Vitamin E Supplementation: An Update
By Diane McKay, PhD, Dr. McKay is an Adjunct Assistant Professor, Gerald J. and Dorothy R. Friedman School of Nutrition Science and Policy, Tufts University, and a Scientist at the Antioxidants Research Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Boston, MA; she reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study.
In early 2005, Miller et al published the results of a meta-analysis including nine of 11 high-dose vitamin E trials (≥ 400 IU) conducted primarily among high-risk cardiovascular disease (CVD) patients.1 A small but statistically significant increased risk of all-cause mortality was reported among the supplemented subjects prompting many physicians to caution their patients against taking vitamin E supplements. Sales of vitamin E supplements dropped 40% as the safety of this nutrient was called into question.
In contrast to Miller et al,1 three other published meta-analyses of randomized, controlled vitamin E trials concluded that vitamin E supplementation at doses up to 800 IU had no effect on either cardiovascular or all-cause mortality.2-4 After reviewing 20 studies, Hathcock et al found the "evidence supporting potential harmful effects of high vitamin E intakes in humans not convincing," and concluded from clinical trial evidence that vitamin E supplements appear safe for most adults in amounts ≤ 1,600 IU.5 The tolerable upper intake level of vitamin E in healthy adults was set at 1,500 IU in 2000 by the Food and Nutrition Board of the Institute of Medicine.6
Despite the negative press generated by Miller et al,1 vitamin E is still essential for health, and many studies continue to show its importance in maintaining health and preventing chronic disease. This update will focus on the most recent vitamin E findings relevant to clinical practice.
Background
Vitamin E is naturally present in certain oils, nuts, and seeds. It can also be found in many ready-to-eat fortified breakfast cereals (see Table, below). Unfortunately, 92-98% of Americans consume less than the required amount of vitamin E (≤ 22 IU of RRR-alpha-tocopherol, see box below for an explanation of vitamin E forms and conversions) from their diet alone.7 While overt deficiencies of this vitamin are rare in generally healthy populations, low dietary intake and/or status of vitamin E and other antioxidant nutrients has been associated with an increased risk of developing coronary heart disease (CHD)8-11 and certain cancers12 in several large observational studies. Vitamin E is considered to be the most studied single nutrient supplement, although the results of clinical interventions with vitamin E have been equivocal.
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| Conversion Factors for Different Forms of Vitamin E Alpha-tocopherol is the most active form of vitamin E in humans; however, vitamin E exists in eight different isomeric forms: alpha, beta, gamma, and delta tocopherol alpha, beta, gamma, and delta tocotrienol. Supplements made from entirely natural sources contain only RRR-alpha-tocopherol (also labeled Dalpha-tocopherol). RRR-alpha-tocopherol is the most bioavailable form. Synthetic alpha-tocopherol, often found in food additives and some nutritional supplements, is labeled all-rac-alpha-tocopherol or DL-alpha-tocopherol. The biological activity of all-rac-alpha-tocopherol is lower than RRR-alpha-tocopherol because only half of the alpha-tocopherol isomers present are bioavailable. To convert from international units (IU) of vitamin E to milligrams, use the following equations: RRR-alpha-tocopherol (natural or D-alpha-tocopherol):IU x 0.67 = mg RRR-alpha-tocopherol. all-rac-alpha-tocopherol (synthetic or DL-alphatocopherol):IU x 0.45 = mg RRR-alphatocopherol. |
Mechanisms of Action
In the body, vitamin E functions primarily as an antioxidant, preventing the propagation of free radical damage in biological membranes and plasma lipoproteins. This potent peroxyl radical scavenger is particularly good at protecting polyunsaturated fatty acids against lipid peroxidation, but it also has the ability to affect other cellular functions. Vitamin E has been shown to inhibit platelet aggregation, enhance vasodilation, inhibit the activity of protein kinase C, and modulate the inflammatory and immune responses.13
Cardiovascular Disease
