LINUS PAULING INSTITUTE SPRING/SUMMER 2005 RESEARCH REPORT
Recent Research on Vitamins C and E
A number of controversial studies on vitamin C or E have been published recently, and some of these that attracted media attention are discussed in the following sections. Several are meta-analyses, which are statistical studies that pool the results of selected previous studies that share similar research objectives. Meta-analyses are generally highly regarded and can provide an excellent overview of complicated subjects. The relationship between micronutrients and health and disease is so complex and difficult to study in humans that few definitive studies have been published, and none of the following studies should be considered definitive. I thank Drs. Balz Frei, Jane Higdon, and Maret Traber for their helpful comments.
Diabetes and supplemental vitamin C
A study published in the American Journal of Clinical Nutrition in 2004 on supplemental vitamin C and the risk of cardiovascular disease reported that the use of vitamin C supplements was associated with an increased risk of mortality from cardiovascular disease in postmenopausal diabetic women. The study was part of the Iowa Women’s Health Study and enrolled 1,923 women who, at baseline, reported diabetes but were free from cardiovascular disease. Their intake of dietary and supplemental vitamin C was assessed by food-frequency questionnaires at the beginning of the study, and the group was followed for 15 years. Deaths from cardiovascular disease, coronary artery disease, and stroke were analyzed at the end of the study, revealing that the risk of mortality from these causes was not significantly affected by the intake of vitamin C from food, but significantly increased in the group that consumed at least 300 mg/day of supplemental vitamin C. As the authors noted, the study has several serious limitations. Diabetes was self-reported at baseline and no attempt was made to verify the diagnosis. Blood levels of lipids or vitamins were never measured, nor was blood pressure. Information on supplemental vitamin use was obtained only at the beginning of the study, and participants’ behavior may have changed appreciably over 15 years. The authors speculated that the increased risk for mortality may be due to a pro-oxidant activity of vitamin C, but most studies have found that vitamin C acts as a powerful antioxidant in the body. Moreover, a larger study of 85,000 women followed for 16 years found that the risk of fatal and non-fatal coronary heart disease was reduced in women—including 2% who were diabetic—who consumed at least 400 mg/day of vitamin C from supplements. This study was published in the Journal of the American College of Cardiology in 2003. It has been proposed that genes may affect the influence of antioxidants on the risk of cardiovascular disease in diabetic women. In one study published in Diabetes Care in 2004, diabetic women with two copies of the haptoglobin 1 gene benefited from supplementation with 1,000 mg/day of vitamin C plus 800 IU/day of vitamin E, whereas the supplements were detrimental in those with two copies of the haptoglobin 2 gene.
• The verdict: These studies are inconclusive and surprising, but present a possible cause for concern in some diabetic women, possibly depending on genotype. LPI generally recommends consuming at least 400 mg/day of vitamin C, but diabetic individuals may want to refrain from taking more than 300 mg/day of supplemental vitamin C until more is known about its health effects in diabetes.
Gastrointestinal cancers and antioxidants
Headlines like “Vitamins can’t fight cancer” on CBS, “Vitamin pills do not stop cancer” on the BBC, and “Vitamins ‘may raise death risk from cancer’” in Britain’s The Guardian emerged after publication in 2004 of a study in the British medical journal The Lancet claiming that antioxidant vitamin supplements not only didn’t prevent gastrointestinal cancers, their use actually increased mortality. As usual, the headlines over-simplified a complicated story and unfairly indicted all vitamins. The Lancet study was a meta-analysis of 14 placebo-controlled, randomized trials involving over 170,000 subjects who were supplemented with vitamin A (1.5-15 mg), vitamin C (120-2,000 mg), vitamin E (30-600 mg), beta-carotene (15-50 mg), and selenium (0.05-0.23 mg) alone or in various combinations. Subjects were supplemented either daily or on alternate days for 1 to 12 years, depending on the study. Four trials used selenium alone, while only two trials used vitamin C or vitamin E alone. Only selenium reduced the risk of gastrointestinal cancers, while the use of beta-carotene in combination with either vitamin A or vitamin E resulted in an increased risk of mortality.
Only 9 of the 14 trials reported mortality data. Most of the trials reported a slightly increased or slightly decreased risk of death associated with antioxidant supplement use. According to The Lancet meta-analysis, the trial reporting the highest increased risk of mortality involved supplementation with beta-carotene and vitamin C. This small, placebo-controlled, randomized trial, published in the Journal of the National Cancer Institute in 2000, evaluated the effect of an anti-Helicobacter pylori drug, vitamin C, and beta-carotene, alone and in combinations, on the precancerous process in the gastric system. It enrolled 976 subjects, 631 of whom completed the 6-year trial. Infection with the bacterium Helicobacter pylori is associated with gastric lesions that can lead to cancer. In this study, 18 subjects in the various groups receiving beta-carotene, vitamin C, and/or the drug died, while no one died in the placebo group. However, the authors noted that none of the deaths in the treatment groups were related to gastric cancer, although no specific causes were reported. Subjects who took 30 mg of beta-carotene or 2,000 mg of vitamin C daily had significant regression of premalignant lesions.
