Advances In The Treatment of Hyperlipidemia Hallie Lee PharmD Candidate 2013 Mercer University COPHS...
Transcript of Advances In The Treatment of Hyperlipidemia Hallie Lee PharmD Candidate 2013 Mercer University COPHS...
Advances In The Treatment of
HyperlipidemiaHallie Lee
PharmD Candidate 2013Mercer University COPHS
December 2012
Objectives
Background: Lipoproteins & lipid metabolism
Etiologies of lipid disorders
NCEP ATP III Guidelines
NCEP ATP III 2004 update
Treatment Options
NCEP ATP IV
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%)
Lipoproteins 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
Lipoprotein
Density(g/ml)
Triglyceride
Lipid cholesterol (free/ester)
Phospholipid
Chylomicrons
0.95 85-95% 1-3%/2-4% 3-6%
VLDL 0.96-1.006 50-60% 4-8%/16-22%
15-20%
IDL 1.006-1.019 20-50% 20-40% total
15-25%
LDL 1.019-1.063 4-8% 6-8%/45-50%
18-24%
HDL 1.063-1.210 2-7% 3-5%/15-20%
26-32%
VLDL-very low density lipoproteinIDL-intermediate density lipoprotein
LDL-low density lipoproteinHDL-high density lipoprotein
Apolipoproteins make up the rest
Apoplipoproteins
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
Apolipoprotein Lipoprotein Function Site of Synthesis
Apo A-1 HDL, chylomicrons Structural protein on HDL, activator of LCAT
Liver, intestine
Apo A-II HDL, chylomicrons Structural protein on HDL
Liver
Apo A-IV HDL, chylomicrons, VLDL
Unknown, possibly facilitates transfer of apos
Intestine
Apo B-48 Chylomicrons Synthesis/secretion of chylomicrons form the SI
Intestine
Apo B-100 LDL, VLDL Synthesis/secretion of VLDL from liver, ligand for binding to LDL receptor
Liver
Apo C-I HDL, chylomicrons, VLDL
Activator of Lecithin cholesterol acyltransferase
Liver
Apo C-II HDL, chylomicrons, VLDL
Activator of Lipoprotein lipase
Liver
Apo C-III HDL, chylomicrons, VLDL
May inhibit hepatic uptake of chylomicron and VLDL
Liver
Apo E HDL, chylomicrons, VLDL
Binds to LDL receptor on membrane of liver and macrophage cells
Liver
Lipid Metabolism
Exogenous pathway = transport of dietary lipids
1. Lipids from diet absorbed into intestinal villa as fatty acids and cholesterol
2. Re-esterification of fatty acids TG & cholesterol cholesteryl ester occurs in mucosal cells
3. TG and cholsteryl ester combined with Apo B-48 and Apo A-I within intestinal wall to form immature chylomicron particles
4. Chylomircons enter the systemic circulation via the lymphatic system
5. Apo C-II and Apo E transferred to chylomicrons from HDL particles in the bloodstream
6. 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
7. Remnants are cleared by receptors on surface of liver cells that recognize Apo E
Lipid Metabolism
Endogenous pathway = transport of lipids produced by the body
1. 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
2. TG core hydrolyzed by lipoprotein lipase in capillary beds releasing fatty acids into tissues
3. Remaining VLDL is now IDL, most surface apos (minus Apo B-100) are transferred to HDL, mediated by cholesteryl ester transfer protein (CETP)
4. IDL removed from liver by Apo E binding to LDL receptor, remaining IDL is converted to LDL via hepatic lipase
Lipid Metabolism
Reverse cholesterol transport
1. Apo A-I is produced in the liver and intestine, acts as the building block for nascent(immature) HDL
2. Nascent HDL particles act as initial acceptors of free cholesterol from peripheral cells through the receptor ATP binding cassette AI
3. Lecithin cholesterol acetyl transferase (LCAT) converts free cholesterol to cholesteryl ester to form the core of HDL3, LCAT is activated by Apo A-I
4. Enrichment of HDL3 with cholesteryl ester results in formation of HDL2
5. 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)
6. Cholesteryl ester may be delivered directly to the liver by HDL itself
Etiology
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 atherosclerosis
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 hypercholesterolemia
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
Etiology
Secondary hyperlipoproteinemia: elevated lipoprotein levels occur as part of an underlying disorder or drug therapy
1. Hypercholesterolemia
Hypothyroidism, liver disease, nephrotic syndrome
Meds: progestins, thiazides, glucocorticoids, BB, cyclosporine, mirtazepine
2. Hypertriglyceridemia
Obesity, DM, Pregnancy, acute hepatitis
Meds: alcohol, estrogens, isotretinoin, BB, glucocorticoids, azole antifungals
3. Low HDL
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
NCEP ATP III Focus
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
CHD and CHD risk equivalents
Multiple (2+) risk factors
Zero to one risk factor
*Per the 2001 NCEP ATP III Guidelines
LDL Goal (mg/dL)
<100
<130
<160
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 Equivalents
Established CHD
MI
Myocardial ischemia
Coronary angioplasty/stent placement
CABG
Prior unstable angina
Risk Equivalents
CAD
Stroke
TIA
Carotid stenosis >50%
PAD
Abdominal aortic aneurysm
Diabetes
LDL goal is < 100mg/dL for these patients per the 2001 Guidelines
Goals
LDL
Optimal < 100 Near Optimal
100-129 Borderline
130-159 High 160-189 Very high ≥
190
Total Cholesterol
Desirable < 200
Borderline 200-239
High ≥ 240
Goals
Triglycerides
Normal < 150 Borderline
150-199 High 200-499 Very high
>500
HDL
Low < 40 High > 60
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
Example:
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 therapies
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 therapies
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
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.
