High-Density Lipoprotein Cholesterol, Size, Particle Number, and Residual Vascular Risk After Potent Statin Therapy

Study Questions:

What is the relative value of alternative high-density lipoprotein (HDL) measures such as HDL size or particle number (HDL-P) as determinants of residual risk after potent statin therapy?


In the JUPITER (Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) trial, HDL size and HDL-P were measured by nuclear magnetic resonance spectroscopy, and HDL cholesterol (HDL-C) and apolipoprotein A-I (apoA-I) were chemically assayed in 10,886 participants without cardiovascular disease (CVD) before and after random allocation to rosuvastatin 20 mg/day or placebo.


Median baseline HDL-C, apoA-I, and low-density lipoprotein cholesterol (LDL-C) were 49 mg/dl, 164 mg/dl, and 109 mg/dl, respectively. Levels were examined with first CVD (N = 237). HDL-P correlated better with apoA-I (Spearman r = 0.69, p < 0.0001) than with HDL-C (r = 0.55, p < 0.0001). Rosuvastatin lowered LDL-C (49%) and raised HDL-C (6.1%), apoA-I (2.1%), HDL-P (3.8%), and HDL size (1.2%); all p < 0.0001. Among placebo-allocated individuals, on-treatment HDL-C, apoA-I, and HDL-P had similar inverse associations with CVD (risk factor-adjusted hazard ratio and 95% confidence interval per 1-standard deviation: 0.79 [0.63-0.98], 0.75 [0.62-0.92], and 0.81 [0.67-0.97], respectively). Among rosuvastatin-allocated individuals, on-treatment HDL-P had a statistically significant and somewhat stronger association with CVD (0.73, 0.57-0.93, p = 0.01) than HDL-C (0.82, 0.63-1.08, p = 0.16) or apoA-I (0.86, 0.67-1.10, p = 0.22). Among rosuvastatin-allocated individuals, on-treatment HDL-P remained significant (0.72, 0.53-0.97, p = 0.03) after additionally adjusting for HDL-C. In risk factor-adjusted models, HDL size showed no significant association with CVD.


The authors concluded that in the setting of potent statin therapy, HDL-P may be a better marker of residual risk than chemically measured HDL-C or apoA-I. This has potential implications for evaluating novel therapies targeting HDL.


This is an important observation, but should not influence clinical practice at this time. Both high and low HDL particle cholesterol content are risk predictors, but do not necessarily reflect the functional characteristics of HDL particles. While HDL-P may be a better on-statin predictor of CV events than HDL-C, it also does not reflect reverse cholesterol transport (RCT). There is a considerable effort to develop clinically useful measures of RCT for assessing both attributable risk of HDL and potential for novel HDL-modifying drugs.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Fluorobenzenes, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Apolipoprotein A-I, Pyrimidines, Lipoproteins, Risk Factors, Biological Transport, Cholesterol, Dyslipidemias, Biological Markers, Troponin I, Blood Glucose, Cardiovascular Diseases, Confidence Intervals, Magnetic Resonance Spectroscopy, Sulfonamides

< Back to Listings