JAMA meta-analysis of antioxidants - flawed data, biased analysis, and inappropriate conclusions

Recent news stories sensationalizing the results of a new controversial study reported in the February 28, 2007 issue of the Journal of the American Medical Association (JAMA) imply that antioxidants do not have health benefits, and in fact, may lead to increased mortality. In our analysis of this study, we see little or no evidence to support this conclusion.

Source: Mortality in Randomized Trials of Antioxidant Supplements for Primary and Secondary Prevention: Systematic Review and Meta-analysis, Bjelakovic et al, JAMA. 2007;297:842-857

It is important to understand that this current study is not a new clinical trial, but a statistical analysis determined from many studies (called a meta- analysis). Meta-analysis studies are actually designed to pool similar studies for statistical comparison. However for this meta-analysis, the authors combined studies that differed vastly in design, use rates, duration, and study population. After careful review, it appears that the authors simply analyzed data that fit a predetermined conclusion, which is an invalid use of a statistical method. This is a great example of improper statistical use in research methodology.

There is a large body of data including observational studies, prospective epidemiological studies and randomized clinical studies that have shown positive benefits of antioxidant supplementation (including reduced cardiovascular disease, some cancers, immune support and reduced progression of eye disease). Interestingly, these studies were excluded from the analysis. And while the initial analysis examined 1201 research papers from 815 trials, only 68 trials were actually used in the final analysis. Furthermore, when the initial results from this data did not show any effect on death rates, the authors removed an additional 21 studies (called a sub analysis) to draw their conclusion that supplements increase risk of mortality.

Interestingly, in these 47 remaining studies, the doses used greatly exceeded normal use rates, and in many cases, were well above tolerable upper intake limits (UL) (i.e. they used doses that may not be safe). In contrast, the studies eliminated from this study generally used doses that did not exceed the UL and were more in line with actual use rates.

Finally, the majority of the studies examined are secondary prevention studies. That is, the study populations had already been diagnosed with diseases such as heart disease and cancers. This is a very risky population to study, and conclusions from these studies should not be used to make recommendations for prevention in generally health populations.

We are not the only ones who have criticized these results. Several scientific organizations and other researchers have already published criticisms of this paper. Professor Balz Frei director of the Linus Pauling Institute at Oregon State University stated:

"This is a flawed analysis of flawed data, and it does little to help us understand the real health effects of antioxidants, whether beneficial or otherwise. Instead of causing harm, the totality of the evidence indicates that antioxidants from foods or supplements have many health benefits, including reduced risk for cardiovascular disease, some types of cancer, eye disease and neurodegenerative disease. In addition, they are a key to an enhanced immune system and resistance to infection.

The "meta-analysis" published in JAMA, which is a statistical analysis of previously published data, looked at 815 antioxidant trials but included only 68 of them in its analysis. And two of the studies excluded " which were published in the Journal of the National Cancer Institute and the prominent British medical journal Lancet " found substantial benefits and reduced mortality from intake of antioxidant supplements."

"If these two large studies had been included, none of the reported effects on increased mortality would have been significant, with the exception of the effects of beta carotene. And the research showing a higher incidence of lung cancer in smokers who take supplements of beta carotene or vitamin A is old news, that's been known for many years. Very high doses of vitamin A are known to have multiple adverse health effects."

"All the new study really demonstrates, is a bias toward identifying studies or research that show harm caused by antioxidants, and selective removal of research that shows benefits."

We don't know why the authors chose to evaluate this small carefully selected group of studies, or why they ignored the larger body of evidence published on the benefits of antioxidants. But it appears to be an obvious attempt to sensationalize incomplete data that serves no purpose other than to alarm a large portion of the supplement using population. We are not fooled by this report. Furthermore, we will continue to provide our associates and customers with a wide array of antioxidants to be used as part of an overall comprehensive nutritional program.

John Cuomo, Ph.D. Executive Director R&D USANA Health Sciences, Inc.

The full text of the Linus Pauling Institute press release can be found here.

