Advances In The
Treatment of
Hallie Lee
PharmD Candidate 2013
Mercer University COPHS
December 2012
 Background: Lipoproteins & lipid metabolism
 Etiologies of lipid disorders
 NCEP ATP III Guidelines
 NCEP ATP III 2004 update
 Treatment Options
 New Potential Goal Modifiers
Plasma Lipids
 Lipids are transported in the plasma as lipoproteins
 The major lipid classes present in lipoproteins
 Triacylglycerols (16%)
 Phospholipids (30%)
 Cholesterol (14%)
 Cholesterol esters (36%)
 Free fatty acids (4%)
 A core of nonpolar cholesteryl esters and triglycerides covered by
a polar surface monolayer made up of phospholipids, free
cholesterol, and apolipoproteins
Lipoprotein components
 Cholesterol-structural component of all cell membranes and a
precursor for steroid biosynthesis and bile acids
Present in tissues and in plasma either as free cholesterol or
combined with a long-chain fatty acid as cholesteryl ester, the
storage form
A little more than half comes from the body itself synthesized from
acetyl-CoA, the rest comes from the diet
 Triglyceride-fatty acids used for energy by the liver and peripheral
tissues i.e. muscle
 Phospholipid-component of cell membranes
Lipids are water insoluble and require lipoprotein transporters to
reach body tissues from the bloodstream
Lipoprotein Classes
Chylomicrons 0.95
20-40% total
VLDL-very low density lipoprotein
IDL-intermediate density lipoprotein
LDL-low density lipoprotein
HDL-high density lipoprotein
Apolipoproteins make up the rest
 Apolipoproteins carry out several roles:
1. They form part of the structure of the lipoprotein
2. They are enzymes, cofactors, or inhibitors
3. They act as ligands for interaction with lipoprotein
receptors in tissues
 “Nametags” attached as identifiers
Site of Synthesis
Apo A-1
HDL, chylomicrons
Structural protein on
HDL, activator of
Liver, intestine
Apo A-II
HDL, chylomicrons
Structural protein on
Apo A-IV
HDL, chylomicrons,
Unknown, possibly
facilitates transfer of
Apo B-48
Synthesis/secretion of
chylomicrons form the
Apo B-100
Synthesis/secretion of
VLDL from liver,
ligand for binding to
LDL receptor
Apo C-I
HDL, chylomicrons,
Activator of Lecithin
Apo C-II
HDL, chylomicrons,
Activator of
Lipoprotein lipase
HDL, chylomicrons,
May inhibit hepatic
uptake of chylomicron
and VLDL
Apo E
HDL, chylomicrons,
Binds to LDL receptor
on membrane of liver
and macrophage cells
Lipid Metabolism
Reverse Transport
Lipid Metabolism
Exogenous pathway = transport of dietary lipids
Lipids from diet absorbed into intestinal villa as fatty acids and cholesterol
Re-esterification of fatty acids  TG & cholesterol  cholesteryl ester occurs in
mucosal cells
TG and cholsteryl ester combined with Apo B-48 and Apo A-I within intestinal wall
to form immature chylomicron particles
Chylomircons enter the systemic circulation via the lymphatic system
Apo C-II and Apo E transferred to chylomicrons from HDL particles in the
Apo C-II enhances interactions of chylomicron and lipoprotein lipase on the
capillary endothelial cell surfaces in tissues, TG hydrolyzed into free fatty acids for
storage or energy use by muscle
Remnants are cleared by receptors on surface of liver cells that recognize Apo E
Exogenous Pathway
Lipid Metabolism
 Endogenous pathway = transport of lipids produced by the body
VLDL assembled and secreted by hepatocytes: TG and cholesterol
are packaged with Apo B-100 and phospholipids, Apo C-II and Apo
E added after VLDL enters the plasma
TG core hydrolyzed by lipoprotein lipase in capillary beds releasing
fatty acids into tissues
Remaining VLDL is now IDL, most surface apos (minus Apo B100) are transferred to HDL, mediated by cholesteryl ester transfer
protein (CETP)
IDL removed from liver by Apo E binding to LDL receptor,
remaining IDL is converted to LDL via hepatic lipase
Endogenous Pathway
Lipid Metabolism
 Reverse cholesterol transport