• The verdict: The use of beta-carotene supplements has not generally been demonstrated to provide substantial protection against gastrointestinal or other cancers, and may actually increase the risk of lung cancer in smokers or those exposed to asbestos. This meta-analysis indicates that supplemental beta-carotene in combination with vitamins A or E also does not protect against gastrointestinal cancers and may increase mortality risk. However, the evidence mainly suggests that supplemental beta-carotene, and not antioxidant vitamins, may be the culprit. Additionally, gender may influence the effect of antioxidants on cancer risk. For example, many studies have reported that a low intake of vitamin C is associated with increased cancer risk, particularly lung cancer, in men. LPI does not make a recommendation for supplemental beta-carotene because of the generally weak evidence of benefit and possible detrimental effects.
Antioxidant vitamins and cancer chemotherapy
The concomitant use of high-dose antioxidants, especially vitamin C, and chemotherapy has been debated for decades. In their 1979 book Cancer and Vitamin C, Linus Pauling and Ewan Cameron speculated that high-dose vitamin C might interfere with chemotherapy by drug detoxification and that patients undergoing aggressive chemotherapy expected to cure cancer might refrain from taking high-dose vitamin C at the same time. However, they noted that many patients taking chemotherapeutic drugs and vitamin C experienced decreased side effects. Only a few small studies have investigated the effects of chemotherapy combined with antioxidants in humans. A Finnish study published in Anticancer Research in 1992 reported that the use of high-dose antioxidants in conjunction with chemotherapy and radiation significantly prolonged survival in patients with small-cell lung cancer. A randomized, double-blind, placebo-controlled Dutch study, published in 2004 in the European Journal of Cancer, investigated the effect of antioxidant supplementation in 50 cancer patients undergoing cisplatin chemotherapy. Half received placebo, and half were supplemented twice a day with 1,000 mg of vitamin C, 400 mg of synthetic vitamin E, and 0.1 mg of selenium. Although the antioxidant supplements did not significantly prevent kidney or inner ear toxicity, supplemented patients had less loss of high-tone hearing.
The latest study, published in February 2005 in the Journal of the American College of Nutrition, was conducted in 136 patients with stage III or IV non-small-cell lung cancer. About half the patients received chemotherapy (paclitaxel/carboplatinum) alone; the other half received chemotherapy and daily high-dose antioxidants, including about 6 grams of vitamin C, 1 gram of synthetic vitamin E, and 60 mg of beta-carotene. Although not statistically significant, there was a trend toward improved response in those who received both chemotherapy and antioxidants. A recent paper in the Journal of Nutrition suggested that oxidative stress, while generated by many chemotherapeutic drugs, may not play a crucial role in killing cancer cells and, therefore, antioxidant vitamins may help ameliorate this unwanted side effect. Of the wide array of chemotherapeutic drugs, only a few, such as bleomycin and mitomycin-C, have been definitively shown to depend on free radicals to kill cells.
• The verdict: While too few clinical studies have been published to conclude that high-dose antioxidants, such as vitamins C and E, would never interfere with any specific chemotherapeutic drug, the available evidence suggests that, for at least a few commonly prescribed drugs, especially those that do not depend on free radicals for their effectiveness, concern may be unwarranted. Cancer patients should be careful to discuss the use of antioxidants with their physician.
Vitamin C and coronary heart disease
No clinical trials on the primary prevention of heart disease by vitamin C have yet been published. Instead, trials have investigated secondary prevention—the prevention of plaque progression, heart attacks, strokes, and/or mortality in people who already have heart disease. An abstract of one controversial study in 573 people, part of the Los Angeles Atherosclerosis Study in 2000, claimed that supplemental—but not dietary—vitamin C was associated with thickening of the carotid arterial wall. In contrast, an earlier study in Circulation of over 11,000 people reported that supplemental vitamin C in men and women and supplemental vitamin E in women were associated with reduced carotid artery wall thickness. Evidence on the primary prevention of heart disease by vitamin C is limited to epidemiological studies, which correlate dietary factors with disease risk. A meta-analysis of nine such studies with a total of about 293,000 subjects followed for 10 years was published in the American Journal of Clinical Nutrition in 2004. At baseline, the subjects were older than 35 years and did not have heart disease. Intake of dietary and supplemental antioxidants was estimated from questionnaires, which may not truly assess actual dietary intake and supplement use over time. Although the investigators found that vitamin E did not reduce the risk for heart disease, they did find that the intake of more than 700 mg/day of supplemental vitamin C significantly reduced the risk of heart disease by about 25%. Dietary vitamin C had little effect on heart disease risk. The report noted that these results are aligned with previous studies that found a protective effect for an intake of vitamin C greater than 500 mg/day. The biochemical mechanism responsible for vitamin C’s salubrious effects remains uncertain, but may be related to its ability to lower blood pressure, its function as an antioxidant to help attenuate oxidative stress, or its ability to relax arteries, resulting in better blood flow.
