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Letters to the Editor Issue 107

by Letters(more info)

listed in letters to the editor, originally published in issue 107 - January 2005

Vitamin E, Heart Disease, and Mortality: Doctor Murray’s Newsletter

The recent proclamation by a set of researchers that vitamin E may actually increase the risk of mortality and the resulting media fervour reporting this story is not surprising to me at all. In fact, I predicted it and based upon the research it is easy to understand how this conclusion could be made.

Although many experts and organization will be focusing on the shortcomings in the methodology in the recent meta-analysis, my feeling is that time is better spent trying to understand the results instead of trying to discredit them. The results simply reflect some inherent defects in the manner in which research is conducted with antioxidant nutrients. Nonetheless, it is important to point out that the interpretation of the data is based upon an analysis of 19 earlier published vitamin E studies with a built-in bias toward the risk of harm rather than potential benefit. Focusing on the impact on the all-cause mortality outcome seems inappropriate given that none of the 19 studies analyzed were designed with this as the primary endpoint; the studies chosen represented quite a diversity of subjects, disease conditions, treatments and durations of intervention; and the follow-up time was relatively short ranging from 1.4 years to 8.2 years. It is also important to point out that while these studies were not designed to evaluate all-cause mortality statistics as the primary outcome, many of the studies used in the meta-analysis showed positive results on the primary outcomes they were designed to measure such as reduced progression of advanced age-related macular degeneration and cataracts; reduced incidence of heart attacks, and slowed progression of atherosclerosis and Alzheimer’s Disease.

The Beta-carotene Analogy
The results from this analysis of vitamin E research are quite similar to those of synthetic beta-carotene in cancer prevention. In case you missed this line of research with beta-carotene, studies indicated that synthetic beta-carotene supplementation contributed to earlier death in high-risk groups for cancer and cardiovascular disease. These studies did not invalidate the hundreds of studies showing the preventive effect of a diet rich in carotenes and nutritional antioxidants against cancer and cardiovascular disease. These results seem to indicate the need for a diet high in carotenes and, if carotene supplementation is desired, people should not smoke, natural forms should be used, and the beta-carotene needs to be protected against the formation of toxic derivatives by taking extra vitamin C and E, and selenium.

It is important to realize that not all antioxidants are created equal. When it comes to quenching free radicals, antioxidant compounds exert different (and usually very narrow) range of activity. For example, beta-carotene is an effective quencher of a free radical known as singlet oxygen, but is virtually powerless against the dozens of other types of free radicals. As a result, it has a very narrow range of benefit and is very susceptible to being damaged itself and forming a free radical without additional antioxidant support. Most antioxidants require some sort of ‘partner’ antioxidant that allows it to work more efficiently. And scientists have discovered that beta-carotene itself can become damaged if it’s used alone (that is, without its partner antioxidants vitamin C, vitamin E, and selenium). For example, while studies showed that synthetic beta-carotene supplements given alone actually increased the risk of cancer in smokers, when beta-carotene was given along with vitamin E and selenium, it reduced cancer deaths by a significant 13 percent. Damaged beta-carotene is extremely toxic to the liver, the lining of the arteries, and the lungs. This fact alone may explain some of the disappointing results from the recent beta-carotene studies.

Undoubtedly there will be similar discoveries about the importance of other antioxidant nutrients in the support of vitamin E’s antioxidant benefit.

The Importance of Synergy
While the scientific research is quite clear that diets high in antioxidants are protective against many diseases, the data is not as solid with antioxidant supplements. There are three main points to keep in mind when looking at research with antioxidant supplements:

The antioxidant system of the body relies on a complex interplay of many different dietary antioxidants. Taking any single antioxidant nutrient is not enough. Total protection requires a strategic, comprehensive dietary and supplement program. Although dietary supplements are important, they cannot replace the importance of consuming a diet rich in antioxidants.

A shortcoming of many of the intervention studies with antioxidant nutrients is that researchers often focus on the effects of just one factor. In a way, this is like judging an entire symphony by listening to a single trombone. Such research has its value, but it’s not complete and often raises more questions than it answers.