Summary Treatment Categories
Risk Category LDL-C GoalConsider Drug
Therapy
CHD or CHD risk equivalent <100 mg/dL 130 mg/dL*
2 Risk Factors 10-yr risk 10–20% 10-yr risk <10%
<130 mg/dL<130 mg/dL
130 mg/dL160 mg/dL
<2 Risk Factors <160 mg/dL 190 mg/dL
* 100–129 mg/dL = after TLC, consider statin, niacin, or fibrate therapy
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 high-risk 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
1. CAD + multiple risk factors, especially diabetes
2. CAD + severe or poorly controlled risk factor(s)
3. CAD + metabolic syndrome
4. Acute coronary syndrome
5. 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.
NCEP ATP IVWhen 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
1. Should the goals for LDL in primary prevention be lowered?
2. Where does CRP fit in– routine use in risk stratification, secondary target?
3. What about Apo-B?
4. What about secondary targets?
Non-HDL-C, HDL-C, LDL Particle concentration?
5. Move from a 10-year to lifetime risk?
Potential Goal Modifiers
Lp(a)/Apo A
Apo AI
High sensitivity CRP
Lp-PLA2
Metabolic Syndrome
Apo B
LDL-P vs. LDL-C
Apo E and lipoprotein Genetics
Definitions
LDL-C: amount of cholesterol in LDL particles
LDL-P: number of LDL particles
Non-HDL: amount of cholesterol in atherogenic particles
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
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:
Desirable:
< 14 mg/dL (< 35 nmol/l)
Borderline risk:
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 MI
C-Reactive Protein
Produced by the liver
Level rises when there is inflammation throughout the body
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 Association:
You are at low risk of developing cardiovascular disease if your hs-CRP level is < 1.0mg/L
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 mg/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 mg/dL
Lp-PLA2
A blood enzyme that hydrolyzes oxidized phospholipids, causing atherogenic vascular inflammation
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 level
A 1:1 relationship between LDL particles and the total number of atherogenic particles
The controversy remains
Apo-B GoalsA look at the Clinical Trials
Trial Apo-B
Major Statin Trials 67-98
PROVE-IT 67
JUPITER 71
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 therapy 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 vs LDL-P
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
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
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 risk
What do the Advancements in the Treatment of Hyperlipidemia mean for the
future ?
How Should the Guidelines Change?
Citations Wasan, K. et al. Impact of Lipoproteins on the biological activity and
disposition of hydrophobic drugs: implications for drug discovery. Nat Rev Drug Discov. 2008 Jan;(7):84-99.
Kishor M. Wasan, Dion R. Brocks, Stephen D. Lee, Kristina Sachs-Barrable & Sheila J. Thornton. Nature Reviews Drug Discovery 7, 84-99.
Talbert RL. Chapter 28. Dyslipidemia. In: Talbert RL, DiPiro JT, Matzke GR, Posey LM, Wells BG, Yee GC, eds. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York: McGraw-Hill; 2011. http://www.accesspharmacy.com/content.aspx?aID=7974214. Accessed December 8, 2012.
Botham KM, Mayes PA. Chapter 25. Lipid Transport & Storage. In: Murray RK, Kennelly PJ, Rodwell VW, Botham KM, Bender DA, Weil PA, eds. Harper's Illustrated Biochemistry. 29th ed. New York: McGraw-Hill; 2011. http://www.accesspharmacy.com/content.aspx?aID=55883242. Accessed December 9, 2012.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.
Thomas, A. Lipid Management Standard and Advanced Preview of ATP-IV. Mayo Clinic. 2012. Available at: www.cardiologia.spc.org.py/wp.../Lipid-Talk-Paraguay-final.ppt. Accessed December 9, 2012.
Citations
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. 2007;298(11):1300-1311.
Jelliger, P. American Association of Clinical Endocrinologists’ Lipid and Atherosclerosis Guidelines. Endocr. Pract. 2012;18(Suppl 1). Available at https://www.aace.com/files/lipid-guidelines.pdf. Accessed December 9, 2012.