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Vitamin E Supplementation, Cardiovascular Events, and Cancer—Reply

Vitamin E Supplementation, Cardiovascular Events, and Cancer—Reply In Reply: Dr Richey raises the potential confounding effect of glitazone use on heart failure. We did not collect detailed data on glitazone use in HOPE and HOPE-TOO because the trial was designed in the early 1990s, before recognition of the potential impact of glitazones on heart failure. However, HOPE is a randomized double-blind trial, so that it is unlikely that glitazones would be preferentially used in the vitamin E group. Furthermore, we did collect data on overall use of oral hypoglycemic agents and this was similar in the vitamin E and placebo groups (22.2% vs 21.4% at baseline, 23.8% vs 21.3% at 4 years, and 24.5% vs 24.6% at study end, respectively). We have previously reported that vitamin E has a neutral effect on glycemic control and on the development of new-onset diabetes mellitus,1 which further makes a differential use of glitazones unlikely. Dr Gaby correctly points out that use of high-dose α-tocopherol may change the availability of γ-tocopherol, recently recognized to be important in mediating various biological actions of vitamin E. He suggests that the use of mixed tocopherols may be safer than α-tocopherol alone and may lead to improved clinical outcomes. Although γ-tocopherol and other naturally occurring antioxidants may be important, and overwhelming naturally occurring redox systems with pharmacological rather than physiological doses of α-tocopherol is not beneficial, α-tocopherol remains the most commonly used vitamin E isomer in commercially available supplements and it is often used in doses equal to or higher than those tested in our trial. Before any recommendations supporting the widespread use of γ-tocopherol or of combination antioxidants, the benefits and safety of such approaches need to be proven. The SU.VI.MAX study2 used a combination of antioxidant vitamins and minerals in doses similar to the recommended dietary requirements and found no benefit in the prevention of cardiovascular diseases. This study also found no benefit in cancer prevention for the overall study population, although in a subgroup analysis, men had slightly lower rates of cancer and total mortality. This subgroup finding requires further confirmation, particularly since no specific cancer type was conclusively prevented and a substantial number of study participants did not complete the trial. Dr Jarski and colleagues question the study design testing the hypothesis that vitamin E supplementation for 7 years may reduce cardiovascular events and cancer in middle-aged and elderly patients with established vascular disease. However, this hypothesis had not been adequately tested in a well-designed, randomized clinical trial. Members of this study population are at highest risk for recurrent events and often take vitamin E supplements in the hope of reducing their risk. Given their average life expectancy, the duration of vitamin supplementation is often similar to or only slightly longer than the duration of our trial. Targeting this population for vitamin E treatment detracts from a focus on proven effective preventive therapies, including lifestyle modifications and pharmacological approaches. Moreover, we are aware of no evidence that starting treatment with vitamin E supplements earlier in life, before developing advanced atherosclerotic changes, and/or extending it for longer periods of time confers vascular protection. Trials of high-dose vitamin E in younger individuals without vascular disease have also failed to demonstrate benefits.3-5 Possibly most compelling is the Women’s Health Study, with close to 40 000 women aged 45 years or older, that found no benefit in the prevention of major vascular events after 10 years of treatment with high-dose vitamin E.5 Back to top Article Information Financial Disclosures: None reported. References 1. Lonn E, Yusuf S, Hoogwerf B. et al. Effects of vitamin E on cardiovascular and microvascular outcomes in high-risk patients with diabetes. Diabetes Care. 2002;25:1919-192712401733Google ScholarCrossref 2. Hercberg S, Galan P, Preziosi P. et al. The SU.VI.MAX study: a randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals. Arch Intern Med. 2004;164:2335-234215557412Google ScholarCrossref 3. Collaborative Group of the Primary Prevention Project (PPP). Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice. Lancet. 2001;357:89-9511197445Google ScholarCrossref 4. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med. 1994;330:1029-10358127329Google ScholarCrossref 5. Lee IM, Cook NR, Gaziano JM. et al. Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial. JAMA. 2005;294:56-6515998891Google ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA American Medical Association

