ENDOGENOUS AND EXOGENOUS SOURCES OF CHOLESTEROL

1
The New Era in the Lipid Management
Cindy Tsai Mar. 2006
2
Content

• Cholesterol and CHD
• Cholesterol Metabolism
• Dyslipidemia
• Currently Available Pharmacologic Agents
• Mechanism of Action and Pharmacology of Ezetimibe
• Efficacy and Tolerability with Statin
  Co-administration

3
Cholesterol and CHD
4
CHD Deaths Increase with Rising Total Cholesterol
15
11.06
10
CHD deaths/1000 patients/6 years
7.14
5.60
4.18
5
3.23
0
?4.68
4.715.22
5.255.69
5.726.31
?6.34
Quintiles of total cholesterol (mmol/L)
CHD coronary heart disease Adapted from Stamler
J et al JAMA 19862562823-2828.
5
Lowering Total Cholesterol Concentration Reduces
CHD Events

• WOSCOPSpravastatin therapy
• 6595 men, 4564 years of age
• Randomized, double-blind placebo-control
• Pravastatin ? total cholesterol by 20, ? risk
  of coronary events by 31 (plt0.001)
• AFCAPS/TexCAPSlovastatin therapy
• 5608 men, 4573 years of age 997 women, 5573
  years of age
• Randomized, double-blind placebo-control
• Lovastatin ? total cholesterol by 18, ? risk of
  first acute major coronary event by 37 (plt0.001)

WOSCOPS West of Scotland Coronary Prevention
Study AFCAPS/TexCAPS Air Force/Texas Coronary
Atherosclerosis Prevention Study Adapted from
Shepherd J et al N Engl J Med 19953331301-1307
Downs JR et al JAMA 19982791615-1622.
6
Cholesterol Absorption Correlateswith Plasma
LDL-C
50

Cholesterol absorption
45
40
0
3.0
4.0
5.0
0
LDL-C (mmol/L)
LDL-C low-density lipoprotein
cholesterol plt0.02 vs. lowest decile number
of subjects in each group is 14 Adapted from
Kesäniemi YA, Miettinen TA Eur J Clin Invest
198717391-395.
7
Cholesterol Metabolism
8
Plasma Cholesterol Comes Continuously From Both
Production and Absorption
Intestinal cholesterol absorption (chylomicron,
TG, plant sterols)
Endogenous cholesterol production (VLDL, IDL,
LDL)
Small intestine
Peripheral tissue

• Intestinal cholesterol comes from bile (75)
  and the diet (25)²
• Approximately 50 is absorbed into the plasma³

Liver

• Approximately 10 of cholesterol is synthesized
  in the liver, which plays a key role in
  regulating cholesterol balance¹
• Approximately 90 is synthesized in other cells
  in the body¹

Blood vessel
1. Dietschy JM. Am J Clin Nutr. 199765(suppl)
1581S1589S. 2. Turley SD, Dietschy JM. Prev
Cardiol. 200362933. 3. Homan R et al. Curr
Pharm Design. 199732944.
9
Cholesterol Synthesis
Acetyl-CoA
Acetoacetyl-CoA
HMG-CoA
HMG-CoA reductase
Hepatocyte
Mevalonate
Cholesterol
Adapted from Dietschy JM Am J Clin Nutr
1997651581S-1589S.
10
Cholesterol Absorption
ABCA1
ABCA1adenosine triphosphatebinding cassette
protein ACATacyl-coenzyme Acholesterol
acyltransferase CMchylomicron Adapted from
Champe PC, Harvey RA. Lippincotts Illustrated
Reviews Biochemistry. 2nd ed. Philadelphia
Lippincott-Raven, 1994.
11
Cholesterol Balance
Extrahepatic organs
Liver
Intestine
Dietary and biliary cholesterol
LDL
VLDL
Cholesterol
Cholesterol
HMG-CoA reductase
HDL
Acetyl-CoA
Fecal sterols
Synthesized cholesterol
Adapted from Dietschy JM Am J Clin Nutr
1997651581S-1589S.
12
Dyslipidemia
13
Major Clinical Manifestations of Atherothrombosis
Ischemic stroke
Transient ischemic attack
Myocardial infarction

• Angina
• Stable
• Unstable

• Peripheral arterial
• disease
• Intermittent claudication
• Rest Pain
• Gangrene
• Necrosis

