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LDL-C, Non-HDL-C, Measures of LDL Particle Number (apoB and LDL-P): And the Winner is…
LDL-C, Non-HDL-C, Measures of LDL Particle Number (apoB and LDL-P): And the Winner is…
William Cromwell, MD, FAHA, FNLAWilliam Cromwell, MD, FAHA, FNLA
DiplomateDiplomate, American Board of Clinical Lipidology, American Board of Clinical Lipidology
ChiefChiefLipoprotein and Metabolic Disorders InstituteLipoprotein and Metabolic Disorders Institute
Adjunct Associate ProfessorAdjunct Associate ProfessorWake Forest University School of MedicineWake Forest University School of Medicine
William Cromwell, MD, FAHA, FNLAWilliam Cromwell, MD, FAHA, FNLA
DiplomateDiplomate, American Board of Clinical Lipidology, American Board of Clinical Lipidology
ChiefChiefLipoprotein and Metabolic Disorders InstituteLipoprotein and Metabolic Disorders Institute
Adjunct Associate ProfessorAdjunct Associate ProfessorWake Forest University School of MedicineWake Forest University School of Medicine
Disclosures
William Cromwell, MD, FAHA, FNLAWilliam Cromwell, MD, FAHA, FNLA
Chief Lipoprotein and Metabolic Disorders InstituteChief Lipoprotein and Metabolic Disorders Institute
Speaker: Abbott, Kowa, LipoScience, Merck
Consultant: Genzyme, Health Diagnostic Laboratory, I sis LabCorp
1. What lipoproteins are represented by unique, but related, lipid and lipoprotein biomarkers?
2. What is the impact of discordance between alternate lipid and lipoprotein measures?
3. What evidence is needed to support utilization of alternate lipid and lipoprotein measures for risk assessment versus risk management?
Factors Affecting Outcome Associations of Lipid and Lipoprotein Measures
Factors Affecting Outcome Associations of Lipid and Lipoprotein Measures
2
Executive Summary of the Third Report of NCEP ATP I II. JAMA. 2001;285:2486–2497. Blaha MJ, et al. J Clin Lipidol. 2008;2:267–273. Ballantyne CM, Clinical Lipidology: A companion of Braunwald’s Hea rt Disease. Philadelphia, PA: Saunder Elsevier; 2009
Cholesterol /Ester
Triglyceride
All Apo B-Containing Lipoproteins
Non–HDL-C
Apo A Apo B Apo B Apo B Apo B
Relationship of Cholesterol and ApoB Lipoproteins
BAD“BAD”
LDL-C
Total Cholesterol
GOOD“GOOD”
HDL-C
HDL LDL IDL VLDLChylomicron /
RemnantsWhy are non-HDL-C and ApoB more strongly associated with CHD risk than LDL-C?
A. Benefit from inclusion of non-LDL ApoB containi ng lipoproteins
B. Better represent LDL quantity than LDL-C
Values are from multivariable logistic regression analyses adjusted for age, gender, BP, smoking, and lipid rx. Hazard ratios (HRs) are per 1 SD increment of the lipoprotein variable.
