The truth about antioxidants supplements

One minute you hear they are good for you, then bad for you. Find out the truth, about antioxidants and why smokers need to be careful.

For years the evidence was coming in showing that extra antioxidants worked very well. One group who seemed to be benefiting were smokers, who have a very high exposure to oxidants, which are also created when anything, from bacon to tobacco, is burnt. Beta-carotene, the stuff in carrots, was coming up trumps in thousands of studies linking a high intake, or high blood levels to low disease risk, particularly of cancer. For example, a ten-year study of several thousand elderly people in Europe, conducted by the Centre for Nutrition and Health at the National Institute of Public Health and the Environment in the Netherlands, found that the higher the beta-carotene level, the lower the overall risk of death, especially from cancer. Eating probably the equivalent of a carrot a day (raising blood level by 0.39mcmol/l) meant cutting cancer risk by a third.[1]

Heart disease, the biggest western killer, was being linked to oxidative damage to cholesterol and the arteries and vitamin E, a fat-based antioxidant, was the best contender for protecting your arteries. The signs were good. The New England Journal of Medicine published two studies the first of which involved 87,200 nurses. Those taking in 67mg or more of vitamin E for more than two years had 40 per cent less fatal and non-fatal heart attacks compared to those not taking vitamin E supplements.[2]

In another study, 39,000 male health professionals taking 67mg of vitamin E for the same length of time had a 39 per cent reduction in heart attacks.[3] Then, the first placebo-controlled trial, carried out by researchers at the UK’s Cambridge University Medical School in 1996, gave some 2,000 people vitamin E or a placebo. Those given vitamin E had a 75 per cent reduced risk of a non-fatal heart attack. The research showed vitamin E to be almost four times as effective as aspirin in reducing heart attacks. But then in the mid-nineties this positive picture began to change when the results began to come in from a number of studies that had been set up to test the effects of giving smokers, and people with heart disease, antioxidants, especially beta-carotene and vitamin E respectively. The first to rock the antioxidant boat, the CARET trial by the National Cancer Institute, was published in 1996. It found a small, non-significant increased incidence of lung cancer in smokers given beta-carotene, and an equivalent decreased incidence in non-smokers taking the supplement.[4]

Then, another trial reported an increased risk for smokers given beta-carotene. Male smokers were given either vitamin E, vitamin E plus beta-carotene, or beta-carotene on its own. The first two groups showed no significant change, but the beta-carotene-only group showed an increased risk.[5] Once again, giving beta-carotene on its own to smokers shows up as very slightly raising the risk of cancer. Although the negative effect was small it has been confirmed by some more recent studies. For example, a study in which people received radiation therapy for head and neck cancer found that those given supplements of beta-carotene and vitamin E during radiation therapy who continued to smoke increased their risk of a cancer recurrence and death, while those who did not smoke didn’t.[6] Other studies have also found an increased risk among smokers taking supplements and a decreased risk among non-smokers. The question is why? What does this mean for smokers?

The second nail in the coffin for antioxidants were results of trials giving vitamin E to those with cardiovascular disease. All was looking good with vitamin E until 2000, when around 20,000 people with cardiovascular disease were given vitamins (600mg of vitamin E, 250mg of vitamin C and 20mg of beta-carotene) or placebos in a large-scale double-blind trial. This trial was part of a much larger study testing the effects of statin drugs. It found no difference in those taking the vitamins versus the placebos, but statins performed well in comparison. Then, things got worse for vitamin E. An American study, the HOPE (Heart Outcomes Prevention Evaluation) trial, published in the New England Journal of Medicine, hinted at a slight increased risk of heart attack in heart patients who were on medication and taking vitamin E.[7] The trial was extended for a further 2.5 years and, in 2005, the results of what was called the HOPE2 trial were published in the Annals of Internal Medicine, showing a slight increased risk of heart attack in heart patients who were on medication and taking vitamin E. This prompted a review of all trials in which vitamin E had been given to people with cardiovascular disease. The results showed that vitamin E, in higher doses, seemed to increase mortality, while at lower doses, seemed to decrease mortality.[8]

The overall conclusion was that ‘vitamin E supplementation did not affect all-cause mortality’ – in other words, the same number of people overall died in the group that took vitamin E as did in the group that didn’t. But as with beta-carotene, there was a group that did slightly worse (those on a high dose, above 268mg), and a group that did slightly better (on a low dose, below 268mg). Either way, though, the results looked pretty damning. The effect of taking vitamin E, for these people, was not that greatly positive or negative – and certainly not as positive as the preventive power of giving vitamin E to reasonably healthy people. The question is why, and why the difference between the high and low doses?

