tue22812 - lipidology - pamela morris
TRANSCRIPT
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ATP IV, CVD Risk Assessment,
and Dyslipidemia: Update 2012
Pamela B. Morris, MD, FACC, FACP, FACPM, FAHA
Diplomate, American Board of Clinical Lipidology
Director, Seinsheimer Cardiovascular Health Program
Co-Director, Womens Heart Care
Medical University of South Carolina
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Points of Discussion
New guidelines on obesity, hypertension, andhyperlipidemia
ATP IV
CVD Risk Assessment
NLA position paper on role of biomarkers in CVD risk
assessment
Low levels of LDL-C
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Upcoming NCEP ATP IVGuidelines:
What Can We Expect?
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Evolution of NHLBI Supported Guidelines
Angiographictrials (FATS,
POSCH, SCOR,
STARS, Ornish,
MARS)
Meta-analyses(Holme, Rossouw)
NCEP ATP I1988
NCEP ATP II1993
NCEP ATP III2001
HPSPROVE-IT
ASCOT-LLA
PROSPERALLHAT-LLT
Updated NCEPATP III2004
FraminghamMRFIT
LRC-CPPT
CoronaryDrug ProjectHelsinki Heart
CLAS
4SWOSCOPS
CARE
LIPIDAFCAPS/TexCAPS
TNTIDEAL
AHA/ACCUpdate
20062* Prev.
Guidelines
More Intensive Treatment Recomm endat ions
NHLBI = National Heart, Lung, and Blood Institute.
NCEP ATP = National Cholesterol Education Panel Adult Treatment Panel.
AHA = American Heart Association.ACC = American College of Cardiology.
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AHA/ACC guidelinesfor patients with CHD*,2
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NHLBI Integrated Cardiovascular RiskReduction Guidelines
Cardiovascular Risk Reduction Guidelines inAdults:
Cholesterol Guideline Update (ATP IV)
Hypertension Guideline Update (JNC 8)
Obesity Guideline Update (Obesity 2)
The National Heart, Lung, and Blood Institute is leading the development of an integrated set of cardiovascular riskreduction guidelines for adults using state-of-the-art methodology.
Cholesterol, hypertension, and obesity guidelines are being updated, and an integrated cardiovascular risk reductionguideline is being developed.
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Methodology
NHLBI expert panels are putting final touches on new guidelinesfor
Adult obesity
Hypertension
Hyperlipidemia
New methodology discussed at AHA Scientific Sessions 2011
Most comprehensive review of the literature ever with a systematicreview process to evaluate evidence and establish recommendations
Goes well beyond anything NHLBI has ever attempted
Recommendations of effective methods of implementation Guidelines that will improve lives and sit on the shelf unused
High priority on conflicts of interest
Integrated guidelinesmultiple guidelines in a common format
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Methodology: Whats New
Each committee created a list of critical questions its guidelineswould answer
Exhaustive literature review
Relevant articles graded for the quality of evidence
Only good to fair articles included
Distilled each qualified paper into an evidence statement to be used increation of recommendations
Less than 50-60% of papers identified as relevant were considered ofusable quality
Stronger emphasis on randomized clinical trials
Limited use of expert opinion
Concerned effort to SIMPLIFY guidelines
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Methodology: Whats Similar
Focus on LDL-Cholesterol (LDL-C)
Greatest intensity of treatment for patients at highestrisk
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Methodology
Obesity Panel Critical Questions What are the risks of being overweight?
What are the benefits of weight loss?
What amount of weight loss is necessary to achieve specific benefits?
What is the most effective diet for weight loss? What is the evidence for short- and long-term efficacy of a comprehensive
lifestyle approach?
What are the benefits of obesity surgery?
Guidelines will NOT address pharmaceutical interventions due tolack of sufficient evidence
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Methodology
JNC 8 Critical Questions
1. Does initiating antihypertensive pharmacological therapy atspecific BP thresholds improve health outcomes? When should youinitiate treatment?
2. Does treatment with an antihypertensive pharmacological therapyto a specified BP goal lead to improvements in health outcomes?How low should you go?
3. Do various antihypertensive drugs or drug classes differ in
comparative benefits and harms on specific health outcomes? Howdo you get there?