14
Risk Factors for Atherothrombosis
Life-style (eg, smoking, diet, lack of exercise)
Atherosclerosis
Gender
Atherothrombotic Manifestations(MI, Stroke,
Vascular Death)
American Heart Association. Heart and Stroke
Facts 1997 Statistical Supplement Wolf. Stroke
199021(suppl 2)II-4II-6 Laurila et al.
Arterioscler Thromb Vasc Biol 1997172910-2913
Grau et al. Stroke 1997281724-1729 Graham et
al. JAMA 19972771775-1781 Brigden. Postgrad
Med 1997101(5)249-262.
15
Currently Available Pharmacologic Agents
16
Currently Available Pharmacologic Agents

• Bile acidbinding resins
• Interrupt enterohepatic bile acid circulation
• Increase LDL-C receptors
• Decrease LDL-C by 2030
• Decrease VLDL-C
• Increase HDL-C

• HMG-CoA reductase inhibitors
• Inhibit cholesterol synthesis
• Increase LDL receptors
• Decrease LDL-C by 2540
• Decrease VLDL-C

Ginsberg HN, Goldberg IJ. In Harrisons
Principles of Internal Medicine. 14th ed. New
York McGraw-Hill, 19982138-2149.
17
Currently Available Pharmacologic Agents (contd)

• Fibric acid derivatives
• Activate PPARs
• Induce lipoprotein lipolysis
• Reduce triglyceride production
• Increase LDL removal
• Reduce neutral lipid exchange
• Increase HDL production and reverse cholesterol
  transport
• Decrease triglycerides by 2540
• Increase HDL-C

• Nicotinic acid (niacin)
• Inhibits lipoprotein secretion
• Decreases LDL and VLDL synthesis
• Decreases LDL-C by 1525
• Decreases VLDL-C by 2535
• May increase HDL-C

PPARsperoxisome proliferator activator
receptors Ginsberg HN, Goldberg IJ. In Harrisons
Principles of Internal Medicine. 14th ed. New
York McGraw-Hill, 19982138-2149 Illingworth
DR Med Clin North Am 200084(1)23-42 Staels B
et al Circulation 1998982088-2093.
18
NCEP ATP III LDL-C Goals (2004 Updates)
Moderately High Risk
Moderate Risk
Lower Risk
High Risk
? 2 risk factors ( 10-yr risk 10-20 )
CHD or CHD risk equivalents ( 10-yr risk gt20 )
? 2 risk factors ( 10-yr risk lt10 )
lt 2 risk factors
190
Target 160 mg/dL
LDL-C level
160
Target 130 mg/dL
Target 130 mg/dL
130
or optional 100 mg/dL
Target 100 mg/dL
100
or optional 70 mg/dL
70
Therapeutic option in very high-risk patients
and in patients with high TG, non-HDL-Clt100
mg/dL Therapeutic option 70 mg/dL 1.8
mmol/L 100 mg/dL 2.6 mmol/L 130 mg/dL
3.4 mmol/L 160 mg/dL 4.1 mmol/L
Grundy SM et al. Circulation 2004 110227-239
19
Pharmacologic Therapy Statins-Dose
Response
Response to Minimum/Maximum Statin Dose
Lovastatin 20/80 mg
Fluvastatin 20/80 mg
Pravastatin 20/80 mg
Simvastatin 20/80 mg
Atorvastatin10/80 mg
Rosuvastatin 10/40 mg
Reduction in LDL-C
31
37
40
47
55
55
Adapted from Illingworth. Med Clin North Am.
20008423.Pravachol (pravastatin)
PI. CRESTOR (rosuvastatin) for active control
study PI.
20
Limited of Therapy with Statins
Physicians Desk Reference (PDR)
21
Mechanism of Action and Pharmacology of Ezetimibe
22
Mechanism ofIntestinal-Acting Agents
NPC1L1
23
www.sciencemag.org SCIENCE VOL 303 20 FEBRUARY
2004
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Structure of Ezetimibe
OH
OH
N
O
F
F
Ezetimibe is a potent and specific inhibitor of
dietary andbiliary cholesterol absorption
Adapted from Catapano A Eur Heart J Suppl
20013(suppl E)E6-E10.
25
Mechanism of Action of Ezetimibe

• Localizes at the brush border of the small
  intestine to prevent and decrease the delivery
  of intestinal cholesterol to the liver
• The reduction of hepatic cholesterol stores leads
  to an increase in clearance of cholesterol from
  the blood

