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