The antihy pertensive gu idel ines are only usin g random ized con trol ledtr ial evid ence
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ATP IV Report
Aim:
Assist clinicians in prevention to make decisions oncholesterol treatment by developingrecommendations based on a detailed study of:
Randomized clinical trials (RCTs)
High quality meta-analyses of RCTs
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Expert Panel Membership
Co-Chairs
Alice H. Lichtenstein, D.Sc.Tufts University
Boston, Massachusetts
Neil Stone, M.D.
Northwestern University School of MedicineChicago, Illinois
Detection, Evaluation, and Treatment of HighBlood Cholesterol in Adults (Adult Treatment Panel IV)
D t ti E l ti d T t t
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C. Noel Bairey Merz, M.D.
University of California, Los Angeles
Conrad Blum, M.D.
Columbia University
Robert H. Eckel, M.D.
University of Colorado, Denver
Anne Carol Goldberg, M.D., FACP, FAHA
Washington University
Ronald M. Krauss, M.D.
Children's Hospital Oakland
Research Institute
Donald M. Lloyd-Jones, M.D., Sc.M.
Northwestern University
Patrick McBride, M.D., M.P.H.
University of Wisconsin
Daniel Rader, M.D.
University of Pennsylvania
Jennifer Robinson, M.D, M.P.H.
University of Iowa
Frank M. Sacks, M.D.
Harvard UniversitySchool of Public Health
J. Sanford Schwartz, M.D.
University of Pennsylvania
Sidney C. Smith, Jr. M.D.
University of North Carolina
Karol Watson, M.D., Ph.D.
University of California at Los Angeles
Peter W. F. Wilson, M.D.
Emory University School of Medicine
Detection, Evaluation, and Treatmentof High Blood Cholesterol in Adults
(Adult Treatment Panel IV)
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ATP IV Developing In-depth Answers to TheseCritical Questions
Critical question 1: What evidence suppo rts LDL-Cgoals for secon dary prevent ion?
Critical question 2: What evidence suppo rts LDL-Cgoals for pr imary prevent ion?
Critical question 3: What is the impact of the majorcho lestero l drugs on eff icacy and safety?
Diet and exercise are being addressed separately by the Lifestyle WorkingGroup
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Critical Question 1
What evidence supports LDL-c goals fo rsecondary prevent ion?
This question being evaluated in all adults andspecific subpopulations of interest
Women
Diabetics
Metabolic syndrome
Chronic kidney disease
Current smoking
Baseline LDL-c
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Critical Question 1: Background
What evidence supports LDL-c go als for secondaryprevent ion?
ATP III recommended LDL-c goals of
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Critical Question 1: Publications screened
Publications
Screened
2221
Included
62
Good quality
13
Fair quality
29
Total ABSTRACTED
42
Poor quality
20
Excluded
2159
Studies excluded if they
did not meet pre-specified
inclusion/exclusion
criteria
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Critical Question 2
What evidence supports LDL-c goals fo rpr imary prevent ion?
This question being evaluated in all adults andspecific subpopulations of interest
Diabetics 10-year CHD risk categories: 20%
For all adults and each of the above groups
Men and women separately
Adults 18-64 years of age and > 65 years
Men 18-35 years and women 18-45 years
Race/ethnicity
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Critical Question 2: Publications screened
Publications
Screened
1958
Included
20
Good quality
7
Fair quality
12
Total ABSTRACTED
19
Poor quality
1
Excluded
1938
Studies excluded if they
did not meet pre-specified
inclusion/exclusion
criteria
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Critical Question 3
What is the impact of the major cholestero l drug s oneff icacy /safety in the popu lat ion?
Baseline untreated LDL-c
160 md/dl (including patients with familialhypercholesterolemia)
Triglycerides > 150 mg/dl
HDL-c
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CVD Risk Assessment
More stringent targets versus a fixed dose strategy adjustingdose to risk
hs-CRP
Alternative treatment targets: Role of advanced lipoproteintesting
Apo B, LDL-P, non HDL-C
Direct targeting of HDL-C and triglycerides
Role of fibrates, niacin, ezetimibe, BAS
Role of imaging of subclinical atherosclerosis
" Let 's pu t i t th is way. If wh at people are doing now is correct , and th ere's no ch angerecomm ended, then we're f ine. I f we do come up w i th very su bstant ial changes, we w antto be very careful that they are strongly based in evidence. Dr. Sidney Smith, UNC
Chapel Hil l
Issues for ATP-IV: ??????
