Is LDL Cholesterol the Best CHD Lipid Marker?

Special report

By Harold L. Karpman, MD, FACC, FACP, Clinical Professor of Medicine, UCLA School of Medicine. Dr. Karpman reports no financial relationship to this field of study.

Illnesses produced by vascular diseases are far and away the most common cause of death in the developed world and, amazingly enough, will become the leading cause of death even in the developing world by 2020.1 Identifying individuals at increased risk of coronary artery heart disease (CHD) is critical in preventing CHD and, in 2002, the Adult Treatment Panel III (ATP III)2 reaffirmed its previous position by concluding that low-density lipoprotein cholesterol (LDL-C) would remain the cornerstone of lipid management. However, the Panel also noted the increased CHD risk associated with hypertriglyceridemia in patients with the metabolic syndrome and suggested that non-HCL-C might be an appropriate treatment target for this specialized group of patients.2 Use of apolipoprotein B (apoB) lipid measurements were not recommended because the Panel concluded that non-HDL-C and apoB measurements were highly correlated and therefore only non-HDL-C need be calculated when standard lipid studies were obtained.

Pischon and colleagues compared apoB, non-HDL-C, LDL-C and other lipid markers as predictors of CHD in a case-control study among 18,225 participants in the Health Professionals Follow-up Study.3 When non-HDL-C and LDL-C were mutually adjusted, only non-HDL-C was predictive of CHD and, when non-HDL-C and apoB were mutually adjusted, only apoB was predictive. Triglycerides added significant information to non-HDL-C but not to apoB for CHD risk prediction. The authors concluded that although non-HDL-C and apoB were both strong predictors of CHD in this male cohort (more so than LDL-C), the findings support the concept that the plasma concentration of atherogenic lipoprotein particles measured by apoB is more useful in predicting CHD development than is the cholesterol (ie, measured by non-HDL-C) carried by these particles.

Commentary

Atherosclerosis is a complex series of biological responses to atherogenic particles which are trapped within arterial walls and is not a response simply to cholesterol accumulation. These particles injure the endothelium and trigger an extensive and intricate series of inflammatory and healing responses. Cholesterol is simply carried as a passenger into the arterial wall within an atherogenic particle and, of course, it should be noted that the smaller LDL particles more easily enter the arterial walls than do the larger very low-density lipoprotein (VLDL) particles.

Measuring LDL-C levels only incompletely measures atherogenic lipoproteins because VLDL remnants also are likely to contribute to CHD. The apoB level is a more accurate and direct measurement of the atherogenic burden (ie, the concentration of proatherogenic particles) because each VLDL and LDL particle has one molecule of apoB.4 ATP III guidelines recommended measuring non-HCL-C by subtracting HDL-C from the total cholesterol. Although animal experiments have suggested that a high apoB particle concentration may be more important prognostically than the cholesterol concentration,5 the 3 measures of atherogenic lipoproteins (ie, LDL-C, non-HDL-C, and apoB) had not previously been compared directly in a large prospective study in humans. The Pischon study3 corrected this deficiency and, in essence, demonstrated that the plasma concentration of atherogenic lipoproteins as measured by apoB may be more informative regarding the risk of development of atherosclerosis than the amount of cholesterol that the lipoproteins carry into the arterial wall. They also demonstrated that the non-HDL-C level appears to be superior to LDL-C in predicting CHD3,6 probably because it also measures triglycerides—rich atherogenic lipoproteins such as VLDL.

The practical application of these findings suggests that apoB levels instead of LDL-C and non-LDL-C should be measured and treated since apoB is a direct measurement of the number of atherogenic lipoprotein particles and is more closely related to the risk of developing CHD than is the cholesterol concentration contained within these particles. ApoB has been extensively validated in epidemiological studies and clinical trials3,7 and, therefore, when the Adult Treatment Panel next meets, it should consider approving and reimbursing widespread measurements of apoB levels. It should be noted that the measurements of apoB levels are standardized, automated, inexpensive and fasting samples are not required.8 Whether the additional costs of switching to and subsequently measuring only apoB levels is justified by the potential improvement in risk prediction over currently available measurements (ie, LDL-C and non-HCL-C) would depend upon the results of additional studies. Finally, it should also be clearly recognized that the current guidelines are heavily identified with the cholesterol and LDL-C levels and that extensive campaigns to educate health professionals and the public over the past 25 years were necessary to achieve this admirable result. At this time, eliminating cholesterol measurements would be a major and quite difficult change but it would appear important to at least consider measuring and utilizing apoB levels in place of or along with the current lipid measurements in order to possibly improve CHD care.

References

1. Levenson JW, et al. Reducing the global burden of cardiovascular disease: the role of risk factors. Prev Cardiol. 2002;5:188-199.

2. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-2497.

3. Pischon T, et al. Non-high-density lipoprotein cholesterol and apolipoprotein B in the prediction of coronary heart disease in men. Circulation. 2005;112: 3375-3383.

4. Sniderman, AD, et al. Apolipoproteins versus lipids as indices of coronary risk and as targets for statin treatment. Lancet. 2003;361:777-780.

5. Veniant MM, et al. Lipoprotein size and atherosclerosis susceptibility in Apoe(-/-) and Ldlr(-/-) mice. Arterioscl Thromb Vasc Biol. 2001;21:1567-1570.

6. Cui Y, et al. Non-high density lipoprotein cholesterol level as a predictor of cardiovascular disease mortality. Arch Intern Med. 2001;161:1413-1419.

7. Sattar N, et al. Comparison of the associations of apolipoprotein B and non-high-density lipoprotein cholesterol with other cardiovascular risk factors in patients with the metabolic syndrome in the Insulin Resistance Atherosclerosis Study. Circulation. 2004; 110:2687-2693.

8. Marcovina SM, et al. International Federation of Clinical Chemistry standardization project for measurements of apolipoproteins A-I and B. IV. Comparability of apolipoprotein B values by use of International Reference Material. Clin Chem. 1994;40:586-592.