A Change of Heart on Vitamins?

Antioxidants seemed all but certain to stave off heart disease--until researchers put them to the test in clinical trials.

Robert Floyd, an antioxidant expert at the Oklahoma Biomedical Research Foundation in Oklahoma City, was once so sure of vitamin E's health benefits that he regularly downed pills packed with four-and-a-half times the recommended daily allowance (RDA). He wasn't alone. "Five years ago, cardiologists were all taking vitamin E," says Jay Heinecke, an endocrinologist at the University of Washington, Seattle. Physicians too began recommending that their patients load up on such antioxidants after several large epidemiological studies linked the supplements to a decreased risk of cardiovascular disease.

But the randomized clinical trials that followed the observational studies failed to produce evidence that vitamins could thwart disease. An analysis of seven such trials of vitamin E and eight of beta-carotene published in The Lancet last month concluded that the supplements do not protect against heart disease. Two weeks later, the United States Preventive Services Task Force (USPSTF) released clinical guidelines warning doctors that vitamin supplements cannot ensure a healthy heart. How did vitamins go from hot to not?

The theory that vitamin E, beta-carotene, and other antioxidants could prevent heart disease arose in part from epidemiological studies such as the Nurses' Health Study, which tracked more than 80,000 female nurses and found that those who popped high-dose vitamin E supplements (four-and-a-half times the RDA or more) had a 37% reduction in coronary heart disease over the course of 8 years, compared with those who didn't take the pills. Several other studies, including one of nearly 40,000 male health care professionals, also suggested that antioxidants could deflect heart trouble. Although the data appeared strongest for the protective effects of vitamin E and beta-carotene, studies also hinted that vitamin C could stave off disease.

And the idea made sense. Researchers believe that interactions between low-density lipoprotein--"bad cholesterol"--and reactive molecules generated inside cells play an important role in forming the plaques that clog arteries, says Heinecke. Antioxidants disarm these reactive free radicals before they can inflict damage, so it seemed natural that antioxidants might keep arteries clear and thus avert heart disease. What's more, vitamin E seemed to prevent heart disease in animal studies.

But when researchers tested vitamins in randomized, controlled studies--considered the gold standard of clinical trials--the supplements' power to protect against cardiovascular disease evaporated. Together, the Lancet authors and the USPSTF panel scrutinized more than 22 randomized trials of vitamins E, C, and A, beta-carotene, multivitamins, and antioxidant combinations, and both concluded that the evidence does not support a link between vitamins and heart disease prevention.

Worse yet, studies suggest that in some cases vitamins might cause harm. A 2001 study published in Atherosclerosis, Thrombosis, and Vascular Biology showed that antioxidant supplements blunted the effectiveness of two common cholesterol-lowering treatments: niacin and simvastatin. Furthermore, two other clinical trials uncovered a significant increase in the incidence of lung cancer among smokers taking beta-carotene supplements.

The recent studies are "a good reminder that epidemiology doesn't prove cause and effect," says Cynthia Morris, an epidemiologist at Oregon Health & Science University in Portland and an author of the USPSTF report. Compared with people who don't swallow supplements, those who swear by them are generally better educated, less likely to smoke or drink heavily, and more likely to exercise regularly--all traits linked to better health. The observational studies probably ended up identifying people who had a healthy lifestyle, says Marc Penn, a cardiologist at the Cleveland Clinic Foundation in Ohio and an author of the Lancet study.

Some experts argue that the question of whether antioxidants stem heart disease is still unresolved because researchers jumped from epidemiological studies to clinical trials before they had nailed down the right compound to test. To select the optimal antioxidant, Heinecke argues, researchers must better understand the oxidation reactions involved in heart disease.

Others point to the pitfalls of applying findings from animal studies to humans. In the animal studies that showed a significant benefit from vitamin E, for example, the treatment was always started before the animal had any disease, says Penn: "The equivalent would be putting vitamin E in Happy Meals for kids." Few scientists would advocate such an approach, and megadosing with isolated individual supplements might turn out to be the wrong approach anyway.

Morris agrees. "One of the things we're coming to understand is that nutrients given through supplements are probably different from how they're consumed in food," she says. "It's a single source rather than the complex ways that they're found in food." A diet rich in vitamin E is associated with good health, adds Floyd, but "that doesn't necessarily mean that you can load yourself up with more and more and it will be good. It may in fact be the opposite." Many people assume that because vitamins occur naturally in food, they are safe even in high doses, but the results of the beta-carotene studies dispute this belief.

Assumptions about the supplements' safety coupled with their easy availability led many people to jump on the vitamin bandwagon before all the evidence was in. "There's a message here for all of us," says Morris. "Relationships in science aren't always as simple as we'd like."

Yet Penn stresses that the studies don't debunk the idea that antioxidants could work against the maladies of aging, such as heart disease. "People are still interested in the concept," he says, but they now realize that the picture is more complicated than previously believed.

"The studies have certainly changed my lifestyle," says Floyd, who has quit scarfing down megadoses of vitamin E. "Multivitamins are fine," adds Penn. "It's really the supersupplements that go beyond the RDA that we're trying to discourage." In any case, nutritional supplements are no match for lifestyle factors such as regular exercise and a balanced diet, which are proven to cut the risk of cardiovascular disease. "You can't abuse your diet and then think that taking supplements on top of it will help," Penn says. So for now, people hoping to hold off heart disease might consider setting aside the supplements and heading for the Stairmaster.

Christie Aschwanden is a Switzerland-based science writer who shuns vitamin pills and munches megadoses of arugula instead.