ANTIOXIDANTS - WHO DO YOU BELIEVE

by Nick Lane PhD, EuroTimes, October, 2003

With, or without, your blessing, the chances are good that your patients are taking any number of patent medicines, natural cures and nutraceutical products to better their health. Some of these products are especially marketed for patients worried about their vision.

What are the potential benefits and risks of self-administered vitamin supplements? With the deluge of information on the Internet driving consumer demand, ophthalmologists need to know the facts about antioxidants. In this article, EuroTimes takes a look at the current state of the science and marketing of nutraceuticals and mineral supplements and vision. Antioxidant and vitamin supplements are popularly perceived as healthy, natural, safe and effective – a view promoted by their manufacturers. Claims for safety and efficacy that might be queried by the FDA or the EMEA are permitted in the more lax regulatory environment of nutraceutical oversight.

Forever Moving the Goalposts

In June 2003, the latest recommendations on the use of vitamin supplements to prevent cancer and cardiovascular disease were published by the US Preventive Services Task Force (USPSTF)."The available evidence from randomised trials is either inadequate or conflicting, and the influence of confounding variables on observed outcomes cannot be determined," said the Panel. In the same month, a large meta-analysis (more than 200,000 patients) in The Lancet showed absolutely no benefit of vitamin E and beta-carotene in preventing long-term cardiovascular mortality and morbidity. But keep taking the pills, countered Annette Dickinson, PhD, President of the Council for Responsible Nutrition: "It is important to bear in mind that cancer and heart disease are not the only – or even the primary – reasons for using vitamins... potential benefits include strengthening immune function and protecting against cataracts and macular degeneration".

She also drew attention to positive studies suggesting benefits in heart disease, and cited a BMJ report, also published in June, on a ‘polypill' "composed of several components – including the B vitamin folic acid – that researchers say could prevent 80%- 90% of heart disease and stroke." The Council for Responsible Nutrition is not quite as disinterested as their name might suggest. It is the trade association representing dietary supplement industry ingredient suppliers and manufacturers, a multibillion-dollar business. Do they give balanced information? What did the cited BMJ article say about which supplements produced a remarkable 90% reduction in the risk of heart disease and stroke? The answer? Aspirin, a statin, three blood-pressure lowering agents (in half dose) and folic acid. Hardly a nutrient supplement. Shifting goalposts make it very difficult to form a scientific judgement on the benefits of antioxidants. You soon begin to sympathise with the USPSTF. Many studies are too small to prove a robust effect, and have suspiciously marginal p values. Others are not double-blind, or use proxy methods, such as dietary questionnaires, to determine antioxidant status. Positive studies that randomise a meaningless 17 patients are published, whereas studies with negative results may never see the light of day. Cause and effect are regularly conflated. But it's only a matter of time before the benefits are proved in more rigorous trials; and antioxidants don't do any harm, right?

Vitamins and the Eye

Antioxidants counter oxidative stress, the excess production of oxygen (and nitrogen) free radicals. Oxidative stress is implicated in aging and many age-related diseases, including AMD and cataract formation. The eye is vulnerable to oxidative stress, as sunlight, oxygen and light-absorbing pigments interact to produce a destructive photodynamic effect. As in photodynamic therapy (PDT) the damage is oxygen-dependent and is caused by singlet oxygen and other reactive oxygen species such as superoxide and hydrogen peroxide. In photosensory cells and the RPE, oxidative stress may contribute to drusen formation. In the lens, photochemically generated reactive oxygen species may contribute to early lens opacification and cataract formation (at least they do in animal models). Given the importance of oxidative photochemistry in the eye, the rationale for using antioxidants is stronger than elsewhere in the body. But poor methodology and conflicting results still confound clinical consensus. For every study claiming that antioxidants are beneficial, another claims they are not. In AMD, for example, the Eye Disease Case-Control Study showed that subjects who had high blood levels of carotenoids (notably lutein and zeaxanthin), selenium, and vitamins C and E, had a ‘marked reduction' in the risk of macular degeneration, to less than half that of subjects with low blood levels. Similarly, a Dutch case-control study (which used a questionnaire), showed that the prevalence of AMD in patients with high antioxidant and lutein intake was about half that in patients with a low intake.

In contrast, the Beaver Dam Eye Study (which also used dietary questionnaires) found no significant association between antioxidant and zinc intake and the incidence of early AMD. The Blue Mountains Eye Study in Australia found no link between dietary intake of antioxidants and zinc (including supplement use) and the five-year incidence of early AMD. The Physicians Health Study found small but non-significant reductions in the risk of age-related maculopathy in male physicians taking vitamin E or multivitamin supplements over 12.5 years follow-up. The third National Health and Nutrition Examination Survey (NHANES) found no relationship between the risk of age-related maculopathy, and dietary or serum levels of lutein and zeaxanthin.

