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Systematic Review: Association of Low-Density Lipoprotein Subfractions With Cardiovascular Outcomes

Stanley Ip, MD; Alice H. Lichtenstein, ScD; Mei Chung, MPH; Joseph Lau, MD; and Ethan M. Balk, MD, MPH
[+] Article, Author, and Disclosure Information

From Tufts Medical Center and Tufts University, Boston, Massachusetts.

Disclaimer: This report is based on an update of a technology assessment performed as part of the Evidence-based Practice Center program of the Agency for Healthcare Research and Quality. The technology assessment was performed by request of the Centers for Medicare & Medicaid Services (Centers for Medicare & Medicaid Services. Low Density Lipoprotein Subfractions: Systematic Review of Measurement Methods and Association with Cardiovascular Outcomes. Accessed at http://www1.cms.hhs.gov/mcd/viewtechassess.asp?where=index&tid=56 3 February 2009), in response to a public hearing on lipoprotein subfractions held by the U.S. Food and Drug Administration in December 2006 (U.S. Food and Drug Administration. Clinical Chemistry and Clinical Toxicology Devices Panel of the Medical Advisory Committee. Accessed at http://www.fda.gov/OHRMS/DOCKETS/ac/06/transcripts/2006-4263t1-01t.pdf February 2009). The Agency for Healthcare Research and Quality participated in determining the key questions, defining the methodology, and reviewing and approving the technology assessment and the manuscript. However, the authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.

Grant Support: By the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services, under contract 290-02-0022.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Ethan M. Balk, MD, MPH, Tufts Evidence-based Practice Center, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Box 63, 800 Washington Street, Boston, MA 02111; e-mail, ebalk@tuftsmedicalcenter.org.

Current Author Addresses: Drs. Ip, Lau, and Balk and Ms. Chung: Tufts Medical Center, 800 Washington Street, Box 63, Boston, MA 02111.

Dr. Lichtenstein: Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, 711 Washington Street, Boston, MA 02111.

Ann Intern Med. 2009;150(7):474-484. doi:10.7326/0003-4819-150-7-200904070-00007
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Background: Measures of low-density lipoprotein (LDL) subfractions have been proposed as an independent risk factor for cardiovascular disease.

Purpose: To review published studies that reported relationships between LDL subfractions and cardiovascular outcomes.

Data Sources: MEDLINE (1950 to 5 January 2009), CAB Abstracts (1973 to 30 June 2008), and Cochrane Central Register of Controlled Trials (2nd quarter of 2008), limited to English-language studies.

Study Selection: 3 reviewers selected longitudinal studies with 10 or more participants that reported an association between LDL subfractions and incidence or severity of cardiovascular disease and in which plasma samples were collected before outcome determination.

Data Extraction: Data were extracted from 24 studies. The 10 studies that used analytical methods available for clinical use (all of which used nuclear magnetic resonance) had full data extraction, including quality assessment (good, fair, or poor). All studies were extracted by 1 researcher and verified by another.

Data Synthesis: All 24 studies, and the subset of 10 nuclear magnetic resonance studies, were heterogeneous in terms of the specific tests analyzed, analytical methods used, participants investigated, and outcomes measured. Higher LDL particle number was consistently associated with increased risk for cardiovascular disease, independent of other lipid measurements. Other LDL subfractions were generally not associated with cardiovascular disease after adjustment for cholesterol concentrations. No study evaluated the incremental value of LDL subfractions beyond traditional cardiovascular risk factors or their test performance.

Limitation: Publication bias was a possibility.

Conclusion: Higher LDL particle number has been associated with cardiovascular disease incidence, but studies have not determined whether any measures of LDL subfractions add incremental benefit to traditional risk factor assessment. Routine use of clinically available LDL subfraction tests to estimate cardiovascular disease risk is premature.


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Study flow diagram.

CVD = cardiovascular disease; NMR = nuclear magnetic resonance.

* Description of methods used to measure low-density lipoprotein (LDL) subfractions, comparison of different methods, variability of measures, link between therapies to alter LDL subfractions and CVD outcomes, and association between LDL subfractions and incident and prevalent CVD.

† No clinical CVD outcome, not LDL subfractions, not an analysis of baseline lipoprotein subfractions, or no original data.

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LDL Particle Concentrations and LDL Subfractions Do Not Equate
Posted on July 28, 2009
Robert Rosenson
No Affiliation
Conflict of Interest: None Declared

In the April 2009 issue of the Journal, Dr. Ip et al (1) provided an extensive review of the association of low-density lipoprotein (LDL) subfractions with cardiovascular outcomes. The objective of the paper was to review published studies that reported relationships between LDL subfractions. However, throughout the paper the authors were intertwining and equating LDL particle concentration and LDL subfractions, misinterpreting the ADA/ACC consensus paper, and misrepresenting the use of lipoprotein subfractions by clinical laboratories (i.e. NMR measurement method).

