Approach to Management of Hypercholesterolemia:

1
Approach to Management of Hypercholesterolemia F
rom Diet to Apheresis
Timothy A. Denton, M.D. Divisions of Cardiology
and Cardiothoracic Surgery Medical Director, LDL
Apheresis Program Cedars-Sinai Medical Center Los
Angeles, CA
2
Who are we talking about?

• Known vascular disease CAD Carotid PVD Aortic
  Aneurysm
• Vascular equivalents DM
• High risk 10 year risk gt 20

NCEP III -- JAMA 20002852486
3
LDL Cholesterol Goals and Cutpoints for
Therapeutic Lifestyle Changes (TLC)and Drug
Therapy in Different Risk Categories
4
Atherosclerosis
5
Egg McMuffin
http//www.mcdonalds.com/countries/usa/
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Egg McMuffin
Calories 290 Calories from fat 110 Total fat 12
g Saturated fat 4.5 g Cholesterol 235
mg Sodium 790 mg Carbohydrates 27g Protein 17g
http//www.mcdonalds.com/countries/usa/
7
Lipids
C 8 - 24
Fatty Acids
HO
O
O
O
Triglycerides
O
O
O
O
O
G
O
P
O
Phospholipids
O
O
O
O
8
Fatty Acids

• Number of carbons are multiples of 2 (from
  Acetyl-CoA)
• Length of FA Short chain 2-6 carbons Medium
  chain 8-14 carbons Long chain 16
• Saturated FA contain no double bonds
• Monounsaturated FA contain 1 double bond
• Polyunsaturated FA (PUFA) contain 2 or more
  double bonds
• Many, many other types of FA

9
Fatty Acids
H
H
H
H
cis
C
C
C
C
C
C
H
H
H
H
H
H
H
H
H
H
H
trans
C
C
C
C
C
C
H
H
H
H
H
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PUFA (polyunsaturated fatty acid) Nomenclature
1 2 3 4 5 6 7 8 9 10
11 12 13 14 15 16 17 18
O
? ? ?
?
HO

? ? ?
18 17 16 15 14 13 12 11 10 9 8
7 6 5 4 3 2 1
Common name - ?-Linoleic
acid Systematic name - all
cis-9,12-octadecadienoic acid Systematic name
- cis-9, cis-12-octadecadienoic
acid Chemists name - 182 (9Z, 12Z)
(Zcis, Etrans) Chemists name -
182 ?9,12 (assume cis, indicate
trans) Nutritionists name 1 - 182
(n-6) Nutritionists name 2 - 182 ?-6
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Essential Fatty Acids

• Linoleic acid (182, n-6)
• ?-Linolenic acid (183, n-3)
• Arachidonic
• Eicosapentaenoic
• Docosahexaenoic acids

Linoleic acid
Arachidonic ?-Linolenic acid
Eicosapentaenoic
Docosahexaenoic acids
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REALLY, REALLY Essential Fatty Acids
Corn oil Cotton seed oil Linseed oil
(flax) Rapeseed (canola) oil Soya oil Walnut oil,
walnuts Peanuts Beef Spinach Fish
oils eicosa docosa Sardines, Salmon, Mackerel,
Cod, Halibut, Herring, Trout, Tuna, Haddock
Linoleic acid (182, n-6)
O
HO
?-Linolenic acid (183, n-3)
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Fatty Acid
Cholesterol
O
OH
C
HO
Cholesterol Ester
O
O
C
H O H
14
LDL
3,000,000 daltons 22 nm 800 phospholipid
molecules 500 free cholesterol molecules 1 B-100
protein 1,500 ester molecules

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Methods for Modifying Cholesterol Levels
1 - Diet 2 - Exercise 3 - Drugs 4 - Partial ileal
bypass 5 - Portacaval shunting 6 -
Apheresis adsorption column (LDL
apheresis) plasma exchange double
membrane dextran sulfate precipitation immunoabs
orption 7 - Liver transplantation
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Lipid Metabolism
Chylomicron
VLDL
Gut
What you eat
IDL
LIPOPROTEIN LIPASE
What you make
Fatty acids
Chylomicron remnant
Bile
LDL
300 mg/day
1,000 mg/day
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Diet
18
Lifestyle Heart Trial
Ornish D, et al. Lancet 1990336129
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Lifestyle Heart Trial
Ornish D, et al. Lancet 1990336129
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Lifestyle Heart Trial
Intervention group LDL after 1 year
Mean 93 mg/dl 43 mg/dl
NCEP Goal
55.3
44.7
Ornish D, et al. Lancet 1990336129
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Biosphere
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Biosphere2 Dietary Restriction

