Lipoprotein(a) concentrations, rosuvastatin therapy, and residual vascular risk: an analysis from the JUPITER Trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin)

Abstract

Background: Lipoprotein(a) [Lp(a)] is a low-density lipoprotein-like particle largely independent of known risk factors and predictive of cardiovascular disease. Statins may offset the risk associated with elevated Lp(a), but it is unknown whether Lp(a) is a determinant of residual risk in the setting of low low-density lipoprotein cholesterol after potent statin therapy.

Methods and results: Baseline and on-treatment Lp(a) concentrations were assessed in 9612 multiethnic participants in the JUPITER trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin) before and after random allocation to rosuvastatin 20 mg/d or placebo, with outcomes reported for whites (n=7746). Lp(a) concentrations (median [25th-75th percentile], in nmol/L) were highest in blacks (60 [34-100]), then Asians (38 [18-60]), Hispanics (24 [11-46]), and whites (23 [10-50]; P<0.001). Although the median change in Lp(a) with rosuvastatin and placebo was zero, rosuvastatin nonetheless resulted in a small but statistically significant positive shift in the overall Lp(a) distribution (P<0.0001). Baseline Lp(a) concentrations were associated with incident cardiovascular disease (adjusted hazard ratio per 1-SD increment in Ln[Lp(a)], 1.18; 95% confidence interval, 1.03-1.34; P=0.02). Similarly, on-statin Lp(a) concentrations were associated with residual risk of cardiovascular disease (adjusted hazard ratio, 1.27; 95% confidence interval, 1.01-1.59; P=0.04), which was independent of low-density lipoprotein cholesterol and other factors. Rosuvastatin significantly reduced incident cardiovascular disease among participants with baseline Lp(a) greater than or equal to the median (hazard ratio, 0.62; 95% confidence interval, 0.43-0.90) and Lp(a) less than the median (hazard ratio, 0.46; 95% confidence interval, 0.30-0.72), with no evidence of interaction. Similar results were obtained when analyses included nonwhites.

Conclusion: Among white JUPITER participants treated with potent statin therapy, Lp(a) was a significant determinant of residual risk. The magnitude of relative risk reduction with rosuvastatin was similar among participants with high or low Lp(a).

Clinical trials registration url: http://www.clinicaltrials.gov. Unique identifier: NCT00239681.

Keywords: lipoproteins; risk factors; statins, HMG-CoA.

Figure 1

Efficacy of rosuvastatin according to baseline lipoprotein(a) concentration. Hazard ratios and 95% confidence intervals according to intention-to-treat analysis for the primary endpoint (top) and the expanded endpoint (bottom) by baseline lipoprotein(a) concentrations. For the primary endpoint, hazard ratio with rosuvastatin therapy was 0.47 (95%CI 0.30 – 0.72) for participants with baseline Lp(a) concentration below the median and 0.62 (95%CI 0.43 – 0.90) in those above the median (p-interaction = 0.33). Similarly, for the expanded endpoint, hazard ratios were 0.46 (95%CI 0.32 – 0.69) and 0.72 (95%CI 0.52 – 0.97) for those below and above the median respectively (p-interaction = 0.10).