During the past decade, the perception flourished that
lipid and
antioxidant therapy were 2 independent avenues for cardiovascular protection. However, studies have shown that commonly used
antioxidant vitamin regimens do not prevent cardiovascular events. We found that the addition of
antioxidant vitamins to
simvastatin-
niacin therapy substantially blunts the expected rise in the protective
high density lipoprotein (
HDL)2 cholesterol and
lipoprotein(A-I) subfractions of HDL, with apparent adverse effects on the progression of
coronary artery disease. To better understand this effect, 12
apolipoproteins, receptors, or
enzymes that contribute to reverse
cholesterol transport have been examined in terms of their relationship to HDL2 and
lipoprotein(A-I) levels and the potential for
antioxidant modulation of their gene expression. Three plausible candidate mechanisms are identified: (1)
antioxidant stimulation of
cholesteryl ester transfer protein expression/activity, (2)
antioxidant suppression of macrophage
ATP binding cassette transmembrane transporter A1 expression, and/or (3)
antioxidant suppression of hepatic or intestinal
apolipoprotein A-I synthesis or increase in
apolipoprotein A-I catabolism. In summary,
antioxidant vitamins E and C and
beta-carotene, alone or in combination, do not protect against
cardiovascular disease. Their use for this purpose may create a diversion away from proven
therapies. Because these
vitamins blunt the protective
HDL2 cholesterol response to
HDL cholesterol-targeted
therapy, they are potentially harmful in this setting. We conclude that they should rarely, if ever, be recommended for cardiovascular protection.