Antioxidants: no magic bullet.

Antioxidants. Was there anything vitamin C, vitamin E, and beta-carotene couldn't do? For years, people assumed that they could prevent everything from cancer to heart attacks, strokes, cataracts, and more.

The concept was so appealing: Damage caused by wayward oxygen could trigger tumors, ruin arteries, and blur vision. And safe, cheap antioxidants could flush away all that damage.

It's been a decade or two since researchers started to put antioxidants through the same rigorous tests that they use to prove other theories. The vitamins passed some and flunked others.

Now enough research has been done to step back and take stock of the evidence from these trials. Here's the antioxidant story so far.

"The evidence on antioxidants so far is disappointing," says JoAnn E. Manson of Harvard Medical School. In several major trials, antioxidants failed to prevent heart disease and cancer. But some results--on prostate cancer and macular degeneration--are promising. And three large ongoing trials are looking not just at heart attacks and cancer, but at eye disease and memory loss. "We haven't closed the door on antioxidants," says Manson.

But researchers now approach them less as a class of miracle-workers than as individual agents that may prevent disease. "It's not really useful to think of antioxidants as a category," says Meir Stampfer of the Harvard School of Public Health. "Take beta-carotene. Just because it doesn't protect against heart disease and cancer, we can't assume that other antioxidants don't."

HEART DISEASE

It was an elegant theory. LDL, or low-density lipoproteins, are the kind that carry "bad" cholesterol. In test-tube studies in the 1980s, LDL seemed capable of damaging artery walls only when it was oxidized. And when researchers gave people antioxidants, their LDL seemed less susceptible to oxidation.

"If you removed some of the LDL from their blood and hit it with a pro-oxidant, it took longer to oxidize than the LDL from people who didn't get antioxidants," says Alice H. Lichtenstein of the Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University in Boston. "But in the body, blood contains other antioxidants, so the story isn't that simple. That's why we had to take those studies with a grain of salt."

And people might have done just that, were it not for two Harvard studies that hit the news wires in November 1992.

In one study of 87,000 women and another of 40,000 men, those who reported taking at least 100 IU of vitamin E a day were roughly 35 percent less likely to have a heart attack than those who didn't take vitamin E.

The question: Was it vitamin E or something else about people who take vitamin E that protects the heart? "There was only one way to tell," says Lichtenstein. "We had to do clinical intervention trials."

Rather than studying people who chose to take (or not take) vitamin E, researchers randomly assigned people to take the vitamin or a dummy pill. In some of the studies, participants got an antioxidant cocktail (usually vitamin E, beta-carotene, and vitamin C). Then the investigators waited to see who got heart attacks.

Now, ten years later, most of the studies are done. All but one of them--the least reliable--flopped.

"There's no denying that the trials found no benefit," says researcher Meir Stampfer of Harvard Medical School. "They do put a damper on our enthusiasm."

Among the largest trials: the HOPE (Heart Outcomes Prevention Evaluation) study gave vitamin E to 9,500 people for five years. They had no fewer heart attacks than those given a placebo. And in the Heart Protection Study, which gave vitamin E, beta-carotene, and vitamin C to 20,000 people for six years, the antioxidants also bombed.

"Vitamin E has no place in treating patients at high risk for heart disease," says Gilles Dagenais of the Quebec Heart Institute at Laval University in Ste-Foy, Canada, who co-authored the HOPE study.

"Roughly 50,000 patients have gone into trials, and it doesn't matter whether they get a high dose or a low dose, with other vitamins or without. It's clear that vitamin E doesn't prevent recurrent events."

Worse yet, when researchers gave antioxidants to people who were taking both statin drugs and high doses of niacin to raise their HDL ("good") cholesterol, the antioxidants blunted the rise in HDL and raised the risk of heart attacks and strokes.

"The use of antioxidants could be hazardous ...," wrote the University of Pittsburgh's Lewis Kuller in an editorial accompanying the study. But for people who aren't taking both niacin and statins, antioxidants don't appear to hurt ... or help.

