LDL-C, Non-HDL-C, Measures of LDL Particle...

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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


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


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

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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


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)

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Concordant

No DifferenceIn Outcomes

Between Biomarkers


“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)



Low LDL-CLow LDL-P (n=1,249)

High LDL-CHigh LDL-P (n=1,251)



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

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• 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


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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


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


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


LDLLDL--P and LDLP and LDL--C Discordance in MESA C Discordance in MESA CVD Event Rates in Subgroups with Low LDL-P

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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.


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)


Concordant 10,949 (51%) Reference Group

Discordant 10,516 (49%)

Odds Ratio 0.72

Odds Ratio 1.48

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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.”


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


JAMA. 2009;302(18):1993-2000.

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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.

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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

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Boekholdt SM, et al. JAMA 2012;307(12):1302-1309


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.


Alternate LDL Measures on Lipid Altering TherapyAlternate LDL Measures on Lipid Altering Therapy

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• 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.




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




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

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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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