Clinical implications of discordance between low-density lipoprotein cholesterol and particle number

James D. Otvos, PhD, Samia Mora, MD, MHS, Irina Shalaurova, MD, Philip Greenland, MD, Rachel H. Mackey, PhD, MPH, David C. Goff Jr., MD, Ph

BACKGROUND: The amount of cholesterol per low-density lipoprotein (LDL) particle is variable and related in part to particle size, with smaller particles carrying less cholesterol. This variability causes concentrations of LDL cholesterol (LDL-C) and LDL particles (LDL-P) to be discordant in many individuals.

METHODS: LDL-P measured by nuclear magnetic resonance spectroscopy, calculated LDL-C, and carotid intima-media thickness (IMT) were assessed at baseline in the Multi-Ethnic Study of Atherosclerosis, a community-based cohort of 6814 persons free of clinical cardiovascular disease (CVD) at entry and followed for CVD events (n 5 319 during 5.5-year follow-up). Discordance, defined as values of LDL-P and LDL-C differing by $12 percentile units to give equal-sized concordant and discordant subgroups, was related to CVD events and to carotid IMT in models predicting outcomes for a 1 SD difference in LDL-C or LDL-P, adjusted for age, gender, and race.

RESULTS: LDL-C and LDL-P were associated with incident CVD overall: hazard ratios (HR 1.20, 95% CI [CI] 1.0821.34; and 1.32, 95% CI 1.1921.47, respectively, but for those with discordant levels, only LDL-P was associated with incident CVD (HR 1.45, 95% CI 1.1921.78; LDL-C HR 1.07, 95% CI 0.8821.30). IMT also tracked with LDL-P rather than LDL-C, ie, adjusted mean IMT of 958, 932, and 917 mm in the LDL-P.LDL-C discordant, concordant, and LDL-P, LDL-C discordant subgroups, respectively, with the difference persisting after adjustment for LDL-C (P 5.002) but not LDL-P (P 5.60).

CONCLUSIONS: For individuals with discordant LDL-C and LDL-P levels, the LDL-attributable atherosclerotic risk is better indicated by LDL-P.

Journal of Clinical Lipidology, 2011;5(2);105-113

Clinical Utility of Inflammatory Markers and Advanced Lipoprotein Testing: Advice from an Expert Panel of Lipid Specialists

Michael H. Davidson, MD, FNLA, Chair*, Christie M. Ballantyne, MD, FNLA, Co-Chair, Inflammatory Biomarkers Sub-group, Terry A. Jacobson, MD, FNLA, Co-Chair, Lipoprotein Biomarkers Sub-group, Vera A. Bittner, MD, MSPH, FNLA, Lynne T. Braun, PhD, CNP, FNLA, Alan S. Brown, MD, FNLA, W. Virgil Brown, MD, FNLA, William C. Cromwell, MD, FNLA, Ronald B. Goldberg, MD, FNLA, James M. McKenney, PharmD, FNLA, Alan T. Remaley, MD, PhD, Allan D. Sniderman, MD, Peter P. Toth, MD, PhD, FNLA, Sotirios Tsimikas, MD, Paul E. Ziajka, MD, PhD, FNLA

Non-Panel Scientists: Kevin C. Maki, PhD, FNLA, Mary R. Dicklin, PhD

ABSTRACT: The National Cholesterol Education Program Adult Treatment Panel guidelines have established low-density lipoprotein cholesterol (LDL-C) treatment goals, and secondary non-high-density lipoprotein (HDL)-C treatment goals for persons with  hypertriglyceridemia. The use of lipid-lowering therapies, particularly statins, to achieve these goals has reduced cardiovascular disease (CVD) morbidity and mortality; however, significant residual risk for events remains. This, combined with the rising prevalence of obesity, which has shifted the risk profile of the population toward patients in whom LDL-C is less predictive of CVD events (metabolic syndrome, low HDL-C, elevated triglycerides), has increased interest in the clinical use of inflammatory and lipid biomarker assessments. Furthermore, the cost effectiveness of pharmacological intervention for both the initiation of therapy and the intensification of therapy has been enhanced by the availability of a variety of generic statins. This report describes the consensus view of an expert panel convened by the National Lipid Association to evaluate the use of selected biomarkers [C-reactive protein, lipoprotein-associated phospholipase A2, apolipoprotein B, LDL particle concentration, lipoprotein(a), and LDL and HDL subfractions] to improve risk assessment, or to adjust therapy. These panel recommendations are intended to provide practical advice to clinicians who wrestle with the challenges of identifying the patients who are most likely to benefit from therapy, or intensification of therapy, to provide the optimum protection from CV risk.