"Someone can always argue that these trials didn't see anything because they only lasted five years," says Dagenais. "And the HOPE study is still going on in 6,000 people, so it's possible that we'll see an impact after eight years. But if we have to wait eight years, I wonder if that's good medicine."

The only hope for vitamin E: So far, all the intervention trials have tested people who already had heart disease or were at high risk.

"The biology suggests that if vitamin E works, it prevents LDL oxidation, which occurs at the early stage of atherosclerosis," says Stampfer. "So the best kind of evidence would come from trials on healthy adults with no evidence of coronary disease."

Only two trials--the Women's Health Study and the Physicians' Health Study II--fit that description. Their results are due in the next six years. "I still take vitamin E because it's safe and cheap," says Stampfer. "But if those studies come up empty, I'll have to reconsider."

THE BOTTOM LINE

Everyone should take an ordinary Centrum-like multivitamin-and-mineral to make sure that they get enough folic acid, vitamins B-12, D, and K, and other hard-to-get nutrients. Most people should also take extra calcium (which most multis have in only small quantities). In addition:

* If you have advanced macular degeneration, take a mixture of vitamin C (500 mg), vitamin E (400 IU), and beta-carotene (25,000 IU), as well as zinc (80 mg) and copper (2 mg), either as part of your daily multi or in a separate supplement.

* To (possibly) reduce the risk of prostate cancer, middle-aged and older men should consider taking selenium (200 mcg) and vitamin E (400 IU), either as part of their daily multi or in a separate supplement.

* If you have a high risk of heart attack or stroke, don't take antioxidant vitamins if you're taking both statin drugs (like Zocor) and high doses of niacin.

* To prevent heart disease, stroke, cancer (other than prostate), macular degeneration, or cataracts, taking vitamin E or vitamin C probably won't hurt. But until the ongoing studies are complete, there's no way to tell whether they'll help.

* If you want to slow aging, curb muscle pain, erase wrinkles, etc., keep in mind that no one has done major trials on those or other potential benefits of antioxidant vitamins (C, E, and beta-carotene) or other antioxidants (lycopene, grape seed extract, etc.).

About the Timelines

The timelines on pages 4-8 show only clinical trials, but researchers also consider evidence from other human (and animal) studies before they reach conclusions. Most of the clinical trials looked not just at heart attacks and strokes or cancer, but at angioplasty, coronary bypass, angina, congestive heart failure, death, and other cardiovascular events. The number of participants in each study has been rounded and may include people on statin drugs, aspirin, and other treatments.

1996

2,000 people with heart disease take vitamin E (400 or 800 IU daily) or a placebo for 3 to 981 days. Vitamin-E-takers have fewer non-fatal heart attacks, but poor design raises questions. (1)

1997

300 anqioplasty patients take antioxidant vitamins (30,000 IU of beta-carotene, 500 mg of vitamin C, and 700 IU of vitamin E), the drug probucol, or a placebo twice daily for 4 weeks before and 6 months after angioplasty. Arteries are least likely to close up again on probucol alone, more likely on probucol plus antioxidants, and most likely on antioxidants or the placebo alone. (2)

1998

29,000 Finnish male smokers take vitamin E (110 IU), beta-carotene (33,000 IU), both, or a placebo daily for 5 to 8 years. No difference in heart attack rates. (3) In another study of the same men, beta-carotene-takers who had previous heart attacks were more likely to die of heart disease. (4)

1999

11,000 heart attack survivors take omega-3 fats (1 gram), vitamin E (670 IU), both, or a placebo daily for 4 years. Unlike other trials, patients knew which they were getting. No difference between vitamin E and the placebo in heart attack rates. (5)

2000

In the HOPE Study, 9,500 people with either cardiovascular disease or diabetes take vitamin E (400 IU) or a placebo daily for 5 years. No difference in rates of heart attack. (6)

