ApoB in Risk Assessment and the Diagnosis and Treatment of the
Atherogenic Dyslipoproteinemias
Allan Sniderman
McGill University
Disclosures
• Pfizer: Lecture on Hypertriglyceridemia
NLA Recommendations for patient-centered management of dyslipidemia
“Non-HDL-C is favored over apoB by the NLA Expert Panel because it is universally available, requiring no additional expense and because apoB has not been consistently superior to non-HDL-C in predicting ASCVD risk. “
“ApoB is considered an optional secondary target for treatment.”
Journal of Clinical Lipidology 2014;8: 473-488
ERFC: the strongest evidence that non-
HDL-C =apoB JAMA: 2009; 302; 1993-2000
What did ERFC actually find? TC is as good as non-HDL-C
ERFC JAMA 2009: 302:1993-2000
“Third, HRs were similar with non–HDL-C as with directly measured
LDL-C”
ERFC: JAMA 2012; 307: 2499-2506
In contrast with some existing guidelines,(1,6,7,9) the current analysis
has shown that replacement of information on total cholesterol and
HDL-C with various lipid parameters does not improve CVD prediction.
For example, none of the following measures were superior to total
cholesterol and HDL-C when they replaced traditional cholesterol
measurements in risk prediction scores: the total cholesterol:HDL-C
ratio; non–HDL-C; (emphasis added)...
Conventional Observational Epidemiological Studies that contradict ERFC
ApoB> LDL-C ApoB> LDL-C+ Non-HDL-C Non-HDL-C=ApoB> LDL-C
Quebec CV INTERHEART AMORIS
Stetler Type I DM Carlo Monferrato EPIC-NORFOLK
Finland Chin-Shan Cohort ARIC
Apolipoproteins & IHD Health Professionals F/U Copenhagen Heart Men
4S Placebo ISIS
THROMBO The Tromso Study
Northwick Park Heart Study
North Italian Brianza MS Cohort
Quebec CV Framingham
MONICA/KORA Casale Monferrato
Copenhagen Heart Women
Schmidt & Bergstom
The second best study: Boekholdt et al. JAMA 2012; 307:1302
Marker On Rx HR
LDL-C 1.13 (1.10-
1.17)
Non-HDL-C 1.16 (1.12-
1.19)
Apo B 1.14 (1.11-
1.18)
Non-HDL-C vs LDL-C p<0.002; Non-HDL-C vs apoB p<0.02
Association of LDL cholesterol, non-HDL cholesterol and apolipoprotein B with the risk of cardiovascular
events. Boekholdt et al. JAMA 2012; 307:1302
Marker On Rx HR On-Rx CI HR On-Rx CI
HR best case
LDL-C 1.13 (1.10-
1.17) 1.134
Non-HDL-C 1.16 (1.12-
1.19) 1.154
1.124-1.194 1.158
Apo B 1.14 (1.11-
1.18) 1.144
Non-HDL-C vs LDL-C p<0.002; Non-HDL-C vs apoB p<0.02
Marker RRR (95% CI) P-value
LDL-C 1.25* (1.18 to 1.33) <0.001
Non-HDL-C 1.34 (1.24 to 1.44) <0.001
ApoB 1.43 (1.35 to 1.51) <0.001
Marker 1st marker % over 2nd (95% CI)
P-value
Non-HDL-C vs. LDL-C
5.0% (0.9% to 9.1%) 0.017
ApoB vs. Non-HDL-C
5.7%* (2.4% to 9.1%) 0.001
ApoB vs. LDL-C 12.0%* (8.5% to 15.4%) <0.001
Meta-analysis of 13 epidemiology studies: overall vascular relative risk ratios (95% confidence intervals) per standard deviation increase
Calculated Gains of non-HDL C
& apoB over LDL C
ALM Saves
Non-HDL C 300,000
apoB 500,000
Sniderman A et al Circ Cardiovasc Qual Outcomes 2011;4:337-45
al Circulation: Cardiovascular Quality
and Outcomes 2011;4:337-April 12
Benefit as HR per SD decrease in marker
Marker Benefit
LDL C 1.24 (1.18-1.31)
Non-HDL C 1.24 (1.18-1.31)
apoB 1.31 (1.22-1.40)
Relations of change in plasma levels of LDL-C, non-HDL-C and apoB with risk reduction from statin therapy: a meta-analysis of randomized trials. Thanassoulis G, Williams K, et al J Am Heart Assoc. 2014 ;3(2):e000759
Discordance Analysis
• LDL-C, non-HDL-C, apoB and LDL P are closely correlated. Conventional statistical methods were not designed to take this into account.
