LDL-Cholesterol Particle Concentrations Replace LDL Levels to Assess Risk

Relationship Between ApoB and Lipoprotein Goals in High-Risk Patients

The ADA/ACCF consensus report sets out suggested serum cholesterol targets as goals for treatment of LDL-C, non-high-density lipoprotein cholesterol (HDL-C), and apoB in patients with metabolic risk factors, who, by definition, have a high risk for cardiovascular disease ( Table 1 ).

Two studies that examined the effect of statins on the relationship between these targets for apoB and those for LDL-C and non-HDL-C in high-risk patients were presented at AHA 2008 by Christie M. Ballantyne, MD (Baylor College of Medicine and Methodist DeBakey Heart and Vascular Center, Houston, Texas).^[5,6] The ATP III treatment goal for LDL-C is < 100 mg/dL; a goal of < 70 mg/dL is recommended in very high-risk patients.^[7] But the non-HDL-C goal for patients with elevated triglycerides (≥ 200 mg/dL) is 30 mg/dL higher than the LDL-C goal. Dr. Ballantyne explained that this difference was because reducing LDL-C to current treatment targets may still leave an excess of atherogenic lipoproteins, as reflected in levels of apoB.

The results of the 2 studies indicated that non-HDL-C (total cholesterol minus HDL-C) may be a useful surrogate for direct apoB measurement, but that in patients on statin therapy, it may be necessary to aim for LDL-C and non-HDL-C targets closer to those currently recommended in very high-risk patients if those patients are to achieve an apoB goal of 90 mg/dL. These findings support those of a previous analysis, also by Dr. Ballantyne and colleagues, of data from the Measuring Effective Reductions in Cholesterol Using Rosuvastatin therapY (MERCURY II) trial, which examined patients with high CHD risk who were treated with rosuvastatin, atorvastatin, or simvastatin for 16 weeks.^[8]

For the studies reported in New Orleans, Dr. Ballantyne and colleagues at Cleveland Clinic in Ohio, The Heart Research Institute (Sydney, Australia), and AstraZeneca (Wilmington, Delaware) used a pooled analysis of data from the rosuvastatin clinical development program. The VOYAGER (indiVidual patient data meta-analysis Of statin therapY in At-risk Groups: Effects of Rosuvastatin, atorvastatin and simvastatin) database is derived from 37 rosuvastatin studies that examined rosuvastatin, atorvastatin, or simvastatin. ApoB levels were compared with those of LDL-C and non-HDL-C, both at baseline and on therapy, and the relation of apoB levels to LDL-C and non-HDL-C levels was modeled using linear regression.

First Study: Diabetic vs Nondiabetic Patients

The first study compared lipid goals in diabetic and nondiabetic patients among 12,269 identified at high risk of CHD, 5156 of whom had type 2 diabetes mellitus and 7113 were nondiabetic.^[5] In both diabetic and nondiabetic patients, achieving apoB goals (90 mg/dL or 80 mg/dL) required much more aggressive statin therapy ( Table 2 ). In diabetic patients, an apoB level of 90 mg/dL was equivalent to an LDL-C level of 115 mg/dL at baseline, but to achieve 90 mg/dL on statin therapy it was necessary to reach an LDL-C equivalence level that was much lower, at 82.5 mg/dL. To achieve a target of apoB of 80 mg/dL required reaching an LDL-C level of 72.8 mg/dL. In both cases, apoB correlated well with LDL-C during statin therapy (R² = 0.77-0.81).

If the cholesterol measure used is instead non-HDL, the apoB target of 80 mg/dL was equivalent to 139.8 mg/dL non-HDL-C at baseline and 136.3 mg/dL on statin therapy in patients with diabetes ( Table 3 ). Both these values were slightly lower for patients with no diabetes. To achieve a target apoB of 80 mg/dL required lowering LDL-C to 97.1 mg/dL in diabetic patients compared with 94.3 mg/dL in patients without diabetes. During statin therapy apoB coordinated even better with non-HDL-C levels than with LDL-C (R² = 0.88-0.90).

A total of 4578 patients had high triglycerides and the remaining 7691 patients had normal levels of triglycerides. There were greater differences in LDL-C levels needed to achieve apoB targets between patients with normal triglycerides (n = 7691) or high triglycerides (n = 4578) than between the diabetes/no diabetes groups ( Table 4 ).

