LDL-Cholesterol Particle Concentrations Replace LDL Levels to Assess Risk

Introduction

Until very recently, guidelines for the assessment of coronary heart disease (CHD) risk, such as the third report Adult Treatment Panel of the National Cholesterol Education Program (NCEP ATP III),^[1] focused on low-density lipoprotein cholesterol (LDL-C) as the primary target for preventive therapy, based on the assumption that cholesterol is the most important lipoprotein-related proatherogenic risk factor. However, CHD risk is more directly related to the number of atherogenic lipoprotein particles circulating in the serum than it is to the total volume of cholesterol. The total volume of LDL-C is used as a surrogate for measuring LDL particles, although the same LDL-C volume can correspond with a widely varying LDL particle number; it fails to account for the possibility that an extremely atherogenic level of small, dense LDL particles might be measured as a "normal" LDL-C level.

Recently there has been growing emphasis on the fact that each LDL particle contains a single molecule of the atherogenic apolipoprotein (apo) B, meaning that measuring the concentration of apoB provides a direct measure of the number of circulating atherogenic lipoprotein particles. Increasing evidence from clinical and epidemiologic studies indicates that measurement of apoB is superior to measuring LDL-C for predicting probability of fatal and nonfatal CHD. In addition, therapy with statins has been shown to reduce LDL-C content more than LDL particle concentration, which may explain the observation that so many patients on optimum statin therapy will still experience CHD events and also emphasize that apoB may provide a better assessment of residual risk for patients on statin therapy.

On the basis of all this evidence, it has been recommended that assessment of apoB should be included in all guidelines as an indicator of cardiovascular risk.^[2] Measurement of apoB has been incorporated into both the last Canadian guidelines for the management of dyslipidemia and prevention of cardiovascular disease^[3] and the recent consensus conference report for management of lipoproteins in patients with cardiometabolic risk recently issued jointly by the American Diabetes Association (ADA) and the American College of Cardiology Foundation (ACCF).^[4] Both reports note that increased apoB levels and triglyceride concentrations are prevalent in patients with the metabolic syndrome and type 2 diabetes mellitus and that apoB measurement is warranted in patients at risk for determining cardiovascular risk and monitoring statin treatment. It is in this context that several reports at the American Heart Association (AHA) 2008 Scientific Sessions have important implications for clinicians treating dyslipidemic patients.

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

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