Cromwell et al. J Clin Lipidol 2007
HR (95% CI) p
Cholesterol Measures
LDL-C 1.11 (1.01-1.22) 0.03
Non-HDL-C 1.21 (1.10-1.33) <0.0001
Particle Measures
LDL-P 1.28 (1.17-1.39) <0.0001
(LDL-P + VLDL-P) 1.28 (1.18-1.40) <0.0001
Relations of Alternate Measures of Atherogenic Relations of Alternate Measures of Atherogenic Lipoproteins with Future CVD EventsLipoproteins with Future CVD Events
Framingham (431 events)
IDL VLDLChylomicron /
Remnants
All Apo B-Containing Lipoproteins
Non–HDL-C
Apo B Apo B Apo B
Relationship of Cholesterol and ApoB Lipoproteins
Except for type III hyperlipidemia, more than 90% of total plasma ApoB particles are LDL particles (even among high TG patients) [1,2]
1 Sniderman A, et al. Atherosclerosis 1991; 89: 109-16. 2 Durrington PN,et al. Clin Chim Acta 1978; 82: 151-60
Apo B
LDL
LDL
Apo B
3
Conventional Explanation
Different Measures of Atherogenic Lipoproteins
LDL LDL + VLDL
LDL-C non-HDL-C
apoB
Contemporary View
4 Different Ways to Assess LDL
Cholesterol Content Particle Number
LDL-C LDL-P
Non-HDL-C apoB
Evolving Views of LDLEvolving Views of LDL
Total Population
Evaluation of Individual Biomarker Outcome Associations
Highest Quintile
Lowest Quintile
Hazard Ratio
Evaluation of Individual Biomarker Outcome Associations
4
Impact of Discordance Between Alternate Measures on Outcome Associations
Total PopulationConcordant Discordant
Adapted from Glasziou P, et al. Ann Intern Med. 2008;149(11):816-822.
Concordant
No DifferenceIn Outcomes
Between Biomarkers
Impact of Discordance Between Alternate Measures on Outcome Associations
Where Concordance Is Dominant There Is No Ability To Detect
A Difference In Performance Of The
New Measure
Discordant
Potential SignificanceDifference in Outcomes
Between Biomarkers
Adapted from Glasziou P, et al. Ann Intern Med. 2008;149(11):816-822.
Adapted from Sniderman AD, et al. Am J Cardiol 2003;91:1173-1177
ApoB versus LDL-C
Quintile Concordant (%) Discordant (%)
1st Quintile 66 34
Middle 3 Quintiles 38 62
5th Quintile 64 36
Overall 49 51
ApoB versus Non-HDL-C
Quintile Concordant (%) Discordant (%)
1st Quintile 76 24
Middle 3 Quintiles 47 53
5th Quintile 73 27
Overall 63 37
Discordance Between Alternate LDL MeasuresQuebec Cardiovascular Study (n=2,103)
5
Concordant
No DifferenceIn Outcomes
Between Biomarkers
Impact of Discordance Between Alternate Measures on Outcome Associations
“The contradictory results of
observational studies and clinical
trials in which discordant and
concordant subjects have not been
separated has led to persistent
uncertainty as to whether there is
advantage to alternate measures
of atherogenic lipoprotein-related
risk of vascular disease.” 1
Discordant
Potential SignificanceDifference in Outcomes
Between Biomarkers
1. Sniderman AD, et al. Atherosclerosis 2012;225:444-449.Adapted from Glasziou P, et al. Ann Intern Med. 2008;149(11):816-822.
CHD Event Associations of LDLCHD Event Associations of LDL--P versus LDLP versus LDL--CCFramingham Offspring Study (n=3,066)
Cromwell WC et al. J Clin Lipidology 2007;1(6):583-592.
0.74
0.76
0.78
0.80
0.82
0.84
0.86
0.88
0.90
0.92
0.94
0.96
0.98
1.00
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Years of Follow-up
Eve
nt-F
ree
Sur
viva
l
Concordant
Discordant
0.74
0.76
0.78
0.80
0.82
0.84
0.86
0.88
0.90
0.92
0.94
0.96
0.98
1.00
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Years of Follow-up
Eve
nt-F
ree
Sur
viva
l
Low LDL-CLow LDL-P (n=1,249)
High LDL-CHigh LDL-P (n=1,251)
Better survivalLower risk
Worse survivalHigher risk
Concordant
Discordant
0.74
0.76
0.78
0.80
0.82
0.84
0.86
0.88
0.90
0.92
0.94
0.96
0.98
1.00
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Years of Follow-up
Eve
nt-F
ree
Sur
viva
l
Low LDL-CHigh LDL-P
(n=282)
High LDL-CLow LDL-P
(n=284)
Better survivalLower risk
Worse survivalHigher risk
Low LDL-CLow LDL-P (n=1,249)
High LDL-CHigh LDL-P (n=1,251)
Better survivalLower risk
Worse survivalHigher risk
Low LDL-CHigh LDL-P
(n=282)
High LDL-CLow LDL-P
(n=284)
Concordant
Discordant
Better SurvivalLower Risk
Worse SurvivalHigher Risk
Clinical Implications of Discordance Between Low-Density Lipoprotein Cholesterol and Particle Number
Clinical Implications of Discordance Between Low-Density Lipoprotein Cholesterol and Particle Number
James D. Otvos, PhD, Samia Mora, MD, MHS, Irina Shalaurova, MD, Philip Greenland, MD, Rachel H. Mackey, PhD, MPH, David C. Goff Jr., MD, PhD
Journal of Clinical Lipidology 2011;5:105-113
James D. Otvos, PhD, Samia Mora, MD, MHS, Irina Shalaurova, MD, Philip Greenland, MD, Rachel H. Mackey, PhD, MPH, David C. Goff Jr., MD, PhD
Journal of Clinical Lipidology 2011;5:105-113
6
• Large NHLBI observational study of the pathogenesis and progression of subclinical atherosclerosis.