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CVD Risk Assessment
More stringent targets versus a fixed dose strategy
hs-CRP
Alternative treatment targets: Role of advanced lipoproteintesting
Apo B, LDL-P, non HDL-C
Direct targeting of HDL-C and triglycerides
Role of fibrates, niacin, ezetimibe, BAS
Role of imaging of subclinical atherosclerosis
Issues for ATP-IV: ??????
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CVD Risk Assessment
More stringent targets versus a fixed dose strategy
hs-CRP Alternative treatment targets: Role of advanced lipoprotein
testing
Apo B, LDL-P, non HDL-C
Direct targeting of HDL-C and triglycerides
Role of fibrates, niacin, ezetimibe, BAS
Role of imaging of subclinical atherosclerosis
Issues for ATP-IV: ??????
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CVD Risk Assessment
More stringent targets versus a fixed dose strategy
hs-CRP ? Alternative treatment targets: Role of advanced lipoprotein
testing
Apo B, LDL-P, non HDL-C
Direct targeting of HDL-C and triglycerides
Role of fibrates, niacin, ezetimibe, BAS
Role of imaging of subclinical atherosclerosis
Issues for ATP-IV: ??????
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CVD Risk Assessment
More stringent targets versus a fixed dose strategy
hs-CRP ? Alternative treatment targets: Role of advanced lipoprotein
testing ? Apo B, LDL-P, non HDL-C
Direct targeting of HDL-C and triglycerides
Role of fibrates, niacin, ezetimibe, BAS
Role of imaging of subclinical atherosclerosis
Issues for ATP-IV: ??????
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CVD Risk Assessment
More stringent targets versus a fixed dose strategy
hs-CRP ? Alternative treatment targets: Role of advanced lipoprotein
testing ? Apo B, LDL-P, non HDL-C
Direct targeting of HDL-C and triglycerides
Role of fibrates, niacin, ezetimibe, BAS
Role of imaging of subclinical atherosclerosis
Issues for ATP-IV: ??????
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CVD Risk Assessment
More stringent targets versus a fixed dose strategy
hs-CRP ? Alternative treatment targets: Role of advanced lipoprotein
testing ? Apo B, LDL-P, non HDL-C
Direct targeting of HDL-C and triglycerides
Role of fibrates, niacin, ezetimibe, BAS
Role of imaging of subclinical atherosclerosis ?
Issues for ATP-IV: ??????
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CVD Risk Assessment
More stringent targets versus a fixed dose strategy
hs-CRP ? Alternative treatment targets: Role of advanced lipoprotein
testing ? Apo B, LDL-P, non HDL-C
Direct targeting of HDL-C and triglycerides
Role of fibrates, niacin, ezetimibe, BAS
Role of imaging of subclinical atherosclerosis ?
Issues for ATP-IV: ??????
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Cardiovascular Risk Prediction
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Continuum of DiseaseAsymptomatic
Disease-freeRisk factors may be
present
Asymptomatic
Subclinical disease present
Onset of symptoms
Heart attack, stroke,
angina
Risk factoridentification
Preventivestrategies
Early disease detection
Aggressive preventivestrategies
Primary PreventionSecondaryPrevention
Secondary preventivestrategies
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Cardiovascular Risk Prediction
CVD is leading cause of death in US and entire westernworld
At age 50 the lifetime risk of CVD is
50% for men
39% for women
Variations due to risk factor burden
NCEP ATP III (and ATP IV ?)
Risk calculation based on assumption that the intensity oftreatment and risk factor reduction should match the level ofabsolute predicted risk.
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Office-based Assessment(National Cholesterol Education Program, American Heart Association, American
College of Cardiology)
Risk prediction algorithm derived from the FraminghamHeart Study
Age
Total cholesterol
HDL
Blood pressure
Smoking
Current Guidelines
JAMA 2001; 285: 2486-2497
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2004 PPS
Point Total 10-Year Risk Point Total 10-Year Risk
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2004 PPS
Note: Determine the 10-year absolute risk for hard CHD(MI and coronary death) from point total.