Cataracts are a similar story. The Blue Mountains Eye Study found an inverse association between multivitamin supplement use and the prevalence of nuclear cataract, with a borderline p value of 0.05. Folate and vitamin B12 supplements were ‘strongly protective' against cortical cataracts, with a p value of 0.03. The Beaver Dam Eye Study provided ‘weak support' for a reduction in cataract formation by lutein and vitamins C and E. Those in the highest quintile of lutein intake ‘in the distant past' were half as likely to have incident cataract as people in the lowest quintile of intake. A Finnish study found participants with high plasma vitamin E levels had a lower risk of progression of early cortical lens opacities, but not of progression from nuclear lens opacities to cataract. Another Finnish study of middle-aged smoking men found that supplementation with alpha-tocopherol or beta-carotene for five to eight years did not influence cataract prevalence.

Antioxidants and Diet – a Confounding Association

One trouble with these contradictory studies is a faulty chain of logic. Fruit and vegetables are rich in antioxidants. A well-balanced diet – five portions of fruit and vegetables a day – is definitely beneficial to overall health. Epidemiological studies show a relationship between a well-balanced diet, high plasma antioxidant levels, and a low risk of disease. Ergo, antioxidants are beneficial. But fruit and vegetables are rich in many dietary constituents, and antioxidant status might just be a surrogate for other factors. For example, an epidemiological study in The Lancet by KT Khaw et al (2001) showed that high plasma ascorbate levels correlate inversely with risk of myocardial infarction and death. The study was interpreted to mean that ascorbate lowered the risk of cardiovascular events, but people who took ascorbate supplements gained no such benefit: there was no association between ascorbate supplementation and the risk of cardiovascular disease. Ascorbate levels may have been a surrogate for a well-balanced diet. But this post-hoc analysis of a retrospectively designated subgroup was not powered to prove anything. This problem typifies the field.

Even when antioxidants have a positive effect, it's hard to say why. Perhaps they correct for a dietary deficiency and don't benefit people with a balanced diet. Zinc deficiency is common and most people eat an average of three, not five, portions of fruit and vegetables a day. Perhaps they are not even acting as antioxidants at all – both zinc and ascorbate have many other roles in the body. Then there are factors relating to people who take antioxidant supplements. They are generally more health conscious, eat a well-balanced diet, exercise regularly, and protect themselves from over-exposure to the sun – all of which confound attempts to quantify the benefit of antioxidants. To determine whether vitamin supplements are worthwhile requires properly controlled, large-scale, prospective interventional studies. Remarkably few such studies have been reported for the eye. Only seven trials, randomising a total of 4,119 people with signs of AMD, were eligible for the 2002 Cochrane Review of antioxidant vitamin and mineral supplements in AMD. Of this modest population, 88% were randomised in a single trial – the Age Related Eye Disease Study (AREDS), which examined the effect of vitamin supplements on the risk of both AMD and cataract formation.

The Age-Related Eye Disease Study

AREDS was an 11-centre double blind, prospective clinical trial run by the US National Eye Institute, and sponsored by Bausch and Lomb, a manufacturer of vitamin supplements. It was organised more than a decade ago and published in 2001, which just goes to show how long it takes to produce valid information in this field. The AREDS investigators enrolled 4,757 subjects, and followed them for an average of 6.3 years. Subjects were randomised to a high-dose formulation of antioxidants (500 mg vitamin C, 400 IU vitamin E, and 15 mg beta-carotene) or to zinc (80 mg of zinc as zinc oxide, with 2 mg of copper as cupric oxide to prevent anaemia), zinc plus the antioxidant formulation, or placebo. In the cataract arm, the primary endpoints were progression of age-related lens opacities, and visual acuity loss. In the AMD arm, the primary endpoints were development of advanced AMD (defined as choroidal neovascularisation, exudative maculopathy or geographical atrophy involving the centre of the macula), and visual acuity loss.

In the cataract arm, the use of supplements had ‘no apparent effect on the seven-year risk of development or progression of age-related lens opacities or visual acuity loss.' Don't believe anyone who tells you otherwise until a highly powered and well-designed trial proves it: it's wishful thinking or commercial manipulation. The AMD arm was more encouraging. Subjects were stratified at randomisation into four categories of severity: category 1 had few if any drusen; category 2 had small or intermediate drusen, or pigment abnormalities; category 3 had intermediate or large drusen, or geographical atrophy; and category 4 had second eye involvement and some visual acuity loss (<20/32).