Apo A-I is produced in the liver and intestine, acts as the building block for
nascent(immature) HDL
Nascent HDL particles act as initial acceptors of free cholesterol from peripheral
cells through the receptor ATP binding cassette AI
Lecithin cholesterol acetyl transferase (LCAT) converts free cholesterol to
cholesteryl ester to form the core of HDL3, LCAT is activated by Apo A-I
Enrichment of HDL3 with cholesteryl ester results in formation of HDL2
Cholesteryl ester may be transferred from HDL to VLDL, IDL, or LDL (Apo B
lipoproteins) in exchange for triglyceride molecules by cholesterol ester transfer
protein (CEPT)
Cholesteryl ester may be delivered directly to the liver by HDL itself
Reverse Cholesterol
Primary hyperlipoproteinemia: lipoprotein abnormalities direct result of
specific defects in synthesis/degradation of particles
1. Familial hypercholesterolemia
Defective gene for LDL receptor
Characterized by sever elevations of LDL, tendon xanthomas, and premature
2. Polygenic hypercholesterolemia
variety of genetic defects resulting in less active LDL receptor
Possibly the underlying disorder in as many as 80% of people with
Elevated LDL and premature atherosclerosis
3. Familial combined hyperlipidemia
Associated with overproduction of VLDL due to increased production of Apo B-100
Elevated LDL and/or TG and premature atherosclerosis
Secondary hyperlipoproteinemia: elevated lipoprotein levels occur as
part of an underlying disorder or drug therapy
Hypothyroidism, liver disease, nephrotic syndrome
Meds: progestins, thiazides, glucocorticoids, BB, cyclosporine, mirtazepine
Obesity, DM, Pregnancy, acute hepatitis
Meds: alcohol, estrogens, isotretinoin, BB, glucocorticoids, azole
Malnutrition, obesity
Meds: anabolic steroids, isotretinoin, progestins
Disease Terminology
 Hyperlipoproteinemia - high lipoproteins
 Hypercholesterolemia -high TC or LDL
 Hyperlipidemia -high TC, TG, or LDL
 Hypertriglyceridemia -high TG
 Dyslipidemia -high TC, TG, LDL or low HDL
TC-total cholesterol TG-triglycerides
National Cholesterol
Education Program
Adult Treatment Panel III
Current Treatment
All adults ≥ 20 years old should have a fasting lipid panel performed
every 5 years
A complete lipoprotein profile is preferred
Fasting TC, LDL, HDL, and TG
Secondary option
Non-fasting TC and HDL
Proceed to lipoprotein profile if TC ≥ 200 or HDL < 40
LDL is the primary target
If TG are > 500mg/dL, TG should be targeted first
Once LDL goal is achieved, attention should be focused on the other
parameters (non HDL cholesterol)
Non HDL-C = Total cholesterol - HDL cholesterol
3 Categories of Risk that
Modify LDL Goals*
Risk Category
LDL Goal (mg/dL)
CHD and CHD risk equivalents
Multiple (2+) risk factors
Zero to one risk factor
*Per the 2001 NCEP ATP III Guidelines
Risk Factors
 Positive Risk Factors
 Age : M ≥ 45 F ≥ 55
 Family history :
premature CHD in
1st degree relative
M <55 F <65
 Current smoker
 HTN >140/90 or
on medication
 Low HDL <40
 Negative Risk Factors
 High HDL ≥ 60
Risk Assessment
 All patients without CHD or CHD risk equivalents:
 Count the number of risk factors
 If multiple risk factors ≥ 2 use Framingham scoring to
determine 10 year CHD risk
 For patient with 0-1 risk factors
 10 year risk assessment not required
Managing lipids for risk reduction: Focus on the new National Cholesterol Education Program guidelines. Vascular Biology Working Group. University of Flordia 2001. Available at
http://www.vbwg.org/quickorder/resource_slides.cfm?itemID=6&TypeID=4&StartRow=6#mark. Accessed December 9, 2012.
Managing lipids for risk reduction: Focus on the new National Cholesterol Education Program guidelines. Vascular Biology Working Group. University of Flordia 2001. Available at
http://www.vbwg.org/quickorder/resource_slides.cfm?itemID=6&TypeID=4&StartRow=6#mark. Accessed December 9, 2012.