Point Total 10-Year Risk Point Total 10-Year Risk
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Women Hardly Reach 10% FRS by Traditional Risk
Factor Assessment
0%
20%
40%
60%
80%
100%
30-39 40-49 50-59 60-69 70-79
Age (years)
Perce
nt >20%
10-20%6-10%
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How Good Is NCEP III At Predicting MI?JACC 2003:41 1475-9
222 patients with 1stacute MI, no prior CADmen
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2
Cardiovascular Risk Prediction: Basic Concepts, Current Status, and Future Directions.
Lloyd-Jones, Donald; MD, ScM Circulation. 121(15):1768-1777, April 20, 2010.DOI: 10.1161/CIRCULATIONAHA.109.849166
Currently Available CVD Risk Prediction Scores
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2
Cardiovascular Risk Prediction: Basic Concepts, Current Status, and Future Directions.
Lloyd-Jones, Donald; MD, ScM Circulation. 121(15):1768-1777, April 20, 2010.DOI: 10.1161/CIRCULATIONAHA.109.849166
Currently Available CVD Risk Prediction Scores
5- and 10-year risk estimates are most widely used
Risk score is converted into an absolute probability ofdeveloping CVD within that time frame
Consideration of 10-year risk identifies patients most likely
to benefit from therapy in the near term
Improves cost-effectiveness and safety of therapy
FRS performs poorly in women and younger men
Algorithm heavily weighted by age
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2
Cardiovascular Risk Prediction: Basic Concepts, Current Status, and Future Directions.
Lloyd-Jones, Donald; MD, ScM Circulation. 121(15):1768-1777, April 20, 2010.DOI: 10.1161/CIRCULATIONAHA.109.849166
Currently Available CVD Risk Prediction Scores
Risk for CVD associated with traditional risk factors iscontinuous
No obvious natural thresholds
Thresholds used by ATP III for clinical decision making are
based on population data and cost-effectiveness estimatesin an era when statins were more expensive
Majority of events occur in the intermediate risk population(simply because that is where the vast majority of the
population at risk is found.)
Risk Classification Algorithm Used in the ATP-III
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Cardiovascular Risk Prediction: Basic Concepts, Current Status, and Future Directions.
Lloyd-Jones, Donald; MD, ScM Circulation. 121(15):1768-1777, April 20, 2010.DOI: 10.1161/CIRCULATIONAHA.109.849166
Risk Classification Algorithm Used in the ATP-III
2004 Update
Likely that future guidelines will choose lower thresholds fortherapy in light of
Demonstrated benefit in populations at predicted risk
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Berger JS et al, JACC 2010;55:1169
Newer CVD Risk Prediction Algorithms
Concept of vascular age from CAC or CIMT
Lifetime risk
30 year risk
Composite endpoints (all CVD, PAD, stroke, heart failure,include angina/revascularization, fatal and nonfatal)
Validation/calibration in other populations
Inclusion of family history, hs-CRP, HgbA1C, socialdeprivation, BMI
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Effectiveness*-Based Guidelines for Cardiovascular DiseasePrevention in Women2011 Update
*(therapies with sufficient evidence of clinical benefit for CVD outcomes)
American Heart Association Guidelines
Endorsed by the American Col lege of Cardio logy, American
Col lege of Physicians, AMWA, WomenHeart , American Soc iety
for Prevent ive Cardio logy , and others
Mosca, L. et al. Circulation 2011;123:1243-1262
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Wh i i k ?
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Who is at risk among women?
Highest risk women
Known heart disease, stroke,vascular disease (PAD or
carotid disease), or aneurysm ESRD or CKD
Diabetes
10 yr predicted CVD risk >10%
Mosca, L. et al. Circulation 2011;123:1243-1262
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Who is at risk among women?
At-risk women
1 or more of the following risk factors
Smoking
Poor diet
Sedentary
Obesity, especially if belly fat
Family history (female < 65, male < 55)
High blood pressure (>120/80)
Abnormal lipids (high bad cholesterol,low good cholesterol, high triglycerides)
Metabolic syndrome
Poor exercise tolerance
Subclinical atherosclerosis
Systemic autoimmune collagen-vasculardisorder (SLE, RA)
Hx of preeclampsia, gestational DM
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Who is at risk among women?
Optimal risk women
Ideal healthy lifestyle
No risk factors
Only 1 ou t of
3 women!
Wh i t i k ?
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Who is at risk among women?
