Swan song for antioxidant supplements?

For the past few years, antioxidant supplements have been experiencing a steady fall from grace. Once hailed as a cheap and easy way to ward off chronic diseases, antioxidants such as vitamin C, beta carotene, and vitamin E haven't panned out as a way to prevent heart disease and stroke.

In 2003, the federal Agency for Healthcare Research and Quality looked at the most rigorous studies of three antioxidants — vitamin C, vitamin E, and coenzyme Q10 — and heart disease. Perhaps a little smoke, but no fire, the agency concluded.

The American Heart Association's Nutrition Committee set itself much the same task. It evaluated 15 large trials in which more than 100,000 volunteers didn't know whether they were taking an antioxidant pill or a placebo. The result of this analysis? No evidence that antioxidant supplements affect heart disease. The committee's report, published in the August 3, 2004, issue of Circulation , warns against using antioxidant pills or potions to ward off heart attacks or heart disease.

These two assessments seem to slam the door on antioxidant supplements. Yet optimistic presentations made at a three-day symposium on vitamin E held this May in Boston could represent the proverbial foot in the door.

What's the real story on antioxidant supplements? The first question that needs answering is: Where did people first get the delightful idea that you could take a simple vitamin pill to prevent or treat heart disease? Let's look at the case of vitamin E.

Over the years, study after study after study has shown that people who eat plenty of fruits and vegetables are less likely to have heart disease than people who shy away from these foods. Eager to understand how fruits and vegetables protect the heart and blood vessels (and other systems, too), scientists looked for likely suspects. They turned first to compounds that were abundant in food and easy to identify and extract. The early list included antioxidants such as vitamin C, beta carotene, and vitamin E.

The discovery that a chemical reaction akin to rusting, called oxidation, activated LDL (bad) cholesterol in the body and kicked off the artery-clogging process of atherosclerosis heightened interest in these vitamins. By protecting LDL from oxidation, so the thinking went, vitamin E could block an early event leading to heart disease. Studies in which people were asked about their dietary habits backed this up, showing that people who took vitamin E supplements or got plenty of vitamin E from food were less likely to develop heart disease.

Yet studies testing vitamin E against placebo have been disappointing, to say the least. In five trials, rates of heart disease and death were the same for vitamin E and placebo. In three others, vitamin E reduced nonfatal heart attacks but not deaths. In another, it seemed to counteract the beneficial effects of a cholesterol-lowering statin.

Why do the results from clinical trials seem to contradict the positive picture for vitamin E and other antioxidants? There are several reasons.

People who choose to take vitamin E or eat foods rich in it could also do other healthy things, like maintain a healthy weight or get more exercise, and it may be that these other factors offer protection against heart disease. It is also possible that randomized trials are too short, and that it takes more than a few years to see what antioxidants can do. Plus, many of the vitamin E trials included people who already had heart disease, and it could be that antioxidants have no effect once arteries are already pocked with cholesterol-filled plaque, but may work earlier in life. Or maybe single antioxidants, or even combinations of them, aren't what we really need.

We tend to think of antioxidants as interchangeable. That's misleading. Each antioxidant has a unique set of chemical behaviors and biological properties. They work together as parts of an elaborate network, with each different substance (or family of substances) playing a slightly different role. No single antioxidant can do the work of the whole crowd. And it may be that taking too much of any one could throw the network off balance.

At the vitamin E symposium in Boston, researchers described what this vitamin can do in laboratory studies: It acts as an anti-inflammatory agent and prevents platelets from clumping, much as aspirin does; it boosts production of nitric oxide, a substance that keeps blood vessels healthy and relaxed; it affects the activity of some genes; and it influences the production of cell-signaling molecules. But no one knows just what it does in our bodies, how much we really need, or in what form we should take it.

Natural vitamin E is an amalgamation of eight different substances: four tocopherols (alpha, beta, gamma, and delta) and four tocotrienols (also alpha, beta, gamma, and delta). Vitamin supplements contain all or mostly alpha tocopherol, yet research on gamma tocopherol suggests it — and the other six components — might also be important for fighting disease.

December 2004 Update

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