• Baseline Lipid and NMR measurements of entire cohort.
Study DesignStudy Design
• 319 incident CVD events (incident CVD included myocardial infarction, coronary heart disease death, angina, stroke, stroke death, or other atherosclerotic or CVD death) during 5.5-yr follow-up.
Outcome Measures
• To compare incident CHD events in subjects with concordant versus discordant LDL-C and LDL-P measures
Objective
Multi-Ethnic Study of Atherosclerosis (MESA)
Otvos et al. J Clin Lipidol 2011;5:105-13
Multi Ethnic Study of Atherosclerosis [MESA] (n=6,6 97)
Otvos, JD, et al. J Clin Lipidol 2011;5:105-13
LDL-C percentile
LDL-
P p
erce
ntile
10 20 30 40 50 60 70 80 90
LDL-
P (
nmol
/L)
LDL-C (mg/dL)
10
20
30
40
50
60
70
80
90
10
20
30
40
50
60
70
80
90 1750
1580
1460
1360
1270
1190
1100
1000
880
1750
1580
1460
1360
1270
1190
1100
1000
880
79 90 100 108 116 123 131 141 157
Discordant
LDL-P > LDL-C cholesterol-poor
LDL-P < LDL-C cholesterol-rich
Concordant
Analytic Relations of Lipid and Particle Number Measures
Multi-Ethnic Study of Atherosclerosis (MESA)
Relations with CVD Events in Concordant/Discordant LDL Subgroups
From Cox regression analyses adjusted for age, sex, and race.
LDL-C LDL-P
HR p HR p
Overall 1.20 0.0009 1.32 <0.0001
Concordant 1.27 0.0003 1.27 0.0002
Discordant 1.07 0.52 1.45 0.0003
Otvos et al. J Clin Lipidol 2011;5:105-13
7
LDLLDL--P and LDLP and LDL--C Discordance in MESAC Discordance in MESARelations with Incident CVD Events (n=319)
Follow-up (years)0 1 2 3 4 5
Cum
ulat
ive
Inci
denc
e
0.02
0.04
0.06LDL-P < LDL-C
Concordant
LDL-P > LDL-C
0 1 2 3 4 5
LDL-P > LDL-C
LDL-P < LDL-C
Concordant
LDL-P > LDL-C
LDL-P < LDL-C
Concordant
16%
33%
54%
MetSyn
LDL-C underestimates LDL-attributable risk
LDL-C overestimates LDL-attributable risk
HDL-C
44
50
57
mg/dL
LDL-C
104
117
130
mg/dL
LDL-P
1372
1249
1117
nmol/L
Otvos et al. J Clin Lipidol 2011;5:105-13
0 1 2 3 4 5
0.02
Follow-up (years)
Cum
ula
tive
Inci
denc
e
0
0.04
0.06
LDL-P LDL-C
Not Low Low
Low Low
Low: < 30th percentileLDL-C < 100 mg/dLLDL-P < 1060 nmol/L
Concordant
LDLLDL--P and LDLP and LDL--C Discordance in MESA C Discordance in MESA CVD Event Rates in Subgroups with Low LDL-C
Otvos et al. J Clin Lipidol 2011;5:105-13
DiscordantHigh LDL-P
0 1 2 3 4 5
0.02
Follow-up (years)
Cum
ula
tive
Inci
denc
e
0
0.04
0.06
LDL-P LDL-C
Not Low Low
Low Low
Low Not Low
Low: < 30th percentileLDL-C < 100 mg/dLLDL-P < 1060 nmol/L
Concordant
DiscorcordantHigh LDL-P
DiscorcordantLow LDL-P
Otvos et al. J Clin Lipidol 2011;5:105-13
LDLLDL--P and LDLP and LDL--C Discordance in MESA C Discordance in MESA CVD Event Rates in Subgroups with Low LDL-P
8
Allan D. Sniderman, Shofique Islam, Salim Yusuf, Matthew J. McQueen
Atherosclerosis 2012;225:444-449