In category 1, only five of 1,117 participants developed advanced AMD over five years (0.45%), so they were excluded from the analysis, leaving a total of 3,640 subjects. In category 2, 15 of 1,063 subjects (three in the placebo group) progressed to advanced AMD (1.4%) making statistical analysis impossible. Basically the risk of advanced AMD is so low in people with early drusen that it is impossible to show a benefit of antioxidant supplements except in a very much larger and longer trial. Until this is carried out, there is no evidence that antioxidants can prevent the onset of AMD.

In categories 3 and 4 (a pooled total of 2,577 subjects), the estimated five-year probability of progression to advanced AMD was 28% for placebo, 23% for antioxidants, 22% for zinc and 20% for antioxidants plus zinc. Only the combination of zinc plus antioxidants was statistically significant (p = 0.001) – a relative risk reduction of 25% (OR = 0.66, 99% CI = 0.47-0.91). The lower risk of progression was corroborated by a lower risk of losing visual acuity (again, only significant for antioxidants plus zinc, p = 0.008). Over five years, the estimated probability of losing at least 15 letters of visual acuity was 29% for placebo, 26% for antioxidants, 25% for zinc, and 23% for antioxidants plus zinc – a relative risk reduction of 21% (OR = 0.79; 99% CI = 0.60-1.04). In an accompanying editorial, Lee M. Jampol MD, concluded that the results ‘demonstrate impressive efficacy of the interventions for intermediate and advanced AMD. This contrasts with the disappointing results to date of similar supplementation for the prevention of cancer, stroke, and cardiovascular disease.'

Who Benefits from Antioxidant Supplements?

The number of people with early AMD who need to be treated with antioxidants plus zinc to prevent loss of 15 or more letters of visual acuity in one patient (i.e. number needed to treat, NNT) at two years is 40; the five-year NNT is 16; and the seven-year NNT is 14. Clearly it's worth taking the pills – and persisting in taking them.These figures relate to the prevention of advanced AMD in people who already have dry AMD. There is no proven benefit of taking antioxidant plus zinc for people with small drusen or who have not been diagnosed with AMD. Nor is there proof of a reduced risk of vision loss in people who have advanced AMD, such as those with subfoveal CNV, who would qualify for PDT with verteporfin. In this case, the two-year NNT to prevent loss of 15 or more letters visual acuity in one patient with predominantly classic CNV is 3.6. Clearly PDT should be considered in these cases: refer to a retinal specialist. Even though AREDS was a rigorous trial, it was probably not representative of a ‘normal' population. For example, 67% of the trial population continued to take multivitamin supplements along with their study medication, implying this was a very health-conscious study population. Mortality in AREDS was about half that of the general population, but this was not related to antioxidant usage – mortality was actually slightly higher in the antioxidants-alone arm.

If antioxidants plus zinc supplements delay the onset of advanced AMD in people already diagnosed with AMD, it may be worthwhile for people with just a few drusen (categories 1 and 2 of AREDS) to take prophylactic antioxidant supplements. This is a matter of risk and benefit. Despite the claims that antioxidants and zinc are safe, there are some concerns. Epidemiological studies suggest that beta-carotene carries a higher risk of mortality in people who smoke. Supplementing with beta-carotene may also disturb the retinal homeostasis of other carotenes, such as lutein and zeaxanthin. Substituting lutein for beta-carotene might solve these problems, but there are as yet no clinical data for lutein supplements from reliable prospective clinical trials.

Supplementing with antioxidants plus zinc is not without risk. Interestingly (given the claims that antioxidants strengthen immune function) people receiving antioxidants alone were at twice the risk of hospitalisation for infections (1.6% vs. 0.8%; p = 0.04). Genitourinary hospitalisations (such as prostatic hyperplasia) were more frequent in participants randomised to the zinc arm (7.5% vs 4.9%, p = 0.001). This means that people at the age of 55 who do not have AMD have a 0.4-1.4% risk of developing advanced AMD over six years, regardless of whether or not they take antioxidants plus zinc, but they have a 2.6% excess risk of hospitalisation for genitourinary problems if they take them.

So, when patients come in asking about the potential value to eye health of adding antioxidant supplements, the judicious response would be to say that, other than in the particular subgroup observed to benefit in the AREDS study, the jury is still out. This may be received as less than a satisfactory response, but it is an honest one.

Nick Lane studied biochemistry at the University of London and did his doctoral research on oxygen free radicals at the Royal Free Hospital in London . He is the author of the recently published popular science book "Oxygen: the Molecule that Made the World (Oxford Press).