Effects of Niacin on LDL Particle Number

Haseeb Jafri; Richard H Karas; Jeffrey T Kuvin


Clin Lipidology. 2009;4(5):565-571. 

In This Article

LDL-P & Outcomes

The importance of LDL-P as a marker of atherosclerotic risk is increasingly being recognized. Recent consensus guidelines from the American College of Cardiology (ACC) and the American Diabetes Association (ADA) suggest that, in addition to LDL-C and non-HDL-C, LDL-P may be a valuable target of therapy to better assess cardiovascular risk.[24] Of note, there are multiple methods to measure LDL subclasses and particle number, including NMR, gradient gel electrophoresis, ultracentrifugation-vertical auto profile and tube gel electrophoresis. Given that there is considerable variation amongst these methods and there is no adequate data to choose one or another method as the standard, we have decided to focus this review on studies utilizing NMR methodology as the ACC/ADA guidelines on lipoprotein management rely extensively on these studies.[24–26]

Initially, it was believed that the number of small and total LDL-P were the more important subtypes related to cardiovascular outcomes. In a nested, case–control analysis of the Cardiovascular Health Study, Kuller et al. showed that in females, with mean age greater than 70 years, total LDL-P as well as small LDL-P showed a greater association with the risk of angina or myocardial infarction (MI) than did LDL-C.[27] This correlation was no longer present when men were analyzed in this study. In a post hoc analysis of the Pravastatin Limitation of Atherosclerosis in Coronary arteries (PLAC-I) trial, Rosenson et al. demonstrated that high levels of LDL-C and small LDL-P were associated with greater rates of coronary artery luminal narrowing (p < 0.05 and p < 0.01, respectively[28]). Of note, at baseline, large LDL-P were not associated with coronary artery disease (CAD) progression. Furthermore, within treatment groups, CAD progression was strongly associated with total LDL-P, after adjusting for other lipid levels, and a small LDL-P level of over 30 mg/dl was associated with a ninefold increased risk in CAD progression (p < 0.01).

In another prospective nested case–control study among healthy middle-aged women, Blake et al. assessed the relation between LDL-P size and concentration as risk factors for future MI, stroke or death from CAD. In this study, women who subsequently had a cardiovascular event had a higher number of total LDL-P (p = 0.0001), and a greater concentration of small LDL-P (p = 0.046). Although, the predictive value of these parameters for CAD was lower than the ratio of total cholesterol to HDL-C and of CRP, they remained significant predictors of future risk.[29] El Harchaoui et al., in a nested case–control study, analyzed the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk study and the relationship between LDL-P number and size with risk of future CAD. Univariate analysis of this study revealed that the total number of LDL-P (OR: 2.00; 95% CI: 1.58–2.59), as well as non-HDL-C, was more closely associated with CAD than was the level of total LDL-C.[30] Of note, this relationship was no longer present after controlling for HDL-C and triglycerides. Additionally, the authors of this study suggest that other approaches, such as measuring multiple lipid components or ApoB, may be equal to or superior to LDL-P in the primary prevention setting.

In addition to total and small LDL-P, large LDL-P is also predictive of risk. In the Multi-Ethnic Study of Atherosclerosis (MESA) study, both large and small LDL-P were associated with subclinical atherosclerosis as evidenced by carotid-intima media thickness (p < 0.001 for both). Mora et al. concluded that this relationship was not appreciated before because previous studies did not adequately control for the inverse correlation between small and large LDL-P concentrations.[31] In the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT), Otvos et al. demonstrated that both baseline and on-trial values (with gemfibrozil) of large and small LDL-P were predictors of coronary heart disease events (p < 0.005 for all[32]).

Although the importance of LDL-P and its relation to CAD risk is still being evaluated, there appears overall to be a strong relationship between LDL-P and future cardiac events.


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