Allan D. Sniderman, Shofique Islam, Salim Yusuf, Matthew J. McQueen
Atherosclerosis 2012;225:444-449
Discordance analysis of Apolipoprotein B and non-high density lipoprotein
cholesterol as markers of cardiovascular risk in the INTERHEART study
Discordance analysis of Apolipoprotein B and non-high density lipoprotein
cholesterol as markers of cardiovascular risk in the INTERHEART study
• Subjects were recruited from 262 centers in 52 countries.
• Blood samples were obtained from 9,345 cases (first acute myocardial infarction) and 12,120 age and sex-matched controls without known cardiovascular disease.
Study DesignStudy Design
Sniderman AD, et al. Atherosclerosis 2012;225:444-449.
Subjects
• To compare the odds ratio of cases to controls for discordant groups compared to the ratio of cases to controls in the concordant group (reference group).
• Values of apoB and non-HDL-C were expressed as percentiles of the study population. Difference > + 5 percentile points defined discordance.
• 10,949 (51%) subjects were concordant and 10,516 (49%) were discordant
Objective
Relationship of ApoB and Non-HDL CholesterolRelationship of ApoB and Non-HDL CholesterolInterheart (n=21,465)
Sniderman AD, et al. Atherosclerosis 2012;225:444-449.
Concordant 10,949 (51%) Reference Group
Discordant 10,516 (49%)
Odds Ratio 0.72
Odds Ratio 1.48
9
ConclusionsConclusionsInterheart (n=21,465)
1. “In summary, LDL-C, non-HDL-C and apoB are closely related metabolic markers of cardiovascular risk. Nevertheless, based on differences in cholesterol content, subjects who are discordant for non-HDL-C and apoB can be distinguished from those who are concordant.”
2. “In those who are concordant, apoB and non-HDL-C will be equivalent markers of risk.”
3. “Our data demonstrate that in those who are discordant, apoB is superior to non-HDL-C.”
Sniderman AD, et al. Atherosclerosis 2012;225:444-449.
The Emerging Risk Factors Collaboration Writing Group
JAMA. 2009;302(18):1993-2000
The Emerging Risk Factors Collaboration Writing Group
JAMA. 2009;302(18):1993-2000
Major Lipids, Apolipoprotein, and Risk of Vascular Disease
Major Lipids, Apolipoprotein, and Risk of Vascular Disease
• Evaluated the odds ratio (first versus fifth quintiles ) for lipid and lipoprotein biomarkers with CHD events (ie, first-ever MI or fatal CHD).
• Analyses were based on 91,307 participants (involving 4,499 cases) from 22 studies.
• Regression analyses were stratified, where appropriate, by sex and trial group and adjusted for age, systolic blood pressure, smoking status, history of diabetes mellitus, and body mass index.
Emerging Risk Factors CollaborationEmerging Risk Factors Collaboration
Study DesignStudy Design
JAMA. 2009;302(18):1993-2000.