• Biosphere 2
• Isolated, confined environment, 2 years
• 8 subjects
• Green and yellow vegetables
• Animal products of 1 egg, 112 g of meat, 500 cc
  of goat milk per WEEK
• All had consistent weight loss for 2 years
• Blood samples q 1-2 months

Verdery, et al. Arch Intern Med 1998158900
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Biosphere2 Dietary Restriction
Verdery, et al. Arch Intern Med 1998158900
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Biosphere2 Dietary Restriction
LDL after 2 years
Mean 58 7 mg/dl
NCEP Goal
100
0
Verdery, et al. Arch Intern Med 1998158900
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Dietary Success
26
Mediterranian Diet
J. THOMSON "Chart of the Mediterranean Sea"
Edin.18I7
27
Lyon Heart Trial

• lt35 energy as fat
• lt10 energy saturated fat
• lt4 energy as linoleic acid
• gt0.6 of energy as alpha-linolenic
  (183 or n-3)
• Eat more bread
• Eat more fish, less meat
• Eat more vegetables
• Must have fruit every day
• All butter and margarine replaced
  with olive oil and canola oil

• First MI
• Randomized
• Mediterranian vs Prudent
• 5 year trial stopped early

De Lorgeril et al Circulation 199999779
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Lyon Heart Trial
Survival with No MI
Survival with No MI Angina CHF CVA PE Periph
embol Stable angina PTCA, CABG Restenosis
Survival with No MI Angina CHF CVA PE Periph
embol
De Lorgeril et al Circulation 199999779
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Lyon Heart Trial
Differences in LDL-C
De Lorgeril et al Circulation 199999779
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A Diet, is not a Diet, is not a Diet

• Diabetes
• Renal
• Weight loss
• Low fat
• Low sodium
• Survival
• etc

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Digestion
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Pancreatic Lipase
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Orlistat

• Inhibits pancreatic lipase
• Primary use in weight loss
• Reduces fat by 30

Lindgarde et al. J Intern Med 2000 248 245-254
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Bile Acid/Cholesterol Binders
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Bile Acid/Cholesterol Binders
Binder
95
5
Small Intestine
36
Bile Acid/Cholesterol Binders
Resins contraindicated with high TGs
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Competetive Inhibitors
Cholesterol
Small Intestine
Plant stanols Plant sterols
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Plant Stanols and Sterols
Lower LDL from 10-14
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Transport Blockade
pump
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Ezetimibe

• New class of drugs
• Competitive? Inhibitor of the cholesterol pump
• Entero-hepatic circulation

Kosoglou et al. Atherosclerosis 2000151135
(abstr)
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Partial Ileal Bypass
42
POSCH -- Program On Surgical Control of
Hyperlipidemias
Arch Int Med 19981581253
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Lipid Metabolism
Chylomicron
VLDL
Gut
What you eat
IDL
LIPOPROTEIN LIPASE
What you make
Fatty acids
Chylomicron remnant
LDL
44
Cholesterol Metabolism Modifying Agents

• Statins
• Fibrates
• Niacin

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Achievement of NCEP Goal
atorva atorvastatin (Lipitor) simva
simvastatin (Zocor) lova lovastatin
(Mevacor) fluva fluvastatin (Lescol) colest
colestipol (Colestid)
Brown, JACC 1998 32665
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Achievement of NCEP Goal
Brown, JACC 1998 32665
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Effect of Fibrates on Lipid Levels

• Increased Lipoprotein lipase activity
• Increased liver uptake of FA, decreased TG
  production
• Increased LDL affinity for receptor
• Lower exchange between LDL and VLDL
• Increased HDL production

VA-HIT NEJM 1999341410
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Effect of Fibrates on Lipid Levels
VA-HIT NEJM 1999341410
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Niacin
Nicotinic acid Niacin (Vit B3)
Nicotinamide (no antilipemic activity)
O
O
HO
NH2
N
N
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Apo B Pathway
Apo B-100
HDL
Nascent VLDL
Cholesterol esters
Apo C-II, C-III
Apo E
Mature VLDL
Apo E