What none of the negative studies or the hostile press stories have commented on, however, is the very interesting finding that the apparent risk of taking an antioxidant on its own seems to vanish when you also take a multivitamin. For example, the recent Cochrane Review by Bjekalovic [9] (which was also published in the Journal of the American Medical Association last February [10] ) found that people who took BOTH multivitamin AND antioxidant supplements showed no increased risk, and in some cases, a significant decrease in risk. Now why should that be, and what does it tell us about the way antioxidants work? I believe it points to a simple explanation as to why high dose vitamin E increases cardiovascular risk, why beta-carotene increases smokers’ risk, and why multivitamins eradicate this risk.

Statins Make High Dose Vitamin E Dangerous
It is an established fact that the now widely taken cholesterol-lowering drugs, taken by the vast majority of cardiovascular patients, turn vitamin E from a protective antioxidant into a potentially harmful oxidant. We know it does and we know why it does. For example, quoting one of the studies included in the Cochrane review on antioxidants in which people with cardiovascular disease, taking cholesterol-lowering statin drugs, were given high dose vitamin E “These results indicate that the antioxidant effect of Vitamin E is attenuated when given in conjunction with this statin.”[11] Why would statins stop vitamin E acting as an antioxidant? The answer is that vitamin E’s ability to function as an antioxidant is totally dependent on another antioxidant, Co-enzyme Q10, and statins block the enzyme that makes CoQ10. For example, a paper published in May reported that plasma levels of CoQ10 were reduced by atorvastatin.[12]

The reason this is bad news is that the heart uses a huge amount of CoQ10. The severity of heart failure correlates with people who have the lowest levels. In one trial 10 out of 14 subjects with no history of heart problems developed heart rhythm abnormalities when given statins, while giving CoQ10 reversed the abnormality in 8 out of 9.[13] If you are on statins, you need at least 90mg a day of CoQ10. A warning on statin packets are now mandatory in Canada, saying that CoQ10 reduction ‘could lead to impaired cardiac function’. Of course the drug companies are well aware of statins’ effect on CoQ10. One has a patent on a statin/CoQ10 combo that has yet to be marketed. Given that the vast majority of people participating in the negative trials on vitamin E which were often trials also testing statins, or funded by drug companies making statins, a skeptic might even wonder if the trials were set up to create a negative result. Either way, there is a fundamental flaw in most of these trials which is that they didn’t actually measure whether or not the vitamin E was having an oxidant or an antioxidant effect, which can be done with a simple blood test.

I have contacted many of the authors of these trials a) to ask if the participants were also taking statins and b) if they had, or were willing to analyse their data looking at the effect of vitamin E on patients not taking statins versus those taking statins. Those who have replied confirmed that the majority of their trial participants were on statins. None have been willing to examine the difference in outcome in those on or off statins. So these apparent negative effects of high dose vitamin E might actually be because it’s taken with a drug that makes it harmful (and without CoQ10)! This kind of confounding variable really should be taken into account in good quality research. But it is not.

Detoxifying Cigarette Smoke is a Two-Step Process
In the case of smokers the confounding process involves the vitamins themselves and provides the answer to question as to why beta-carotene, and possibly other antioxidants, be harmful to smokers unless they also take a multivitamin

The liver is the major detoxifying organ in the body. It detoxifies harmful substances, including oxidants from tobacco smoke, in a two-step dance called Phase 1 and Phase 2 detoxifcation (see below) Phase 1 is dependent on anti-oxidants such as beta-carotene and vitamin E but it doesn’t actually completely disarm toxins such as those created from smoking. In fact, it can create toxic ‘intermediary metabolites’. If you have a toxic diet or lifestyle, for example, by smoking, and then increase your intake of individual antioxidants, you can actually create more toxins in a kind of log jam effect. What you need is to simultaneously support Phase 2 detoxification. This depends on other nutrients such as B vitamins, selenium, glutathione, glucosinolates and sulphur. I suspect that what is happening in these trials where smokers are given only beta-carotene is that Phase 2 liver detoxification can’t cope, or possibly that beta-carotene needs its other team players to work (see below). This could certainly explain why studies giving either multivitamins alongside beta-carotene, or an antioxidant complex, don’t report a negative result. It would also explain why foods high in beta-carotene seem to be only beneficial. Most of these also contain vital Phase 2 supporting nutrients. Broccoli and other cruciferous vegetables contain both folate and glucosinolates, while onions and garlic contain sulphur and glutathione derivatives. It might also explain why selenium, which helps both Phase 1 and Phase 2 to work, has the most positive effect of all the antioxidants if given singly.

