This article originally appeared in the February 2003 Harvard Men's Health Watch and is provided courtesy of Harvard Health Publications.

Antioxidant supplements: Bad news and good news

If only there were a pill.

ItÍs no secret that vitamin-rich foods are healthful and that they appear to reduce the risk of heart disease. And during the past 20 years, many laboratory experiments have demonstrated that antioxidants protect vascular tissue from the damage caused by cholesterol. The logical next step was to skip the veggies and try antioxidant vitamins straight up, as pills.

Despite the early promise, it’s been a flop. But many men have held on to their antioxidants, believing that even if they don’t help, they can’t hurt. Unfortunately, new data show that some popular supplements can do more harm than good, at least for some men. At the same time, though, research has identified one area in which antioxidant supplements really do seem worthwhile.

What are antioxidants?
The chain of events starts with oxygen free radicals, unstable, high-energy molecules that the body generates as a byproduct of carbohydrate metabolism. Free radicals have an important role in preventing infection. They can latch on to bacteria and other microbial invaders, then zap the bugs with their extra energy, neutralizing or killing them. But oxygen free radicals are a double-edged sword; they can injure human tissues just as they damage bacteria.

The body has an elaborate system of antioxidants that try to keep free radicals in check, but if the free radicals get the upper hand, they may contribute to a wide variety of problems, from heart disease and cancer to neurological diseases such as Alzheimer’s and Parkinson’s, eye disorders such as cataracts and macular degeneration, and even aging itself.

Antioxidants in food
Our diet can help decide the struggle between free radicals and the antioxidants that neutralize them. Although oxygen free radicals are not present in natural foods, processing and cooking may produce them. In particular, frying can generate them from polyunsaturated fatty acids. Fortunately, the natural antioxidants in foods, including vitamin C, vitamin E, and the caroteneÆvitamin A family, can fight back by neutralizing free radicals.

Studies from around the world have linked low blood levels of antioxidant vitamins to a high risk of heart attack and stroke. In contrast, people who eat lots of deep green and yellow-orange vegetables and citrus fruits enjoy a low risk of atherosclerosis. In addition, new studies suggest that antioxidant-rich diets may reduce the risk of AlzheimerÍs disease. But are the vitamins themselves responsible for the apparent protection? Scientists began to answer the question by testing antioxidants in the lab; heart disease has received the most attention.

Laboratory studies
The research gathered steam in the 1980s, when scientists discovered that LDL (“bad”) cholesterol is not as bad as it seems—at least until it’s bombarded by oxygen free radicals. Oxidized LDL cholesterol is the result, and it’s the real culprit in atherosclerosis, triggering the cascade of events that leads to heart attacks (see Harvard MenÍs Health Watch, September 2000). The first step is the buildup of plaques in artery walls. Next, inflammation develops in the plaques, which can become unstable, then rupture. Finally, a clot develops on the ruptured plaque, blocking the artery and causing a heart attack.

If oxidative damage to LDL cholesterol triggers the entire chain of events, then perhaps antioxidants can halt the process in its tracks. And in test tubes they do protect LDL from oxidative damage. Vitamin E seems the most potent: It can even protect rabbits from the devastating effects of atherosclerosis.

Impressed by the effects of antioxidant vitamins in the lab, scientists next turned to human studies.

Observational studies
No less an authority than Yogi Berra pointed out that ñyou can observe a lot just by watching.î Epidemiologists agree; the first human antioxidant research depended on observational studies that compared people who took antioxidant supplements with those who did not.

The results seemed encouraging. In most studies, the people who took antioxidant vitamins had a lower incidence of heart disease. As in the lab experiments, vitamin E appeared the most promising, which was particularly encouraging since it’s the hardest to get from foods, at least in the high doses that were thought to help.

The antioxidant boom was on. But even as sales soared and doctors recommended antioxidants for their patients (and themselves!), researchers were not content. Observational studies are useful but not definitive. ThatÍs because itÍs so hard to account for all the possible differences between the people who did and did not take the vitamins. For example, vitamin use could merely reflect a healthier lifestyle without actually adding to protection. Epidemiologists did their best to consider the impact of smoking, drinking, exercise, cholesterol, blood pressure, obesity, and all the other factors that influence cardiac risk— but they also began randomized clinical trials.

Clinical trials of individual antioxidants
People who volunteer for a randomized clinical trial agree to be assigned by chance to take either the treatment being tested or a placebo. In double-blind trials, neither the scientists nor their subjects know who is getting the real thing (see HMHW, March 2002).

Randomized clinical trials showed postmenopausal women that hormone replacement treatment is not beneficial, although many observational studies raised expectations to the contrary. And thatÍs just what happened with antioxidant vitamins and heart disease. The table on page 2 shows the results of seven major studies of individual antioxidants. With the partial exception of the relatively small CHAOS study, none found any cardiac protection.

Despite these very disappointing results, some hope persisted. Even if individual antioxidant supplements fail, perhaps a combination of them would be successful.

Combination antioxidants and the heart
In 2002, two studies answered the question about combination therapy and cardiovascular disease. In the Heart Protection Study, more than 20,500 patients with atherosclerosis or diabetes were randomly assigned to take a daily supplement (600 mg of vitamin E, 250 mg of vitamin C, and 20 mg of beta carotene) or a placebo. At the end of five years, there were no differences in heart attacks, strokes, deaths from cardiovascular disease, or deaths from noncardiac causes. Three antioxidants were no better than none.

Still, vitamin pills are not very expensive and medical science is imperfect, so why not take an antioxidant ñjust in case?"

