LDL-Cholesterol Particle Concentrations Replace LDL Levels to Assess Risk

Residual Risk After Lipid Goal Achievement in Metabolic Syndrome

The results of an analysis presented by Robert Rosenson, MD (University of Michigan, Ann Arbor), showed that in patients with the metabolic syndrome, lowering LDL-C does not reflect similar reductions in LDL particle levels.^[11] Although lowering LDL-C improves CHD risk, LDL-C may be normal in patients with the metabolic syndrome while at the same time LDL particle levels may be increased. Thus, achieving LDL-C goals may underestimate CHD risk in these patients, whereas managing them to LDL particle goals may minimize residual risk and optimize treatment in this population.

Together with investigators from LipoScience (Raleigh, North Carolina) and AstraZeneca, Dr. Rosensen examined the effects of statins on LDL particle level and LDL-C in a secondary analysis of the COmparative study with rosuvastatin in subjects with METabolic Syndrome (COMETS), an international, multicenter clinical trial supported by AstraZeneca.^[12]

Study design. COMETS was carried out in 401 men and women aged 18 years and older with the metabolic syndrome as defined by the presence of at ≥ 3 of the following: abdominal obesity (waist circumference > 102 cm [40 inches] for men and > 88 cm [35 inches] for women); triglycerides ≥ 1.70 mmol/L (150 mg/dL); HDL-C < 1.04 mmol/L (40 mg/dL) for men and < 1.30 mmol/L (50 mg/dL) for women; blood pressure ≥ 130/85 mm Hg or receiving antihypertensive treatment; and fasting blood glucose ≥ 6.11 mmol/L (110 mg/dL).^[1] Patients were also required to have LDL-C ≥ 3.36 mmol/L (130 mg/dL) and additional multiple risk factors conferring a 10-year CHD risk score of > 10%.

Patients were randomized in a double-blind fashion to receive rosuvastatin 10 mg/day, atorvastatin 10 mg/day, or placebo from baseline to week 6. From week 6 to week 12, patients who had been on rosuvastatin 10 mg/day or placebo received rosuvastatin 20 mg/day and those previously on atorvastatin 10 mg/day took atorvastatin 20 mg/day. LDL-C was determined by beta-quantification; LDL particles were measured by nuclear magnetic resonance spectroscopy.

Study results. A significantly greater reduction in LDL-C at 6 weeks, the primary efficacy endpoint of the study, was seen in patients receiving rosuvastatin 10 mg compared with those receiving atorvastatin 10 mg (41.7% vs 35.7%, P < .001). Significant LDL-C reductions were also observed in patients receiving rosuvastatin compared with those receiving atorvastatin at 12 weeks (P < .001). More patients achieved LDL-C goals (European guidelines for 1998^[13] and 2003^[14] and NCEP ATP III^[1]) with rosuvastatin compared with atorvastatin. Rosuvastatin increased HDL-C by 15% compared with placebo, significantly more than atorvastatin.

Dr. Rosensen and his colleagues found differences in the effects of the statins in lowering LDL-C and lowering LDL particle concentration. In the rosuvastatin group, LDL-C decreased by 50% (from an average of 168 to 84 mg/dL) over 12 weeks, but LDL particle concentration decreased by only 38% (from an average of 1960 to 1210 nmol/L) over the same period ( Table 11 ). There was no change in average LDL particle size. Similar results were seen with atorvastatin, with a 44% reduction in LDL-C but only a 33% reduction in LDL particles. Differences were also seen between increases in HDL-C and HDL particles, although rosuvastatin raised each to a significantly greater extent compared with atorvastatin, Dr. Rosensen noted.

Dr. Rosensen and colleagues further analyzed the effects of the 2 statins on LDL particles and LDL-C in these patients by calculating the proportion achieving LDL-C < 100 mg/dL (< 20th percentile of NHANES III), those achieving LDL particle concentrations < 1000 nmol/L (< 20th percentile according to the Multi-Ethnic Study of Atherosclerosis [MESA] scale),^[15] and those achieving LDL particle concentration below 1300 nmol/L (< 50th MESA percentile). They found that most patients achieved LDL-C < 100 mg/dL and LDL-particle < 1300 nmol/L goals after 6 and 12 weeks of treatment, although reductions in both LDL-C and LDL particles were smaller with atorvastatin ( Table 12 ). However, far fewer patients (12% to 27%) reached the more appropriate LDL particle goal of < 1000 nmol/L, Dr. Rosensen noted.

These results lend further support to the ADA/ACCF consensus report on lipoprotein management in patients with the metabolic syndrome,^[4] Dr. Rosensen said. He noted that there are some "underappreciated" classes of agents such as fibrates and nicotinic acid that lower LDL particle concentration more than LDL-C. "Fenofibrate lowers LDL-C by only 8% but lowers LDL particles by 19% and apoB by 16%," he said. "There is a disconnect between how certain agents lower LDL-C versus how they lower LDL particle concentration."

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

Residual Risk After Lipid Goal Achievement in Metabolic Syndrome

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