10
Hazard Ratios for Coronary Heart Disease Across Hazard Ratios for Coronary Heart Disease Across
Fifths of Usual Lipids or Fifths of Usual Lipids or ApolipoproteinsApolipoproteins
JAMA. 2009;302(18):1993-2000.
Allan D. Sniderman, MD; Ken Williams, MSc; John H. Contois, PhD; Howard M. Monroe, PhD;
Matthew J. McQueen, MBChB, PhD; Jacqueline de Graaf, MD, PhD; Curt D. Furberg, MD, PhD
Circulation. Cardiovascular quality and outcomes. 2011;4(3):337-345.
Allan D. Sniderman, MD; Ken Williams, MSc; John H. Contois, PhD; Howard M. Monroe, PhD;
Matthew J. McQueen, MBChB, PhD; Jacqueline de Graaf, MD, PhD; Curt D. Furberg, MD, PhD
Circulation. Cardiovascular quality and outcomes. 2011;4(3):337-345.
A Meta-Analysis of Low-Density Lipoprotein Cholesterol,
Non-High-Density Lipoprotein Cholesterol, andApolipoprotein B as Markers of
Cardiovascular Risk
A Meta-Analysis of Low-Density Lipoprotein Cholesterol,
Non-High-Density Lipoprotein Cholesterol, andApolipoprotein B as Markers of
Cardiovascular Risk
MetaMeta--Analysis of LDLAnalysis of LDL--C, NonC, Non--HDLHDL--C, and ApoB as C, and ApoB as Markers of Cardiovascular Risk Markers of Cardiovascular Risk
Study Design:
• Meta-analysis of all published epidemiologic studies with estimates of relative risks of fatal or nonfatal ischemic cardiovascular events and measures of non-HDL-C and apoB.
• 12 independent reports, including 233,455 subjects and 22,950 events, were analyzed.
Major Findings:
• Whether analyzed individually or in head-to-head comparisons, apoB was the most potent marker of cardiovascular risk.
Biomarker RRR 95% Confidence Interval
ApoB 1.43 1.35 – 1.51
Non-HDL-C 1.34 1.24 – 1.44
LDL-C 1.25 1.18 – 1.33
Sniderman AD, Williams K, et al. Circulation. Cardiovascular quality and outcomes. 2011;4(3):337-345.
11
MetaMeta--Analysis of LDLAnalysis of LDL--C, NonC, Non--HDLHDL--C, and ApoB as C, and ApoB as Markers of Cardiovascular Risk Markers of Cardiovascular Risk
Sniderman AD, Williams K, et al. Circulation. Cardiovascular quality and outcomes. 2011;4(3):337-345.
• “The present analysis indicates that non-HDL-C is superior to LDL-C as a marker of cardiovascular risk.”
• “The conventional explanation would be that the gain in predictive power is due to the cholesterol in VLDL.”
• “The superiority of non-HDL-C over LDL-C is due to the fact that non-HDL-C is a better marker of LDL-P than LDL-C.”
• “When apoB and non-HDL-C are concordant, they will predict risk equally, whereas when they are discordant, apoB will be superior.”
S. M. Boekholdt, B. J. Arsenault, S. Mora, T. R. Pedersen, J. C. LaRosa, P. J. Nestel, R. J. Simes, P. Durrington, G. A.
Hitman, K. M. Welch, D. A. DeMicco, A. H. Zwinderman, M. B. Clearfield, J. R. Downs, A. M. Tonkin, H. M. Colhoun, A.
M. Gotto, Jr., P. M. Ridker and J. J. Kastelein
JAMA. 2012;307(12):1302-1309.
S. M. Boekholdt, B. J. Arsenault, S. Mora, T. R. Pedersen, J. C. LaRosa, P. J. Nestel, R. J. Simes, P. Durrington, G. A.
Hitman, K. M. Welch, D. A. DeMicco, A. H. Zwinderman, M. B. Clearfield, J. R. Downs, A. M. Tonkin, H. M. Colhoun, A.
M. Gotto, Jr., P. M. Ridker and J. J. Kastelein
JAMA. 2012;307(12):1302-1309.