CHD and CHD Risk
 Established CHD
 MI
 Risk Equivalents
 Myocardial ischemia
 Stroke
 Coronary
 Carotid stenosis
 Prior unstable angina
 Abdominal aortic
 Diabetes
LDL goal is < 100mg/dL for these patients per the 2001 Guidelines
 Total Cholesterol
 Optimal < 100
 Desirable < 200
 Near Optimal
 Borderline 200239
 Borderline 130159
 High ≥ 240
 High 160-189
 Very high ≥ 190
 Triglycerides
 Normal < 150
 Low < 40
 Borderline 150199
 High > 60
 High 200-499
 Very high >500
Calculating LDL
 LDL = TC – HDL – ( TG/5 )
 LDL equals total cholesterol minus HDL minus
triglycerides divided by five
 TG must be <400 to use
 VLDL = TG/5
TC=225 HDL=32 TG=170
LDL = 225-32-(170/5) = 159
LDL-Lowering Therapies In Patients
With CHD and CHD Risk Equivalents
 Baseline LDL cholesterol ≥ 130 mg/dL
 Intensive lifestyle therapies
 Maximal control of other risk factors
 Consider starting LDL-lowering drugs simultaneously
with lifestyle therapies
 Baseline (or on treatment) LDL 100-129mg/dL
 LDL lowering therapy; lifestyle therapy or drugs
 Treatment of metabolic syndrome
 Weight reduction and increased physical activity
 Drug therapy for other lipid risk factors
LDL-Lowering Therapies In Patients
With CHD and CHD Risk Equivalents
 Baseline LDL < 100mg/dL
 Further LDL lowering not required
 Therapeutic Lifestyle Changes (TLC) recommended
 Consider treatment of other lipid risk factors
 Ongoing clinical trials are assessing benefit of further
LDL lowering
LDL-lowering Therapy in Patients With
Multiple Risk Factors
and 10 Year Risk ≤ 20%
 10 Year Risk 10-20%
LDL-lowering goal <130mg/dL
Aim to reduce short and long term risk
Immediate initiation of TLC if LDL goes >130
Consider drug therapy if LDL > 130 after 3 months of lifestyle
 10 Year Risk < 10%
LDL goal <130mg/dL
Aim to reduce long term risk
Initiate therapeutic lifestyle changes if LDL > 130
Consider drug therapy if LDL > 160 after 3 months of lifestyle
LDL-Lowering in Patients with
0-1 Risk Factor
 Aim to reduce long term risk
 LDL goal <160
 Initiate therapeutic lifestyle changes is LDL > 160
 If LDL is ≥ 190 after 3 months of lifestyle therapies
consider drug therapy
 If LDL is ≥ 160-189 after 3 months of lifestyle therapies
drug therapy is optional
Summary Treatment Categories
Risk Category
CHD or
CHD risk equivalent
2 Risk Factors
10-yr risk 10–20%
10-yr risk <10%
<2 Risk Factors
LDL-C Goal
Consider Drug
<100 mg/dL
130 mg/dL*
<130 mg/dL
<130 mg/dL
130 mg/dL
160 mg/dL
<160 mg/dL
190 mg/dL
* 100–129 mg/dL = after TLC, consider statin, niacin, or fibrate therapy
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA
NCEP ATP III 2004 Update
 For high risk patients: LDL-Lowering Therapies In Patients
With CHD and CHD Risk Equivalents LDL goal < 70 in
patients with established CHD plus:
 Multiple risk factors, esp. diabetes
 Severe or poorly controlled risk factors
 Metabolic syndrome
 Acute coronary syndromes
 Consideration of drug treatment in addition to lifestyle
therapy for LDL levels ≥100 mg/dL in high-risk patients, and
characterizes drug treatment as optional for LDL<100 mg/dL
NCEP ATP III 2004 Update
 For moderately high-risk patients--Individuals who have
multiple (2+) CHD risk factors together with a 10-20% risk for a
heart attack within 10 years:
 The overall goal for moderately high-risk patients is still an LDL
< 130 mg/dL
 There is a therapeutic option to set the treatment goal at LDL <100
mg/dL and to use drug treatment if LDL is 100-129 mg/dL
 For high-risk and moderately high-risk patients:
 Advises that the intensity of LDL-lowering drug treatment in highrisk and moderately high-risk patients be sufficient to achieve at
least a 30 percent reduction in LDL levels
Goals for Therapy:
The 2004 Addendum
NCEP ATP III guidelines for LDL Therapy
LDL-C <160 for 1 or less risk factors
LDL-C <130 for 2+ risk factors
< 100 is a therapeutic option
LDL-C <100 for CAD and CAD equivalents
<70 is option for very high risk patients
CAD + multiple risk factors, especially diabetes
CAD + severe or poorly controlled risk factor(s)
CAD + metabolic syndrome
Acute coronary syndrome
CAD event despite baseline LDL-C < 100
LDL Therapy
 Lifestyle Changes
