New Research Indicates Antioxidants May Not Reduce Chronic Disease Risk

OXFORD, England--Taking antioxidant vitamins does not significantly reduce the risk of mortality from or incidence of vascular disease, cancer or other major causes of morbidity, according to researchers from the Heart Protection Study at the Clinical Trial Service Unit and Epidemiological Studies Unit of Radcliffe Infirmary. The researchers published their study in the July 6 issue of The Lancet (360, 9326:7-22, 2002) (www.thelancet.com).

Researchers randomly assigned 20,536 subjects (aged 40 to 80) either a vitamin regimen--600 mg/d of synthetic alpha-tocopherol, 250 mg/d of vitamin C and 20 mg/d of beta-carotene--or placebo for five years. Of the more than 20,000 subjects, 8,510 reported previous myocardial infarction, 4,876 a history of coronary disease, and 7,150 no history of coronary disease. Of the 7,150 participants without a history of coronary disease, 1,820 had cerebrovascular disease, 2,701 had peripheral arterial disease, and 3,982 had diabetes mellitus (with some having more than one of these three conditions).

With an average of 83-percent adherence to treatment during the five-year trial, subjects taking vitamins exhibited a two-fold increase in plasma concentrations of alpha-tocopherol, a one-third increase in vitamin C levels and a four-fold increase in beta-carotene levels. However, the vitamin regimen was not seen to reduce the risk of mortality--1,446 deaths were reported in the vitamin group versus 1,389 deaths reported in the placebo group.

Additionally, vitamin supplementation was not found to reduce the risk of any of the primary outcomes, which included the effects of supplementation on "major coronary events" (defined as non-fatal myocardial infarction or death from coronary disease) and on fatal coronary heart disease. Nor did supplementation reduce the risk of any of the secondary outcomes, which included: 1) the effects on major coronary events and on "major vascular events" (defined as major coronary events, strokes of any type and coronary or non-coronary revascularizations) during the first two years and during the latter years of scheduled treatment; and 2) on non-fatal or fatal strokes of any type. And, supplementation was not found to reduce the risk of tertiary outcomes, including site-specific cancer, cerebral hemorrhage, vascular procedures and hospitalization for various causes.

Of the primary outcomes, vitamin supplementation did not reduce the risk of death from vascular causes; there were 878 deaths in the vitamin group versus 840 deaths in the placebo group. Nor did supplementation reduce the risk of non-vascular causes; there were 568 deaths in the vitamin group versus 549 in the placebo group. "Moreover, this antioxidant regimen produced small, but definite, increases in the measured values of plasma triglycerides and LDL [low-density lipoprotein] cholesterol with a 3-percent higher mean LDL cholesterol concentration corroborated by a five percent higher mean apolipoprotein B concentration," the authors noted.

Of the secondary outcomes, there was no significant reduction of risk for non-fatal coronary infarction or death from coronary causes (1,063 vitamin supplemented versus 1,047 placebo), from non-fatal or fatal stroke (511 versus 518), or from coronary or non-coronary revascularization (1,058 versus 1,086). "The non-significant excess of vascular mortality was not supported by any excess of non-fatal vascular events, so it may well have been largely or wholly due to chance," researchers wrote.

Of the tertiary outcomes, new primary cancers (excluding non-melanoma skin cancer) were diagnosed in 800 of the participants taking vitamins, 359 of whom died, compared with 817 of those taking placebo, 345 of whom died. "These differences were not significant, nor were there significant differences between the treatment groups and the incidence of cancers in any particular body system or in non-melanoma skin cancer," the authors wrote.

The effects on other outcomes were not significant either, according to researchers. Vitamins did not reduce the risk for neuropsychiatric disorders (cognitive decline), respiratory disease, bone health (fractures and osteoporosis) or cataracts.

"Based on the presumption that the likelihood of benefit outweighs any low probability of harm, daily supplementation with a few hundred mg of vitamin E (and with other vitamins) has been recommended for middle-aged and older people," the authors wrote in their conclusion. "But, despite assessing the combined effects of several years of substantial daily doses of different antioxidant vitamins (including 600 mg of vitamin E) in a large number of high-risk people, the Heart Protection Study has not been able to demonstrate any benefit from such supplementation."

This study was funded by the UK Medical Research Council, the British Heart Foundation, Merck & Co. (manufacturer of the cholesterol-lowering drug simvastatin) and Roche Vitamins (manufacturer of the vitamins).

In contrast to this study, researchers from Beth Israel Deaconess Medical Center and Harvard Medical School compiled a research review, which was published in the June 19 issue of the Journal of the American Medical Association (287, 23:3116-26, 2002) (www.jama.com), indicating vitamin intake is essential for health. "Inadequate intake of several vitamins has been linked to chronic diseases, including coronary heart disease, cancer and osteoporosis," the researchers wrote. Their review included English-language articles about chronic disease and vitamin intake that were published from 1966 through Jan. 11, 2002.

In an accompanying editorial, the same authors wrote, "[L]ow levels of the antioxidant vitamins--vitamins A, E, and C--may increase risk for several chronic diseases. Most people do not consume an optimal amount of all vitamins by diet alone. Pending strong evidence of effectiveness from randomized trials, it appears prudent for all adults to take vitamin supplements."

In late June, the Council for Responsible Nutrition (CRN) released a 100-plus page report--The Benefits of Nutritional Supplements (www.crnusa.org/benefits.html)--which provides an overview of more than a decade's worth of scientifically relevant studies supporting the health benefits of multivitamins and antioxidants, as well as calcium, omega-3 fatty acids and vitamins D, B6, B9 (folic acid) and B12. "These nutrients are the ones that we considered to be the best developed, based on the science behind them," said Annette Dickinson, Ph.D., vice president of scientific and regulatory affairs at CRN as well as the report's author.

"The impact of a rational use of dietary supplements can help reduce health care costs that escalate every year as our population grows older," said Jeffrey Blumberg, Ph.D., a professor at the School of Nutrition Science and Policy at Tufts University who reviewed the CRN report before it was published.