Antioxidants and Heart Disease
The research is quite clear that dietary antioxidant nutrients like vitamin E, lycopene, lutein, selenium, and vitamin C offer significant protection against the development of cardiovascular disease. Fats and cholesterol are particularly susceptible to free radical damage. When damaged, fats and cholesterol form lipid peroxides and oxidized cholesterol which can then damage the artery walls as well as accelerate the progression of atherosclerosis (hardening of the arteries). Antioxidants block the formation of these damaging compounds.

While diets rich in antioxidant nutrients have consistently shown tremendous protection against cardiovascular disease, clinical trials utilizing antioxidant vitamins and minerals have produced inconsistent results.[1,2] This failure may be due to several factors, most importantly the fact that the human antioxidant system represents a complex scenario of interacting components. It is unlikely that any single antioxidant would be proven to be effective especially in the absence of a supporting cast. Most antioxidants require some sort of ‘partner’ antioxidant that allows it to work more efficiently. The most salient example of this point is the partnership between the two primary antioxidants in the human body – vitamin C and vitamin E. Vitamin C is an ‘aqueous phase’ antioxidant while vitamin E is a ‘lipid phase’ antioxidant. Although some studies have shown that supplementation with these nutrients reduces atherosclerotic lesions, more protection is likely required to insure optimal effect.[3] In addition to vitamin C, vitamin E also requires selenium and coenzyme Q10 to work efficiently (discussed in more detail below). Further adding to the shortcoming of many of the studies on antioxidant nutrients is the lack of consideration on the importance of phytochemicals and plant-derived antioxidants that, in addition to exerting benefit on their own, are well-known to potentiate the activities of vitamin and mineral antioxidants.

The support of non-antioxidant vitamins and minerals may also be important in assisting the effectiveness of antioxidants. Taking a multiple vitamin and mineral supplement seems appropriate.

The Research on Vitamin E
Although clinical studies have shown inconsistent effects, it is clear that vitamin E does play a role in the protection against the oxidation of LDL cholesterol because of its ability to be easily incorporated into the LDL molecule. Vitamin E may offer additional benefit in protecting against heart disease and strokes by its ability to:

•    Reduce LDL cholesterol peroxidation and increase plasma LDL breakdown
•    Inhibit excessive platelet aggregation
•    Increase HDL cholesterol levels
•    Increase fibrinolytic activity
•    Reduce C-reactive protein levels
•    Improve endothelial cell function
•    Improve insulin sensitivity

Two early large-scale studies with relatively low dosages of vitamin E supplements demonstrated a significant reduction in the risk of dying of a heart attack or a stroke. The Nurses Health Study of 87,245 nurses concluded that those who took 100IU of vitamin E daily for more than 2 years had a 41% lower risk of heart disease compared with non-users of vitamin E supplements.81 In the Physicians Health Study of 39,910 male health care professionals found similar results: a 37% lower risk of heart disease with the intake of more than 30 IU of supplemental vitamin E daily.[4] Subsequent studies have been equivocable.[5]

Large-scale studies examining the impact of vitamin E supplementation in patients with existing heart disease have also shown somewhat conflicting results.[6] Some the disappointing results may have been the choice of synthetic vitamin E (D,L-alpha tocopherol) versus the more active natural form (D-alpha tocopherol). There is also the problem with interference by statin drugs of vitamin E and coenzyme Q10 metabolism – thereby increasing the needs for both compounds. In fact, one of the reasons why more recent studies with vitamin E have not shown the same benefit as earlier studies may turn out to be that higher dosages of vitamin E alone and in combination with CoQ10 are required to compensate for the detrimental effects of the now extremely popular statin drugs have on their metabolism.

Vitamin E and CoQ10 work synergistically and each is required for the regeneration of the other. For example, CoQ10 is present in the blood in both oxidized (inactive) and reduced (active) form. During times of increased oxidative stress or low vitamin E levels, more CoQ10 will be converted to its oxidized (inactive form). Thus, by providing higher levels of vitamin E and the biological activity and function of CoQ10 is enhanced and vice versa. Several studies in humans and animals have shown that the combination of vitamin E and CoQ10 work better than either alone. For example, in a study in baboons, while supplementation with vitamin E alone reduced C-reactive protein (CRP) levels, co-supplementation with CoQ, however, significantly enhanced this effect of vitamin E. Similar results have been seen in other animal studies on other aspects associated with atherosclerosis including LDL oxidation and lipid peroxide content within the aorta.[7-9] It appears that taking 50 mg of CoQ10 for every 400 IU of vitamin E offers a rational approach to supporting the antioxidant activities of both nutrients.