Adapted from van Heek M et al Br J Pharmacol
20001291748-1754.
26
Metabolism of Ezetimibe
Ezetimibe
OH

• Rapidly metabolized to an active glucuronide
  metabolite
• Both parent drug and metabolite inhibit
  cholesterol absorption
• Glucuronide metabolite more potent than parent
  drug in inhibiting cholesterol absorption
• Repeated enterohepatic circulation results in
  long duration of action

OH
N
F
O
Glucuronidation
F
Glucuronide
Adapted from Catapano AL Eur Heart J Suppl
20013(suppl E)E6-E10 van Heek M et al Br J
Pharmacol 20001291748-1754 Patrick JE et al
Drug Metab Dispos 200230430-437 Ezzet F et al
Clin Ther 200123871-885.
27
Pharmacokinetics of Ezetimibe

• Elimination half-life of ezetimibe approximately
  22 hours
• Enterohepatic recirculation of glucuronide
  metabolite extends duration of action
• Long half-life
• Permits once-daily dosing
• Increases convenience
• May improve compliance

Adapted from Bays HE et al Clin Ther
2001231209-1230 Kirsten R et al Clin
Pharmacokinet 199834457-482.
28
Drug Interactions of Ezetimibe

• Ezetimibe does not induce cytochrome P450 enzymes
• Statins no significant pharmacokinetic
  interactions with atorvastatin, simvastatin,
  pravastatin, lovastatin, or fluvastatin
• Other drugs no effect on pharmacokinetics of
  dapsone, dextromethorphan, digoxin, oral
  contraceptives, glipizide, tolbutamide,
  midazolam, or warfarin
• Cimetidine no effect on bioavailability of
  ezetimibe
• Antacids decreased absorption rate of
  ezetimibenot clinically significant
• Cholestyramine decreased mean AUC of ezetimibe
  55
• May lessen incremental LDL-C reduction
• Fibrates safety and efficacy of fibrate
  co-administration not established

29
Ezetimibe Dosage and Administration

• Recommended dose of ezetimibe is 10 mg once daily
• Ezetimibe can be administered at any time of the
  day, with or without food
• Ezetimibe may be administered concurrently with a
  statin for 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 interactions with commonly used
  drugs
• Coadministration of ezetimibe and fibrates is not
  recommended
• Caution should be exercised when initiating
  ezetimibe in the setting of cyclosporine