The moral of this story is that nutrients work in synergy and are best supplemented as a group, not in isolation. The worst thing a smoker could do is to eat a lousy diet and supplement beta-carotene on its own. The best thing they could do is to quit smoking. Therefore, a smoker would most likely benefit the most from taking both an all-round optimum nutrition level multivitamin, and a comprehensive antioxidant containing selenium, glutathione and/or N-acetyl cysteine, and possibly extra vitamin C, but most importantly, eating antioxidant rich foods which naturally contain these nutrients.

Why the Cochrane Review is Flawed
Now you know that vitamin E and statins, and beta-carotene and smoking don’t mix, we can examine the recent Cochrane ‘meta-analysis’ which spawned headlines such as ‘ Vitamin Pills May Cause Early Death’.

This study by Bjekaolvic and colleagues lumped together the data of 67 disparate studies the majority of which involved older people (average age 61) with life-threatening diseases, many of which were not set up to measure mortality and actually found no change in mortality overall. But, by excluding any studies in which people were given a multivitamin, or selenium, alongside other antioxidants, and studies they deemed ‘high bias’ they were able to come up with a negative effect for antioxidants overall.

Many top scientists don’t agree with this kind of approach: “Blenderising these diverse trials to come up with one simple proclamation is just silly. There was no difference (in mortality) based on vitamin intake,” said Bernadine Healey, the first woman to head the National Institutes of Health, the world’s largest funder of health research. “It’s flawed results based on flawed data,” said top antioxidant expert Dr Balz Fry from Oregon State University. This meta-analysis was also criticised for how it selected the trials it included.

To give you an example, one excellent trial (called the NIT trial) was eliminated because there wasn’t enough information on why those who dropped out had done so. Admittedly, if you give a drug with short-term side-effects and half your participants drop out this might be relevant, but there are no known or reported short-term side effects of antioxidants. Anyway, leaving all these flaws aside, what is remarkable about this damning review is that if you exclude studies in which beta-carotene is given to smokers, and high dose vitamin E is given to cardiovascular patients, not only does any evidence of risk for antioxidants vanish, but you are left with more studies showing benefit. Here’s how it works: 26 trials left after exclusions (including those with a zero weighting, meaning those that reported either no, or no difference in deaths) of which.. 2 (ATBC and CARET) only show negative effect in smokers on beta-carotene and 7 give high dose vitamin E to cardiovascular patients presumably on statins If we know that combining smoking and beta-carotene, or statins plus vitamin E, is a confounding variable, then these 9 studies should be excluded.

That leaves 17 studies. Six of these show a positive effect and only two show a substantial negative effect, in terms of mortality. The first was headed by Dr Pelayo Correa from Louisiana State University whose group tested whether antioxidant supplements would help gastric cancer. When I told him how his trial had been used in this review he was ”amazed”, he said, because his research, “far from being negative, had shown clear benefit from taking vitamins”. “It did not intend, and did not have the power, to study mortality and has no value to examine mortality of cancer.” The second, nick named REACT (Roche European American Cataract Trial), gave elderly people vitamins A, C and E to see if it would slow down the progression of cataracts. Again, a positive result. The conclusion reads “Daily use of the micronutrients for three years produced a small deceleration in progression of age-related cataracts.” During this three year trial three people died in the placebo group and six people died in the supplement group. This was not significant. Of these 17 studies 10 reported a benefit from taking antioxidants for the change that their trial had set out to measure, for example reducing cataract or gastric cancer risk, while 7 showed no significant difference. One reported a negative effect, but only for smokers and drinkers. But even though many of these trials weren’t designed to examine mortality what Bjekaolvic and colleagues did was to add up the total number of deaths. (The vast majority of these trials were in old people with life-threatening diseases hence there were a number of deaths during these trials, most of which were conducted over years.) So they had a total of 46,410 people in the 17 studies who took supplement and 45,124 who got a placebo. Among those taking supplements 2678 died (5.8%) compared to 2521 (5.6%) in the ‘control’ group, What this shows is that there was no difference in risk of mortality from taking anti-oxidants and many positive effects. That’s a far cry from the damning headlines in the papers.

Of course, it would be nice if taking antioxidants on their own (excluding multivitamins and selenium) had shown a reduction in mortality but that’s quite a tall order in a group of mainly elderly people, the majority of which have life-threatening diseases. It may be a case of too little too late. Professor Bruce Ames, a biochemist at the Children’s Hospital Oakland Research Institute in California and one of the originators of the antioxidant theory of ageing, is highly skeptical of relying on this kind of pooled analyses of randomized controlled trials to test for the effects of vitamins.”They are extremely difficult to do properly,” he says. “They must be conducted for decades to detect effects on diseases like cancer and heart disease that take a long time to develop and it is very difficult to make sure that those in the placebo group don’t start taking a multivitamin. This is why they are not likely to yield definitive answers.” In addition he goes on to ask if we really want to wait, perhaps decades, for results of these long-term randomised controlled trials, which anyway will almost certainly will not provide definitive evidence. Instead, he suggests, it makes more sense to run trials that can be done more quickly. So his research team have, instead, focused on the effects of antioxidants on the ageing that is going on all the time in our cells.