In addition to CoQ10, vitamin E also requires adequate selenium status for optimal antioxidant effects. Selenium functions primarily as a component of the antioxidant enzyme glutathione peroxidase. This enzyme works closely with vitamin E to prevent free radical damage to cell membranes. Studies looking only at vitamin E’s ability to reduce cancer and heart disease are often faulty because they failed to factor in the critical partnership between selenium and vitamin E not to mention the interrelationship between vitamin E and coenzyme Q10. Several studies have clearly demonstrated that low selenium status is significantly associated with CAD.[10,11] Failure to co-supplement with selenium as well as vitamin C and CoQ10 may be a major reason for the inconsistent results in intervention trials with vitamin E supplementation alone. A dosage of 100 to 200 mcg of selenium per day is all that is usually required.

The ‘Take Home’ Message
In regards to supplementation with vitamin E at higher dosages (e.g., >400 IU daily), I will continue to make this recommendation to people with heart disease, diabetes, etc., and will do so in the same manner that I have consistently done over the past 20 years. I have repeatedly written and stated that the use of any single antioxidant nutrient at higher dosages must be made within the context of a truly comprehensive approach that focuses on a diet rich in antioxidant nutrients (i.e., vegetables, fruits, nuts, seeds, and legumes) and a strong foundation of nutritional supplementation. The three key dietary supplements that I recommend to provide a strong foundation for a proper nutritional supplement plan are:

•    A high-potency multiple vitamin and mineral formula (MultiStart);
•    A ‘greens’ drink product (Enriching Greens);
•    A pharmaceutical grade fish oil supplement (RxOmega-3 Factors).

The dietary recommendations and foundational supplements work synergistically and in harmony with each other because of the key roles they each play in promoting vibrant health.

Key References:

1.    Clarke R and Armitage J. Antioxidant vitamins and risk of cardiovascular disease. Review of large-scale randomised trials. Cardiovasc Drugs Ther. 16: 411-5. 2002.
2.    Vivekananthan DP, Penn MS, Sapp SK, et al. Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials. Lancet. 361: 2017-23. 2003.
3.    Salonen RM, Nyyssonen K, Kaikkonen J, et al. Six-year effect of combined vitamin C and E
supplementation on atherosclerotic progression: the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) Study. Circulation. 107: 947-53. 2003.
4.    Stampfer MJ, Hennekens CH, Manson JE. Vitamin E consumption and the risk of coronary disease in women. N Engl J Med. 328: 1444-9. 1993.
5.    Rimm EB, Stampfer MJ, Ascherio A. Vitamin E
consumption and the risk of coronary heart disease in men. New Engl J Med. 328: 1450-6. 1993.
6.    Eidelman RS, Hollar D, Hebert PR, Lamas GA, Hennekens CH. Randomized trials of vitamin E in the treatment and prevention of cardiovascular disease. Arch Intern Med. 164(14): 1552-6. 2004.
7.    Kaikkonen J, Nyyssonen K, Tomasi A, et al. Antioxidative efficacy of parallel and combined supplementation with coenzyme Q10 and d-alpha-tocopherol in mildly hypercholesterolemic subjects: a randomized placebo-controlled clinical study. Free Radic Res. 33: 329-40. 2000.
8.    Wang XL, Rainwater DL, Mahaney MC, et al. Cosupplementation with vitamin E and coenzyme Q10 reduces circulating markers of inflammation in baboons. Am J Clin Nutr. 80: 649-55. 2004.
9.    Thomas SR, Leichtweis SB, Pettersson K, et al. Dietary cosupplementation with vitamin E and coenzyme Q(10) inhibits atherosclerosis in apolipoprotein E gene knockout mice. Arterioscler Thromb Vasc Biol. 21: 585-93. 2001.
10.    Yegin A, Yegin H, Aliciguzel Y, et al. Erythrocyte selenium-glutathione peroxidase activity is lower in patients with coronary atherosclerosis. Jpn Heart J. 38: 793-8. 1997.
11.    Bor MV, Cevik C, Uslu I, et al. Selenium levels and glutathione peroxidase activities in patients with acute myocardial infarction. Acta Cardiol. 54: 271-6. 1999.

Sepp Hasslberger


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