The Effects of Niacin on Lipoprotein Subclass Distribution

John M. Morgan, MD; Christina M. Carey, PA-C; Anne Lincoff, MD; David M. Capuzzi, MD, PhD

In This Article

Lipoprotein Subclasses and CHD Risk

Multiple studies have shown a strong relationship between small LDL particles and the development or progression of CHD. In a population-based study, subjects with smaller LDL particle size (<0.256 nm) had 2.2 times the risk of developing CHD compared with those with larger particle size, independent of all traditional lipid risk factors.[21] Moreover, the degree of risk attributable to LDL cholesterol, TG, and HDL cholesterol was significantly influenced by LDL size. Small LDL particle size was associated with increased risk even in patients with average LDL cholesterol levels. The Stanford Coronary Risk Intervention Project (SCRIP) found that baseline levels of small, dense LDL (LDL-IVb=0.220-0.233 nm) were the best predictor of coronary stenosis progression over 4 years.[22] The annual rate of progression was six times greater among CHD patients with LDL-IVb levels in the fourth quartile compared with the first quartile. Similar results were seen in the Pravastatin Limitation of Atherosclerosis in the Coronary arteries trial (PLAC-I), where small LDL was associated with a five-fold greater risk of angiographic progression.[23]

Support for a role for small, dense LDL as a potential target for therapy in CHD patients has come from a post-hoc analysis of the Familial Atherosclerosis Treatment Study.[24] Combination therapy with niacin-colestipol or lovastatin-colestipol increased LDL buoyancy, and this change was the most powerful predictor of coronary stenosis regression, accounting for 37% of the variance. Reductions in apo B accounted for only 5% of the variance while changes in other lipid and non-lipid risk factors had little effect. Similarly, in the Diabetes Atherosclerosis Intervention Study, fenofibrate treatment increased LDL size and decreased apo B-containing lipoproteins, and these changes were associated with decreased coronary stenosis progression.[25] This suggests that both quality and quantity of LDL particles play a role in the increased CHD risk in diabetes.

The potential for risk stratification based on lipoprotein subclasses has been explored in other populations at increased CHD risk. In a study of postmenopausal women, elevations in small LDL, large VLDL, and number of LDL particles were each significant and independent correlates of extensive coronary artery calcification.[26] Small LDL particle predominance is a hallmark of the atherogenic dyslipidemia associated with the metabolic syndrome.[1] It has also been advanced as part of the definition of familial combined hyperlipidemia.[16] Despite the accumulating evidence, other studies in both healthy and CHD populations have not found small LDL particles to be independently associated with CHD risk after controlling for other risk factors, leading to some uncertainty about its predictive and clinical value.[27,28]

Multiple studies have shown a strong relationship between HDL particle size and CHD risk. In SCRIP, coronary stenosis progression was significantly related to baseline level of HDL3a (p=0.02) and inversely related to HDL2 (p=0.02).[22] Similar results were seen in PLAC-I.[23] In a study from the Milwaukee Cardiovascular Data Registry, men with CHD and high levels of small HDL particles or large VLDL particles were three to four times more likely to have angiographic evidence of extensive disease than men with low levels.[28] Moreover, men with both abnormalities were 15 times more likely to have severe disease. Support for a role for small HDL particle size as a potential target for therapy in patients with CHD has come from a post-hoc analysis of the HDL Atherosclerosis Treatment Study.[29] Combination therapy with simvastatin-niacin decreased small HDL particles and increased large apo A-I containing HDL particles. Patients with elevated large HDL (third tertile) showed no progression, while those in the first tertile showed a 2.1% increase in stenosis. However, in a subanalysis of the Monitored Atherosclerosis Regression Study, coronary stenosis progression was most strongly correlated with low levels of HDL3 and elevations of small VLDL, suggesting a protective role for these subclasses.[27]