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

Abstract

Background— Chemically measured high-density lipoprotein cholesterol (HDL-C) may not be the best clinical measure of HDL. Little is known about alternative HDL measures such as HDL size or particle number (HDL-P) as determinants of residual risk after potent statin therapy. Methods and Results— In Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), HDL size and HDL-P were measured by nuclear magnetic resonance spectroscopy, and 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/d or placebo. Levels were examined with first CVD (n=234). 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 low-density lipoprotein cholesterol (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. Conclusions— In the setting of potent statin therapy, HDL particle number 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. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00239681.