Additional comments on the JAMA study can be found at the following links:

Council for Responsible Nutrition
NutraIngredients.com
Natural Products Association
Alliance for Natural Health

Part IV of IV - Safety of Multivitamins and Antioxidants

Nutritional supplements have been widely used and highly valued by American consumers ever since vitamins were discovered and commercialized, beginning in the early decades of the 1900's. According to recent national health survey, as many as 78 million Americans adults use multivitamins on a regular basis.

Multivitamin/mineral supplements are an effective means of delivering adequate amounts of most essential nutrients to help people achieve recommended intakes. The great majority of dietary supplements, including multivitamins, are safe for regular use. Despite widespread usage, there have been no specific published reports of toxicity or adverse effects associated with the use of multivitamins.

A series of well-publicized clinical trials conducted in diseased patients utilizing relatively high doses of single nutrients or combinations of nutrients (such as vitamin E and/or beta-carotene), have yielded disappointing results. However, those trials were conducted in patients with serious illnesses (ie. cancer or cardiovascular disease) who were on multiple medications or who were current heavy smokers. The results of these trials should be placed in context and are not applicable to the generally healthy population.

Advanced levels of antioxidants are a common thread among nearly every population that is less prone to premature chronic degenerative disease. The Japanese have high levels of fruit, vegetables, green tea and soy as part of their traditional diet. Vegetarians have lower levels of heart disease and cancer, compared to the typical mixed diet, likely in part due to higher intakes of antioxidants. While high levels of single nutrients and foods may pose a risk of danger and toxicity, there is no known unsafe intake level of total antioxidants in normally healthy individuals.

Source: USANA Health Sciences

Part III of IV - Health Benefits of Antioxidants

Plentiful intakes of antioxidants have been associated with reduced risk of some chronic diseases, in the same way that generous intakes of fruits, vegetables and grains have been associated with similar health benefits.

Some examples of scientific evidence are the following:

Cancer

People with high beta-carotene intakes have about one-third the cancer risk as people with low beta-carotene intakes.
Source: Peto R. Cancer Surveys 1983;2:327-340.

People with higher intakes of vitamin C have about half the risk for many types of cancer, compared to people with low vitamin C intakes.
Source: Block G. Am J Clin Nutr 1991;53:270S-282S.

People with low intakes of several antioxidants have more DNA damage than people with generous intakes.
Source: Ames BN. Metat Res 2001;475:7-20.

People with the highest intakes of vitamin C, E, and beta-carotene have a significantly lower risk of lung cancer.
Source: Yong LC et al. Am J Epidemiol 1997;146:231-43.

Men who took vitamin E supplements for 10 years or more had a 30% lower risk of bladder cancer.
Source: Michaud DS et al. Am J Epidemiol 2000;152:1145-53.

There are over 66 studies showing cancer-prevention activity of green tea, black tea, and their constituents. These include cancer reduction in the skin, lung, oral cavity, esophagus, stomach, liver, pancreas, bladder, small intestine, colon and prostate.
Source: Lambert JD et al. Am J Clin Nutr 05;81:284S- 291S.

Heart Disease

Elderly people who took dietary supplements of both vitamin C and vitamin E had a decreased risk of death from heart disease as well as overall mortality.
Source: Losonczy KG, Harris TB, Havlik RJ. Am J Clin Nutr 1996;64:190- 196.

Men who took vitamin supplements had a 70% lower risk of dying from heart disease and a 50% lower risk of a heart attack. Source: Meyer F, Bairati I, Dagenasis GR. Can J Cardiol 1996;12:930-934.

In the Nurses' Health Study involving over 87,000 women, there was a 41% reduction in risk of heart disease for those who took vitamin E for more than two years.
Source: Stampfer MJ, Hennekens CH, Manson JE, et al. New Engl J Med 1993;328:1444-1449.

In the Nurses' Health Study vitamin C supplements were also related to a lower risk of heart disease.
Source: Osganian SK et al. J Am Coll Cardiol 2003;42:246-52.

