National guidelines for primary and secondary prevention of coronary heart disease (CHD) recommend lowering low-density lipoprotein (LDL) cholesterol to specific values based on other risk factors. However, other cholesterol particles contribute to atherosclerosis, and a small number of patients with acceptable LDL cholesterol levels may have an increased CHD risk. Non–high-density lipoprotein (non-HDL) cholesterol (i.e., total cholesterol minus HDL cholesterol) and apolipoprotein B (APOB) measurements may predict CHD risk with greater accuracy than LDL cholesterol measurements. Pischon and colleagues compared the predictive values of LDL cholesterol, non-HDL cholesterol, and APOB for nonfatal and fatal CHD.

The case-control study included data from the Health Professionals Follow-up Study, which involved 51,529 male health professionals in the United States who were 40 to 75 years of age. Participants provided blood samples at enrollment and completed questionnaires about lifestyle and health status every two years during the study. The current study identified participants without previous CHD who provided blood samples between 1993 and 1995 and suffered nonfatal myocardial infarctions or fatal CHD (ascertained by hospital records, autopsy reports, and death certificates) during the six-year follow-up. Randomly selected control participants were matched based on age, date of blood draw, and smoking status. Participants who used cholesterol-lowering drugs were excluded. The final analysis included 243 participants and 496 in the control group. Participants were more likely than those in the control group to have a history of diabetes or hypertension; aspirin use was similar in both groups. Participants were divided into five groups based on their three lipid marker levels.

Although elevated levels of all three markers strongly predicted CHD, APOB outperformed non-HDL cholesterol and LDL cholesterol. When participants with the highest levels were compared with those with the lowest levels, the relative risks for CHD were 3.01 (95% confidence interval [CI], 1.81 to 5.00) for APOB, 2.76 (95% CI, 1.66 to 4.58) for non-HDL cholesterol, and 1.81 (95% CI, 1.12 to 2.93) for LDL cholesterol. Notably, after adjustment for the LDL cholesterol level, an elevated APOB level correlated with elevated CHD risk, but an elevated non-HDL cholesterol level did not.

The authors conclude that APOB and non-HDL cholesterol measurements are superior to LDL cholesterol measurements in predicting CHD risk in men. Noting that APOB identified a subset of high-risk patients with low or average levels of the other two markers, the authors suggest that substituting APOB for current cholesterol measurements should be considered.

editor's note: Two editorialists in the same issue of Circulation debate whether this study is persuasive enough for the National Cholesterol Education Program to replace low-density lipoprotein (LDL) cholesterol with apolipoprotein B (APOB) in the next version of its Adult Treatment Panel (ATP) guideline.^1,2 The 2002 ATP guideline (ATP III) suggests using non–high-density lipoprotein (non-HDL) cholesterol as a secondary target only for patients with hypertriglyceridemia and metabolic syndrome; it does not recommend APOB testing. On one hand, APOB testing costs less than a standard lipid profile; does not require a fasting sample; and, in this study, was more likely than non-HDL cholesterol to identify patients with low LDL cholesterol levels who were at a high CHD risk. On the other hand, the marginal additional predictive value of APOB compared with non-HDL cholesterol, which is calculated from the lipid profile, may not be worth instituting such a dramatic, and most likely confusing, change in practice. While awaiting the verdict, physicians should remember that CHD risk is a global assessment, of which cholesterol is only one component —K.W.L.