The answer comes from the second 2002 study. In the WAVE trial, 423 postmenopausal women with coronary artery disease were randomly assigned to take 400 IU of vitamin E and 500 mg of vitamin C or a placebo twice daily. During five years of observation, the volunteers who took the vitamins had more heart attacks, strokes, and deaths than those who took the placebo. ItÍs sobering news, but we still have to ask if antioxidants have the potential to harm men as well as women.

More worries
In the case of beta carotene the answer is clear: Since 1994, doctors have known that the supplement increases the risk of lung cancer in male smokers. Beta carotene has not been linked to cancer in nonsmokers, but the CARET and ATBC results took this once-promising supplement out of most medicine chests. And new information may discourage people with cholesterol problems from taking the other antioxidants.

The Heart Protection Study of combination antioxidants found that the supplements produced small but significant elevations in three cardiac risk factors: LDL cholesterol, triglycerides, and apolipoprotein B. Since all the subjects had atherosclerosis or diabetes, itÍs likely that many of them were taking cholesterol-lowering medications throughout the study. Unfortunately, the researchers did not try to correlate the rise in cholesterol with the use of such medications, but another recent investigation suggests that antioxidants may blunt the effect of certain medications.

Scientists from the University of Washington conducted a three-year randomized clinical trial of simvastatin (Zocor), niacin, and antioxidants in 160 men and women with coronary artery disease.

The participants were divided into four groups: placebo, cholesterol-lowering medications, antioxidants (800 IU of vitamin E, 1,000 mg of vitamin C, 25 mg of beta carotene), or cholesterol-lowering medication plus antioxidants. Compared with the placebo, the medication had its expected favorable impact, lowering LDL and boosting HDL (“good”) cholesterol. The antioxidants themselves had no effect on cholesterol for better or worse. But in the combination group, the antioxidants reduced the expected benefit of the medications, blunting the protective rise in HDL. Even more distressing, patients in the medication group had improvements in their coronary angiograms, while those in the antioxidant plus medication group experienced additional narrowing of their arteries and a greater risk of cardiac events.

These results donÍt prove that all antioxidants are harmful. The University of Washington study used selenium in addition to vitamins, and, like the WAVE trial, it used very high doses of antioxidants. Other laboratory and clinical investigations have raised the possibility that excessive doses of vitamin C may actually have a paradoxical pro-oxidant effect.

Still, the research suggests it would be prudent for people taking cholesterol-lowering medication to avoid antioxidants. And it also suggests that instead of assuming antioxidants are safe until proven harmful, we might do well to assume the reverse.

All in all, the once-mighty antioxidants have taken quite a fall. But another recent clinical trial provides hope that an antioxidant-mineral combination may provide a bit of light at the end of the tunnel for patients with a common disease that can progress to blindness.

The good news
Antioxidant vitamins, either singly or in combinations, do not help the heart„and in certain circumstances they may even do more harm than good. But researchers have finally identified an antioxidant vitaminÆmineral combination that can help fight an important disease, age-related macular degeneration (AMD; see HMHW, July 2001).

The Age-Related Eye Disease Study evaluated 3,640 people between the ages of 55 and 80 at 11 centers in the U.S. All the subjects had ocular abnormalities that ranged from small pigment deposits in the retina (drusen) to moderate or advanced macular degeneration. The volunteers were randomly assigned to receive one of four regimens: antioxidants (500 mg of vitamin C, 400 IU of vitamin E, and 15 mg of beta carotene); 80 mg of zinc with 2 mg of copper; antioxidants plus zinc and copper; or a placebo.

The volunteers were evaluated carefully for an average of 6.3 years. During that time, the people who started out with the mildest abnormalities fared equally well whether or not they took a supplement. But participants with intermediate problems did benefit. The antioxidantÆmineral combination was best, reducing the risk of progression to advanced disease by 25%. The minerals alone reduced the risk of progression by about 21%; the antioxidants alone reduced the risk by about 17%. None of the supplements influenced the development of cataracts, but none produced significant side effects.

Even with these encouraging results, researchers are continuing to study the antioxidantÆmineral combination to see if it remains safe and effective after seven years. Scientists are also studying lutein and zeaxanthin, potent antioxidants in the beta carotene family that seem promising for macular degeneration. But a separate Australian study of 1,193 healthy volunteers ages 55Æ80 showed that 400 IU of vitamin E a day had no effect on the development of early macular degeneratIon

The Age-Related Eye Disease Study is good news for antioxidants—and even better news for people with macular degeneration. About 1.7 million Americans have the disease, and 100,000 are legally blind because of it. People with early drusen donÍt seem to need antioxidants, and people who are already blind canÍt benefit. But the new research suggests that people at intermediate stages should consider taking a daily antioxidant—zinc plus copper supplement, which is now being marketed as Ocuvite. Zinc plus copper would be a better choice for people at risk for antioxidant-related problems, including smokers who must avoid beta carotene and possibly people taking certain cholesterol-lowering medications. The study is also an important reminder that everyone over 50 should get regular eye care.

Perspectives
Antioxidant-rich foods appear to have important benefits for human health. Supplements that combine antioxidants with zinc are proving beneficial for patients with macular degeneration. Supplements once seemed very promising to help fight heart disease, but research has deflated those hopes and has found that in some cases antioxidants may do more harm than good.

Even though antioxidant supplements wonÍt protect you against heart disease, a simple daily multivitamin may help. It will provide vitamins B6, B12, and folic acid. They are not antioxidants, but they do reduce blood levels of homocysteine, an important cardiac risk factor (see HMHW, December 2000). A multivitamin will also provide the vitamin D that so many Americans lack (see HMHW, February 2001). Randomized clinical trials will be needed to find out if multivitamins really help, but a daily supplement seems responsible, even wise, while we wait for new results. Above all, perhaps, don’t forget to eat your veggies.