For non-HDL-C the corresponding levels were higher at baseline in the group with high triglycerides but these levels were similar on therapy for each apoB target ( Table 5 ).

These data support current goals for patients in the highest cardiometabolic risk category, ie, LDL-C < 70 mg/dL, non-HDL-C < 100 mg/dL, and apoB < 80 mg/dL for patients with diabetes or high triglycerides, Dr. Ballantyne concluded. To reach apoB 80 mg/dL, non-HDL-C should ideally be reduced to 97 mg/dL and LDL-C should be reduced to 73 mg/dL (diabetes) or 85 mg/dL (high triglycerides) ( Table 6 ). However, to achieve apoB < 90 mg/dL will require, on average, reducing LDL-C levels substantially below 100 mg/dL and reducing non-HDL-C levels substantially below 130 mg/dL, Dr. Ballantyne cautioned. "Putting it simply, if you get your LDL-C to 70 mg/dL and non-HDL-C to 100 mg/dL, your apoB will be less than 90 and pretty close to 80 mg/dL," he explained. "If your LDL-C is running at 100 mg/dL and your non-HDL-C is 130 mg/dL, however, the odds are, if you are diabetic, that you will have an apoB substantially above 90 mg/dL." During statin therapy, high-risk patients with diabetes or without diabetes require lower LDL-C and non-HDL-C targets to reduce apoB to the recommended level.

Non-HDL-C may be a useful surrogate for direct measurement of apoB. "So if you don't measure apoB, at least look at the non-HDL-C, because this will provide most of the data," Dr. Ballantyne said. He added that since apoB is improved on statin therapy, non-HDL-C is a much better surrogate when a patient is on a statin than when off a statin.

Second Study: Race and Ethnicity

The second study using data from the VOYAGER database examined the effect of race and ethnicity on the relationship between apoB and LDL-C or non-HDL-C. Cholesterol levels were measured at baseline and during statin therapy in 10,046 white, 665 black, 658 Asian, and 873 Hispanic/Latino patients at high risk of CHD.^[6] Non-whites have been under-represented in clinical trials of statin therapy and the patients in MERCURY II were predominantly white, Dr. Ballantyne noted. Analysis of the VOYAGER data showed that at baseline, LDL-C and non-HDL-C correlated "reasonably well" with apoB in all groups, with the lowest concentrations observed in Asians and the highest in blacks. An apoB of 90 mg/dL corresponded to an LDL-C of 114.4 mg/dL for blacks and 108.5 mg/dL for Asians and Hispanics ( Table 7 ). On statin therapy, to reach an apoB of 90 mg/dL, blacks required an LDL-C of 87.2 mg/dL, while Hispanics required an LDL-C of 78.3 mg/dL.

The baseline non-HDL-C that corresponded to an apoB of 90 mg/dL was highest for whites and lowest for Asians, with almost no differences observed among the ethnic groups on statin therapy ( Table 8 ). To achieve the apoB target of 90 mg/dL, statin therapy required 20-30 mg/dL lower targets for both LDL-C and non-HDL-C.

The strong correlation between apoB and non-HDL-C on statin therapy (R² = 0.88-0.92) indicated that non-HDL-C may be a useful surrogate for apoB in all high-risk patients, Dr. Ballantyne said. Regardless of race or ethnicity, LDL-C and non-HDL-C need to be close to those currently recommended for very high-risk CHD patients to achieve apoB targets, he advised.

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)

Commenting is limited to medical professionals. To comment please Log-in.

Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.

My Alerts

Add to Email Alerts

Your Name is required.

Subject is required.

Please enter a Recipient Address and/or check the Send me a copy checkbox.

Your email has been sent.

is an Invalid Email Address.

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

November 8 - 12, 2008, New Orleans, Louisiana

Relationship Between ApoB and Lipoprotein Goals in High-Risk Patients

First Study: Diabetic vs Nondiabetic Patients

Second Study: Race and Ethnicity

Tables

Tables

Tables

Tables

Tables

Tables

Tables

Tables

Tables

Tables

Tables

Tables

References

Authors and Disclosures

Authors and Disclosures

Comments

Email This

Feedback