Antioxidant supplements and cardiovascular disease in men

To the Editor:

The conclusion of Dr Sesso and colleagues¹ that vitamin C does not affect cardiovascular outcome in male physicians is not surprising because of an experimental design that did not consider human vitamin C physiology and did not include vitamin C measurements. In humans, plasma and tissue vitamin C concentrations are tightly controlled. Plasma concentrations have a steep sigmoidal response in relation to dose, and a similar steep response occurs in tissue.^2–5 At doses above approximately 100 mg daily, circulating immune cells are saturated, and at doses of 200 mg daily or greater, there are only marginal increases in plasma concentrations.^2–5 Physicians in the control group, who likely consumed at least 3 servings of fruits or vegetables daily, would have ingested more than 100 mg of vitamin C per day. Even a single glass of orange juice would have provided 90 mg of vitamin C. Those who took an allowed multivitamin would have had further intake of 60 mg daily. Additional intake of 500 mg daily in the treatment group would not affect tissue concentrations at all and would increase plasma concentrations only marginally.

Therefore, neither plasma nor tissue vitamin C concentrations are likely to have differed in the treatment vs placebo groups. To detect differences, plasma vitamin C concentrations in control and treatment groups should have been measured.

To determine whether vitamin C affects outcome, an appropriate design is to compare participants with low plasma vitamin C concentrations to participants with high concentrations.³ It remains unknown whether supplementation will produce health outcomes in populations who start with low plasma vitamin C concentrations and whose concentrations are increased by the intervention. Such studies are feasible, as the lowest 10th percentile of US men aged 51 to 70 years consume only 37 mg per day of vitamin C.⁵ Candidate participants tend to be poor and not well-educated, the opposite of the group studied by Sesso et al. Future studies in this area should determine whether those with marginal vitamin C status based on measurements will benefit from supplementation, rather than studying those with a surfeit of wealth or vitamins, to whom the law of diminishing returns surely applies.