 Statins
 Bile Acid Sequestrants
 Ezetimibe
 Niacin
 Plant Stanols, Sterols, Phytosterols
Therapeutic Lifestyle Changes (TLC)
 TLC Diet
 Reduced intake of cholesterol-raising nutrients
 Saturated fats <7% of total calories
 Dietary cholesterol <200mg per day
 LDL-lowering therapeutic options
 Plant stanols/sterols
 Soluble fiber 10-25gram per day
 Weight reduction
 Increased physical activity
 Smoking cessation
ATP III Guidelines Slide Show. National Heart Lung, and Blood Institute.. Available at http://hp2010.nhlbihin.net/ncep_slds/atpiii/slide31.htm. Accessed December 9, 2012.
ATP III Guidelines At a Glance Quick Desk Reference. National Cholesterol Education Program. National Institutes of Health. Available at
http://www.nhlbi.nih.gov/guidelines/cholesterol/atglance.pdf. Accessed on December 9, 2012.
When will it be available?
Draft Completed: Expert panelists have completed a full draft of the
systematic review and recommendations.
Federal Review Completed: Federal agency representatives of the NHLBI's
National Program to Reduce Cardiovascular Risk (NPRCR) coordinating
committee provide review and comment.
Expert Review Completed: External peer reviewers with expertise in the
relevant risk factors provide review and comment.
Advisory Council In Progress: The National Heart, Lung, and Blood
Advisory Council provides review and comment and recommends approval.
Public Comment: The draft will eventually be offered publicly for review
and comment.
HHS Clearance: The U.S. Department of Health and Human Services
provides editorial review, comment, and approval once it is made available.
Issues for ATP-IV
Should the goals for LDL in primary prevention be
Where does CRP fit in– routine use in risk
stratification, secondary target?
What about Apo-B?
What about secondary targets?
Non-HDL-C, HDL-C, LDL Particle concentration?
Move from a 10-year to lifetime risk?
Potential Goal Modifiers
 Lp(a)/Apo A
 Apo AI
 High sensitivity CRP
 Metabolic Syndrome
 Apo B
 LDL-P vs. LDL-C
 Apo E and lipoprotein Genetics
 LDL-C: amount of cholesterol in LDL particles
 LDL-P: number of LDL particles
 Non-HDL: amount of cholesterol in atherogenic
 Apo-B: number of atherogenic particles
Lp(a) / Apo a
Physiological function is still unknown
High level in the blood is a risk factor
for CHD, CVD, atherosclerosis,
thrombosis, and stroke
Most LDL-lowering drugs do not effect
the blood levels
Borderline risk:
Apo(a) contains domains that are very
similar to plasminogen (PLG)
Lp(a) accumulates in the vessel wall
and inhibits binding of PLG to the cell
surface, reducing plasmin generation
which increases clotting
Suggests it can cause the generation of
clots and atherosclerosis
Lp(a) Levels:
< 14 mg/dL (< 35 nmol/l)
14 - 30 mg/dL (35 - 75 nmol/l)
High risk:
31 - 50 mg/dL (75 - 125 nmol/l)
Very high risk:
> 50 mg/dL (> 125 nmol/l)
Apo AI
 The American Association of Clinical Endocrinologists
(AACE) Guidelines for Management of Dyslipidemia
and Prevention of Atherosclerosis States:
 The assessment of Apo AI may be useful in certain cases
 A normal Apo AI level in a patient with low HDL-C
suggests the existence of an adequate number of HDL-C
particles that contain less cholesterol and may be an
indication of less risk
 The INTERHEART study found that the Apo B to Apo
AI ratio was among the most significant risk factors for
C-Reactive Protein
Produced by the liver
Level rises when there is
inflammation throughout the
High-sensitivity C-reactive protein
(hs-CRP) assay tests are available
Determine a person's risk for
heart disease
Many consider a high CRP
level to be a risk factor for
heart disease
It is not known whether it is
merely a sign of cardiovascular
disease or if it actually plays a role
in causing heart problems
According to the American Heart
You are at low risk of developing
You are at average risk of developing
cardiovascular disease if your levels
are between 1.0 - 3.0 mg/L
You are at high risk for cardiovascular
disease if your hs-CRP level is > 3.0
cardiovascular disease if your hs-CRP
level is < 1.0mg/L
AACE recommends CRP testing to stratify
CVD risk in patients with a standard risk
