETION
Absorption
Cholesterol Absorption Inhibition
INTESTINE
Excretion
DIETARY CHOLESTEROL
3
Inhibition of Cholesterol Absorption
4
Ezetimibe Phase III Pooled Monotherapy
Efficacy Results
LDL-C
TG
HDL-C
Placebo
Placebo (n409)
Ezetimibe 10 mg (n1234)
Ezetimibe10 mg (n1234)
Placebo (n409)
Placebo (n409)
Ezetimibe 10 mg (n1234)
EZ 10 mg
3.5
0.3
1.0
0 -5 -10 -15 -20
-1.6
Mean Change in LDL from Baseline at Week 12
-4.2
-17.4
p lt0.01 vs. placebo
5
Ezetimibe Phase III MonotherapyPooled Safety
Results
No. of Patients/Total ()

• Placebo Ezetimibe
• (n431) (n1288)
• 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 (lt1) 7 (lt1)
• AST 3 (lt1) 6 (lt1)
• GGT 10 (2) 20 (2)
• Total bilirubin
  0 0
• ALP
  0 0
• Creatine kinase (CK) elevations
• 5-10 x ULN 0 8 (lt1)
• ?10 x ULN 1 (lt1) 3 (lt1)

6
Results Added Efficacy Across the Lipid Profile
Regardless of Statin Used











Lovastatin
Pravastatin
Simvastatin
Atorvastatin

plt0.01 for EZE statin vs statin alone
p0.22 for EZE statin vs statin alone
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Ezetimibe Co-administered with Statins

• Ezetimibe co-administered with low dose statins,
  offers broader lipid control than that achieved
  by increasing the dose of the statin alone

Additional 5
6
HDLC
TG
40
Additional -10
LDLC
20 TG
Additional -14 to 18
8
Homozygous FH Study Efficacy on LDL-C When Added
to Ongoing 40 mg of Statin
Change From Baseline (Statin 40 mg)
14
21


n50 Plt0.01 vs statin 80 mg
9
Structure of Ezetimibe (SCH 58235)