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)

Study Questions:

Lipoprotein(a) [Lp(a)] is a low-density lipoprotein–like particle largely independent of known risk factors and predictive of cardiovascular disease (CVD). Is Lp(a) a determinant of residual risk in the setting of low levels of low-density lipoprotein cholesterol (LDL-C) after potent statin therapy?

Methods:

Baseline and on-treatment Lp(a) concentrations were assessed in 9,612 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 = 7,746). Lp(a) in mg/dl = nmol/L ÷ 2.8.

Results:

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). Baseline Lp(a) concentrations were associated with incident CVD (adjusted hazard ratio [HR] per 1-standard deviation increment in Ln[Lp(a)], 1.18; 95% confidence interval [CI], 1.03–1.34; p = 0.02). Similarly, on-statin Lp(a) concentrations were associated with residual risk of CVD (adjusted HR, 1.27; 95% CI, 1.01–1.59; p = 0.04), which was independent of LDL-C and other factors. Rosuvastatin significantly reduced incident CVD among participants with baseline Lp(a) greater than or equal to the median (HR, 0.62; 95% CI, 0.43–0.90) and Lp(a) less than the median (HR, 0.46; 95% CI, 0.30–0.72), with no evidence of interaction. Similar results were obtained when analyses included nonwhites.

Conclusions:

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).

Perspective:

Lp(a) is both proatherogenic and prothrombotic and has been associated with premature myocardial infarction, strokes, deep-vein thrombosis/pulmonary embolism, and thrombosis of saphenous grafts. Many trials have demonstrated it remains a risk factor in persons with coronary disease on statins. This is the first to demonstrate it remains an important risk predictor in low-risk persons in whom the statin-treated LDL-C is very low. New developments in lipid therapy include a drug that directly targets Lp(a) (RNA anti-sense), which will clarify the attributable risk.

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

Keywords: Fluorobenzenes, Myocardial Infarction, Stroke, Pulmonary Embolism, Hydroxymethylglutaryl-CoA Reductase Inhibitors, RNA, Antisense, Coronary Disease, Pyrimidines, Hispanic Americans, Cholesterol, Dyslipidemias, Cardiology, Cardiovascular Diseases, Venous Thrombosis, Confidence Intervals, Sulfonamides


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