Association of LDL Cholesterol,Non–HDL Cholesterol, and Apolipoprotein
B Levels With Risk of Cardiovascular Events Among Patients Treated With
Statins: A Meta-analysis
Association of LDL Cholesterol,Non–HDL Cholesterol, and Apolipoprotein
B Levels With Risk of Cardiovascular Events Among Patients Treated With
Statins: A Meta-analysis
• Individual level patient data obtained from 8 statin trails in which LDL-C, non-HDL-C and ApoB levels were measured at 1 year
• Among 38,153 patients allocated to statin therapy:
– 158 fatal myocardial infarctions,
– 1,678 nonfatal myocardial infarctions
– 615 fatal events from other coronary artery disease
– 2,806 hospitalizations for unstable angina,
– 1,029 fatal or nonfatal strokes occurred during follow-up.
• Hazard ratios (HRs) and corresponding 95% CIs for risk of major cardiovascular events adjusted for established risk factors by 1-SD increase in LDL-C, non–HDL-C, and apoB.
Boekholdt SM, et al. JAMA 2012;307(12):1302-1309
MetaMeta--Analysis of Outcome Association with Analysis of Outcome Association with
Alternate LDL Measures on Statin TherapyAlternate LDL Measures on Statin Therapy
12
Boekholdt SM, et al. JAMA 2012;307(12):1302-1309
MetaMeta--Analysis of Outcome Association with Analysis of Outcome Association with
Alternate LDL Measures on Statin TherapyAlternate LDL Measures on Statin Therapy
J. G. Robinson, S. Wang and T. A. Jacobson
American Journal of Cardiology 2012;110(10):1468-76.
J. G. Robinson, S. Wang and T. A. Jacobson
American Journal of Cardiology 2012;110(10):1468-76.
Meta-analysis of comparison of effectiveness of lowering apolipoprotein B versus low-density lipoprotein cholesterol
and non-high-density lipoprotein cholesterol for cardiovascular risk
reduction in randomized trials.
Meta-analysis of comparison of effectiveness of lowering apolipoprotein B versus low-density lipoprotein cholesterol
and non-high-density lipoprotein cholesterol for cardiovascular risk
reduction in randomized trials.
• Study evaluated the relation between apolipoprotein B (apoB) decrease and coronary heart disease, stroke, and cardiovascular disease risk.
• Bayesian random-effects meta-analysis was used to evaluate the association of mean absolute apoB decrease (mg/dL) with relative risk of:
– CHD (nonfatal myocardial infarction and coronary heart disease death)
– stroke (nonfatal stroke and fatal stroke)
– CVD (coronary heart disease, stroke, and coronary revascularization).
Robinson JG, et al. Am J Cardiol. Nov 15 2012;110(10):1468-1476.
MetaMeta--Analysis of Outcome Association with Analysis of Outcome Association with
Alternate LDL Measures on Lipid Altering TherapyAlternate LDL Measures on Lipid Altering Therapy
13
• Analysis included 25 trials (n=131,134):
– 12 statin therapy
– 4 fibrate therapy
– 5 niacin therapy
– 2 simvastatin – ezetimibe therapy
– 1 on ileal bypass surgery
– 1 on aggressive versus standard low-density lipoprotein (LDL) cholesterol and blood pressure targets.
Robinson JG, et al. Am J Cardiol. Nov 15 2012;110(10):1468-1476.
MetaMeta--Analysis of Outcome Association with Analysis of Outcome Association with
Alternate LDL Measures on Lipid Altering TherapyAlternate LDL Measures on Lipid Altering Therapy
Combining the 25 trials:
• Each 10-mg/dl decrease in apoB was associated with a 9% decrease in CHD, no decrease in stroke, and a 6% decrease in major CVD risk.
• non-HDL-C decrease modestly outperformed apoB decrease for prediction of CHD and CVD risk reduction;
In the 12 statin trials:
• apoB and non-HDL-C decreases similarly predicted cardiovascular disease risk;
• apoB decreases added information for predicting CHD beyond LDL-C and non-HDL-C decreases, but did not improve CVA or CVD disease risk prediction
Robinson JG, et al. Am J Cardiol. Nov 15 2012;110(10):1468-1476.
