Vascular disease is already the most common cause of death in the developed world and by 2020 will become the leading cause of death in the developing world as well.[1] No society can afford to offer everyone every therapy. Accordingly, improving the identification of individuals at increased risk of cardiovascular disease to receive preventive therapy must be one of our highest priorities. The study by Pischon and colleagues, [2] which appears in this issue of Circulation and which demonstrates that apolipoprotein B (apoB) is superior to non–high-density lipoprotein cholesterol (non–HDL-C) to identify the risk of vascular events, represents an important step forward in this process.
In 2002, the Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program reaffirmed their previous position, namely, that low-density lipoprotein cholesterol (LDL-C) would remain the cornerstone of lipid management. At the same time, they acknowledged the increased risk associated with hypertriglyceridemia and the metabolic syndrome and introduced non–HDL-C as a treatment target for this large group of patients. [3] Use of apoB was not recommended. Rather, based on the fact that apoB and non–HDL-C are highly correlated (generally >0.85), they stated the 2 were equivalent in terms of risk prediction and non–HDL-C would be preferable because no additional test need be performed. The prestige of the ATP process and the fact that major payers such as Blue Cross Blue Shield used the ATP decision as a justification not to reimburse for apoB [4] effectively excluded apoB from widespread clinical application.
Were they right on each of these decisions? As to the first point—retaining LDL-C as the prime index of the risk of vascular disease—it appears they were not. Most reports since then [2,5–13] have put both apoB and/or non–HDL-C ahead of LDL-C as an index of the risk of vascular disease. Consequently, there should now be a fundamental revision of the risk paradigm. The issue is no longer whether non–HDL C or apoB are better than LDL-C as risk predictors; they are. The issue now is whether one or other is superior. Taken as a whole, the evidence indicates that they are not equivalent; the majority of studies in which they were compared found apoB to be more informative than non–HDL-C. [2,10–13] There are exceptions, however, with the most substantial being a recent study by Ridker et al, [5] which showed that apoB and non–HDL-C were equivalent in predicting risk. How can their findings be reconciled with those of Pischon et al? [2]
Without much difficulty, I believe. The study by Ridker and associates [5] was conducted in healthy middle-age women, a group at low risk in which relatively few subjects would have increased numbers of small, dense LDL particles, the group in which apoB has greatest predictive value. By contrast, Pischon and colleagues [2] studied men, a group with higher risk and with a much higher incidence of hyperapoB. It should not be surprising that risk markers that are indistinguishable in low-risk populations can be separated in higher-risk groups. The results, therefore, are complementary, not contradictory.
The central thesis of the cholesterol hypothesis is that the extent of disease within the arterial wall is a simple and direct function of the amount of cholesterol deposited within the wall which, in turn, is a simple and direct function of the amount of cholesterol within the atherogenic lipoproteins. That view is no longer tenable. Atherosclerosis is a complex series of biological responses to the trapping of an atherogenic particle within the arterial wall, not simply a piling up of cholesterol. Injury to the endothelium, oxidation of the apoB and phospholipids as well as the cholesterol within the LDL particle, and uptake of LDL by macrophages all trigger a wide, intricate, and damaging series of inflammatory and healing responses.
The prime mover in the sequence is the entry and trapping of an atherogenic particle within the arterial wall. Cholesterol is carried into the wall within a particle. It is a passenger and the whole vehicle, including the passenger, matter more than just the passenger. Furthermore, cholesterol captures only a portion of the risk resulting from atherogenic particles because neither LDL nor non–HDL-C translates accurately into atherogenic particle number. Very LDL-C (VLDL-C) can easily account for 25% of non–HDL-C, but the cholesterol within VLDL is not as dangerous as the cholesterol within LDL because the larger VLDL particles are less likely than the smaller LDL particles to enter the arterial wall. [14] Each atherogenic particle contains 1 molecule of apoB, and therefore plasma apoB represents the total atherogenic particle number. [15] Except for the rare instance of type III hyperlipoproteinemia, LDL accounts for about 90% of the atherogenic particles in plasma; thus, LDL apoB determines plasma apoB. [15]
If apoB and non–HDL-C are metabolically equivalent, they should keep the same biological company. Not so: ApoB is more closely associated with increased body mass index, abdominal obesity, hyperglycemia, insulin resistance, and prothrombogenic and proinflammatory markers than non–HDL-C.[16,17] In other words, apoB relates more closely to the other features of the metabolic syndrome than non–HDL-C. On these grounds, apoB, not non–HDL-C, should be the proatherogenic index of choice in these patients.
Finally, was ATP III right to assume equivalence of apoB and non–HDL-C simply because they correlate? Obviously not, if they differ in prognostic power and metabolic associations. There is yet another issue—the inherent limitation of correlation to demonstrate equivalence. Correlation quantifies the tendency for changes in 1 variable to be reflected by changes in the other whereas concordance quantifies the extent to which changes in 1 variable reflect the same changes in the other. Non–HDL-C and apoB are highly correlated but only moderately concordant. [16] This means that estimates of risk for an individual by 1 method will frequently differ substantially from the risk predicted by the other. Unfortunately, little attention has been paid to this error in the evaluation of individuals.
The National Cholesterol Education Program faces tough choices. If LDL-C remains in third place as a risk predictor and therapeutic target, then it must be replaced in their diagnostic and treatment algorithms. Of the 2 choices, apoB and non–HDL-C, apoB has been more extensively validated in epidemiological studies and clinical trials [14] and therefore is the evidence-based choice. Moreover, which will be more comprehensible to patients and physicians: non–HDL-C, which is defined negatively as all of the cholesterol that is not HDL-C, or apoB, which is defined positively as total atherogenic particle number? In addition, the measurement of apoB is standardized, automated, inexpensive, and fasting samples are not required. [18]
Clinical practice cannot change because apoB is not in the guidelines. Is this justifiable? There is no evidence that any of the cholesterol indices are superior; on the contrary, the evidence is considerable that they are not. On what grounds should the apolipoproteins remain excluded, even as an alternative? Guidelines may not intend to retard advances in care, but they can. The cholesterol-based algorithm has become progressively more complex over time whereas apolipoproteins offer the opportunity to simplify and improve care simultaneously. The first major studies showing the value of apoB appeared 25 years ago.[19,20] The results of Pischon et al [2] add urgency to the effort to revise how we determine the lipoprotein-related risk of vascular disease.

References
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