In the Health Professionals Follow-Up Study involving almost 40,000 men, there was a 37% reduction in risk of heart disease in men who took vitamin E for more than two years. The average intake in the lowest risk group was 400 IU per day.
Source: Rimm EB, Stampfer MJ. Ascherio A, et al. New Engl J Med 1993;328:1450-1456.

To date, 17 human group studies have been published on flavonoid intake and the risk of coronary artery disease and stroke. Positive studies have shown reduction in mortality risk of up to 65%.
Source: Arts ICW and Hollman PCH. Am J Clin Nutr 2005;81:317S-325S.

The largest and longest study to date, done as part of the Harvard- based Nurses' Health Study and Health Professionals Follow-up Study, included almost 110,000 men and women whose health and dietary habits were followed for 14 years. The higher the average daily intake of fruits and vegetables, the lower the chances of developing cardiovascular disease. Compared with those in the lowest category of fruit and vegetable intake (less than 1.5 servings a day), those who averaged 8 or more servings a day were 30% less likely to have had a heart attack or stroke.
Source: Joshipura KJ, et al. Ann Intern Med 2001 Jun 19;134(12):1106-14.

Other Chronic diseases

Several long-term studies have shown a reduced risk of cataracts in those who have taken vitamin C and/or Vitamin E for more than 10 years.
Source: Jacques PF et al. Arch Ophthalmol 2001;119:1009-19.

The Age-Related Eye Disease Study (AREDS) at NIH found that daily supplementation with antioxidants, zinc, and copper delayed progression of age- related macular degeneration.
Source: AREDS report no. 8. Arch Ophthalmol 2001;119:1417-36.

Research has shown a significant relationship between flavonoid intakes and the occurrence of asthma.
Source: Knekt P et al. Am J Clin Nutr 2002;76:560-8.

Other research suggests antioxidants may help support lung function and protect the lungs from oxidative damage.
Source: Schunemann HJ et al. Am J Respir Crit Care Med 2001;163:1246-55.

In a study on Alzheimer's disease, high levels of vitamin E delayed progression of the disease.
Source: Sano M et al. N Engl J Med 1997;336:1216- 22.

Source: USANA Health Sciences

Part II of IV: Antioxidants - Sources and Dietary Intakes Antioxidants

Sources and Dietary Intakes Antioxidants can be vitamins, minerals, enzymes or plant derived nutrients called phytonutrients. The major vitamin antioxidants are vitamin C, vitamin E, beta-carotene, while selenium is the major mineral antioxidant. Many researchers and nutritionists discuss and report on "antioxidants" as if these were the only sources of importance. A thorough examination of antioxidants and their importance to human health must include a much larger list of compounds that are present in healthy, varied diet. The following list is an example of the wide variety of phytonutrient antioxidants present in a healthy diet:

Phytochemical : Food Source
Allyl Sulfides : Onions, garlic, leeks, chives
Carotenoids (e.g. lycopene, lutein, zeaxanthin) : Tomatoes, carrots, watermelon, kale, spinach
Curcumin : Turmeric
Flavonoids (e.g. anthocyanadins, resveratrol, quercitin, catechins) : Grapes, blueberries, strawberries, cherries, apples, grapefruit, cranberries, raspberries, blackberries
Glutathione : Green leafy vegetables
Indoles : Broccoli, cauliflower, cabbage, brussels sprouts, bok choy
Isoflavones : Legumes (peas, soybeans)
Isothiocyanates (e.g. sulforaphane) : Broccoli, cauliflower, cabbage, brussels sprouts, bok choy
Lignans : Seeds (flax seeds, sunflower seeds)
Monoterpenes : Citrus fruit peels, cherries, nuts
Phytic Acid : Whole grains, legumes
Phenols, polyphenols, phenolic compounds (e.g. ellagic acid, ferrulic acid, tannins) : Grapes, blueberries, strawberries, cherries, grapefruit, cranberries, raspberries, blackberries, tea
Saponins : Beans, legumes

Recommendations by the National Cancer Institute, the U.S.D.A., other government agencies and nutrition experts are to eat a minimum of 5-13 servings of fruits and vegetables per day, depending on calorie needs. Based on these recommendations, a typical varied diet would provide approximately 200-600 mg of vitamin C and 10-20 mg (16,000-32,000 IU) of carotenoids.