Several randomized, controlled clinical trials of vitamin E have reported null findings with regard to CVD outcomes. However, according to data from the Women's Health Study presented by Lee et al, a true primary prevention effect may be present in older women.14 The Women's Health Study (WHS) is the largest randomized trial of vitamin E supplementation to date with the longest duration of treatment. This double-blind, placebo-controlled trial randomized 39,876 healthy females age 45 years and older to receive a natural source vitamin E supplement or placebo and aspirin or placebo for 10.1 years. There was no modification of the effect of vitamin E by random assignment to aspirin. At baseline, subjects had no history of CHD, cerebrovascular disease, cancer (except nonmelanoma skin cancer), or other major chronic illnesses, and did not use individual supplements of vitamins A, E, or beta-carotene more than once per week. Overall, a nonsignificant 7% reduction for major cardiovascular events (a composite endpoint including myocardial infarction [MI], stroke, or cardiovascular death) was observed. Among women age 65 years and older, a significant 26% reduction in this endpoint was observed (RR 0.74; 95% confidence interval [CI] 0.59-0.93, P = 0.009). This important reduction among older women was attributed largely to a 34% reduction in MI (RR 0.66; 95% CI 0.45-0.98, P = 0.04) and a 49% reduction in CVD deaths (RR 0.51; 95% CI 0.33-0.77, P < 0.001). In addition, the number of CVD deaths in the WHS was 24% lower among women in the vitamin E group (RR 0.76; 95% CI 0.59-0.98, P = 0.03). The single largest contribution to this reduction in cardiovascular deaths was fewer sudden deaths among women assigned to receive vitamin E (38 in vitamin E group vs. 51 in placebo group). Fewer deaths from cardiovascular disease other than ischemic heart disease and cerebrovascular disease (20 vs. 34, respectively) was also a major factor.
Cancer
In this same WHS report, Lee et al found the incidence rates of the main site-specific cancers (breast, lung, or colon) and cancer deaths were not influenced by vitamin E supplementation.14 It should be noted that in the WHS and most other trials evaluating the effects of vitamin E, only clinical outcomes were considered, and no direct measures of oxidative stress, biomarkers of oxidative stress, lipid peroxidation, or plasma vitamin E concentrations were assessed. Lee et al did attempt to assess the effects of vitamin E supplementation among subjects with higher levels of oxidative stress by analyzing a subgroup of smokers and subjects with hypertension, hyperlipidemia, and diabetes.14 The authors found no evidence that vitamin E was beneficial among this subgroup.
In contrast to the WHS, Wright et al did measure plasma vitamin E concentrations of Finnish male smokers enrolled in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study at baseline, and followed them for up to 19 years.15 This randomized, double-blind, placebo-controlled primary chemoprevention trial tested whether daily supplementation with 50 mg vitamin E as all-rac-alpha-tocopherol acetate (the equivalent of 111 IU RRR-alpha-tocopherol) or 20 mg beta-carotene reduced the incidence of lung and other cancers compared with a placebo. This prospective cohort included 29,133 males, age 50-69 years, who smoked at least 5 cigarettes/d for any duration. ATBC is the "largest serologic study of vitamin E and mortality to date" and the first to be conducted entirely within a population of smokers. Because only 10% of participants reported vitamin E supplement use at baseline, serum concentrations in this cohort reflected dietary intake of vitamin E, as well as demographic characteristics, lifestyle behaviors, and hereditary predisposition related to vitamin E transport and metabolism.
The results of this study suggest that serum concentrations of vitamin E up to 13-14 mg/L, which is within the normal range, are associated with moderately lower total and cause-specific mortality in older male smokers, independent of several important predictors of mortality. In proportion hazards models, subjects in the highest quintile of serum alpha-tocopherol (> 13.5 mg/L) experienced significantly lower overall mortality and deaths due to cancer, CVD, and other causes combined than did those in the lowest quintile (< 10.0 mg/L). Overall mortality increased as serum vitamin E concentrations decreased below the reference value of 9.1 mg/L, and improved as serum vitamin E values increased from 9.1 mg/L to about 13 mg/L. The lowest relative mortality due to CVD and other causes combined occurred at serum vitamin E concentrations of about 14 mg/L, suggesting an apparent threshold effect at this level.