assessment that is borderline, or in those
with an LDL-C con- centration < 130
A blood enzyme that hydrolyzes oxidized phospholipids, causing atherogenic vascular
Accumulation of macrophages and lymphocytes in atherosclerotic inflammation is
accompanied by increased expression of Lp-PLA2 in plaques
According to the AACE:
There are studies that have demonstrated Lp-PLA2 showing more specificity than
highly sensitive CRP, when it is necessary to further stratify a patient’s CVD risk,
especially in the presence of systemic highly sensitive CRP elevations
Lp-PLA2 :
<200ng/mL is normal
≥ 200 and <233 ng/mL is intermediate
≥ 223 ng/mL is high
Synergistic with CRP
However, CRP is marker of general inflammation and Lp-PLA2 appears to
specifically indicate vascular inflammation and not be influenced by obesity
Apo B
 Smaller denser LDL particle
 A MEDLINE search of the literature published from January 1,
1975, - December 1, 2010 : “Opening a New Lipid ‘Apo-thecary’:
Incorporating Apolipoproteins as Potential Risk Factors and
Treatment Targets to Reduce Cardiovascular Risk” (Jacobson, T.)
“On the basis of data from most population studies, elevated
Apo B was more strongly associated with incident coronary
heart disease than similarly elevated LDL cholesterol”
 “Apo B was also a superior benchmark (vs LDL cholesterol) of
statins' cardioprotective efficacy”
Apo B continued
 Potentially has a greater propensity to cause oxidative
arterial wall damage
 If a patient has increased levels of Apo B the total number
of LDL particles may be higher than the LDL cholesterol
 A 1:1 relationship between LDL particles and the total
number of atherogenic particles
 The controversy remains
Apo-B Goals
A look at the Clinical Trials
Major Statin Trials
Fredrickson, S. LDL-C, Apo-B, LDL-P, and The Winner Is Slideshow. March 2012. Available at
http://www.acponline.org/about_acp/chapters/va/12mtg/fredrickson.pdf. Accessed December 10, 2012.
Apo B Goals
 AACE recommends:
 For patients at risk of CAD (including those with diabetes)
goal of < 90 mg/dL
 For patients with established CAD or diabetes who have 1 or more
additional risk factor(s) should goal of < 80 mg/dL
 When the triglyceride level is >150 mg/dL or the HDL-C level is <
40 mg/dL, the Apo B or the Apo B/Apo AI ratio may be particularly
useful in assessing residual risk in patients at risk for CAD
 Apo B measurements to assess the success of LDL-C–lowering
Apo B reflects the LDL particle number, which may be elevated in
patients at or below LDL-C goal and a more potent predictor of CV
disease risk
LDL-C is calculated using Friedewalde equation
Inaccurate when:
TG high
Glucose high
LDL-C very low
LDL-C can underestimate LDL particle number (LDL-P), particularly
in patients with insulin resistance
CVD risk is more closely associated with number of LDL particles
rather than amount of cholesterol carried by LDL particles
LDL-C underestimates LDL particle number when cholesterol depleted
LDL is present
The AACE states LDL particle number is a more potent measure of
CVD risk than LDL-C or LDL particle size
Cardiovascular Risk is more strongly
associated with LDL-P than LDL-C
Source: Journal of Clinical Lipidology 2011; 5:338-367 (DOI:10.1016/j.jacl.2011.07.005 )
Metabolic Syndrome
A name for a group of risk factors that occur together and increase the risk for
CAD, Stroke, and Type II Diabetes
The two most important risk factors:
Central Obesity-Extra weight around the middle and upper parts of the body
Insulin resistance-the the body uses insulin less effectively than normal
Diagnosis: three or more of the following signs:
Blood pressure ≥ 130/85 mmHg
Fasting blood sugar (glucose) ≥ 100 mg/dL
Large waist circumference : Men – ≥ 40 inches Women - ≥ 35 inches
Low HDL cholesterol: Men - < 40 mg/dL Women - < 50 mg/dL
Triglycerides equal to or higher than 150 mg/dL
American Association of Clinical Chemistry
Contois JH, et al. Clinical Chemistry 2009; 55:407-419
Recommendations from AACC Lipoproteins
and Vascular Diseases Division
Working Group on Best Practices
“LDL-C, non-HDL-C, LDL-P, and total apoB are all, to varying
degrees, measures of LDL related risk.”
