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

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.