Optimal risk women
Total cholesterol
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Prediction of Lifetime Risk forCardiovascular Disease by Risk Factor
Burden at 50 Years of Age
Donald M. Lloyd-Jones et al
Circulation 2006;113:791-798
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Lloyd-Jones et al Circulation 2006;113:791-798
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Generic Prevention Drugs
Drug Monthly CostStatin $4.00
Beta blocker $4.00
Metformin $4.00
ACE-inhibitor HCTZ $4.00
Amlodipine $4.00
All national discount pharmacy chains
Lower price ($10) for 3 months supply
Can potentially reduce cost further with a pill cutter
Beyond Cholesterol: Predicting Cardiovascular Risk In
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Beyond Cholesterol: Predicting Cardiovascular Risk Inthe 21stCentury
Cardiovascular Risk
LipidsHTN
DiabetesBehavioral
HemostaticThrombotic
Inflammatory Genetic
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BiomarkerPopulation-based approximations
Lower risk Intermediate risk Greater risk
CRP, mg/L 3.0
Lp-PLA2, ng/mL
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Source: Journal of Clinical Lipidology 2011; 5:338-367(DOI:10.1016/j.jacl.2011.07.005 )
http://www.lipidjournal.com/article/S1933-2874(11)00672-6/abstracthttp://www.lipidjournal.com/article/S1933-2874(11)00672-6/abstracthttp://www.lipidjournal.com/article/S1933-2874(11)00672-6/abstracthttp://www.lipidjournal.com/article/S1933-2874(11)00672-6/abstract -
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Source: Journal of Clinical Lipidology 2011; 5:338-367(DOI:10.1016/j.jacl.2011.07.005 )
http://www.lipidjournal.com/article/S1933-2874(11)00672-6/abstracthttp://www.lipidjournal.com/article/S1933-2874(11)00672-6/abstracthttp://www.lipidjournal.com/article/S1933-2874(11)00672-6/abstracthttp://www.lipidjournal.com/article/S1933-2874(11)00672-6/abstract -
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Source: Journal of Clinical Lipidology 2011; 5:338-367(DOI:10.1016/j.jacl.2011.07.005 )
Figure 4
http://www.lipidjournal.com/article/S1933-2874(11)00672-6/abstracthttp://www.lipidjournal.com/article/S1933-2874(11)00672-6/abstracthttp://www.lipidjournal.com/article/S1933-2874(11)00672-6/abstracthttp://www.lipidjournal.com/article/S1933-2874(11)00672-6/abstract -
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Source: Journal of Clinical Lipidology 2011; 5:338-367(DOI:10.1016/j.jacl.2011.07.005 )
http://www.lipidjournal.com/article/S1933-2874(11)00672-6/abstracthttp://www.lipidjournal.com/article/S1933-2874(11)00672-6/abstracthttp://www.lipidjournal.com/article/S1933-2874(11)00672-6/abstracthttp://www.lipidjournal.com/article/S1933-2874(11)00672-6/abstract -
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Source: Journal of Clinical Lipidology 2011; 5:338-367(DOI:10.1016/j.jacl.2011.07.005 )
http://www.lipidjournal.com/article/S1933-2874(11)00672-6/abstracthttp://www.lipidjournal.com/article/S1933-2874(11)00672-6/abstracthttp://www.lipidjournal.com/article/S1933-2874(11)00672-6/abstracthttp://www.lipidjournal.com/article/S1933-2874(11)00672-6/abstract -
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Source: Journal of Clinical Lipidology 2011; 5:338-367(DOI:10.1016/j.jacl.2011.07.005 )
http://www.lipidjournal.com/article/S1933-2874(11)00672-6/abstracthttp://www.lipidjournal.com/article/S1933-2874(11)00672-6/abstracthttp://www.lipidjournal.com/article/S1933-2874(11)00672-6/abstracthttp://www.lipidjournal.com/article/S1933-2874(11)00672-6/abstract -
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Source: Journal of Clinical Lipidology 2011; 5:338-367(DOI:10.1016/j.jacl.2011.07.005 )
http://www.lipidjournal.com/article/S1933-2874(11)00672-6/abstracthttp://www.lipidjournal.com/article/S1933-2874(11)00672-6/abstracthttp://www.lipidjournal.com/article/S1933-2874(11)00672-6/abstracthttp://www.lipidjournal.com/article/S1933-2874(11)00672-6/abstract -
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Is there risk or benefit associated with unusuallyl l l f LDL C?