Overall, polyphenols are the most abundant antioxidants in the diet. Their total dietary intake could be as high as 1 gram/day in a mixed, varied diet of fruits, vegetables, grains, and beverages.

Possible intakes of other phytonutrient antioxidants would be:

• anthocyandins " 2 oz black grapes 1,500 mg;
• proanthocyanidins " 100-300 mg/d red wine;
• catechins " 50 mg day " tea (one cup brewed green tea " 240-320 mg catechins), chocolate, apples, pears, grapes, red wine;
• isoflavones " 50 mg/day from soy foods;
• chlorogenic acid " as high as 800 mg/day coffee drinkers.

Although it may seem reasonable that a consistently healthy and varied diet could provide high doses of antioxidants, the average American gets a total of just three servings of fruits and vegetables a day. The latest dietary guidelines call for five to thirteen servings of fruits and vegetables a day, depending on one's caloric intake. For a person who needs 2,000 calories a day to maintain weight and health, this translates into nine servings, or 4½ cups per day.

The 2001-2002 NHANES survey of dietary intakes shows that 93% of Americans fail to get even the Estimated Average Requirement (EAR) for vitamin E, let alone the RDA. More than half of adults fail to get even the average requirement for vitamin A. About one-third of non-smokers and two-thirds of smokers fall short on minimum vitamin C requirements.

If the governmental dietary recommendations are meant to be taken seriously, then it follows that it would be better for people to achieve recommended amounts of nutrients than to fall short. Obviously, since the average intake of 3 servings or less of fruits and vegetables fails to provide minimum levels of even basic vitamins, intakes of the numerous other antioxidants are sure to be well under optimal and beneficial levels.

It has been established that a good multivitamin can fill in gaps in missing vitamins, but availability of broad spectrum antioxidant supplements has lagged behind. Although there is much to be learned about the characteristics of the literally hundreds of dietary antioxidants, it seems reasonable that providing supplements of various antioxidant classes may fill in nutritional gaps and provide many of the benefits missing from the typical American diet.

Source: USANA Health Sciences

Part I of IV: Antioxidants - What are they?

Oxidation is a natural process that happens to all cells in nature, including the cells in your body. Antioxidants provide an important defense against the daily assault of free radicals on healthy cells. This Essentials of Health four-part series will review the function, benefits, sources, and safety of dietary antioxidants.

Free radicals are atoms or groups of atoms with an odd (unpaired) number of electrons and can be formed when oxygen interacts with certain molecules. Once formed these highly reactive radicals can start a chain reaction, like dominoes. Their chief danger comes from the damage they can do when they react with important cellular components such as DNA, or the cell membrane.

Cells may function poorly or die if this occurs. To prevent free radical damage the body has a defense system of antioxidants. Antioxidants are molecules that can safely interact with free radicals and terminate the chain reaction before vital tissues and cells are damaged. Although there are several enzyme systems within the body that scavenge free radicals, the principle micronutrient (vitamin/mineral) antioxidants are vitamin E, beta-carotene, vitamin C and selenium.

The body cannot manufacture these micronutrients so they must be supplied in the diet. In addition, there are literally hundreds of plant derived nutrients (phytonutrients) that act as important antioxidants in the diet. It is impossible to avoid damage by free radicals.

Free radicals arise from sources both inside (endogenous) and outside (exogenous) our bodies. Oxidants that develop from processes within our bodies form as a result of normal breathing, metabolism, and inflammation. Exogenous free radicals form from environmental factors such as pollution, sunlight, strenuous exercise, X-rays, smoking and alcohol. Our antioxidant systems are not perfect, so as we age, cell parts damaged by oxidation accumulate.

Source: USANA Health Sciences

The Apple Test

Presentation link showing antioxidant power of four supplements.