Similar patterns in risk were observed for deaths due to specific cancers and cardiovascular-related diseases. Subjects in the highest quintile of serum vitamin E concentration had significantly lower mortality due to lung cancer (21%), prostate cancer (32%), CHD (16%), ischemic stroke (37%), hemorrhagic stroke (35%), and respiratory disease (42%) compared with subjects in the lowest quintile (P < 0.02 for all trends). The strongest inverse relationship between serum vitamin E and CVD mortality was noted in men with serum total cholesterol levels < 200 mg/dL (RR 0.58; 95% CI 0.46-0.72, P for interaction = 0.01) and in those with serum HDL cholesterol ≥ 60 mg/dL (RR 0.66, 95% CI 0.49-0.89, P for interaction < 0.0001). Excluding the 12,482 men who at baseline reported a history of CVD, diabetes, or both strengthened the association between serum vitamin E and each mortality endpoint except cancer. This was particularly evident for CVD deaths with a 26% reduction in the highest quintile (RR 0.74; 95% CI 0.64-0.84, P < 0.0001 for trend). These findings support a more robust role for circulating alpha-tocopherol in overall, cancer, and CVD mortality than was suggested by previous studies, and are in contrast with findings from clinical trials that showed little or no effect of supplemental vitamin E on various endpoints.
Vitamin E supplementation was also associated with reduced risk of advanced prostate cancer among 29,361 male smokers enrolled in the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO Trial).16 Kirsh et al evaluated the relationship between intake of the antioxidant nutrients vitamins E, C, and beta-carotene from foods and supplements and the risk of prostate cancer in this cohort. At baseline, subjects completed a food-frequency questionnaire that included detailed questions on 12 individual supplements, and all male subjects were screened for prostate cancer. During up to eight years of follow-up no overall association between prostate cancer risk and the intake of these antioxidant nutrients was seen; however, those who smoked within the past 10 years and used vitamin E supplements at a dose higher than 400 IU/d or for 10 or more years significantly decreased their risk of developing advanced prostate disease by about 70% (P for both trends = 0.01).
Together, the findings from ATBC and PLCO suggest that vitamin E supplementation may be more beneficial in certain subgroups such as smokers. Interestingly, vitamin E supplementation reportedly lowered the incidence rate of the common cold among some smokers in the ATBC study. In their analysis, Hemila et al observed that a subgroup of older, city-dwelling men (n = 14,573), age 72-77 years, who smoked 5-14 cigarettes/d were less likely to come down with the common cold if they were in the vitamin E-supplemented group than the placebo group (RR 0.54; 95% CI 0.37-0.80).17 It has been well established that smokers require higher intake levels of the antioxidant nutrient vitamin C than do nonsmokers. Bruno et al recently presented the first direct evidence in humans that a chronic oxidative stress, smoking, also increases the rate of loss of vitamin E in plasma.18 Additionally, they demonstrated that increasing plasma vitamin C levels slowed the loss of vitamin E in smokers, but not in nonsmokers.
With regard to cancer treatment, studies by Argyriou et al19 and Bairati et al20 indicate a role for vitamin E supplementation in some forms of therapy, but not others. Argyriou et al showed vitamin E supplementation (DL-alpha-tocopherol acetate) at a dose of 300 mg twice daily in chemotherapy patients (n = 32) protected them from paclitaxel-induced peripheral nerve damage (PIPN).19 Patients diagnosed with lung, breast, or ovarian cancer who had at a least nine months to live received six courses of a paclitaxel-based chemotherapy regimen plus either vitamin E supplements or placebo during chemotherapy and for up to three months after its suspension. The incidence of PIPN was 70% lower in the vitamin E-supplemented patients than in the control group (P = 0.03). However, in the study by Bairati et al, head and neck cancer patients (n = 540) undergoing radiation treatments experienced an increase in all-cause mortality when supplemented with 400 IU DL-alpha-tocopherol alone during therapy and for three years after radiation therapy ended compared with the placebo group (HR 1.43, 95% CI 0.98-2.07).20 Overall survival was also consistently lower among patients randomized to the supplemented group (P = 0.033), which included those who took either alpha-tocopherol alone or in combination with beta-carotene (30 mg/d).