MetaMeta--Analysis of Outcome Association with Analysis of Outcome Association with
Alternate LDL Measures on Lipid Altering TherapyAlternate LDL Measures on Lipid Altering Therapy
Evaluating Cardiovascular BiomarkersEvaluating Cardiovascular Biomarkers
Intended Application
Type of Biomarker
Clinical Use Impact on Clinical Decision Making
Evidence Needed to Support Use
Risk Assessment
New Biomarker(Inflammatory
measures, Particle size)
Biomarker is added to other information to enhance risk assessment
Allocate patient to different risk category which may result in more aggressive or
less aggressive therapy
Significant improvement in risk stratification with the
addition of new biomarker, or substitution of new measure of existing
biomarker, in risk models (net reclassification, c-statistic, ROC) 1
New Measure of Established
Biomarker (LDL Quantity)
Risk Management
New Biomarker(inflammatory
measures, particle size)
Biomarker serves as a
treatment target and guides need for additional therapy
Modify therapy (different agents,
dosage, or combinations) as
indicated to achieve new therapeutic
target
Outcome improvement established independent of
other risk factors
New Measure of Established
Biomarker (LDL Quantity)
New measure consistently outperforms the existing measure in the setting of
discordance 2
1. Ge Y, Wang TJ. J Intern Med. 2012;272(5):430-439.2. Glasziou P, et al. Ann Intern Med. 2008;149(11):816-822
14
1. Contois JH et al. Clin Chem. 2009;55:407-419.2. Genest J et al. Can J Cardiol. 2009;25:567-579.3. Brunzell JD et al. J Am Coll Cardiol. 2008;51:1512-1524.
4. Jellinger PS et al. Endocr Pract. 2012;18(Suppl 1):1-78.5. Reiner Ž, et al. Eur Heart Journal. 2011;32:1769–18186. Davidson MH et al. J Clin Lipidol. 2011;5:338-367.
Recommendations for Using LDL Particle Recommendations for Using LDL Particle Number Measures as Targets of TherapyNumber Measures as Targets of Therapy
Percentile Equivalent Concentration
Biomarker Population <5th 20th 50th 80th
LDL-C (mg/dL)Framingham [1]
<75 100 130 160
ApoB (mg/dL) <60 80 100 120
Organization Proposed ApoB Targets of Therapy (mg/dL)
Very High Risk High Risk Moderate Risk
Canadian Cardiovascular Society Guidelines [2] NA <80
American Diabetes Association / American College of Cardiology Foundation Consensus Statement [3] <80 <90 NA
American Association for Clinical Chemistry Lipopro teins & Vascular Diseases Working Group Recommendations [1] * <80 <100
American Association of Clinical Endocrinologists G uidelines for Management of Dyslipidemia [4] <80 <90 NA
ESC/EAS Guidelines for the Managementof Dyslipidaemias [5] <80 <100 NA
National Lipid Association Expert Recommendations [ 6] * Option <70 <80 <100
* NMR LDL-P targets also recommended at population equivalent levels
1. Alternate cholesterol (LDL-C, non-HDL-C) and lipoprotein particle number (apoB, NMR LDL-P) LDL measures are available for clinical use.
2. Although highly correlated, lipid and particle number measures are frequently discordant indicating that one measure can not easily substitute for another.
3. Contradictory results of observational studies and clinical trials in which discordant and concordant subjects have not been separated has led to persistent uncertainty as to whether there is advantage to alternate measures of atherogenic lipoprotein-related risk of vascular disease.
4. The criteria for judging the clinical utility of alternate measures of an established biomarker is the strength of outcome associations for the new measure in the discordant setting.
5. When cholesterol (LDL-C, non-HDL-C) and particle number (apoB, NMR LDL-P) measures are concordant, each predict outcomes equally. When discordant, apoB and NMR LDL-P are more significantly predictive of CHD outcomes than LDL-C or non-HDL-C.
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