• Discordance analysis was designed to compare the cholesterol markers when they differ- ie cholesterol-rich or cholesterol-depleted apoB particles- and the comparison not be diluted by all the instances in which they do not differ- apoB particles with an average mass of cholesterol
Sniderman A et al Am J Cardiol. 2003;91:1173-7
Framingham Offspring Study
Framingham Offspring Study
Discordance Analyses
• Quebec Cardiovascular Study: ApoB>LDL-C
• Framingham: ApoB> LDL-C ApoB> Non-HDL-C
• INTERHEART: ApoB> Non-HDL-C
• Women’s Health Study: ApoB, LDL P, non-HDL-C> LDL-C.
• Framingham: LDL P> LDL-C
• MESA: LDL P>LDL-C
Risk = f apoB particle
NLA: The Evidence
Citation Panel
Author Colleague/Panel Author
12 +
13 +
14 +
17 +
18 +
19 +
Citation
Pro Non-HDL-C Pro ApoB
NLA Recommendations for patient-centered management of dyslipidemia
“Non-HDL-C is favored over apoB by the NLA Expert Panel because it is universally available, requiring no additional expense and because apoB has not been consistently superior to non-HDL-C in predicting ASCVD risk. “
“ApoB is considered an optional secondary target for treatment.”
Journal of Clinical Lipidology 2014;8: 473-488
NLA Recommendations cont’d
• “Measurement of apoB is generally not necessary until the patient has been treated to his or her goal levels for atherogenic cholesterol.” NLA Recommendations 2014
But what about diagnosis? Is diagnosis really of no importance? I will try to show you that it is.
Is this 55 year old woman at high cardiovascular risk ?
•TC 217 mg/dl
•Non-HDL C 165 mg/dl 75th
•LDL-C 144 mg/dl 80th
•HDL C 52 mg/dl
•TG 106 mg/dl
Time to diagnosis of CHD by number of years of hyperlipidemia at baseline.
Ann Marie Navar-Boggan et al. Circulation. 2015;131:451-
458
Copyright © American Heart Association, Inc. All rights reserved.
Time to diagnosis of CHD by number of years of hyperlipidemia at baseline.
How does adding apoB add information?
•TC 217 mg/dl
•Non-HDL C 165 mg/dl 75th
•LDL-C 144 mg/ 80th
•HDL C 52 mg/dl
•TG 106 mg/dl
•apoB 90 mg/dl 51st
Is she really high risk?
Framingham Heart Study: Kaplan-Meier survival for different Non-HDL-C and ApoB combinations
0.75
0.8
0.85
0.9
0.95
1
1 2 3 4 5 6 7 8 9 1011121314151617181920
surv
ival
years
NonHDL≤153, ApoB≤97
NonHDL>153, ApoB≤97
NonHDL≤153, ApoB>97
NonHDL>153,ApoB>97
No
1/3 women with Non-HDL-C are not at increased risk because apoB is not
She is not this.
High non-HDL/C/LDL/C HyperapoB
She is this.
High Non-LDL-C/LDL-C NormoapoB
But if her apoB had been 115, she would be this and would be high risk .
High Non-HDL/C/LDL-C HyperapoB
Is this patient at high or low risk of CVD?