LDL particle concentration and LDL subfractions do not equate. The role of LDL particles in the pathogenesis of atherosclerosis is well established. LDL cholesterol (LDL-C) has long been the basis for measuring patients for coronary heart disease (CHD) risk because its measurement is relatively easy. However, LDL-C is a surrogate marker for LDL-P. Despite the success of cholesterol screening and LDL-lowering therapy, it has been recognized that many patients with low or moderate LDL-C levels experience CHD events (2). It is well documented that the cholesterol and triglyceride content of LDL particles varies from person to person because of differences in particle size and lipid composition. Hence, two patients who have the same measured LDL-C concentrations can have significantly different numbers of LDL particles and therefore a different risk for cardiovascular disease (CVD). The limitation of testing LDL-C is that cholesterol is only one type of lipid carried within LDL particle containers and its measurement provides only an approximation of the numbers of LDL particles. Furthermore, it is recognized that certain patients have elevated numbers of atherogenic LDL particles despite having desirable levels of LDL-C. As a result, the American Diabetes Association convened a consensus in July of 2007 focusing on lipoprotein management in patients with cardiometabolic risk (CMR)(2). A panel of experts developed a consensus position on lipoprotein management in patients with cardiometabolic risk. They suggested that even with adequate LDL cholesterol lowering, many patients on statin therapy have significant residual cardiovascular disease (CVD) risk. A more accurate way to capture the risk posed by LDL may be the measurement of LDL particles directly using nuclear magnetic resonance (NMR) or ApoB.

Following the ADA/ACC consensus paper, the American Association for Clinical Chemistry (AACC) published their position statement on the role of lipoprotein and cardiovascular disease risk (3). In their findings, they suggested that LDL-P is consistently more predictive of cardiovascular disease than is LDL-C. A reduction in apo B and LDL particles, rather than LDL-C, is a better target for monitoring therapeutic effectiveness and residual risk. Patient treated to goal for LDL-C may not have achieved correspondingly low LDL particle concentrations, leaving them with potential residual risk. Furthermore, they stated that Non-HDL-C, like LDL-C, reflects the cholesterol content of atherogenic particles and not the number of atherogenic particles. Therefore, on treatment non-HDL-C concentrations may not reflect residual risk associated with increased LDL particle number.

With respect to the role of lipoprotein subfractions and its clinical utility, the NMR measurement method in the commercial clinical laboratory uses the information for metabolic syndrome markers. Patients with diabetes commonly have dyslipidemia, with an increase in small low density lipoprotein particle concentration (LDL-P), a reduction in large high- density lipoprotein particle concentration (HDL-P), and an increase in large very low density lipoprotein particle concentration (VLDL-P)(4). While LDL subfractions may not independently predict CVD risk after control for LDL-P, lipoprotein subfraction data is helpful in other areas such as cardiometabolic syndrome and diabetes prediction (5).

Lastly, Dr. Ip et al highlights several limitations from the ADA/ACC paper, including availability and accuracy of the NMR method and consistency of the predictive power across ethnic groups. With respect to the availability, the NMR test is available at various laboratories throughout the country (i.e. Labcorp, BioReference, ARUP, and Mayo Medical Labs). The question around accuracy should be put to rest since it is FDA cleared. Finally, the predictive power across ethnic groups has been addressed through the Multi-Ethnic Study of Atherosclerosis (MESA) (6).

I was pleased to see the article acknowledge the role of LDL-P and its association with the incidence of cardiovascular disease, however, I would appreciate clarification and perhaps elucidation around LDL subfractions; LDL-P and LDL subfractions should not be intertwined.


1. Ip S, Lichtenstein AH, Chung M, Lau J, Balk EM. Systematic Review: Association of Low-Density Lipoprotein Subfractions with Cardiovascular Outcomes. Ann Intern Med 2009;150:474-484.

2. Brunzell, J, Davidson, M, Furberg, C, et al. Lipoprotein Management in Patients With Cardiometabolic Risk. Diabetes Care, 2008; 4: 811-822.

3. Contois JH, McConnell JP, Sethi AA, et al. Apolipoprotein B and Cardiovascular Disease Risk : Position Statement from the AACC Lipoproteins and Vascular Diseases Division Working Group on Best Practices. Clinical Chemistry 2009;55:407-10.

4. Jeyarajah EJ, Cromwell WC, Otvos JD. Lipoprotein particle analysis by nuclear magnetic resonance spectroscopy. Clin Lab Med 2006;26:847-70.

5. Garvey WT, Kwon S, Zheng D, et al. The effects of insulin resistance and Type 2 diabetes mellitus on lipoprotein subclass particle size and concentration determined by nuclear magnetic resonance. Diabetes 2003;52:453-62.

6. Mora S, Szklo M, Doff D,Otvos J, OLeary D, Tsai M, Greenland P, Sharrett A Associations Between LDL Particle Number , LDL Cholesterol and Subclinical Atherosclerosis: The Multi-Ethnic Study of Atherosclerosis(MESA). Atherosclerosis 2007;192:211-217.

Conflict of Interest:

Advisory Board for LipoScience with honoarium <_4000 per="per" year="year" and="and" minor="minor" _0.001="_0.001" stock="stock" holder="holder" in="in" liposcience.="liposcience." this="this" has="has" no="no" value="value" at="at" time.="time." />

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