Glass and Witztum, Cell 2001

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Fatty streak lesion in a cholesterol-fed rabbit
stained for macrophages
Human coronary artery at site of thrombotic
lesion causing fatal myocardial infarction
Glass and Witztum, Cell 2001
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One in Six Teenagers Has Atheromas
(Adapted from Tuzcu et al.)
Tuzcu EM et al, in press.
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Consistent Evidence of Early Atherosclerosis

• (Adapted from Berenson et al and Tuzcu et al.)

Berenson GS et al, N Engl J Med, 1998 Tuzcu EM
et al, in press.
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Witztum and Steinberg 2004
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Witztum and Steinberg 2004
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Witztum and Steinberg 2004
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• ACQUIRED DISORDERS OF LIPOPROTEIN METABOLISM
  
• 
  Hypercholesterolemia
• Nephrotic syndrome
• Hypothyroidism
• Dysgammaglobulinemia
• Acute intermittent porphyria
• Obstructive liver disease
• Combined Hyperlipidemia
• Nephrotic syndrome
• Hypothyroidism
• Glucocorticoid excess/Cushing's disease
• Diuretics
• Uncontrolled diabetes
• 
  Hypertriglyceridemia
• Diabetes mellitus
• Uremia
• Sepsis

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• THERAPEUTIC GOAL FOR TREATMENT OF
  HYPERCHOLESTEROLEMIA
• THERAPEUTIC GOAL
  Patient Categories
• LDL CHOLESTEROL (mg/dL)___________________________
  __________________
• lt130 Moderate risk
  for CADPatients with no family history of CAD
  and no other CAD risk factorsYoung adults with
  familial hypercholesterolemia Adults with
  familial hypercholesterolemia and no other risk
  factors
• lt100 High risk for
  CADWith family history of CAD or two or more CAD
  risk factorsAdult familial hypercholesterolemia
  patients with family history of CAD or one or
  more risk factorsIndividual with existing
  CADIndividual after CABGIndividual with low HDL
  cholesterol and family history of CAD

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Helen Hobbs
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HPS Primary and Secondary Prevention Implications
25
20
15
with CAD event
10
5
0
50
210
70
190
170
150
130
110
90
LDL-C (mg/dL)
Adapted from Illingworth. Med Clin North Am.
20008423. At http//www.hpsinfo.org.
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Lyon Diet Heart Study Cumulative Survival
Without Cardiac Death and Nonfatal MI
100
Experimental
90
withoutevent
80
Control
P0.0001
70
1
2
3
4
5
Year
de Lorgeril M et al. Circulation. 199999779-785.
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Statin
VLDL
Niacin
Bile Sequestrant
Witztum and Steinberg, 2000
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Pharmacologic Therapy Statins

• Inhibit cholesterol synthesis, ? LDL receptors

• Beneficial effects on lipid parameters
• LDL-C ? 18-55
• HDL-C ? 5-15
• TG ? 7-30
• 24-40 relative reduction in coronary events
• Potential side effects myopathy, ? liver enzymes
• Contraindications liver disease
• Precautions use with certain drugs

Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults.
JAMA. 20012852486.
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Summary of Effects of Lipid Lowering on Lipids
and Clinical Events in Recent Statin Trials
Nonfatal MI/CHD death
8
10
All-cause mortality
5
5
CHD death
5
LDL-C
TC
0
HDL-C
-5
-10
-9

-15
-20
-20
-20
-20
-22
-25
-24
-25
-26
-30
-28
-30
-31
-35
-33
-34
-35
-40
-42
-45
WOSCOPS (N6,595)
4S (N4,444)
CARE (N4,159)
1o prevention
2o prevention
2o prevention
Nnumber enrolled.
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4S Findings From a Post Hoc Analysis
reduction in coronary events after 1 year
reduction in LDL-C at 1 year
The thinner curves define the 95 CI. Pedersen
TR. Circulation. 1998971453-1460.
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(2.6 mmol/l)
(3.4 mmol/l)
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Pharmacologic Therapy StatinsDose Response
Response to Minimum/Maximum Statin Dose
Lovastatin 20/80 mg
Fluvastatin 20/80 mg
Simvastatin 20/80 mg
Pravastatin 20/80 mg
Atorvastatin10/80 mg
Reduction in LDL-C
31
37
40
47
55
Adapted from Illingworth. Med Clin North Am.
20008423.Pravachol (pravastatin) PI.
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Effects of Statins on Stroke Events A
Meta-analysisof Primary- and Secondary-Prevention
Trials
1 Prevention (-42 to -27)
2 Prevention (13-45)
Combined (11-40)
Relative reductionin rates ()
P0.001.95 confidence interval of percentage
of relative reduction.
Crouse JR et al. Arch Intern Med.
19971571305-1310.
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Statin
VLDL
Niacin
X Chol
Ezetimibe
Bile Sequestrant
Witztum and Steinberg, 2000
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Overview of Cholesterol Transport
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Ezetimibe Reduction of Cholesterol Content in
Atherogenic Lipoproteins
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Selective Cholesterol Absorption Inhibitors
(CAIs) Ezetimibe

• Mechanism of action and selectivity
• Blocks cholesterol absorption at the
  intestinalbrush border
• No effect on absorption of lipid-soluble vitamins

• Pharmacology
• Intestinal wall localization
• Enterohepatic circulation
• Minimal systemic exposure
• Clinical experience and role in management
• Monotherapy
• Combination

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Phase III Combination Therapy Ezetimibe Plus
Simvastatinvs Simvastatin Titration
HDL-C
TG
LDL-C
Reduction from baseline at wk 12
PlaceboSimvastatin 80 mgEzetimibe 10 mg
simvastatin 10 mg
Davidson et al. J Am Coll Cardiol. 200239(suppl
A)Abstract 1084-90.
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69 y/o with Familial Hypercholesterolemia and CAD
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53 y/o female FH with CAD in 40s
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Statin
VLDL
Niacin
Bile Sequestrant
Witztum and Steinberg, 2000
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-
Niacin
Statin
Bile Acid Binding Resin
Intestinal Cholesterol Absorption Inhibitor
Witztum and Steinberg 2004