2001

4,500 people at high risk for heart disease take vitamin E (670 IU) daily for 4 years. E has no effect on heart attacks. Aspirin (100 mg a day) reduces the risk by 44%. (7)

2001

The Heart Protection Study gives 20,000 people at high risk of heart disease vitamin E (1,300 IU), vitamin C (250 mg), and beta-carotene (33,000 IU) or a placebo daily for 6 years. No difference in heart attack rates. (8)

2001

160 patients with heart disease and low HDL ("good") cholesterol levels take the statin drug Zocor plus niacin (to raise HDL) with or without vitamin E (400 IU), vitamin C (500 mg), beta-carotene (21,000 IU), and selenium (50 mcg) twice daily for 3 years. Rates of heart attack and stroke are lowest on statin plus niacin, higher on statin plus niacin plus antioxidants, and highest on antioxidants or the placebo alone. (9)

2005

The Women's Antioxidant and Cardiovascular Study is giving 8,000 women with cardiovascular disease vitamin E (600 IU every other day), vitamin C (500 mg every day), and/or beta-carotene (83,000 IU every other day).

2005

The Women's Health Study is giving 40,000 healthy female health professionals either vitamin E (600 IU), aspirin (100 mg), both, or a placebo on alternate days.

2007

The Physicians' Health Study II is giving 15,000 male physicians vitamin E (400 IU every other day), vitamin C (500 mg every day), and/or beta-carotene (83,000 IU every other day).

Timeline Footnotes

(1) Lancet 347: 781, 1996.

(2) New Eng. J. Med. 337: 365, 1997.

(3) Arch. Intern. Med. 158: 668, 1998.

(4) Lancet 349: 1715, 1997.

(5) Lancet 354: 447, 1999.

(6) New Eng. J. Med. 342: 154, 2000.

(7) Lancet 357: 89, 2001.

(8) Int. J. Clin. Pract. 56: 53, 2002.

(9) New Eng. J. Med. 345: 1583, 2001.

CANCER

Beta-carotene had such promise. In study after study during the 1980s, researchers found that smokers who ate the least carrots, sweet potatoes, and other fruits and vegetables rich in beta-carotene had the highest risk of lung cancer.

But in two major trials on nearly 50,000 people in the 1990s, smokers who were given high-dose beta-carotene pills had a higher rate of lung cancer than smokers who were given no beta-carotene. In a third trial, on 22,000 mostly non-smoking male physicians, beta-carotene had no effect.

What went wrong?

"In the two trials that showed an increased rate of cancer, very high doses of beta-carotene raised blood levels of beta-carotene more than 15-fold," says Regina Ziegler of the National Cancer Institute. "The third trial, which showed no increased rate, used a form of beta-carotene that didn't lead to such high blood levels."

And the smokers in the first two trials may have been more susceptible to harm caused by high doses of beta-carotene than the non-smoking physicians in the third trial. But in some ways the third trial was the most compelling.

"In the Physicians' Health Study, people took relatively normal doses for longer than in the other two trials," explains Ziegler. "If 12 years isn't long enough, it's hard to imagine that beta-carotene is protective."

So why did people who ate beta-carotene-rich fruits and vegetables have a lower risk of lung cancer? It could have been something other than their beta-carotene.

"A high intake of beta-carotene is the single best indicator of a high fruit and vegetable intake," says Ziegler. "But other carotenoids in fruits and vegetables, like alpha-carotene or beta-cryptoxanthin, could have been protecting against cancer. It's also possible that people who eat diets high in fruits and vegetables have a lower risk of cancer because they have healthier lifestyles."

Meanwhile, research on other cancers has not been promising. In two trials, beta-carotene had no impact on skin cancers. And in patients who had already had one precancerous colon polyp removed, a combination of beta-carotene, vitamin C, and vitamin E didn't cut the risk of new polyps. What's more, when researchers went back to the smokers who took beta-carotene or vitamin E, they found no lower risk of cancers of the pancreas, urinary tract, stomach, or colon. Only prostate cancer rates were lower in vitamin-E-takers (see p. 7).