•TC 195 mg/dl
•LDL- C 116 mg/dl 52%
•Non-HDL-C 148 mg/dl 58%
•HDL C 42 mg/dl
•TG 150 mg/dl
Is this patient at Low Risk or High Risk of CVD? •TC 195 mg/dl
•LDL- C 116 mg/dl 52nd
•Non-HDL-C 148 mg/dl 58th
•HDL C 42 mg/dl
•TG 187 mg/dl
•apoB 109 mg/dl 78th
Framingham Heart Study: Kaplan-Meier survival for different LDL and apoB combinations in Men
0.75
0.8
0.85
0.9
0.95
1
1 2 3 4 5 6 7 8 9 1011121314151617181920
surv
ival
years
LDL<130, ApoB<100
LDL≥130, ApoB<100
LDL<130, ApoB≥100
LDL≥130, ApoB≥100
Oops, this patient is at high risk!
He is not this.
HyperTG NormoapoB
HyperTg HyperapoB
He is this.
What is wrong with this patient?
•TC 345 mg/dl
•Non-HDL C 271 mg/dl
•HDL C 36 mg/dl
•TG 539 mg/dl
Let me add apoB
•TC 345 mg/dl
•Non-HDL C 271 mg/dl
•HDL C 36 mg/dl
•TG 539 mg/dl
•apoB 104 mg/dl
ApoB App
ApoB App form
Type III
Frequency of Type III Hyperlipoproteinemia
• 0.68% in a general population of 1700 vs FH 0.2%
• Many cases have triglycerides 150-300 mg/dl
• Prevalence amongst CAD is 2.7%.
• Prevalence by apoB app 10.6% of 3272 consecutive patients in lipid clinic
Hyperlipoproteinemia type 3: the forgotten phenotype.Hopkins PN, Brinton EA, Nanjee MN.
Curr Atheroscler Rep. 2014;16:440
350/3722 (9.4%) consecutive patients in German Lipid Clinic have Type III
ApoE Genotype
Number patients
Type III % apoE2-2 genotype
2-2 108 55 50.9
2-3 338 53 15.7
2-4 105 20 19
3-3 1701 141 8.3
3-4 901 72 8.0
4-4 110 6 5.5
ApoE abn 7 3 5
Evans D et al J Clin Lipidol 2013; 7:671-4
NLA Recommendations cont’d
Non-HDL-C cannot substitute for apoB in diagnosis!!!!!!
“Measurement of apoB is generally not necessary until the patient has been treated to his or her goal levels for atherogenic cholesterol.” NLA Recommendations 2014
National Lipid Association Treatment Targets
Risk Category
Non-HDL-C mg/dl
LDL-C mg/dl
ApoB mg/dl
Low <130 <100 <90
Moderate <130 <100 <90
High <130 <100 <90
Very High <100 <70 <80
National Lipid Association Treatment Targets
Risk Category
Non-HDL-C PP
LDL-C PP
ApoB PP
Low 42 33 51
Moderate 42 33 51
High 42 33 51
Very High 15 8 35
Equivalent Target Levels
LDL C
mg/dl
Non-
HDL C
mg/dl
apoB
mg/dl
High
Risk 100 130 75
Very
High
Risk
70 100 65
Advantages of apoB
Apolipoprotein B improves risk assessment of future CHD in the Framingham Heart Study beyond LDL-C and non-HDL-C European Journal of Preventive Cardiology
Michael J. Pencina, PhD Duke University, DCRI, Ralph B. D’Agostino, PhD Boston University,, USA 02215 Tomasz Zdrojewski, MD PhD Medical University of Gdansk, Ken Williams, MS KenAnCo Biostatistics, San Antonio, TX George Thanassoulis, MD McGill University Health Center, Curt D. Furberg, MD PhD Wake Forest University, Public Health Sciences, Winston-Salem, NC, USA 27157 Eric D. Peterson*, MD MPH Duke University Medical Center, Ramachandran S. Vasan*, MD Framingham Heart Study Allan D. Sniderman*, MD McGill University, Montreal, QC, CAN H3A 1A1 * These authors contributed equally
Apolipoprotein B improves risk assessment of future CHD