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

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0

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sheep cow rabbit

Cat & dogpig lion baby

adults

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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

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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

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(mg/

ml)

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5

Free Cholesterol

0

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30

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l)

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35

40

10

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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

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-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*†

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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

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-5

-10

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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

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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*

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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

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**

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**

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

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-29

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StatinsStatins onlyonly+ EZ 10 mg/d+ EZ 10 mg/d

AtorvastatinPravastatinSimvastatinLovastatin

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9* 9**8

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10

Mea

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* 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

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0Baseline Week 4 Week 8 Week 12

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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