Vitamin E Supplementation, Cardiovascular Events, and Cancer—Reply

JAMA , Volume 294 (4) – Jul 27, 2005

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Publisher
American Medical Association
Copyright
Copyright © 2005 American Medical Association. All Rights Reserved.
ISSN
0098-7484
eISSN
1538-3598
DOI
10.1001/jama.294.4.426-a
Publisher site
See Article on Publisher Site

Abstract

In Reply: Dr Richey raises the potential confounding effect of glitazone use on heart failure. We did not collect detailed data on glitazone use in HOPE and HOPE-TOO because the trial was designed in the early 1990s, before recognition of the potential impact of glitazones on heart failure. However, HOPE is a randomized double-blind trial, so that it is unlikely that glitazones would be preferentially used in the vitamin E group. Furthermore, we did collect data on overall use of oral hypoglycemic agents and this was similar in the vitamin E and placebo groups (22.2% vs 21.4% at baseline, 23.8% vs 21.3% at 4 years, and 24.5% vs 24.6% at study end, respectively). We have previously reported that vitamin E has a neutral effect on glycemic control and on the development of new-onset diabetes mellitus,1 which further makes a differential use of glitazones unlikely. Dr Gaby correctly points out that use of high-dose α-tocopherol may change the availability of γ-tocopherol, recently recognized to be important in mediating various biological actions of vitamin E. He suggests that the use of mixed tocopherols may be safer than α-tocopherol alone and may lead to improved clinical outcomes. Although γ-tocopherol and other naturally occurring antioxidants may be important, and overwhelming naturally occurring redox systems with pharmacological rather than physiological doses of α-tocopherol is not beneficial, α-tocopherol remains the most commonly used vitamin E isomer in commercially available supplements and it is often used in doses equal to or higher than those tested in our trial. Before any recommendations supporting the widespread use of γ-tocopherol or of combination antioxidants, the benefits and safety of such approaches need to be proven. The SU.VI.MAX study2 used a combination of antioxidant vitamins and minerals in doses similar to the recommended dietary requirements and found no benefit in the prevention of cardiovascular diseases. This study also found no benefit in cancer prevention for the overall study population, although in a subgroup analysis, men had slightly lower rates of cancer and total mortality. This subgroup finding requires further confirmation, particularly since no specific cancer type was conclusively prevented and a substantial number of study participants did not complete the trial. Dr Jarski and colleagues question the study design testing the hypothesis that vitamin E supplementation for 7 years may reduce cardiovascular events and cancer in middle-aged and elderly patients with established vascular disease. However, this hypothesis had not been adequately tested in a well-designed, randomized clinical trial. Members of this study population are at highest risk for recurrent events and often take vitamin E supplements in the hope of reducing their risk. Given their average life expectancy, the duration of vitamin supplementation is often similar to or only slightly longer than the duration of our trial. Targeting this population for vitamin E treatment detracts from a focus on proven effective preventive therapies, including lifestyle modifications and pharmacological approaches. Moreover, we are aware of no evidence that starting treatment with vitamin E supplements earlier in life, before developing advanced atherosclerotic changes, and/or extending it for longer periods of time confers vascular protection. Trials of high-dose vitamin E in younger individuals without vascular disease have also failed to demonstrate benefits.3-5 Possibly most compelling is the Women’s Health Study, with close to 40 000 women aged 45 years or older, that found no benefit in the prevention of major vascular events after 10 years of treatment with high-dose vitamin E.5 Back to top Article Information Financial Disclosures: None reported. References 1. Lonn E, Yusuf S, Hoogwerf B. et al. Effects of vitamin E on cardiovascular and microvascular outcomes in high-risk patients with diabetes. Diabetes Care. 2002;25:1919-192712401733Google ScholarCrossref 2. Hercberg S, Galan P, Preziosi P. et al. The SU.VI.MAX study: a randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals. Arch Intern Med. 2004;164:2335-234215557412Google ScholarCrossref 3. Collaborative Group of the Primary Prevention Project (PPP). Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice. Lancet. 2001;357:89-9511197445Google ScholarCrossref 4. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med. 1994;330:1029-10358127329Google ScholarCrossref 5. Lee IM, Cook NR, Gaziano JM. et al. Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial. JAMA. 2005;294:56-6515998891Google ScholarCrossref

Journal

JAMAAmerican Medical Association

Published: Jul 27, 2005

References