Study throws doubt on safety of antioxidants?
they are not effective in reducing the risk of cardiovascular
disease. The authors, writing in tomorrow's Lancet, even go
as far as warning that beta-carotene supplements could actually
contribute to an increase in cardiovascular death. Trade
association CRN however calls the study "irresponsible,
overinterpreted, and old news disguised as something new".
Antioxidant vitamins are not effective in reducing the risk of cardiovascular disease, concludes a meta-analysis of randomised trials in tomorrow's issue of the Lancet. The authors, from the Cleveland Clinic Foundation in the US, designed their analysis to examine the previous findings suggesting that antioxidant vitamins could delay the progression of atherosclerosis and thereby offer protection against cardiovascular disease.
Marc S Penn and colleagues analysed seven randomised trials of treatment with vitamin E and eight trials of treatment with beta-carotene (a source of vitamin A). All the trials included over 1000 participants, and follow-up ranged from one to 12 years.
Vitamin E was not beneficial in reducing death from cardiovascular causes, all-cause mortality, or in reducing the incidence of stroke compared with people given control treatment, they reported. And beta-carotene led to a small (0.4 per cent) but statistically significant increase in all-cause mortality and a 0.3 per cent increase in cardiovascular death.
"Our findings are particularly concerning given that the relevant beta-carotene doses are commonly used in preparations of over-the-counter vitamin supplements and are included in smaller doses in readily available multivitamin supplements," write the researchers.
The results show that use of vitamin supplements containing beta-carotene and vitamin A, beta-carotene's biologically active metabolite, should be actively discouraged, says Penn, because this family of agents is associated with a small but significant excess of all-cause mortality and cardiovascular death.
"We recommend that clinical studies of beta-carotene should be discontinued because of its risks," he continued. "When used as secondary prevention, vitamin E did not reduce the risk of cardiovascular endpoints. Furthermore, given our results and the lack of mechanistic data supporting efficacy of vitamin E as a potent antioxidant in vivo, we do not support the continued use of vitamin E treatment and discourage the inclusion of vitamin E in future primary and secondary prevention trials in patients at high risk of coronary artery disease," he concluded.
The US supplement trade association Council for Responsible Nutrition (CRN) however said the meta-analysis provided overgeneralised interpretations of previously published clinical trials on vitamin E and beta-carotene and their effect on heart health.
Dr John Hathcock, CRN's vice president of scientific and international affairs, said: "This meta-analysis hasn't told us anything we didn't already know. But that didn't stop the researchers from making sweeping statements that are not justifiable based on the studies they reviewed. For example, they discount the potential benefit of vitamin E for heart disease based largely on their review of secondary intervention trials on subjects with established heart disease. But what many researchers refer to as the 'antioxidant hypothesis' is the belief that antioxidants may be effective in decreasing the risk of heart disease if consumed before the atherosclerosis develops."
The researchers did in fact highlight this theory in the discussion section of the study - antioxidants may be more effective in preventing early stages of atherosclerosis, than the advanced stages of most patients participating in clinical trials. They also point out that some studies were based on antioxidant-rich food intake - such foods may provide other beneficial nutrients, such as flavonoids or lycopenes not present in vitamin supplements. The natural forms of vitamins may have biological activity different to those for synthetic vitamins, note the researchers.
But Penn's link between increased risk of death and beta-carotene will raise lively debate in the industry. The researchers note that beta-carotene in particular is a poor inhibitor of in-vivo LDL oxidation and also has adverse effects on lipids. Beta-carotene is also believed to pose a risk to smokers in high doses although Hathcock points out that none of the beta-carotene studies included in the article suggest a risk to non-smokers. The evidence for a small but statistically significant risk with high-dose beta-carotene is derived entirely from two clinical trials in smokers and in others at high risk of heart disease, claims CRN. In both of those trials, the increased risk occurred primarily in people who smoked, and as a result it is generally recommended that smokers should not use high-dose beta-carotene, it explains.
"It is nothing short of irresponsible for the researchers to suggest that research on vitamin E and beta-carotene be stopped. It would be a major disservice to the public health to stop research on antioxidants in relation to heart disease," argues Hathcock.
He added that the meta-analysis is "not the last word" on the benefits of vitamin E and beta-carotene, suggesting that the researchers were "simply trying to make headlines".
Experts at The Linus Pauling Institute Conference on Diet and Optimum Health, a recent conference on antioxidants, emphasised the need for more research to identify optimal intakes of antioxidant nutrients for health promotion and disease prevention.
