Using Apolipoprotein B to Manage Dyslipidemic Patients: Time for a Change?

Low-density lipoprotein cholesterol (LDL-C) concentration has been established as an independent risk factor for the development of atherosclerosis; consequently, multiple practice guidelines recognize LDL-C as the primary target of therapy.1,2 For decades, considerable effort has been committed to educating physicians and the general public about the importance of lowering LDL-C levels. Despite the extensive data relating LDL-C to atherosclerosis, some have suggested that focusing only on LDL-C may not be an optimal strategy.3 Several limitations exist for an approach that focuses only on LDL-C: (1) evidence is increasing that triglyceride-rich lipoproteins, including very low-density lipoproteins (VLDL) and intermediate-density lipoproteins (IDL) (Figure 1)4 are also atherogenic5,6; and (2) a substantial percentage of patients with atherosclerotic vascular disease have LDL-C in the optimal range.7 Furthermore, many patients who receive treatment and achieve recommended LDL-C goals even lower than 70 mg/dL (to convert to mmol/L, multiply by 0.0259) still develop the complications of atherosclerotic vascular disease, which is referred to as residual risk.8 One explanation for these discrepancies is the mismatch that has been described in many patients between the LDL-C concentration reported on a basic lipid panel and the number of atherogenic lipid particles, which is often expressed as low-density lipoprotein (LDL) particle number or the number of apolipoprotein B (apo B)–containing lipoproteins.9 The reason for this mismatch is that LDL particles are extremely heterogeneous with respect to the amount of cholesterol contained in the LDL particle core.10 Patients with a predominance of cholesterol-depleted LDL particles (also called small dense LDL-C) may have a low LDL “cholesterol” concentration as reported on the standard lipid panel but still have a large number of circulating atherogenic LDL particles.11 For example, 2 patients with the same LDL-C concentration on a basic lipid panel may have markedly different LDL particle numbers and different cardiovascular risk (Figure 2).12 Extrapolating information concerning the number of atherogenic LDL particles from the LDL-C content is an unreliable strategy. FIGURE 1. Lipoprotein subclasses and apolipoprotein (apo) B–containing lipoproteins. HDL = high-density lipoprotein; iDL = intermediate-density lipoprotein; LDL = low-density lipoprotein; VLDL = very low-density lipoprotein. FIGURE 2. Same low-density lipoprotein cholesterol (LDL-C) levels, different cardiovascular risk. apo = apolipoprotein. SI conversion factors: To convert LDL-C value to mmol/L, multiply by 0.0259. Recently, some expert panels and national organizations have proposed using apo B in conjunction with standard lipid testing to address the aforementioned limitations.13 Apo B is a key structural component of all the atherogenic lipoprotein particles, including LDL, VLDL, and IDL. Each of these atherogenic particles carries only one apo B molecule; thus, the total apo B level represents the total number of circulating atherogenic lipoprotein particles and provides the clinician a more accurate picture of a patient's risk of cardiovascular events.13 Other advantages to the measurement of apo B include the fact that it does not require a fasting specimen, its relative low cost, and the existence of a World Health Organization–approved standard. Alternatively, some experts advocate calculating and using non–high-density lipoprotein cholesterol (non–HDL-C) instead of LDL-C to improve risk prediction in certain groups of patients, particularly in those with elevated triglyceride values.1 The National Cholesterol Education Program (NCEP)/Adult Treatment Panel (ATP) III guidelines recommend that, in patients with triglyceride levels of 200 mg/dL or higher, non–HDL-C should be calculated and the goal set at 30 mg/dL higher than the LDL-C goal (Table1).1 Substantial evidence supports the idea that non–HDL-C is clearly superior to LDL-C for cardiovascular disease risk prediction. Non–HDL-C is calculated by subtracting the HDL-C from the total cholesterol, and it represents the cholesterol concentration of all atherogenic lipoproteins.14,15 Although non–HDL-C is a good surrogate measure of apo B, it does not measure the same thing. Non–HDL-C measures the “cholesterol” content of all atherogenic lipoproteins (LDL, IDL, and VLDL), whereas apo B represents the total number of circulating atherogenic particles. Although substantial evidence supports the idea that non–HDL-C is clearly superior to LDL-C for cardiovascular disease risk prediction, strong evidence shows that apo B may be superior to both LDL-C and non–HDL-C for both risk stratification and determination of goal attainment during therapy. TABLE 1. ATP III LDL-C Goals and Cutpoints for Drug Therapya In this commentary, we propose how apo B might be used by clinicians involved in the primary and secondary prevention of coronary heart disease. First, we briefly discuss the evidence that suggests the superiority of apo B as a risk predictor compared to non–HDL-C and LDL-C. Then, we suggest certain patient populations in whom clinicians may wish to target apo B because of demonstrated superiority to LDL-C, including those with diabetes and those receiving statin therapy. Finally, we discuss current recommendations for apo B goals of therapy and the evidence for these goals.