Treatment for age-related macular degeneration (AMD) is a topic that seems to attract controversy. On issues such as NHS costs and drug efficacy, arguments surrounding AMD treatment now extend well outside the medical profession and into the public arena.
The role of diet and dietary supplements in AMD is not short on controversy either and again this debate is increasingly being played out in public. When the best nutrients for eye health are published on the pages of The Daily Mail it may be time for all eye care practitioners to join that debate.
For practitioners, controversy around AMD and nutrition arises not from the popular press but from the results of two large-scale, multi-site intervention studies – the Age-Related Eye Disease Study (AREDS) and AREDS2 – funded by the US National Eye Institute and launched more than 20 years ago.
Published in 2001, the original AREDS report looked at the effects of vitamins C and E, Vitamin A (beta-carotene), and zinc supplementation on progression of AMD in those with intermediate or late AMD. High levels of antioxidants and zinc were found to significantly reduce the risk of advanced AMD and associated vision loss in those already in the later stages of the disease.
The authors concluded that those older than 55 years with AMD and at risk of progression, and without contraindications such as smoking, should consider taking a supplement of antioxidants plus zinc such as that used in this study.
The much-anticipated AREDS2 report, published in 2013, investigated whether adding lutein + zeaxanthin (the main components of macular pigment), the omega-3 fatty acids DHA + EPA, or both, to the original AREDS formulation decreased the risk of progression to advanced AMD, as observational studies had suggested. AREDS2 also evaluated the effect of eliminating beta-carotene, lowering zinc dose or both.
The surprising finding was that the addition of these ingredients did not further reduce risk of progression to advanced AMD. However, because of a potential increased incidence of lung cancer in former smokers, lutein + zeaxanthin could successfully replace beta-carotene without the associated toxicity.
Given the findings of these large-scale randomised controlled clinical trials, could that be the end of the story? And what are the clinical implications for eye care practitioners and their patients, not just for AMD progression but also for prevention?
Divided opinion
Experts were divided on their interpretation of AREDS2. Some argued that while this complex study did not provide support for the use of supplements for the primary prevention of AMD, it reinforced the evidence for a specific combination of antioxidant vitamins and minerals, based on the original AREDS formula but with reduced zinc and no beta-carotene, for those AMD patients at greatest risk of progressing.
Some expressed surprise that, in view of other research, omega-3 appeared to make little difference to the risk of progression to advanced AMD.
There was also criticism of AREDS2 for weaknesses in the protocol, including that the population sample constituted ‘the worried well’. The authors themselves acknowledged that ‘the study results may not be generalisable, because the study population is a highly selected group of highly educated and well-nourished people.’
On one issue raised by the AREDS research there was more agreement: the merits of a healthy diet and lifestyle to eye health as well as general wellbeing. But given the quantities of foods that would need to be consumed to achieve the recommended intakes of lutein and zeaxanthin, dietary measures were recognised as less practical than taking a supplement.
Perhaps not surprising, then, that a dozen or more such supplements with differing formulations are now available in the UK, from a variety of suppliers and supply routes. The number of products on the market continues to grow and many of them are labelled and promoted as ‘AREDS2 formula’.
Yet since AREDS2 was released, many more studies have been published into the role of diet and dietary supplements, not just in AMD prevention and treatment but for other ocular conditions such as dry eye. Evidence is emerging that the story may be more complex still.
Is it time to move beyond AREDS and adapt our recommendation habits based on recent research? Or, as some have suggested, should supplement formulations and dietary advice be based only on these two studies? And what can we learn from population-based studies into the prevalence of AMD with, for instance, the Mediterranean diet?
These were the key questions posed at a recent meeting hosted by French pharmaceutical company Laboratoires Théa. Théa markets a nutritional supplement for AMD, Nutrof Total, which contains the AREDS2 ingredients – although, other than for lutein and zeaxanthin, in lower doses than the AREDS2 formula. Nutrof Total also contains selenium, omega-3 (EPA 40 per cent and DHA 20 per cent) and resveratrol.
Pioneering research
Théa invited more than 80 ophthalmologists from 20 countries, including many of the world’s leading authorities, to discuss the latest research into AMD and diet at its Eye Nutrition Meeting in Barcelona in April. This was the inaugural meeting under the auspices of the organisation CEEME, the Committee of European Experts in Micronutrition of the Eye.
Among the line-up of international speakers was the pioneer of nutritional, environmental and genetic risk factors for AMD, Professor Johanna Seddon of Tufts University School of Medicine in Boston, US.
Professor Seddon described her research spanning more than 20 years, from the first systematic study of diet and AMD to her latest book, Feast for the Eyes, subtitled Eat Right for Your Sight: Simple, Tasty Recipes That Help Reduce the Risk of Vision Loss from Macular Degeneration.