Cognitive Function
In the WHS, Kang et al analyzed a subgroup of older women to examine the effects of vitamin E supplementation on cognitive function.21 The study began 5.6 years after 6,377 women age 65 years and older were initially randomized to receive vitamin E or placebo. Subjects were monitored for changes in cognitive function and followed for four years. The primary outcome was a global composite score comprised of subjects' average performance across five cognitive tests. There were no differences over time in cognitive function assessed with the global score, but the vitamin E-supplemented group had a nonsignificant 8% lower risk of substantial decline compared with the placebo group. With regard to the verbal memory score, the vitamin E group had a 15% lower risk of substantial decline compared with the placebo group that reached borderline significance (P = 0.08). Among women with a dietary intake of vitamin E below the median of 6.1 mg/d, those who also took the vitamin E supplement experienced less adverse cognitive change compared with the placebo group. The mean change in rate of cognitive decline over time between the vitamin E and placebo groups was 0.05 (95% CI 0.01-0.09, P = 0.04). Among women with a higher dietary intake of vitamin E, the supplemented and placebo groups were similar in degree of change over time.
Diabetes
Also in the WHS, Liu et al evaluated the primary prevention of Type 2 diabetes with vitamin E supplementation.22 A nonsignificant 5% risk reduction in initially healthy women was reported (95% CI 0.87-1.05, P = 0.31) among the supplemented group, and a borderline significant (P = 0.06) 12% reduction was observed among women without a family history of the disease, but not in those with a family history. Treatment with aspirin did not significantly modify the reported effect of vitamin E on Type 2 diabetes. It should be noted that this study cohort was not prescreened for glucose tolerance at baseline, and the diagnosis of Type 2 diabetes was self-reported.
In a nested case-control study of coronary artery disease in subjects with Type 1 diabetes enrolled in the Pittsburgh Epidemiology of Diabetes Complications Study (EDC), Costacou et al found a protective effect of vitamin E among antioxidant supplement users (HR 0.22; 95% CI 0.10-0.49) and patients with renal disease (HR 0.46; 95% CI 0.23-0.91).23 The EDC was a 10-year prospective study of Type 1 diabetics, with a mean age at baseline of 28 years, and diabetes duration of 19 years. Baseline alpha-tocopherol levels were similar in cases and controls, and the use of supplements was approximately 27% in both groups.
Child/Maternal Health
In the first large-scale epidemiologic study of circulating vitamin E concentrations during pregnancy, Scholl et al examined the effect of vitamin E on fetal growth in a cohort of 1,231 generally healthy pregnant women (mean age 22.9 ± 5.2 years) from 16 to 28 weeks gestation.24 Plasma concentrations of alpha-tocopherol at study entry and week 28 were positively and significantly correlated with increased fetal growth (birth weight for gestation) (P < 0.0001), a decreased risk of small-for-gestational-age births (P = 0.03), and an increased risk of large-for-gestational-age births (P = 0.004). Plasma alpha-tocopherol concentrations were also positively correlated with the use of prenatal multivitamins and dietary vitamin E intake at week 28 (P < 0.05).
According to Litonjua et al, higher maternal intakes of vitamin E during pregnancy were also associated with a lower risk of wheezing illnesses in 2-year-old children.25 In this study, 1,290 mother-child pairs were assessed for dietary intake and vitamin use during gestation (mothers only) and wheezing in their children within the first two years of life. Mothers in the highest quintile of vitamin E intake were 30% less likely to report any wheezing in their 2-year-old children (95% CI 0.48-1.03, P for trend = 0.06), and 51% less likely to report recurrent wheezing (95% CI 0.27-0.90, P for trend = 0.05). The findings of this study provide support for the hypothesis that lower antioxidant intake increases the susceptibility of airways to inflammation and asthma.
Conclusion
Oxidative stress is implicated in the pathogenesis of many degenerative diseases, including cardiovascular disease, cancer, diabetes, cataracts, rheumatoid arthritis, and neurodegenerative diseases. In vitro and experimental studies have demonstrated that the antioxidants, including vitamins E, C, and beta-carotene, act as effective antioxidants in biological systems such as plasma, lipoproteins, and cultured cells. Evidence from observational studies consistently shows that diets rich in antioxidant-containing fruits and vegetables are associated with reduced risk for chronic diseases such as cancer and heart disease. Despite this evidence, clinical trials of single antioxidant micronutrient supplementation have been equivocal with respect to disease outcome.