• The verdict: The majority of studies that investigated the role of vitamin C in heart disease have reported beneficial effects. This new meta-analysis offers further confirmation that supplemental vitamin C lowers the risk of heart disease.
Antioxidant vitamins and lipid-lowering drugs in heart disease
A surprising study was published in The New England Journal of Medicine in 2001 that examined the effects of the lipid-lowering drug simvastatin-niacin and antioxidants on blood lipids and clinical events, such as strokes and heart attacks, in 160 patients with heart disease followed for three years. The daily use of simvastatin-niacin significantly lowered plasma triglycerides, lipoproteins, and total cholesterol, while increasing the “good” HDL cholesterol. In contrast, the daily use of a combination of 800 IU of natural vitamin E, 1,000 mg of vitamin C, 25 mg of beta-carotene, and 0.1 mg of selenium did not substantially change any of these parameters. The thickness of arterial plaque decreased slightly (0.4%) in the simvastatin-niacin group. Plaque thickness increased about 4% in the placebo group, but was slightly retarded by antioxidant therapy (1.8% increase). Simvastatin-niacin substantially decreased the number of clinical events, which were not significantly different between the placebo and antioxidant groups. However, combining antioxidants with simvastatin-niacin blunted the effectiveness of the drug in decreasing clinical events. Another study was published in The Lancet in 2002 that investigated the effect of simvastatin combined with 600 mg of synthetic vitamin E, 250 mg of vitamin C, and 20 mg of beta-carotene on clinical events in 20,536 patients—a population much larger than the aforementioned study—followed for 5 years. This study reported that antioxidant supplementation did not significantly affect mortality or clinical events in the patients taking simvastatin. A new study published this year in Circulation evaluated the effects of daily low-dose lovastatin or high-dose atorvastatin combined with 800 mg of synthetic vitamin E and 1,000 mg of vitamin C in a group of 300 patients with stable heart disease followed for one year. Antioxidants did not significantly influence the effect of atorvastatin on ischemia.
• The verdict: The data suggesting that antioxidants may interfere with statin therapy are limited, and only a few small studies have investigated the influence of vitamin C or E alone on statin therapy. Since it is possible that antioxidant vitamins may affect drug metabolism or block the increase in HDL cholesterol induced by statin-niacin therapy, further research is warranted before recommendations can be confidently made.
High-dose vitamin E and mortality
In January 2005, a meta-analysis of clinical studies that provided information on vitamin E supplementation and the incidence of death was published in the Annals of Internal Medicine. The authors examined 19 clinical trials involving a total of about 136,000 subjects who were followed for at least one year and received either placebo or supplemental vitamin E in doses ranging from 16.5 to 2,000 IU/day, with a median dose of 400 IU/day. Thirty-six trials were initially identified for inclusion in the meta-analysis, but 12 of these were excluded only because they reported fewer than 10 deaths. Five additional trials were excluded because mortality data were not available. The exclusion of trials in which few deaths were reported does not seem justified, since the purpose of the meta-analysis was to determine the relationship between vitamin E supplementation and mortality—all high-quality relevant trials should have been examined. The high-dose trials generally had fewer subjects than the low-dose trials. The authors reported that the use of 400 IU/day or more of vitamin E alone or in combination with some other supplemental vitamins or minerals was associated with a slightly increased risk of mortality from all causes, although the statistical significance was low. A statistically significant increased risk of death was associated with an intake of 2,000 IU/day of vitamin E, which is higher than the tolerable upper intake level of 1,500 IU/day set by the U.S. Institute of Medicine in 2000. The authors speculated that the increased risk of mortality might be attributable to pro-oxidant effects of vitamin E, the displacement of other fat-soluble antioxidants by vitamin E, vitamin E’s anticoagulant properties, or by interfering with the detoxification of drugs or toxins. Other factors may also contribute to the body’s use of vitamin E, such as whether it is taken with a meal containing fat to enhance absorption. This is seldom reported and was not discussed in the paper. Three other meta-analyses have not found increased risks of mortality for vitamin E supplementation up to 800 IU/day. A randomized, controlled study (the HOPE-TOO trial) published in March 2005 in the Journal of the American Medical Association reported that the daily intake of 400 IU of natural vitamin E for 7 years did not protect against cancer incidence or mortality or major cardiovascular events in subjects with heart disease or diabetes. However, use of supplemental vitamin E was associated with increased risk of heart failure. Most patients in the vitamin E and placebo groups also took several medications that may have affected outcomes.