She also presented an update of observational studies into dietary omega-3 fatty acids, all of which she said pointed in the direction of reduced risk of AMD. Among her own recent findings was that increased dietary intake of omega-3 is associated with reduced risk of progression to geographic atrophy and may modify genetic susceptibility.
Other notable findings among the many studies reported at the meeting were that adequate dietary consumption of omega-3 might also be necessary for optimal cognitive performance. And early results suggested that resveratrol – found in some red wines and said to be implicated in the ‘French paradox’ of low mortality from cardiovascular disease – may also have a role in protection against AMD.
The two UK-based speakers Professor Tariq Aslam, consultant ophthalmologist at Royal Manchester Eye Hospital, and dietician Richard Sivioli presented a new app, Eye Nutrition Manager, designed to report weekly intake of nutrients relevant to AMD and identify dietary deficiencies.
After the meeting, UK delegates met to discuss how the new findings reported could be disseminated.
Professor Christine Purslow, head of medical affairs for the UK and Ireland at Théa Pharmaceuticals said that, in continental Europe, ophthalmologists were the biggest advocates of nutritional supplements, as part of the management of patients with AMD, and for dry eye, especially when no surgical or therapeutic intervention was appropriate.
According to Professor Purslow, AREDS was not respected in the rest of Europe. ‘The high doses used and the study weaknesses have meant it has been dismissed by our European counterparts. In fact in countries such as France, the AREDS formulations are not allowed to be sold. The ophthalmologist recommends the supplement to patients; they might then get it regularly via the pharmacy but normally directly from their eye doctor.’
Debate continues
So what was the key message to take away from the Eye Nutrition Meeting? For Professor Purslow, it was the strength of evidence from observational studies that omega-3 was beneficial: ‘In the UK it’s rather drowned out by the AREDS2 story.’
But a recent Cochrane review is likely to stimulate more debate. The review identified 180 references to omega-3 for preventing or slowing the progression of AMD, published between April 2012 and February 2015. Only two – both randomised controlled clinical trials – were included in the meta-analysis: AREDS2 and the NAT2 (Nutritional AMD Treatment 2) Study, conducted in France.
The review found that omega-3 supplementation for up to five years did not reduce the risk of progression to advanced AMD. While acknowledging the results of observational studies, the authors said current evidence did not support increasing dietary intake of omega-3 for the explicit purpose of preventing or slowing AMD progression. The population-based Rotterdam Study, however, found that high dietary intake of nutrients with antioxidant properties reduced the risk of early AMD in those at high genetic risk.
Aside from the role in AMD, a recent meta-analysis of seven studies suggested that omega-3 is an effective therapy for dry eye. Professor Purslow was also interested in the effects of omega-3 on cognitive development: ‘Since we know vision is achieved via the interpretation of impulses to the brain, supporting brain health – if this finding is confirmed – would seem just as vital.’
As a result of the meeting, Professor Purslow said she would be reviewing her recommendation habits for nutritional supplements: ‘I’ll be thinking much more now about dry AMD and what we can do there – I now have more faith in the scientific strength of a recommendation for this purpose.
‘It seems logical that evidence will continue to emerge and we should act now to support patients as much as possible. Much of the research focuses on AMD progression but we really need to give advice to patients before they develop the disease,’ she added.
A pint of protection
Bristol ophthalmologist Mike Potts identified barriers to recommending supplements among his colleagues. ‘For the medical profession, it’s AREDS2. Ophthalmologists know that the original AREDS was a good study and they were all waiting for AREDS2. But a lot of people think AREDS2 was flawed, it wasn’t well designed and we have to move on from it.
‘We need to emphasise that omega-3 is important as well. In AREDS2, findings for omega-3 weren’t negative, they just weren’t significant.’
On whether supplements had a preventative role in the progression from dry to wet form, Potts said the adage ‘a pint of prevention is worth a gallon of cure’ applied. ‘Most ophthalmologists do believe that if AREDS2 gives a 25 per cent reduction in risk of progression to advanced AMD in those who already have the disease, it also does something when you can’t see it.’
GPs generally showed little interest in nutrition and the eye but optometrists had an important role to play. ‘We have to target prevention at optometrists,’ he argued, adding that ocular photography and OCT provided them with the tools for monitoring macular changes. Measuring macular pigment density was another option.
Introducing a simple question on diet to optometrists’ routine or using a risk calculator to include family history of AMD, lifestyle and other exposures, were among the suggestions put forward. And there was support for providing more education – for practitioners and patients – on diet and its effects on eye health.
Théa will host a one-day Eye Health Conference at the Royal College of Physicians in London on September 28, 2015