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low levels of LDL-C?
Can LDL Be Too Low?
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Can LDL Be Too Low?
A safety analysis of theintensive treatment arm of
PROVE IT - TIMI 22
Stephen D Wiviott, David A Morrow, Richard Cairns, Marc A Pfeffer, and Christopher P Cannon for the
PROVE IT - TIMI 22 Investigators
R lt Di t ib ti f 4 M th LDL Ch l t l L l
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3.2
1.4 2.1 3.2
5.6
8.3
13.3
18 19.2
15.2
8.2
1.7
0.5 0.10
5
10
15
20
25
>13
0
120-13
0
110-12
0
100-11
0
90-100
80-90
70-80
60-70
50-60
40-50
30-40
20-30
10to20
100 80-100 60-80 40-60
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0 1 2
40 - 60
>60 - 80
>80 - 100
(multivariable adjustment)
*Age, gender, DM, prior MI, baseline LDL
0.80 (0.59, 1.07)
0.67 (0.50, 0.92)
0.61 (0.40, 0.91)
Hazard Ratio
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Abetalipoproteinemia (ABL) and familialhypobetalipoproteinemia (FHBL)
Rare inborn errors of lipoprotein metabolism.
ABL occurs in less than 1 in 1 million persons.
FHBL occurs in approximately 1 in 500 heterozygotes and inabout 1 in 1 million homozygotes.
Approximately one third of ABL and FHBL cases result fromconsanguineous marriages.
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Abetalipoproteinemia
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Abetalipoproteinemia
Rare disease
LDL and very low-density lipoprotein (VLDL) are essentially absent.
Characterized by fat malabsorption, spinocerebellar degeneration,acanthocytic red blood cells, and pigmented retinopathy.
Homozygous autosomal recessive mutation in the gene for
microsomal triglyceride transfer protein (MTP).
MTP mediates intracellular lipidtransport in the intestine and liver
Ensures the normal function of chylomicrons (CMs) in enterocytesand of VLDL in hepatocytes.[2]
Abetalipoproteinemia
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Abetalipoproteinemia
Affected infants may appear normal at birth, but by the first month
of life, they develop steatorrhea, abdominal distention, and growthfailure.
Children develop retinitis pigmentosa and progressive ataxia,
Death usually occurring by the third decade.
Early diagnosis, high-dose vitamin E(tocopherol) therapy, andmedium-chain fatty acid dietary supplementation may slow theprogression of the neurologic abnormalities.
Obligate heterozygotes (ie, parents of patients with ABL) have nosymptoms and no evidence of reduced plasma lipidlevels.
Abetalipoproteinemia
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Abetalipoproteinemia
Clinical symptoms are the result of defects in the absorption and
transport of vitamin E.
Vitamin E transported from the intestine to the liver, where it isrepackaged and incorporated into the assembling VLDL particle bythe tocopherol-binding protein.
In the circulation, VLDL is converted to LDL, and vitamin E istransported by LDL to peripheral tissues and delivered to cells viathe LDL receptor.
Patients with ABL are markedly deficient in vitamin E
Most of the major clinical symptoms, especially those of the
nervous system and retina, are primarily due to vitamin Edeficiency.
Familial Hypobetalipoproteinemia
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Familial Hypobetalipoproteinemia
Rare autosomal dominant disorder of apoB metabolism.
Most cases of known origin result from mutations in the APOBgene, involving 1 or both alleles.
More than 30 mutations have been described.
Mutations result in impaired synthesis of apoB-containing
lipoproteins, or increased catabolism of these proteins. Heterozygotes may have LDL cholesterol levels less than or equal
to 50 mg/dL, but they often remain asymptomatic and have normallife spans.
In the homozygous state, the absence of apoB leads to significant
impairment of intestinal CM formation and impaired absorption offats, cholesterol, and fat-soluble vitamins.
Leads to the development of degenerative neurologic disease.
Acquired Low LDL C
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Acquired Low LDL-C
Secondary causes
Occult malignancy
Malnutrition
Liver disease
Chronic alcoholism.
These conditions must be excluded before thediagnosis of FHBL can be made.