Non-HDL cholesterol: into the spotlight.

The elevated coronary heart disease (CHD) risk affecting patients with type 2 diabetes may be attributed to a combined dyslipidemia characterized by elevated triglycerides, reduced HDL cholesterol, small dense LDL particles (independent of the LDL cholesterol level), elevated triglyceride-rich remnant lipoproteins (TGRLs), and/or elevated apolipoprotein B (apoB) levels (1). All of these features have individually been implicated as contributors to CHD. Some reports suggest that the combined dyslipidemia may confer a higher magnitude of risk than elevated LDL cholesterol alone (2). The role of triglycerides as a risk factor has been controversial. Much of its risk may be attributed to the associated low HDL cholesterol level, along with contributions from all of the other related variables. Although triglycerides do appear to be an independent risk factor (3), they likely act only as a marker for these associated features. The measurement of apoB has been advocated as an alternative index (4). Since each LDL particle contains a single apoB molecule, the apoB level reflects particle number, thus not only accounting for both remnant and LDL particles but also the density of particles when expressed in relation to particle cholesterol content. Despite these advantages, even the global standardization of apoB assays (5) has not made it routinely available to the clinician. This may be in part due to a general unfamiliarity with its interpretation outside of the research setting and because existing guidelines do not take advantage of the information it imparts. Its cost relative to its potential advantages for clinical decision-making also has not been adequately explored. Existing guidelines, however, do take advantage of non–HDL cholesterol as an index of risk associated with this combined dyslipidemia. The recognition of this index is not new; this “beta” lipoprotein cholesterol fraction has been associated with increased CHD mortality in population-based studies that began in the 1950s (6). Non–HDL cholesterol is simply defined as the difference between total and HDL cholesterol and, thus, represents cholesterol carried on all of the potentially proatherogenic apoBcontaining particles [primarily VLDL, IDL, and LDL as well as chylomicron remnants and lipoprotein(a)]. Many reports confirm a strong correlation between non–HDL cholesterol and apoB (7). In assessing the value of non–HDL cholesterol, it should be remembered that our routine determination of LDL cholesterol is not a measurement, but rather a calculation based on a measurement of triglycerides, total cholesterol, and HDL cholesterol, using the formula of Friedewald (8). The calculated LDL cholesterol level has been shown to be significantly different than a direct LDL cholesterol measurement by ultracentrifugation in type 2 diabetic patients (9). In fact, its very nature is to exclude the cholesterol of TGRLs, which are proatherogenic. Thus, for diabetic patients with the combined dyslipidemia, calculated LDL cholesterol fails to be an adequate index of overall lipid-associated risk. The Third Adult Treatment Panel (ATP III) of the National Cholesterol Education Program (NCEP) has recommended the use of non–HDL cholesterol as a secondary target of lipid lowering, after achieving adequate control of LDL cholesterol and if triglycerides are elevated ( 200 mg/dl) (10). Because of its simple calculation, the non–HDL cholesterol level is easily available to the clinician with every lipid profile ordered, thus eliminating any additional costs. Because it circumvents the measurement of triglycerides, it avoids the potential limitation of triglycerides as a mere marker of CHD risk and instead directly reflects the cholesterol content of all particles that may be proatherogenic. Also, its derivation does not require a lipid profile to be done in the fasting state, and it avoids the potential inaccuracy caused by the inherent intraindividual variability of the triglyceride measurements. A routine calculated LDL cholesterol level cannot circumvent most of these limitations. The Friedewald equation requires a fasting triglyceride level 400 mg/dl in order to accurately calculate LDL cholesterol. Thus, in many cases of fasting hypertriglyceridemia common in diabetes, the clinician has no reliable estimate of LDL cholesterol, and therefore no objective index of lipid-associated CHD risk, unless ultracentrifugation is performed. Recently, an immunoseparation technique for a direct LDL cholesterol determination has been proposed as an alternative to the labor-intensive ultracentrifugation reference method. However, comparison studies demonstrate that in some hypertriglyceridemic samples, a significant bias (usually an overestimate) still exists with this method (11,12). Whiting et al. (13) have reported that the error of this method as a function of hypertriglyceridemia in diabetic patients is greater than that of the Friedewald calculation. In contrast, the non–HDL cholesterol level of a hypertriglyceridemic patient would still be available to the clinician, and could potentially be more accurate than either the directly measured or the calculated LDL cholesterol level (14). Non–HDL cholesterol thus represents a readily obtainable, inexpensive, and convenient measure of CHD risk that may be superior to LDL cholesterol in many respects. All that remains is for its reliability as a predictor of CHD risk to be established. The article by Lu et al. (15) in this issue of Diabetes Care highlights the predictive value of non–HDL cholesterol for CHD and the role that it may play in the management of diabetic dyslipidemia. Many cross-sectional and prospective studies have demonstrated the value of non–HDL cholesterol as an index of CHD risk across different populations, including Europeans (6,16,17), Hawaiians (18), and cohorts in the U.S. (19–21). Non– HDL cholesterol appears to track with multiple CHD risk factors in U.S. ethnic minorities that are disproportionately affected by diabetes (22–24). Previous studies in diabetic subjects also used surrogate indexes such as intima-media thickness (25,26). In these respects, the article of Lu et al. (15) adds to the literature by establishing, in a prospective study, the predictive value of non–HDL cholesterol for clinical end points in a high-risk, ethnic diabetic population. 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