Author + information
- Received May 23, 2012
- Revision received May 30, 2012
- Accepted June 5, 2012
- Published online December 25, 2012.
- Michael H. Davidson, MD⁎ ()
- ↵⁎Reprints and correspondence:
Dr. Michael H. Davidson, The University of Chicago Pritzker School of Medicine, 515 North State Street, Suite 2700, Chicago, Illinois 60654
In the field of lipidology, there is a passionate debate regarding the clinical utility of advanced lipoprotein analysis. In the accompanying viewpoint, Jennifer Robinson presents the opinion that there is insufficient evidence to support the use of advanced lipid analysis (i.e., apolipoprotein B-100 [apo B] or low-density lipoprotein particle number [LDL-P]) in clinical practice based on a lack of evidence that these additional tests improve patient outcomes (1). Although this opinion may represent the majority view among lipidologists, there are dissenting opinions that advocate for the role of these additional measures of lipoproteins to further enhance cardiovascular risk prediction and potentially adjust therapy accordingly. The American Diabetes Association/American College of Cardiology Consensus Statement on Lipoprotein and Cardiometabolic Risk (2), and the National Lipid Association Expert Panel on Biomarkers and Lipoprotein Analysis (3) supported measures of apo B or LDL-P as reasonable in certain clinical settings or patient populations. The disagreement between experts involves the clinical utility of a lipid measure as a risk predictor in a large group of patients versus an individual patient. Basically, if 2 measures of lipoproteins are discordant, which one correctly predicts the risk for that individual patient?
LDL-cholesterol (LDL-C), a measure of the cholesterol content within LDL, became the primary goal of therapy for historic reasons, although there was considerable evidence that the triglyceride-rich very low-density lipoprotein (VLDL) and the remnant lipoproteins are also atherogenic. The CARE (Cholesterol and Recurrent Events) study found that VLDL-C, apo B, and apo C-III are potent predictors of events (4). The CHICAGO (Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone) study found that triglyceride-rich lipoprotein cholesterol (non–high-density lipoprotein-cholesterol [non–HDL-C] minus directly measured LDL-C) showed the greatest association with coronary calcium (5). A recent large meta-analysis with >60,000 patients in statin trials found that when LDL-C was low (LDL-C <100 mg/dl), but non–HDL-C was elevated (non–HDL-C >130 mg/dl) (6), there was an increase in cardiovascular events compared with those with both elevated LDL-C and non–HDL-C (1). Although both lipid profiles represent a patient at high residual risk for a major adverse cardiac event, the patient with the low LDL-C (<100 mg/dl), but with a discordantly high non–HDL-C (>130 mg/dl), is the type of patient who may slip through the cracks because the at-goal LDL-C may mislead the clinician into believing the patient is adequately treated. This new study continues to add to the evidence that non–HDL-C outperforms LDL-C as a risk predictor for patients on a statin. However, a recent survey showed that 44% of providers in practice could not calculate non–HDL-C levels when provided a standard lipid profile, and cardiologists were just as likely as primary care physicians to not understand the calculation or know the non–HDL-C goal of therapy (7).
Should non–HDL-C replace LDL-C as the main target of therapy? The advantages appear clear: non–HDL-C is a better risk predictor, can be performed in a nonfasting state, and does not incur any additional costs to the healthcare system. However, does apo B or LDL-P outperform non–HDL-C as a risk predictor? LDL-C or non–HDL-C are measures of the cholesterol content within the atherogenic lipoproteins, although apo B or LDL-P are parameters that assess the number of atherogenic particles. The answers depends if you evaluate the data for a group of patients or in an individual patient. The meta-analysis of the Emerging Risk Factor Collaboration and the recent analysis of the major statin trials demonstrated that the hazard ratios for non–HDL-C or apo B for major adverse cardiac events did not differ significantly (8). Nevertheless, there are frequent examples of individual patients who have normal non–HDL-C levels and elevated measures of apo B or LDL-P. In studies that evaluated patients with discordance (low levels of cholesterol content but high levels of the measures of the particle number), the measures of particle number frequently outperformed measures of the cholesterol content as risk predictors (9,10). This is the evidence that led expert panels to consider apo B or LDL-P testing in patients who are more likely to have discordance (metabolic syndrome, diabetes, or premature coronary heart disease). Once an individual patient achieves their non–HDL-C target of therapy, consideration can be given for advanced lipoprotein analysis to ascertain if measures of atherogenic particle concentration are also well controlled, and if not, adjust therapy accordingly. Measuring both non–HDL-C and apo B or LDL-P are potentially complementary. When apo B or LDL-P is disproportionately high, particles measure should guide management. In contrast, apo B or LDL-P is insensitive to remnant particles, whereas plasma lipids, in particular cholesterol and triglyceride, do reflect the impact of these atherogenic lipoproteins. Accordingly, when non–HDL-C is disproportionately high, particularly in hypertriglyceridemic patients, non–HDL-C should guide management (9). Although this approach does not yet have an evidence-based clinical trial demonstrating improved outcomes, there remains a consensus that residual risk despite statin therapy remains a challenging and important unmet medical need.
Dr. Davidson is on the advisory board and is a consultant for Amgen, AstraZeneca, Merck, and Sanofi-Aventis; he is also a stockholder and Chief Medical Officer for Omthera Pharmaceuticals, Inc.
- Received May 23, 2012.
- Revision received May 30, 2012.
- Accepted June 5, 2012.
- American College of Cardiology Foundation
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