We take issue with the points Vale (1) has raised. While it is established that vitamin E does not influence myeloperoxidase-catalyzed lipid peroxidation in vitro, this does not exclude possible benefits from vitamin E supplementation in vivo in subjects with increased myeloperoxidase activity and high risk of coronary heart disease. For example, supplementation with vitamin E reduced the risk of myocardial infarction, including sudden death in hemodialysis patients (2). Whether the antioxidant activity of vitamin E is responsible for this improved risk of coronary heart disease is unknown, and other effects of vitamin E may be implicated. As pointed out in our report, vitamin E has a number of effects that are independent of its antioxidant activity, and the mechanism underlying this improvement in insulin sensitivity remains to be determined.
While there is evidence that vitamin E acts as a prooxidant under specific conditions in vitro, there is little direct evidence that it has similar activity in vivo. It is thought that substantial levels of coantioxidants, such as ascorbate, regenerate the tocopherol radical and prevent tocopherol-mediated peroxidation in vivo (3).
Vale claims that high-dose vitamin E may have an acute toxic effect and may increase the risk of coronary death. This is based on the higher number of early deaths in the vitamin E (19/1,035) group compared with the placebo (7/967) group in the Cambridge Heart Antioxidant Study (CHAOS) (4). This study has been criticized because of imbalances in several baseline characteristics, raising the possibility that randomization failed to produce truly comparable groups. In addition, given that the number of cardiovascular end points was small and that the study was of short duration, it has been suggested that the main finding of a 77% decrease in nonfatal acute myocardial infarction in the CHAOS was likely due to chance (5). Moreover, the number of early cardiovascular deaths was substantially lower than the total number of nonfatal acute myocardial infarctions, making the finding of an increased risk of early cardiovascular death even more likely to be due to chance. In addition, most of the deaths in the CHAOS were in those taking the lower dose of vitamin E (400 IU/day) (6). This dose is the same as the dose used in the much larger HOPE (Heart Outcomes Prevention Evaluation) study (5), in which there was no early excess of cardiovascular deaths.
It should also be noted that a number of previous studies (7,8) have supplemented individuals at higher risk of cardiovascular events for similar or longer duration and with comparable dosages to those used in our study and have not reported any adverse effects. Minimal side effects have been noted with vitamin E supplementation at doses much higher than those we used and for up to 11 years in some trials (9). Taken together, the available data do not suggest that our overweight subjects who were assigned to vitamin E were at increased risk of coronary death.
We agree that vigilance on the use of vitamin E supplementation should be observed. Patients receiving statin-niacin therapy or anticoagulants should not receive vitamin E supplements. None of the participants in our study (10) were receiving drug therapy.