"In our clinical trial on mouth and throat cancer, it looked as though beta-carotene might have significantly lowered the risk of a recurrent tumor if the study had been larger," says Susan Taylor Mayne of Yale University. "But we had to stop recruiting new patients when the 1990s trials came out." The potential for beta-carotene to raise the risk of lung cancer in smokers outweighs the possibility that it could prevent mouth and throat cancer.

The take-home message, says Mayne, is to eat more fruits and vegetables, including carrots, sweet potatoes, broccoli, and others that are rich in all carotenoids. "There's no evidence of harm, and the studies that drove the trials in the first place came from looking at people who ate fruits and vegetables."

1994

29,000 Finnish male smokers take beta-carotene (33,000 IU), vitamin E (110 IU), both, or a placebo daily for 5 to 8 years. Lung cancel' risk is 18% higher in beta-carotene-takers. No difference in lung cancer rates between vitamin E and placebo. (1)

1994

860 patients with a history of precancerous colon polyps take beta carotene (42,000 IU), vitamin C (1,000 mg), and/or vitamin E (600 IU), or a placebo daily for 4 years. No differences in the risk of new polyps. (2)

1996

In the CARET Study 18,000 smokers, former smokers, and workers exposed to asbestos take beta-carotene (50,000 IU) and vitamin A (25,000 IU) or a placebo daily for 4 years. Study stops 2 years early because supplement-takers have 28% higher risk of cancer. (5)

1996

22,000 healthy male physicians take beta-carotene (83,000 IU on alternate days) or a placebo for 12 years. No difference in risk of cancer, heart disease, or diabetes. (3,4)

1999

1,600 Australians take beta-carotene (50,000 IU) or a placebo daily for 5 years. No difference in rates of non-melanoma skin cancer. (7)

2001

264 patients treated for an early-stage cancer of the mouth, throat, or voicebox take either beta-carotene (83,000 IU) or placebo daily for 4 years. No difference in new tumors, but study may have been too small to detect a reduced risk. (6)

2005

The Women's Health Study is giving 40,000 healthy female health professionals either vitamin E (600 IU), low-dose aspirin (100 mg), both, or a placebo on alternate days.

2007

The Physicians' Health Study II is giving 15,000 male physicians vitamin E (400 IU every other day), vitamin C (500 mg every day), and/or beta-carotene (83,000 IU every other day).

Timeline Footnotes

(1) New Eng. J. Med. 330: 1029, 1994.

(2) New Eng. J. Med. 331: 141, 1994.

(3) New Eng. J. Med. 334: 1145, 1996.

(4) J. Amer. Med. Assoc. 282: 1073, 1999.

(5) New. Eng. J. Med. 334: 1150, 1996.

(6) Cancer Research 61: 1457, 2001.

(7) Lancet 354: 723, 1999.

PROSTATE CANCER

Gone are the days when people naively assumed that all antioxidants could prevent all cancers. But some of the disappointing antioxidant trials may, by accident, have led researchers to good news.

A case in point: In the mid-1990s, when researchers gave Finnish smokers beta-carotene or vitamin E to reduce their risk of lung cancer (neither worked), the vitamin-E-takers had a lower risk of prostate cancer. And when researchers gave selenium to Southerners in the U.S. to reduce their risk of a recurrence of non-melanoma skin cancer (it didn't work), the selenium-takers ended up with a lower risk of prostate cancer.

"Selenium cut the risk of prostate cancer by almost two-thirds," says study co-author Gerald Combs, currently director of the U.S. Department of Agriculture Human Nutrition Research Center in Grand Forks, North Dakota.

But that's not proof that selenium works. "It was a small trial, with only 1,312 subjects," he explains. "And it was an older group of people from the eastern Carolinas and Georgia who typically had a Celtic skin type, which is why they had a history of skin cancer. Selenium may not work in a more diverse population."