Adapted from Worldwide Product Circular
(ezetimibe), MSP.
30
Monotherapy / Coadministration of Ezetimibe with
Four Major Statins
31
Phase III Pooled Monotherapy Results Efficacy
LDL-C
Triglycerides
HDL-C
5
1.0
1
0
0
2
5
Mean change frombaseline to week 12
8
10
15
18
20
Median change Adapted from Worldwide Product
Circular (ezetimibe), MSP data from Registration
File, MSP.
32
Rationale for Coadministration of Ezetimibe with
Statins
20 mg
40 mg
80 mg
Three-step titration
Statin 10 mg
Ezetimibe 10 mg
One-step coadministration
Statin 10 mg
0
60
50
40
30
20
10
reduction in LDL-C
One-step coadministration of ezetimibe similar
to three-step statin titration
Adapted from Stein E Eur Heart J Suppl
20013(suppl E)E11-E16.
33
Ezetimibe Coadministered with Statins
Consistency of Study Results
Ezetimibe plus statin resulted in 18 to 23 lower
LDL-C than statin alone
3.4
3.4
3.4
21
18
21
2.9
24
2.8
2.6
2.7
23
2.7
2.2
Mean LDL-C (mmol/L) at study end
2.0
Simvastatin initial
Lovastatin initial
Ongoing statin study
Atorvastatin initial
Pravastatin initial
Adapted from data from Registration File, MSP
Davidson MH et al J Am Coll Cardiol
2002402125-2134 Melani L et al Eur Heart J
200324717-728.
34
Percentage of Patients Achieving Goal at Endpoint
Who Were Not at Goal at Baseline
Statin placebo 18.9 Statin
ezetimibe 71.5
Analysis of patients not at goal when
randomized (72 of total population) 18 of
patients were at goal at baseline. Odds ratio
23.7 plt0.001 Adapted from Gagné C et al Am J
Cardiol 2002901084-1091.
35
High-Dose Statin Compared with Ezetimibe
Coadministered with Low-Dose Statin (LDL-C)
Ezetimibe 10 mg atorvastatin 10 mg (n65)
Ezetimibe 10 mg simvastatin 10 mg (n67)
Ezetimibe 10 mg pravastatin 10 mg (n71)
Atorvastatin 80 mg (n62)
Simvastatin 80 mg (n66)
Pravastatin 40 mg (n69)
31
Mean change at 12 weeks
34
45
46
53
54
Adapted from Worldwide Product Circular
(ezetimibe), MSP data from Registration File,
MSP Ballantyne CM et al Circulation
20031072409-2415 Davidson MH et al J Am Coll
Cardiol 2002402125-2134.
36
Efficacy on Triglycerides Ezetimibe
Coadministered with StatinsPooled Results
Ezetimibe atorvastatin (n255)
Ezetimibe simvastatin (n274)
Ezetimibe lovastatin (n192)
Ezetimibe pravastatin (n204)
Atorvastatin (n248)
Simvastatin (n263)
Lovastatin (n220)
Pravastatin (n205)
0
5
8
11
10
17
15
18
Mean change in TG from baseline at 12 weeks
22
20
24
25
25
30
33
35
40
Median change plt0.01 ezetimibe pooled
statin doses vs. pooled statin doses
alone Adapted from Ballantyne CM et al
Circulation 20031072409-2415 Davidson MH et al
J Am Coll Cardiol 2002402125-2134 Melani L et
al Eur Heart J 200324717-728 Kerzner B et al
Am J Cardiol 200391418-424.
37
Efficacy on HDL-C Ezetimibe Coadministered with
StatinsPooled Results
Mean change in HDL-C from baseline at 12 weeks
plt0.01 ezetimibe pooled statin doses vs.
pooled statin doses alone p0.03 ezetimibe
pooled statin doses vs. pooled statin doses
alone Adapted from Ballantyne CM et al
Circulation 20031072409-2415 Davidson MH et al
J Am Coll Cardiol 2002402125-2134 Melani L et
al Eur Heart J 200324717-728 Kerzner B et al
Am J Cardiol 200391418-424.
38
Overall Conclusions

• Coadministration of ezetimibe with a statin
  enables dual inhibition of both
  liver-synthesized and intestinally resorbed
  cholesterol
• Coadministration of ezetimibe with 10 mg of a
  statin provides an LDL reduction similar to 80 mg
  of that statin
• 72 of patients taking a statin and not at goal
  on addition of ezetimibe reach goal
• In combination therapy, ezetimibe and
  atorvastatin
• Lower LDL by up to 56
• Raise HDL by up to 7
• Lower TGs by up to 33

Adapted from Worldwide Product Circular
(ezetimibe), MSP Miettinen TA Int J Clin Pract
200155710-716 Gagné C et al Am J Cardiol
2002901084-1091.
39
Overall Conclusions (contd)

• Ezetimibe reduced LDL-C by an additional 18 to
  23 when coadministered with a statin
• The safety profile of coadministration therapy
  with ezetimibe is comparable to that of the
  statin alone
• Ezetimibe has a safety and tolerability profile
  comparable to placebo
• Not metabolized by the CYP-450 pathway
• No known interactions with commonly used drugs

Adapted from Worldwide Product Circular
(ezetimibe), MSP data from Registration File,
MSP.
40
Dual InhibitionClinical Outcomes Program Overview

• ENHANCE
• Ezetimibe aNd simvastatin in Hypercholesterolemia
  enhANces atherosClerosis rEgression (IMT)
• SEAS
• Simvastatin and Ezetimibe in Aortic Stenosis
• SHARP
• Study of Heart And Renal Protection

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EZETROL (Ezetimibe) ?? 10 mg

• ???
• ?????????
• Primary Hypercholesterlemia
• ??????????????
• Homozygous Familial Hypercholesterlemia
• ????????????(???????)
• Homozygous Sitosterolemia / Phytosterolemia
• ?? ??
• 10 mg ???? ???????
• ???? ?? Statin ???????
• ???????????

42
EZETROL (Ezetimibe) ?? 10 mg

• ?????? (94.6.1)
• ?????????, ??????????????, ????????????(???????)
  ????????????
• ????????????????????? Statin ??????? 3 ?????????,
  ????????? Statin ???
• ????????????????????Statin ???????????????(?
  Severe myalgia, Myositis)?
• ???
• NT 46.3

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A New Class in the 15 Years- 19872002

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Thanks !