LDL-Cholesterol Particle Concentrations Replace LDL Levels to Assess Risk

Association Between ApoB and Coronary Artery Calcification

More support for measurement of apoB in risk assessment, particularly in diabetic patients, came from a study by researchers at the University of Pennsylvania Medical Center, Philadelphia.^[9] Analyses of data from asymptomatic patients in 2 ongoing studies showed that apoB, but not LDL-C, predicts coronary artery calcification (CAC) score, a measure of coronary atherosclerotic burden assessed by computed tomography. NCEP ATP III supports measurement of CAC primarily as an adjunct to modify risk assessment based on the major risk factors.^[1] The latest studies, presented by Seth S. Martin, MD (now at Duke University, Durham, North Carolina), were based on the hypothesis that plasma apoB would be a stronger predictor than LDL-C of CAC scores, particularly in patients with type 2 diabetes, and that apoB would add incremental value to apoB-related cholesterol parameters.

Cross-sectional analyses were performed of data from asymptomatic white subjects who participated in the Study of Inherited Risk of Coronary Atherosclerosis (SIRCA) (434 men and 383 women, median age 48 years, all non-diabetics)^[10] and the Penn Diabetes Heart Study (580 men and 261 women, median age 60 years, all with type 2 diabetes). Both studies recruited patients at the University of Pennsylvania.

SIRCA is an ongoing study that recruited subjects based on having a family history of coronary artery disease but few other traditional risk factors for heart disease. At the study visit they had several physical measurements, including CAC measurement by electron beam computed tomography (EBCT) and fasting lipids.
The Penn Diabetes Heart Study is a study of genetic and biochemical factors related to the development of atherosclerosis in persons with type 2 diabetes. Subjects undergo a number of tests including ankle-brachial index, heart rate variability, electrocardiogram, and CAC by ECBT.

As expected, Dr. Martin and his colleagues found a high correlation between levels of apoB and LDL-C in both diabetic (ρ = 0.78, P < .001) and nondiabetic (ρ = 0.77, P < .001) patients. After controlling for age, gender, statin therapy, and total cholesterol, there was no association between LDL-C and CAC in diabetic patients ( Table 9 ). An association existed between LDL-C and CAC in nondiabetic patients after controlling only for age, gender, medication, and risk factors, but this was lost after adjustment for total cholesterol. In contrast, after controlling for age, gender, statin therapy, and total cholesterol, levels of apoB were strongly positively associated with CAC in diabetic patients and were more modestly associated with CAC in non-diabetic patients.

Interaction analyses by diabetes status in age- and gender-controlled models showed a consistent association of apoB with CAC scores across both diabetic and nondiabetic patients (ρ = 0.25) but a difference between the 2 groups in the association between LDL-C and CAC (ρ = 0.02). Combining data for diabetic and nondiabetic patients and applying the likelihood ratio test showed that apoB provided added value in predicting CAC score when added to LDL-C, total cholesterol, and the total cholesterol/HDL ratio and marginal value when added non-HDL-C ( Table 10 ). In contrast, adding cholesterol parameters to apoB in a similar model showed that LDL, total cholesterol, and non-HDL-C failed to provide additional value, and, as expected, the total cholesterol/HDL ratio added value to apoB.

Despite that fact that this study did not examine clinical outcomes, CAC scores are still regarded as clinically relevant as they are strong predictors of outcomes. Relative to LDL-C, plasma apoB levels may be particularly useful in assessing CVD risk in patients with type 2 diabetes.

Cite this: Should LDL-Cholesterol Particle Concentrations Replace LDL Levels to Assess Risk? - Medscape - Feb 16, 2009.

Table 1. ADA/ACCF Consensus Conference Report: Suggested Treatment Goals in Patients With Cardiometabolic Risk and Lipoprotein Abnormalities
Risk Category	Goal (mg/dL)
Risk Category	LDL-C	Non-HDL-C	ApoB
Highest risk patients, including those with: • Known cardiovascular disease, or • Diabetes plus ≥ 1 other major cardiovascular risk factor	< 70	< 100	< 80
High-risk patients, including those with: • No diabetes or known clinical cardiovascular disease but ≥ 2 other major cardiovascular risk factors, or • Diabetes but no other major cardiovascular risk factors	< 100	< 130	< 90

Other major risk factors (beyond dyslipoproteinemia) include smoking, hypertension, and family history of premature coronary artery disease
From Brunzel JD et al. J Am Coll Cardiol. 2008;51:1512-1524

Table 2. Linear Regression of LDL-C vs ApoB: Diabetes vs No Diabetes
	Target apoB = 90 mg/dL		Target apoB = 80 mg/dL
	Baseline LDL-C (mg/dL)	On-therapy LDL-C (mg/dL)	Baseline LDL-C (mg/dL)	On-therapy LDL-C (mg/dL)
Diabetes (n = 5156)	115.0*	82.5^**	107.2*	72.8^**
No diabetes (n = 7113)	106.4*	80.4^**	97.4*	70.1^**
All patients (n = 12,269)	110.3*	81.4^**	101.8*	71.4^**

*R² = 0.61-0.66
**R² = 0.77-0.81

Table 3. Linear Regression of non-HDL-C vs ApoB: Diabetes vs No Diabetes
	Target apoB = 90 mg/dL		Target apoB = 80 mg/dL
	Baseline non-HDL-C (mg/dL)	On-therapy non-HDL-C (mg/dL)	Baseline non-HDL-C (mg/dL)	On-therapy non-HDL-C (mg/dL)
Diabetes (n = 5156)	139.8*	108.7^**	130.3	97.1^**
No diabetes (n = 7113)	136.3*	106.5^**	126.2*	94.1^**
All patients (n = 12,269)	137.8*	107.5^**	128.0*	95.6^**

