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CLINICAL RESEARCH: STATINS AND HYPERCHOLESTEROLEMIA

The Influence of Pravastatin and Atorvastatin on Markers of Oxidative Stress in Hypercholesterolemic Humans

Bonnie Ky, MD^_*, Anne Burke, MD^_*, Sotirios Tsimikas, MD, Megan L. Wolfe, BS^_*, Mahlet G. Tadesse, ScD^_*, Philippe O. Szapary, MD^_*, Joseph L. Witztum, MD, Garret A. FitzGerald, MD^_* and Daniel J. Rader, MD^_*,_*

^_* Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania
University of California San Diego, La Jolla, California.

Manuscript received September 28, 2007; revised manuscript received January 24, 2008, accepted January 29, 2008.

^_* Reprint requests and correspondence: Dr. Daniel J. Rader, University of Pennsylvania, 421 Curie Boulevard, Room 654 BRB, Philadelphia, Pennsylvania 19104-6160. (Email: rader{at}mail.med.upenn.edu).

Objectives: The aim of this study was to determine the effects of pravastatin and atorvastatin on markers of oxidative stress in plasma.

Background: Hydroxymethylglutaryl coenzyme A reductase inhibitors reduce low-density lipoprotein cholesterol (LDL-C) and cardiovascular risk, but their effects on circulating biomarkers of oxidative stress are not well-defined.

Methods: Hypercholesterolemic subjects (n = 120, ages 21 to 80 years with LDL-C 130 to 220 mg/dl) were randomized in a double-blind, parallel design to pravastatin 40 mg/day (prava40), atorvastatin 10 mg/day (atorva10), atorvastatin 80 mg/day (atorva80), or placebo. At baseline and 16 weeks, urinary isoprostanes (8, 12-iso-iPF₂-VI isoform), plasma lipoprotein-associated phospholipase A2 (Lp-PLA2), Mercodia oxidized LDL (OxLDL) with antibody 4E6, oxidized phospholipids/apolipoprotein B-100 particle (OxPL/apoB) with antibody E06, immunoglobulin (Ig)G/IgM autoantibodies to malondialdehyde (MDA)-LDL, and apolipoprotein B (apoB)-immune complexes (IC) were measured.

Results: After 16 weeks, there were no significant changes in urinary 8, 12-iso-iPF₂-VI. The Lp-PLA2 and OxLDL were reduced in statin-treated groups, but after adjusting for apoB, only prava40 led to a reduction in Lp-PLA2 (–15%, p = 0.008) and atorva10 to a decrease in OxLDL (–12.9%, p = 0.01). The OxPL/apoB increased 25.8% (p < 0.01) with prava40 and 20.2% (p < 0.05) with atorva80. There were no changes in MDA-LDL autoantibodies, but significant decreases in IC were noted.

Conclusions: This study suggests that statin therapy results in variable effects on oxidative stress markers in hypercholesterolemic subjects. Future outcome studies should collectively assess various oxidative markers to define clinical utility.

Abbreviations and Acronyms   atorva10 = atorvastatin 10 mg/day   atorva80 = atorvastatin 80 mg/day   CHD = coronary heart disease   ELISA = enzyme-linked immunosorbent assay   HDL-C = high-density lipoprotein cholesterol   IC = immune complexes   LDL-C = low-density lipoprotein cholesterol   Lp(a) = lipoprotein(a)   Lp-PLA2 = lipoprotein-associated phospholipase A2   MDA = malondialdehyde   OxLDL = oxidized low-density lipoprotein   OxPL = oxidized phospholipids   OxPL/apoB = oxidized phospholipids onapolipoprotein B-100 particles   prava40 = pravastatin 40 mg/day   TC = total cholesterol