Response to Letter Regarding Article, “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

We thank Dr Giral and colleagues for their comments on our recent study of lipoprotein(a) [Lp(a)].1 The quantitative assessment of Lp(a) has historically proven challenging in part because of the (1) highly heterogeneous number of Kringle-IV type-2 repeats (and thus molecular weight), and (2) lack of standardized methodology and calibration across published studies. A 2002 National Heart, Lung, and Blood Institute consensus workshop that recommended use of isoform size-independent assays that express Lp(a) concentrations in terms of particle number (nmol/L) rather than total mass (mg/dL) and provided control samples for calibration served as a major advance in the field.2 In accordance with these standards, our study reported Lp(a) concentrations in nmol/L, and did not formally assess cholesterol mass associated with Lp(a) particles.The Friedewald formula for calculating LDL cholesterol, which was used in the JUPITER study when triglycerides were <400 mg/ dL, remains the current standard for clinical use but has clear limitations as discussed by Dr Giral and colleagues. Calculated LDL cholesterol reflects variable contributions from intermediate-density lipoproteins, low-density lipoproteins, and Lp(a) particles.3 In part to address this, we performed statistical models that either did or did not include calculated LDL cholesterol as a covariable, and Lp(a) was a significant determinant of residual risk in JUPITER regardless of LDL cholesterol inclusion in the models.

Lipoprotein(a)

“…Analysis of data from the Justification for the Use of Statins in Prevention (JUPITER) trial did show a significant residual risk attributable to elevated Lp(a) in rosuvastatin-treated patients. 44 Thus, it appears reasonable at this time to consider the contribution of Lp(a) to a patient's risk even if the patient has existing disease and/or is receiving optimal lipid-lowering therapy.…”

“…42 On the other hand, the large JUPITER trial found that a residual risk associated with elevated Lp(a) may persist in the background of low LDL levels resulting from aggressive statin therapy. 44 It must be emphasized that there have been no randomized clinical trials to date that have specifically addressed the question of whether monitoring Lp(a) concentrations or lowering Lp(a) therapeutically has a clinical benefit. Nonetheless, it seems prudent, given the existing evidence for Lp(a) as a causal risk factor, to measure Lp(a) in specific groups of patients and to tailor their clinical management accordingly.…”

Meta-Analysis Comparing Rosuvastatin and Atorvastatin in Reducing Concentration of C-Reactive Protein in Patients With Hyperlipidemia

“…36 Based on the JUPI-TER trial, the US Food and Drug Administration included asymptomatic JUPITER-eligible individuals with only 1 additional risk factor in the indications for rosuvastatin use. 37,38 The CRP was considered the most powerful inflammatory marker predicting CV events but also triggered considerable controversy. According to some subgroup analyses, some experts thought that the CV protective effect of statins was affected by the baseline CRP level.…”

Accelerated atherosclerosis and elevated lipoprotein (a) after liver transplantation

“…Dr Alsulaimi collected the data. Dr El-Maouche drafted figures (1)(2). Dr Damluji drafted the article, and all authors critically revised it for important intellectual content and approved the final version to be submitted.…”

“…1 Having a similar structure to, but metabolically distinct function from the LDL particle, Lp(a) is an atherogenic lipoprotein that contains a liver-derived apolipoprotein(a) covalently bound to apolipoprotein B100 via a disulfide bond. 2,3 Among the proposed effects of apolipoprotein(a) that increase the risk of atherogenesis are (1) selective retention of Lp(a) within the arterial wall, (2) prothrombotic/anti-fibrinolytic effects secondary to structural resemblance with plasminogen and plasmin, but without fibrinolytic activity, and (3) promotion of smooth muscle cell migration and proliferation.…”