*R² = 0.72-0.73
**R² = 0.88-0.90

Table 4. Linear Regression of LDL-C vs ApoB: Normal Triglycerides vs High Triglycerides
	Target apoB = 90 mg/dL		Target apoB = 80 mg/dL
	Baseline LDL-C (mg/dL)	On-therapy LDL-C (mg/dL)	Baseline LDL-C (mg/dL)	On-therapy LDL-C (mg/dL)
Normal triglycerides (n = 7691)	111.4*	84.9^**	102.2*	74.2^**
High triglycerides (n = 4578)	98.2*	75.0^**	89.2*	65.0^**

*R²=0.67-0.68
**R²=0.80-0.82

Table 5. Linear Regression of non-HDL-C vs ApoB: Normal Triglycerides vs High Triglycerides
	Target apoB = 90 mg/dL		Target apoB = 80 mg/dL
	Baseline non-LDL-C (mg/dL)	On-therapy non-LDL-C (mg/dL)	Baseline non-LDL-C (mg/dL)	On-therapy non-LDL-C (mg/dL)
Normal triglycerides (n = 7691)	134.0*	107.1^**	124.1*	95.1^**
High triglycerides (n = 4578)	151.2*	108.5^**	142.3*	96.7^**

*R² = 0.65-0.74
**R² = 0.88-0.89

Table 6. Summary of Lipoprotein Treatment Goals for ApoB Targets in Patients at High Cardiometabolic Risk
Risk Category	LDL-C (mg/dL)	Non-HDL-C (mg/dL)
For target apoB = 80 mg/dL
Diabetes	73	97
High triglycerides	85	97
For target apoB = 90 mg/dL
Diabetes	82	109
High triglycerides	75	109

Table 7. Linear Regression of LDL-C vs ApoB by Race/Ethnicity
High-Risk Race/Ethnic Group	Target apoB = 90 mg/dL		Target apoB = 80 mg/dL
High-Risk Race/Ethnic Group	Baseline LDL-C (mg/dL)	On-therapy LDL-C (mg/dL)	Baseline LDL-C (mg/dL)	On-therapy LDL-C (mg/dL)
White (n = 10,046)	110.6*	81.2^†	102.1*	71.3^†
Hispanic/Latino (n = 873)	108.6*	78.3^†	100.8*	76.1^†
Asian (n = 685)	108.5^**	82.1^‡	100.0^**	72.7^‡
Black (n = 665)	114.4*	87.2^†	105.5*	68.4^†

*R² = 0.60-0.65
**R² = 0.48
^†R² = 0.79-0.84
^‡R² = 0.68

Table 8. Linear Regression of non-HDL-C vs apoB by Race/Ethnicity
High-Risk Race/Ethnic Group	Target apoB = 90 mg/dL		Target apoB = 80 mg/dL
High-Risk Race/Ethnic Group	Baseline non-HDL-C (mg/dL)	On-therapy non-HDL-C (mg/dL)	Baseline non-HDL-C (mg/dL)	On-therapy non-HDL-C (mg/dL)
White (n = 10,046)	139.2*	107.5^**	129.4*	95.7^**
Hispanic/Latino (n = 873)	130.5*	106.6^**	120.2*	93.6^**
Asian (n = 685)	128.4*	108.4^**	117.2*	96.2^**
Black (n = 665)	132.7*	108.3^**	122.0*	95.6^**

*R² = 0.72-0.76
**R² = 0.88-0.92

Table 9. Association of ApoB and LDL-C With Coronary Artery Calcification
	Diabetic Ratio* (95% CI)	Non-Diabetic Ratio* (95% CI)
ApoB	2.75 (1.31-5.81)	1.30 (0.88-1.94)
LDL-C	1.05 (0.59-1.90)	1.33 (0.88-2.01)

*Tobit regression ratio, adjusted for age, gender, medications, total cholesterol, and risk factors, including smoking, hypertension, family history, alcohol, exercise, hsCRP, and metabolic syndrome

Table 10. Incremental Value of ApoB Added to Cholesterol Parameters
ApoB Added to:	χ²	P Value
LDL-C	15.26	< .001
Total cholesterol	16.65	< .001
Non-HDL-C	3.20	.07
Total cholesterol/HDL ratio	4.32	.04

Model controlled for age, gender, medications, and diabetes status

Table 11. Average Values of LDL-C and LDL Particles
	Atorvastatin			Rosuvastatin
	0 wk	6 wk	12 wk	0 wk	6 wk	12 wk
LDL-C (mg/dL)	171	105	95	168	93	84
LDL-P (nmol/L)	1870	1300	1280	1960	1260	1210

LDL-P = LDL particles

Table 12. Percentage of Patients Who Achieved Lipid Modifying Goals After 6 and 12 Weeks of Statin Treatment
Goal	Atorvastatin		Rosuvastatin
Goal	6 wk	12 wk	6 wk	12 wk
LDL-C < 100 mg/dL*	46%	59%	61%	80%
LDL-P < 1300 nmol/L^†	59%	55%	57%	69%
LDL-P < 1000 nmol/L^†	12%	19%	25%	27%

*Intention-to-treat population (n = 397)
^†Per protocol population (n = 318)

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Should LDL-Cholesterol Particle Concentrations Replace LDL Levels to Assess Risk?

November 8 - 12, 2008, New Orleans, Louisiana

Association Between ApoB and Coronary Artery Calcification

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