Using Apolipoprotein B to Manage Dyslipidemia–Reply–I

We appreciate the excellent discussion of the merits of measuring non–HDL-C provided by Lavie et al1 and the insightful comments from Robinson. However, we still believe that apo B has 2 major advantages compared with non–HDL-C. It is superior to non–HDL-C as a measure of cardiovascular risk and as a measure of the adequacy of lipid-lowering therapy. The first advantage we thoroughly discussed in our article but now further expand. Although a few studies may show that non–HDL-C is equivalent to apo B as a predictor of risk, most clearly demonstrate the superiority of apo B. In fact, we are not aware of any published studies to date that demonstrate the superiority of non–HDL-C compared with apo B. The Emerging Risk Factor Collaboration meta-analysis2 quoted by Robinson has several methodological limitations because it arbitrarily excluded the 2 largest case-control studies in the literature that compared apo B to non–HDL-C. In addition, the study found the rather unexpected result that the measurement of non–HDL-C was no better than the measurement of directly measured LDL-C. Therefore, relying on the results of that study would also negate the use of non-HDL-C as an alternative marker of risk. This meta-analysis has several other important limitations as pointed out by others.3 Regarding the last point by Robinson that apo B is not as useful as non–HDL-C in predicting risk in statin-treated patients, we are not aware of any published literature that supports this statement. Several studies show the superiority of apo B vs LDL-C or non–HDL-C, including the AFCAPS/TexCaps (Air Force/Texas Coronary Atherosclerosis Prevention Study),4 LIPID (Long-term Intervention with Pravastatin in Ischemic Disease),5 IDEAL (Incremental Decrease in End Points through Aggressive Lipid Lowering),6 and PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22)7 studies. In the study by Kastelein et al8 and cited by Robinson, both apo B and non–HDL-C were clearly superior to LDL-C in predicting risk in statin-treated patients. However, we believe that apo B is still better than non–HDL-C in identifying patients who continue to have moderately elevated levels of atherogenic particles and who might benefit from further therapy. In their excellent commentary supporting the guidelines and non–HDL-C, Lavie et al discuss the recent JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin)9 in primary prevention in patients with low LDL-C ( 2 mg/L) values and suggest that CRP should be considered a target of therapy. In fact, an alternative interpretation of JUPITER is that it may be more a trial of apo B than of inflammation. In JUPITER, the mean baseline LDL-C was low (108 mg/dL, ie, about the 20th percentile for the US population) and the mean non–HDL-C was also low (132 mg/dL; about the 30th percentile). However, the average apo B level (109 mg/dL) was moderately high at the 60th percentile in men and the 70th percentile in women.10 Thus, almost half the JUPITER patients had frankly elevated levels of apo B. Although the investigators attributed the benefits in JUPITER to finding patients at increased risk based on CRP level, an alternative viewpoint is that CRP identified those at increased risk due to elevated apo B levels despite normal baseline LDL-C and non–HDL-C levels. Thus, JUPITER may be the most important new evidence about the potential usefulness of apo B for both risk identification and treatment. Indeed, JUPITER may be more about targeting elevated apo B–containing lipoproteins than about targeting inflammation per se. Another advantage of apo B is that it will simplify the management of dyslipidemia for busy clinicians. Non–HDL-C is not a new concept; it was defined and described decades ago and has been a secondary goal in the NCEP/ATP (National Cholesterol Education Program/Adult Treatment Panel) III guidelines for many years. However, non–HDL-C has not resonated with or been adopted by busy clinicians despite ample medical education and ongoing efforts to have it listed on all routine lipid laboratory reports.11 Also, non–HDL-C is a concept that may not be as easily grasped as is apo B. Apo B is a simple concept because it is an integral part of each and every atherogenic particle and it is a direct measure of the total number of atherogenic particles present. Acceptance of a new biomarker in coronary heart disease risk prediction is often difficult because it challenges the status quo. However, apo B meets most of the requirements for the acceptance of a new biomarker, particularly when using the criteria recently proposed by the American Heart Association.12 In the Table, the properties of non-HDL-C are compared to those of apo B from the perspective of the requirements for a new biomarker and some of the practical considerations for its use (eg, availability, reliability, cost). Apo B performs as well as non-HDL-C in most measures, and it is clearly superior to non-HDL-C in cardiovascular disease risk prediction and probably superior in assessing the adequacy of therapy in statin-treated patients. The only evaluation that has not been completed for apo B, or for non–HDL-C, is whether the measurement of apo B (or non–HDL-C) in a clinical setting improves patient outcomes compared with patients managed in the conventional manner. Although this would be an important trial, it is unlikely that such a trial will be performed in the near future or before the release of the new NCEP/ATP IV guidelines. TABLE. Considerations for a New Biomarker: Non–HDL-C vs Apo Ba Finally, a careful review of our commentary indicates that our recommendation is not to completely “supplant” non–HDL-C with apo B in the guidelines, but rather to use it in addition to non–HDL-C. Integrating apo B with the standard lipid profile may also allow conventional laboratories to assist with the diagnosis of the major atherogenic apo B dyslipoproteinemias, including familial combined hyperlipidemia and familial dysbetalipoproteinemia.13 We acknowledge that changing national guidelines is difficult, but it is time to confront the limitations of non–HDL-C and at the very least give physicians the option of incorporating apo B into their management strategies. The simplicity and elegance of apo B as a measurement of the total atherogenic lipoparticle burden cannot be overstated. Albert Einstein once said “Everything should be made as simple as possible but no simpler.”