To find out, the National Cancer Institute has launched the SELECT (Selenium and Vitamin E Cancer Prevention Trial). More than 32,000 men at high risk for prostate cancer will take vitamin E, selenium, or a placebo each day for ten to 12 years.

"SELECT will be the acid test," says Combs. "But we have every reason to expect selenium to work. A huge number of animal studies indicate that selenium is protective."

And, unlike many other clinical trials, this one was driven by other clinical trials, not by studies that saw a lower risk of disease in people who chose to take supplements or eat healthy foods on their own. "Having a positive clinical trial increases our confidence," says Combs.

If selenium and vitamin E do cut the risk of prostate cancer, it wouldn't necessarily be because they're antioxidants, though.

"Selenium functions as a constituent of enzymes that have antioxidant activity," says Combs. The amount the enzymes need is probably well below 55 micrograms a day, which is the Recommended Dietary Allowance. "We find very few people who get less than 55 micrograms a day."

Instead, selenium might stimulate the immune system or slow the process of angiogenesis, the growth of blood vessels that feed tumors. "Or selenium may promote programmed cell death," he explains. "So cells that are transformed into cancer die instead of multiplying."

Vitamin E may also cut the risk of prostate cancer by some means other than acting as an antioxidant.

"Vitamin E and other antioxidants have functions other than just preventing damage from free radicals in cells," says SELECT co-investigator Demetrius Albanes of the National Cancer Institute.

In the NCI's trial testing vitamin E and beta-carotene on Finnish smokers, for example, "vitamin E reduced testosterone levels by eight percent," he explains. High testosterone is a risk factor for prostate cancer. "Vitamin E may also decrease cell proliferation or increase programmed cell death," he adds.

In fact, the trials that found a lower risk of prostate cancer in people who took selenium and vitamin E indicate that neither acted as an antioxidant. "Antioxidants would work early in the cancer process, but the trials suggest that the supplements had a faster impact," says Albanes. "So they may be altering hormones or growth factors that affect a later stage of cancer."

Should people take vitamin E and selenium now, rather than wait for results from the SELECT trial, which won't be in until 2013? Combs won't say, but he does give this advice: "There's no reason to take more than 200 micrograms of selenium a day. We don't know if it will help, but we know that amount is safe."

Vitamin E also appears safe to take at levels up to 400 IU a day (unless you're taking a statin drug plus high doses of niacin--see p. 5). Just don't assume that either is guaranteed protection.

"We don't have much we can do to prevent prostate cancer," says Albanes. "We think and hope that selenium and vitamin E will have an impressive public health impact, but we need to wait ten or 12 years to get the final answer."

1996

1,300 people with a history of non-melanoma skin cancer take selenium (200 mcg) or a placebo daily for 5 years. Selenium-takers have a lower risk of prostate, lung and colon cancer (but not of skin cancer). (1)

1998

29,000 Finnish male smokers take vitamin E (110 IU), beta-carotene (33,000 IU), both, or a placebo daily for 5 to 8 years. Prostate cancer deaths are 41% lower in the vitamin-E-takers. (2)

2007

The Physicians' Health Study II is giving 15,000 male physicians vitamin E (400 IU every other day), vitamin C (500 mg every day), and/or beta-carotene (83,000 IU every other day).

2013

The SELECT study is giving 32,000 men with elevated PSA levels either vitamin E (400 IU), selenium (200 mcg), both, or a placebo daily.

Timeline Footnotes

(1) J. Amer. Med. Assoc. 276: 1957, 1996.

(2) J. Nat. Cancer Inst. 90: 440, 1998.

VISION

"The AREDS surprised me," says Julie Mares-Perlman of the University of Wisconsin.

Last October, the authors of the Age-Related Eye Disease Studies reported that a daily mixture of antioxidants (vitamin E, vitamin C, and beta-carotene) plus zinc slowed macular degeneration in people who already had the disease.

"That's more than we can say about any other medical or surgical approach," she adds.