• The verdict: Relatively low statistical significance, the exclusion of many relevant trials with few deaths, and conflicting results of other meta-analyses undermine the assertion in the recent meta-analysis that high-dose vitamin E supplements are associated with increased mortality. The tolerable upper intake level for vitamin E has been set at 1,500 IU/day due to the possibility that higher doses may interfere with normal blood clotting. When establishing the Dietary Reference Intakes for vitamin E in 2000, the U.S. Institute of Medicine examined the totality of evidence and concluded that vitamin E is safe when taken in amounts less than the upper intake level. The increased risk of heart failure in diabetics and heart disease patients associated with the daily intake of 400 IU of vitamin E has been reported only in the HOPE-TOO trial and awaits further confirmation. LPI recommends a daily intake of 200 IU of natural vitamin E (d-alpha tocopherol).
Vitamin E and amyotrophic lateral sclerosis (ALS)
An epidemiological study published in the Annals of Neurology in 2004 reported that the regular use of vitamin E—but not vitamin C—supplements decreased the risk of developing ALS in a population of about 958,000 men and women followed for 16 years. Participants reported supplement use at baseline, and a sample of the cohort completed a questionnaire about supplement use after 10 years for confirmation. The subjects were not asked for quantitative information about the supplements consumed. Nevertheless, the authors noted that popular vitamin E supplements typically contain 400 IU of synthetic vitamin E. The long-term use of vitamin E supplements decreased the risk of dying from ALS by about 62%, but no protective effect was found for vitamin C or multivitamin supplements. This study, while promising, suffers from a number of common problems, including self-reported use of supplements of unknown dose. Another study published in the Archives of Neurology in 2004 reported that the combined use of vitamin E and vitamin C—but neither vitamin alone—protects against Alzheimer’s disease. In this short-term study of about 4,700 subjects, the regular daily consumption of more than 400 IU of vitamin E and at least 500 mg of vitamin C, as determined by an initial interview, substantially reduced the prevalence and incidence of Alzheimer’s disease.
• The verdict: Vitamin E may protect against ALS and, when combined with vitamin C, may also protect against Alzheimer’s disease. Taken together, these results suggest that oxidative stress may play a role in the development of these neurodegenerative diseases.
Gamma- vs. alpha-tocopherol
There has been some debate about the relative health merits of these two forms of vitamin E. Gamma-tocopherol has been reported to possess stronger anti-inflammatory properties and scavenges certain nitrogen radicals better than alpha-tocopherol. A large study published in the Journal of the National Cancer Institute in 2000 suggested that gamma-tocopherol was much more effective in reducing the risk of prostate cancer. However, the liver synthesizes a special transfer protein that selectively recognizes only alpha-tocopherol for distribution to tissues, indicating that this is the biologically preferred form. Dr. Maret Traber and her colleagues in LPI and elsewhere recently published a study in Free Radical Biology & Medicine in which subjects ingested equal amounts of specially labeled alpha-tocopherol and gamma-tocopherol with breakfast. The two different forms of labeled vitamin E were measured periodically in blood over 72 hours. Both alpha- and gamma-tocopherol peaked in plasma about 12 hours after ingestion, with significantly more alpha-tocopherol detected. The plasma levels of gamma-tocopherol declined faster than those of alpha-tocopherol, indicating increased metabolism and excretion. For example, half of the gamma-tocopherol had disappeared from plasma by 13 hours after ingestion, whereas it took 57 hours for half of the alpha-tocopherol to disappear. Women excreted more gamma-tocopherol metabolites than men and also had higher gamma-tocopherol plasma levels. Interestingly, only gammatocopherol metabolites were detected in urine, indicating conservation of alpha-tocopherol. These results indicate that humans have mechanisms to maintain alpha-tocopherol in the body, but also that gamma-tocopherol is present in plasma long enough to exert biological effects, although its distribution to tissues is unclear.
• The verdict: Alpha-tocopherol is maintained in human plasma longer and at higher levels than gamma-tocopherol, but gamma-tocopherol, the main form of dietary vitamin E in the United States, may be present long enough for biological effects yet to be elucidated.
Last updated May, 2005
Micronutrient Research for Optimum Health
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