Apo C-II
Niacin
Niacin
Liver
LIPOPROTEIN LIPASE

Apo E
Apo C-III
Apo C-II,C-III
LDL
Phospholipids
VLDL Remnant
Fatty acids
HDL
51
Niacin Forms
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Combination Therapy

• 31 patients with heterozygous FH
• Triple therapy crossover trial
• Lovastatin cholestipol (niacin form)
• Regular niacin vs controlled release
• 83 SUCCESS RATE FOR LDL lt 100 MG

Brown et al. Am J Cardiol 199780111
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Other Therapies
54
Exercise

• 6,213 men
• ETT for clinical reasons
• 2,534 normal
• 3,679 with CAD
• Mean f/u 6.2 years
• Age 59 11
• Peak capacity stronger predictor than cigs,
  HTN, DM, Chol

Myers, NEJM 2002346793
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Effect of Exercise on Lipids

• 2906 men
• age 30-64 years
• exercise treadmill test to exhaustion
• classified into 6 groups based on average miles
  run per week

Kokkinos Arch Int Med 1995155415
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Effect of Exercise on Lipids
Kokkinos Arch Int Med 1995155415
57
Estrogen
58
Estrogen

• HERS trial
• Post-menopausal
• 2,763 entrants
• conjugated estrogens progestin

But for secondary prevention, hormones not an
issue.
HERS trial JAMA1998280605
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Garlic

• Antilipidemic
• Antihypertensive
• Antithrombotic
• Antiatherogenic
• Dehydrated and liquid forms
• S-allyl cysteine-S-oxide alliin (allicin
  after hydration)
• 1/2 - 1 clove bid-tid
• Powder 600-900 mg/day

Ackerman et al Arch Int Med 2001161813
60
Ackerman et al Arch Int Med 2001161813
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Fish Oil

• n-3 PUFAs
• Epidemiologic data on survival
• GISSI-Prevenzione
• Effects on Triglycerides

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Fish Oil vs Gemfibrozil
Gemfibrozil 1,200 mg/d Fish oil 4g/day
Stalenhoef et al Atherosclerosis 2000153129
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n-3 PUFAs and SCD
Albert et al NEJM 20023461113
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GISSI-Prevenzione
GISSI group, Lancet 1999354447
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Trans-Fatty Acids
Lichtenstein NEJM 19993401933
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Trans-Fatty Acids
Lichtenstein NEJM 19993401933
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Calcium Supplements in Postmenopausal Women
P0.009
Ca

• RCT
• 223 postmenopausal women
• 800 mg Ca citrate vs Placebo
• 1 year f/u

Placebo
P0.04
Placebo
Ca
P0.0009
Ca
Placebo
Reid et al AJM 2002112343
68
LDL Apheresis
69
Diet
Drugs
?
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Apheresis

• Apheresis Pheresis Hemapheresis
• Apheresis -- (Latin, Greek -- aphairesis) to
  take out, take away, snatch, detach, separation,
  or abstract.

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LDL Apheresis
Re-Priming Solution
Regeneration Solution
Heparin Pump
Regeneration Pump

Blood Pump
Blood Withdrawal
Plasma Separator
s
Blood Return
Waste Line
72
Filter being washed (white)
Filter being used (yellow)
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LDL
TG
HDL
74
Xanthomas -- Homozygous FH
Pre-LDL apheresis
Post-LDL apheresis x10 years
75
Kaplan-Meier Curves Showing the Proportionof
Patients Without Any Coronary Events
Mabuchi, et al., American Journal of Cardiology
1998821489-95
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When to Start Rx
77

• MIRACL

P0.048
Schwartz JAMA 20012851711
78

• CHAMP

Fonarow, AJC 200187819
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Get With the Guidelines!
www.americanheart.org
80
The Guidelines
81
How often do we provide these therapies?
82
Effects of Various Cardiac Therapies
83
Effects of Various Cardiac Therapies
84
Effects of Various Cardiac Therapies
85
End
86
Diet
87
Digestion
88
Modifying LDL Metabolism