Apolipoprotein B versus lipoprotein lipids: vital lessons from the AFCAPS/TexCAPS trial.

© 2001 Canadian Medical Association or its licensors In his Nobel laureate address, Joseph Goldstein referred to cholesterol as the most decorated molecule in history, and certainly there is a lot of evidence relating the levels of total and low-density lipoprotein (LDL) cholesterol to the risk of vascular disease. But does that mean that they will remain tomorrow in the central position that they occupy today? We believe that the answer may well be No, because plasma apolipoprotein B (apo B) appears to be a better marker of the risk due to the atherogenic lipoproteins, namely, very low-density lipoprotein (VLDL) and LDL. The latest critical piece of evidence comes from the AFCAPS/TexCAPS study, which tested whether treatment with lovastatin would reduce the frequency of coronary events in a large asymptomatic group of individuals who did not have marked hypercholesterolemia, many of whom also had low levels of high-density lipoprotein (HDL) cholesterol. Several of these researchers subsequently considered which lipid variables predicted clinical benefit before and during therapy. LDL cholesterol was not the most informative parameter. Rather, the most valuable turned out to be apo B. The authors write, “Apo B was in fact the single most significant and consistent lipid measurement to predict risk at both baseline and on-treatment.” Because apo B is neither generally measured nor familiar to most Canadian practitioners, we believe that their findings, taken with the other evidence that is available, merit serious attention. Within a population, as the levels of cholesterol rise, so does the risk of coronary disease and, unquestionably, individuals with very high levels of cholesterol are at very high risk. However, only a small portion of the population have very high levels of cholesterol. It is not generally appreciated that a major finding of the Framingham study is that most cases of premature vascular disease occurred in individuals with levels of total and LDL cholesterol that were indistinguishable from those of individuals who did not develop premature disease. Moreover, except for those individuals with extremely high values, only a minority at any level will develop premature disease. Thus, cholesterol is a good marker of risk within a large group but, for the most part, is a relatively poor marker of risk for its individual members. One result of this paradox has been a successive lowering of the definition of “high” cholesterol, with the desirable level now being designated as a less than 5.2 mmol/L of total cholesterol and less than 3.4 mmol/L of LDL cholesterol. The drawback to this approach is that about 50% of our population will automatically be designated “hypercholesterolemic.” Even so, 40% of individuals with premature vascular disease will have levels of total and LDL cholesterol below those of the 50th percentile of the population. Measurement of HDL cholesterol and triglycerides does improve the recognition of risk, with lower levels of the former and higher levels of the latter being associated with an increased likelihood of disease. But the questions remain: Can we do better to recognize those at risk and — equally important — can we make clinical practice simpler? The liver secretes a triglyceride-rich lipoprotein, VLDL, which by the removal of most of its triglyceride is converted to a smaller cholesterol-rich lipoprotein, LDL. The biologic half-life of an LDL particle is at least 9 times longer than that of a VLDL particle and, therefore, there are always 9 times more LDL particles than VLDL particles (Fig. 1). Because each VLDL and LDL particle contains one molecule of apo B, measuring plasma apo B measures exactly the total number of VLDL and LDL particles, 90% of which are LDL. In contrast, because LDL particles differ substantially from one another in the amount of cholesterol they contain, total and LDL cholesterol are imprecise measures of the number of apo B particles. Measuring apo B, therefore, provides a direct estimate of the total number of atherogenic particles. The measurement of plasma apo B is standardized, automated and inexpensive. It can be performed on nonfasting samples, and population reference values are now available. The most common atherogenic dyslipoproteinemia consists of mild to moderate hypertriglyceridemia, low HDL cholesterol and increased numbers of small dense LDL particles (Fig. 1). These are the consequence of increased secretion of VLDL particles by the liver. This, in addition to increased “core lipid exchange,” results in the formation of increased numbers of small dense LDL particles and low HDL cholesterol. It should be noted that because the cholesterol content is reduced in small dense LDL, the LDL and total cholesterol levels may be normal even when the number of LDL particles is elevated. A series of basic studies have shown that, particle for particle, small dense LDL particles are more atherogenic than the larger, more cholesterol-rich LDL particles. These are critical findings but they form only part of the evidence. Data from a series of prospective double-blind trials that tested the effect of various LDL-lowering regimens on the rate of progression or regression, or both, of angiographically evident coronary disease showed that a benefit was associated with the reduction in levels of small dense LDL. There have also been several prospective Apolipoprotein B versus lipoprotein lipids: vital lessons from the AFCAPS/TexCAPS trial