“These cholesterol and particle measures are highly intercorrelated,
which explains why they have all been implicated as predictors of
CVD risk in epidemiologic studies, but biologically they reflect
different entities.”
“Despite a high correlation, these markers are only modestly
concordant, indicating that one cannot simply substitute for another
in classifying patients into risk categories.”
“We believe that the medical decision cutpoints should be set so that
the apoB and LDL-P cutpoints are equivalent to those for LDL-C in
terms of population percentiles.”
Contois JH, et al. Clinical Chemistry 2009; 55:407-419
Recommendations from AACC Lipoproteins
and Vascular Diseases Division Working
Group on Best Practices
Suggested Treatment Goals
LDL-C, mg/Non-HDL-C,
ApoB, mg/dL
< 70
< 80
< 100
< 80
< 120
< 100
< 130
< 150
LDL-P, nmol/
< 1100
< 1400
Contois JH, et al. Clinical Chemistry 2009; 55:407-419
Recommendations from AACC Lipoproteins and Vascular
Diseases Division Working Group on Best Practices
Use of ApoB and LDL Particle Number in
Clinical Management
agree that a greater emphasis on non–HDL-C rather than LDL-C will
improve patient care. Data from several prospective studies show non–HDL-C to
be a better predictor of cardiovascular events than LDL-C.
terms of relative risk, non–HDL-C is consistently stronger than LDL-C and, in
many studies, equivalent to apoB or LDL-P.
apoB has been more extensively validated in epidemiological studies
and clinical trials than non–HDL-C, and non–HDL-C, like LDL-C, reflects the
cholesterol content of atherogenic particles and not the number of atherogenic
on-treatment non–HDL-C concentrations may not reflect residual
risk associated with increased LDL particle number
Contois JH, et al. Clinical Chemistry 2009; 55:407-419
Apo E and
Lipoprotein Genetics
 According to a meta-analysis
reviewing the associations of
apolipoprotein E genotype and
coronary disease:
A linear relationships of apo E
genotypes with both LDL-C
levels and coronary risk exists
Compared with individuals with
the ε3/ε3 genotype, ε2 carriers
have a 20% lower risk of
coronary heart disease and ε4
carriers have a slightly higher
What do the Advancements in the Treatment of
Hyperlipidemia mean for the future ?
How Should the Guidelines Change?
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Thornton. Nature Reviews Drug Discovery 7, 84-99.
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Accessed December 9, 2012.
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Metabolic Syndrome. PubMed Health. US National Library of Medicine. 2012. Available at
http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0004546/. Accessed December 9,2012.
Jacobson, T. Opening a New Lipid “Apo-thecary”: Incorporating Apohpoprotezns as Potential Risk Factors and
Treatment Targets to Reduce Cardiovascular Risk. Mayo Clinic Proceedings; Aug 2011. (86):762-780.
Fredrickson, S. LDL-C, Apo-B, LDL-P, and The Winner Is Slideshow. March 2012. Available at
http://www.acponline.org/about_acp/chapters/va/12mtg/fredrickson.pdf. Accessed December 10, 2012.
C-reactive Protein. Medline Plus. US National Library of Medicine. December 2012. Available at
http://www.nlm.nih.gov/medlineplus/ency/article/003356.htm. Accessed December 9,2012.
Bennet, A. et al. Association of Apolipoprotein E Genotypes With Lipid levels and Coronary Risk. JAMA.
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