For some people, supplementing the diet with vitamin E alone can play a positive role in preventing the sudden onset or severity of certain conditions, while for others this practice has no effect at all. The recent vitamin E studies presented here suggest that smokers and healthy older women are likely to benefit from long-term supplementation. Why are benefits shown in these particular subgroups of these studies, but not in others? Genetic variations may be involved. There is some evidence to suggest that antioxidant supplementation in smokers lacking the protective GSTM1 gene would benefit far more than smokers with the normal genotype.26 Future studies will undoubtedly consider the role of genetic polymorphisms related to vitamin E metabolism and function when presenting their results.
While antioxidant nutrients appear to play a role in decreasing the risk of developing diseases, they appear less successful in secondary prevention. Despite a recent and questionable meta-analysis suggesting antioxidant supplements may increase all-cause mortality, the safety of these nutrients is well established with very conservative estimates of tolerable upper levels established by the Institute of Medicine of vitamin E at 1,500 IU, vitamin C at 2,000 mg, and selenium at 400 mg.27 The protection received from proper diet and/or supplements most often comes from combinations of nutrients working together. This is clearly illustrated by the observations of Bruno et al, which provide strong support for the co-antioxidant function of vitamins E and C in vivo.18 The importance of "balanced" antioxidant supplementation, i.e., the need for antioxidants to interact, not just for vitamin E and vitamin C,18 but also with selenium (SELECT Trial28), zinc (AREDS Trial29), and phytochemicals, like carotenoids and flavonoids,30 should be emphasized.
Recommendation
All patients should be encouraged to improve their intake of antioxidant nutrients and phytochemicals through a plant-based diet, and advised not to exceed safe intake levels of any dietary supplement, including vitamin E.
References
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15. Wright ME, et al. Higher baseline serum concentrations of vitamin E are associated with lower total and cause-specific mortality in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Am J Clin Nutr 2006;84:1200-1207.
16. Kirsh VA, et al. Supplemental and dietary vitamin E, beta-carotene, and vitamin C intakes and prostate cancer risk. J Natl Cancer Inst 2006;98:245-254.
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19. Argyriou AA, et al. Preventing paclitaxel-induced peripheral neuropathy: A phase II trial of vitamin E supplementation. J Pain Symptom Manage 2006;32:237-244.
20. Bairati I, et al. Antioxidant vitamins supplementation and mortality: A randomized trial in head and neck cancer patients. Int J Cancer 2006;119:2221-2224.
21. Kang JH, et al. A randomized trial of vitamin E supplementation and cognitive function in women. Arch Intern Med 2006;166:2462-2468.
22. Liu S, et al. Vitamin E and risk of type 2 diabetes in the women's health study randomized controlled trial. Diabetes 2006;55:2856-2862.
23. Costacou T, et al. Antioxidants and coronary artery disease among individuals with type 1 diabetes: Findings from the Pittsburgh Epidemiology of Diabetes Complications Study. J Diabetes Complications 2006;20:387-394.
24. Scholl TO, et al. Vitamin E: Maternal concentrations are associated with fetal growth. Am J Clin Nutr 2006;84:1442-1448.
25. Litonjua AA, et al. Maternal antioxidant intake in pregnancy and wheezing illnesses in children at 2 y of age. Am J Clin Nutr 2006;84:903-911.
26. Mooney LA, et al. Antioxidant vitamin supplementation reduces benzo(a)pyrene-DNA adducts and potential cancer risk in female smokers. Cancer Epidemiol Biomarkers Prev 2005;14:237-242.
27. Bjelakovic, GB, et al. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention. JAMA 2007;297:842-57.
28. Lippman SM, et al. Designing the Selenium and Vitamin E Cancer Prevention Trial (SELECT). J Natl Cancer Inst 2005;97:94-102.
29. Moriarty-Craige SE, et al. Effects of long-term zinc supplementation on plasma thiol metabolites and redox status in patients with age-related macular degeneration. Am J Ophthalmol 2007;143:206-211. Epub 2006 Nov 9.
30. Chen CY, et al. Flavonoids from almond skins are bioavailable and act synergistically with vitamins C and E to enhance hamster and human LDL resistance to oxidation. J Nutr 2005;135:1366-1373.
McKay D. Vitamin E supplementation: An update. Altern Med Alert 2007;10(4):37-42.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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