Macular degeneration is the leading cause of blindness in older people. As the center of the retina--the macula--starts to deteriorate with age, patients slowly lose their sight. And until now, doctors couldn't do much more than watch it get worse.

"AREDS is strong evidence that antioxidants slow the progression of macular degeneration in people with intermediate or advanced disease," says Mares-Perlman. Antioxidants didn't help patients in the early stages of the disease, but the study had too few of them to answer the question definitively.

Nor did supplements keep cataracts--clouding in the lens--from getting worse. But researchers aren't ready to give up.

"In earlier studies, only when we looked at diet over many years did we see a link with cataracts, so it's not surprising that antioxidants don't help in a study that lasts only six years," Mares-Perlman explains.

"Cataracts are a long time in the making," she adds. "Nuclear cataracts, the most common form, are not significant enough to remove until later in life, but they start to develop at the age of 20."

Animal and test-tube studies have long suggested that damage caused by oxidation leads to cataracts and macular degeneration. "Now there is a consensus that oxidative stress promotes those pathological changes," says Mares-Perlman.

But researchers aren't sure why taking a high dose of zinc--80 milligrams a day--slowed macular degeneration. "We've always assumed that zinc acts as a component of superoxide dismutase and other antioxidant enzymes," says Mares-Perlman. "That would mean you only need a small amount of it."

The placebo-takers presumably got enough zinc in their diets or from their multivitamins to make superoxide dismutase, yet the extra zinc still helped.

Just don't assume that you should take 80 mg of zinc a day to protect your eyes. The National Academy of Science's Tolerable Upper Intake Level (UL) for zinc is 40 mg a day from food and pills. Higher doses, taken for long periods of time, might impair the immune system and lower HDL ("good") cholesterol. In fact, the AREDS trial gave participants copper because too much zinc can rob the body of copper.

"AREDS used drug levels of nutrients," says Mares-Perlman. "It's worth the risk of taking a high dose if you have macular degeneration, but not to prevent it."

It's prudent for healthy people to take an ordinary multi. But the best safety net is to eat fruits and vegetables, she adds. "Foods have a mixture of antioxidants that are more diverse and possibly safer than those in supplements."

Another concern: AREDS used a dose of beta-carotene (25,000 IU a day) that could raise the risk of lung cancer, at least in smokers. Future studies may replace beta-carotene with lutein, a carotenoid found in leafy green vegetables that seems to protect eyes.

But so far, all the ongoing trials--like the Women's Antioxidant and Cardiovascular Study and the Physicians' Health Study II--are using beta-carotene.

"The question is: What are the most effective and safe combinations of supplements?" says Mares-Perlman. It's too early to say.

2001

In the AREDS study, 3,640 people with macular degeneration take vitamin C (500 mg), vitamin E (400 IU), and beta-carotene (25,000 IU) or zinc (80 mg) and copper (2 mg), both, or a placebo daily for 6 years. Among those with more severe macular degeneration, the risk of advanced disease is 2.5% lower with antioxidants plus zinc (and copper). (1)

2001

In the AREDS study, 4,600 people take either vitamin C (500 mg), vitamin E (400 IU), and beta-carotene (25,000 IU) or a placebo daily for 6 years. No difference in cataract rates. (2)

2005

The Women's Antioxidant and Cardiovascular Study is giving 8,000 women with cardiovascular disease vitamin E (600 IU every other day), vitamin C (500 mg every day), and/or beta-carotene (83,000 IU every other day).

2005

The Women's Health Study is giving 40,000 healthy female health professionals either vitamin E (600 IU), aspirin (100 mg), both, or a placebo on alternate days.

2007

The Physicians' Health Study II is giving 1S,000 male physicians vitamin E (400 IU every other day), vitamin C (500 mg every day), and/or beta-carotene (83,000 IU every other day).

Timeline Footnotes

(1) Arch. Ophthalmol. 119: 1417, 2001.

(2) Arch. Ophthalmol. 119: 1439, 2001.