Atherogenic Lipoprotein Subfractions Determined by Ion Mobility and First Cardiovascular Events After Random Allocation to High-Intensity Statin or Placebo: The Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) Trial

Abstract

Background: Cardiovascular disease (CVD) can occur in individuals with low low-density lipoprotein (LDL) cholesterol (LDL-C). We investigated whether detailed measures of LDL subfractions and other lipoproteins can be used to assess CVD risk in a population with both low LDL-C and high C-reactive protein who were randomized to high-intensity statin or placebo.

Methods and results: In 11 186 Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) participants, we tested whether lipids, apolipoproteins, and ion mobility-measured particle concentrations at baseline and after random allocation to rosuvastatin 20 mg/d or placebo were associated with first CVD events (n=307) or CVD/all-cause death (n=522). In placebo-allocated participants, baseline LDL-C was not associated with CVD (adjusted hazard ratio [HR] per SD, 1.03; 95% confidence interval [CI], 0.88-1.21). In contrast, associations with CVD events were observed for baseline non-high-density lipoprotein (HDL) cholesterol (HR, 1.18; 95% CI, 1.01-1.38), apolipoprotein B (HR, 1.28; 95% CI, 1.11-1.48), and ion mobility-measured non-HDL particles (HR, 1.19; 95% CI, 1.05-1.35) and LDL particles (HR, 1.21; 95% CI, 1.07-1.37). Association with CVD events was also observed for several LDL and very-low-density lipoprotein subfractions but not for ion mobility-measured HDL subfractions. In statin-allocated participants, CVD events were associated with on-treatment LDL-C, non-HDL cholesterol, and apolipoprotein B; these were also associated with CVD/all-cause death, as were several LDL and very-low-density lipoprotein subfractions, albeit with a pattern of association that differed from the baseline risk.

Conclusions: In JUPITER, baseline LDL-C was not associated with CVD events, in contrast with significant associations for non-HDL cholesterol and atherogenic particles: apolipoprotein B and ion mobility-measured non-HDL particles, LDL particles, and select subfractions of very-low-density lipoprotein particles and LDL particles. During high-intensity statin therapy, on-treatment levels of LDL-C and atherogenic particles were associated with residual risk of CVD/all-cause death.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00239681.

Keywords: hydroxymethylglutaryl-CoA reductase inhibitors; inflammation; lipids; lipoproteins; prevention and control.

© 2015 American Heart Association, Inc.

Figures

Figure 1

Ion mobility apoB-containing subfraction concentrations at baseline (dashed line) and after 1 year of rosuvastatin (shaded area) based on a random subset of 4,000 baseline and 4,000 1-year rosuvastatin samples in JUPITER participants. Abbreviations: VS: very small, S: small, M: medium, L: large.

Figure 2

Adjusted hazard ratios (per 1-SD higher) and 95% confidence intervals according to intention-to-treat analysis (placebo group) for the primary endpoint by baseline lipids, apolipoproteins, and IM-measured lipoproteins and subfractions, adjusted for age, sex, race, smoking, family history, BMI, systolic blood pressure, glucose, and ln hsCRP. Log-transformed variables were triglycerides and LDL III a – IV c subfractions.