Journal of Clinical Lipidology, 2011;5(5);338-367

OBJECTIVE Diabetic dyslipoproteinemia is characterized by low HDL cholesterol and high triglycerides. We examined the association of lipoprotein particle size and concentration measured by nuclear magnetic resonance (NMR) spectroscopy with clinical type 2 diabetes.

RESEARCH DESIGN AND METHODS This was a prospective study of 26,836 initially healthy women followed for 13 years for incident type 2 diabetes (n = 1,687). Baseline lipids were measured directly and lipoprotein size and concentration by NMR. Cox regression models included nonlipid risk factors (age, race, smoking, exercise, education, menopause, blood pressure, BMI, family history, A1C, and C–reactive protein). NMR lipoproteins were also examined after further adjusting for standard lipids.

RESULTS Incident diabetes was significantly associated with baseline HDL cholesterol, triglycerides, and NMR–measured size and concentration of LDL, IDL, HDL, and VLDL particles. The associations of these particles differed substantially by size. Small LDL_NMR and small HDL_NMR were positively associated with diabetes (quintile 5 vs. 1 [adjusted hazard ratios and 95% CIs], 4.04 [3.21–5.09] and 1.84 [1.54–2.19], respectively). By contrast, large LDL_NMR and large HDL_NMR were inversely associated (quintile 1 vs. 5, 2.50 [2.12–2.95] and 4.51 [3.68–5.52], respectively). For VLDL_NMR, large particles imparted higher risk than small particles (quintile 5 vs. 1, 3.11 [2.35–4.11] and 1.31 [1.10–1.55], respectively). Lipoprotein particle size remained significant after adjusting for standard lipids and nonlipid factors.

CONCLUSIONS In this prospective study of women, NMR lipoprotein size and concentrations were associated with incident type 2 diabetes and remained significant after adjustment for established risk factors, including HDL cholesterol and triglycerides.

BACKGROUND: The cholesterol content of low–density lipoprotein (LDL) particles is variable, causing frequent discrepancies between concentrations of LDL cholesterol (LDL–C) and LDL particle number (LDL–P). In managing patients at risk for cardiovascular disease (CVD) to LDL target levels, it is unclear whether LDL–C provides the optimum measure of residual risk and adequacy of LDL–lowering treatment.

OBJECTIVE: To compare the ability of alternative measures of LDL to provide CVD risk discrimination at relatively low levels consistent with current therapeutic targets.

METHODS: Concentrations of LDL–C and non–HDL–C were measured chemically and LDL–P and VLDL–P were measured by nuclear magnetic resonance in 3066 middle–aged white participants (53% women) without CVD in the Framingham Offspring cohort. The main outcome measure was incidence of first CVD event.

RESULTS: At baseline, the cholesterol content per LDL particle was negatively associated with triglycerides and positively associated with LDL–C. On follow–up (median 14.8 years), 265 men and 266 women experienced a CVD event. In multivariable models adjusting for nonlipid CVD risk factors, LDL–P was related more strongly to future CVD in both genders than LDL–C or non–HDL–C. Subjects with a low level of LDL–P (_25th percentile) had a lower CVD event rate (59 events per 1000 person–years) than those with an equivalently low level of LDL–C or non–HDL–C (81 and 74 events per 1000 person–years, respectively).

CONCLUSIONS: In a large community–based sample, LDL–P was a more sensitive indicator of low CVD risk than either LDL–C or non–HDL–C, suggesting a potential clinical role for LDL–P as a goal of LDL management.

J Clin Lipidology. 2007;1:583–592

The key role played by low-density lipoprotein (LDL) particles in the pathogenesis of coronary heart disease (CHD) is well accepted, as is the benefit of lowering LDL in high-risk patients.

What remains controversial is whether we are using the best measure(s) of LDL to identify all individuals who would benefit from therapy. Many studies have shown that, at a given level of LDL cholesterol, individuals with predominantly small LDL particles (pattern B) experience greater CHD risk than those with larger-size LDL. However, it is not clear from this observation that small LDL particles are inherently more atherogenic than large ones because, at a given level of LDL cholesterol, individuals with small LDL have more LDL particles in total.

The phenotype of small LDL particle size co-segregates with a cluster of metabolic factors, including elevated triglycerides and reduced HDL cholesterol, and in multivariate analyses has generally been found not to be independently associated with CHD risk. In contrast, LDL particle number measured by nuclear magnetic resonance has consistently been shown to be a strong, independent predictor of CHD.