The single biggest source of oxidants are the ‘exhaust fumes’ we create every second as a by-product of turning food into energy. This is done inside nearly every cell in the energy factories, known as mitochondria. Ames has studied how to prevent the ageing and decay of mitochondria in animals by giving them different combinations of antioxidants. This work has shown that increasing the intake of antioxidants can produce better liver function, brain function, reduction in blood pressure, inflammation and protection against macular degeneration. This kind of evidence is just as important, if not more so, than large-scale trials that often don’t take into account important variables such as the synergistic effects of antioxidants or the way in which combined medication may distort or negate their benefit. So, at the end of the day, you have to pick your way through the mire of confusing reports and make up your own mind as to the best way to protext your health. Although in recent years we have had a spate of negative findings about antioxidants, they haven’t actually shown us anything new about how they work.

Can you imagine what would happen if you pooled all drug trials? How meaningless would be the conclusions? My personal advice is to start by eating a diet high in antioxidants and to keep taking an optimum nutrition-style multivitamin. Then if you are getting on in years and want to stay healthy, or if you are suffering from a condition, for example heart disease, where the evidence shows that reducing oxidation may help, then also supplement an all-round antioxidant supplement containing CoQ10, lipoic acid, glutathione or N-acetyl cysteine, resveratrol, anthocyandins, vitamins A, C, E and beta-carotene, plus zinc and selenium.

References:

1. B. Buijsse et al.., Plasma carotene and alpha-tocopherol in relation to 10-y all-cause and cause-specific mortality in European elderly: the Survey in Europe on Nutrition and the Elderly, a Concerted Action (SENECA), Am J Clin Nutr, vol 82(4), 2005, pp. 879-86

2. M. J. Stampfer, et al.., Vitamin E consumption and the risk of coronary disease in women, New England Journal of Medicine, vol 328(20), 1993, pp. 1444–9

3. E. B. Rimm et al.., Vitamin E consumption and the risk of coronary heart disease in men, New England Journal of Medicine, vol 328(20), 1993, pp. 1450–6

4. G. Omenn et al.., The Beta-Carotene and Retinol Efficacy Trial (CARET), New England Journal of Medicine, vol 334, 1996, pp. 1150–5

5. D. Albanes et al.., ‘Alpha-tocopherol and beta-carotene supplements and lung cancer’, Journal of the National Cancer Institute, vol. 88, 1996, pp. 1560–70 and ‘The effect of vitamin E and beta-carotene on the incidence of lung cancer’, New England Journal of Medicine, vol. 330(15), 1994, pp. 1029–35

6. F. Meyer et al., International Journal of Cancer, vol. 122, 2008, pp.1679-1683

7. S. Yusuf et al., Vitamin E Supplementation and Cardiovascular Events in High-Risk Patients, N Engl J Med, vol 342, pp. 154-160 (2000)

8. E. Miller et al., Meta-analysis: High Dose Vitamin E Supplementation May Increase All-Cause Mortality, Annals of Internal Medicine, vol 142(1), 2004, pp. 37-46. This study found that among people taking high-dose vitamin E (above 400iu), 34 more people in 10,000 died, while among those taking low-dose vitamin E (below 400iu), 33 fewer people died. This might sound like a lot of people, but in the control group, 1,000 out of 10,000 died. And these were people who were already sick. So, among those with cardiovascular disease, 1 in 10 are expected to die within 8 years, 1 in 300 will die before that if taking high-dose vitamin E, and 1 in 300 will live longer if taking a lower dose of vitamin E.

9. G. Bjelakovic et al. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Database Syst Rev. 2008 Apr 16;(2)

10. G. Bjelakovic et al. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA. 2007 Feb 28;297(8):842-57. Review.

11.Y. Manuel & B. Keenoy et al. Impact of Vitamin E supplementation on lipoprotein peroxidation and composition in Type 1 diabetic patients treated with Atorvastatin. Atherosclerosis. 2004 Aug;175(2):369-76.

12. Kawashiri MA et al. Comparison of effects of pitavastatin and atorvastatin on plasma coenzyme Q10 in heterozygous familial hypercholesterolemia: results from a crossover study.Clin Pharmacol Ther. 2008 Vol 83(5):731-9.

13. M. Silver et al. Effect of on left ventricular diastolic function and ability of coenzyme Q to reverse that dysfunction. The American Journal of Cardiology , Vol 94;10:pp1306 – 1310