Why do homocysteine-lowering B vitamin and antioxidant E vitamin supplementations appear to be ineffective in the prevention of cardiovascular diseases?

Homocysteine has been established as a serious, independent risk factor for atherosclerosis. An elevated plasma homocysteine concentration is accompanied by increased cardiovascular risk; therefore, it can be assumed that lowering the plasma homocysteine level results in a decreased risk. Vitamin B complex (folic acid, and vitamins B6 and B12) substitution therapy decreases the plasma homocysteine level, inhibits oxidative stress, and ameliorates some biochemical and clinical parameters that indicate the progression of atherosclerosis. Vitamin E administration may also reduce atherogenesis through its antioxidant effect. The effectiveness of B and E vitamin substitution in decreasing cardiovascular risk has been suggested by cohort as well as prospective and retrospective studies undertaken during the last two decades. On the other hand, recent large, randomized clinical trials did not substantiate a beneficial effect of homocysteine-lowering B vitamin supplementation or vitamin E antioxidant therapies in reducing cardiovascular risk in humans. We analyzed eight B vitamin and four E vitamin trials from a critical point of view, and in this article we reviewed and commented on their results and focused on the contradictions found in them. We showed that the possible factors implicated in the failure of vitamin therapies included inappropriate designs. The protocols neglected an essential fact: that the impact of some confounding factors, such as concomitant use of statins, acetylsalicylic acid, folic acid, and other drugs, might have led to bias and an inappropriate interpretation of the data. The cardiovascular protective and preventive effects of statins and aspirin might have reduced or abolished the possibility of observing a difference in the number of events between the vitamin and placebo groups for the clinical endpoints. We concluded that the vitamin preventive effect on cardiovascular disease may not be rejected in reference to the negative trial evidence.