The Sight-Saving Evidence of Nutritional Science
AREDS2 promises further validation of the role of diet in eye disease.
BY SEAN McKINNEY
More than 10 years have passed since the Age-Related Eye Disease Study (AREDS) proved that nutritional supplements could minimize the risk of AMD. As ophthalmologists await the results of the next landmark study, AREDS2, many are rethinking chair-side approaches to preventive eye care. More research points to common risk factors for age-related disease as the population ages, even while controversy persists over what to do about the growing body of information.
“The three most expensive treatments covered by Medicare are injections for macular degeneration, cataract surgeries and Nd:YAG posterior capsulotomies,” says Robert Abel Jr., MD, author of The Eye Care Revolution: Prevent and Reverse Common Vision Problems. “Many of these procedures can be prevented.”
This article explores the latest evidence on the role of ocular nutrition in reducing the risk of AMD.
Extent of the Risk
The American Health Assistance Foundation, dedicated to eradicating age-related degenerative diseases, estimates that up to 11 million people in the United States have some form of AMD — a number expected to double by 2050. Estimates of the global cost of visual impairment AMD causes is $343 billion, including $255 billion in direct health care costs, according to the foundation.
AREDS, a prospective, randomized, multicenter, double-masked, placebo-controlled clinical trial, has produced the best evidence that nutritional supplements can help control the runaway incidence of this disease.1 The study evaluated the use of high-dose antioxidants and zinc as possible treatments. AREDS involved 3,640 subjects, ages 55 to 80, at 11 centers between 1992 and 2001. Follow-up of subjects continued until December 2005. Subjects were categorized according to these following risk examination findings:
► No macular changes (category 1).
► Small and few intermediate drusen (category 2).
► Extensive intermediate drusen, large drusen or noncentral geographic atrophy (category 3).
► Advanced AMD in one eye; either geographic atrophy in the center or neovascular AMD (category 4).
The subjects were randomized to receive:
► Antioxidants, including vitamin C, 500 mg/d; vitamin E, 400 IU/d; and betacarotene, 15 mg/d (N=945).
► Zinc, 80 mg/d; cupric oxide (copper), 2 mg/d (N=904).
► Zinc, 80 mg/d; cupric oxide (copper), 2 mg; and antioxidants, including vitamin C, 500 mg/d; vitamin E, 400 IU; and betacarotene, 15 mg/d (N=888).
► Placebo (N=903).
Validating Supplementation
AREDS reported that a combination of high-dose antioxidant vitamins and zinc demonstrated a 25% reduction of risk for development of advanced AMD over a median of 6.3 years of follow-up in high-risk subjects (categories 3 or 4). After the study terminated in 2001, follow-up until December 2005 showed the beneficial effects of the AREDS supplements persisted at a similar level of protection.
AREDS2 is a five-year, controlled clinical trial involving 4,203 subjects at 82 centers. The primary objective of this trial is to determine if oral supplementation with macular xanthophylls and omega-3 long-chain polyunsaturated fatty acids decrease the risk of progression to advanced AMD when compared to placebo, according to Emily Y. Chew, MD, AREDS2 study chair at the National Eye Institute (NEI). The xanthophylls include lutein (10 mg/d) and zeaxanthin (2 mg/d). The omega-3 fatty acids include docosa-hexaenoic acid (DHA 350 mg/d) and eicosapentaenoic acid (EPA, 650 mg/d).
AREDS2 is also studying the effects of these nutritional supplements on moderate vision loss and on the development of cataracts. Dr. Chew says the results of AREDS2 will likely be ready for publication in the spring of 2013, after the final study visits conclude in December.
Evidence of Debate
Most ophthalmologists acknowledge that AREDS2 results should significantly change preventive eye care. But divergent streams of additional evidence fuel debates.
“Look at what causes deterioration of the eye: sunlight, poor diet, lifestyle choices (lack of exercise, excessive drinking and smoking) and stress in general,” Dr. Abel says. “There are plenty of data that can already be used to provide patients with reliable recommendations. Despite these factors, however, very little is being done in this area. We need to look beyond the eyes and start taking care of the whole body, considering every medication and every condition that may be affecting a patient.”
But some physicians believe they need more evidence before they implement changes in practice. “What can you tell patients? Probably not a lot at this point, at least not until the results of the AREDS2 study are available,” says David Boyer, MD, who practices ophthalmology with the Retina-Vitreous Associates Medical Group in Los Angeles and is clinical professor at the Keck School of Medicine of the University of Southern California in Los Angeles.
“You can offer common-sense advice, such as telling them to stop smoking, eat healthy, exercise, and lose weight, but there has not been a lot of new information since AREDS was published, except for what we have seen in population-based diet studies,” Dr. Boyer says. “If patients have a family history of AMD or have category 3 or 4 AMD, I tell them to eat fish and food that is rich in lutein and zeaxanthin.” Examples include spinach, kale, turnip greens, collard greens, corn, lettuce, mustard greens, squash, green peas, broccoli, pumpkin and tangerines. Until category 1 and 2 patients have been studied in randomized controlled trials, he says, “There is not much else I can tell them.”
Good Nutrition Matters
Besides AREDS, several studies have underscored the value of good nutrition in minimizing the risk of AMD.
Dr. Boyer acknowledges that studies have suggested lutein and zeaxanthin play a protective role through light screening and antioxidant activity in the retina.2 Naturally occurring concentrations of these xanthophylls are found in the macula at concentrations 100 to 1,000 times greater than elsewhere in the body.3 As patients age, however, their levels of lutein, zeaxanthin and macular pigment decline, potentially increasing the risk of developing AMD.4,5
Seenu M. Hariprasad, MD, associate professor of ophthalmology and visual science at The University of Chicago Medical Center, believes consumption of lutein and zeaxan-thin in the early stages of AMD could help patients because of the proven effects of these xanthophylls on macular pigment optical density.6
“These carotenoids are believed to help maintain the morphologic and functional integrity of the retina,” says Dr. Hariprasad. “They may help the macula filter blue light and suppress reactive oxygen species, possibly protecting against the light-induced oxidative damage that has been implicated in the pathogenesis of AMD.”7
Isolated Omega-3 Components
Additional studies provide further insight on the role of diet in AMD. Researchers evaluated 38,022 participants in the Women’s Health Study, including 235 who had been diagnosed with AMD.8 After adjusting for age and treatment assignment, the prospective study found that women who had consumed the most dietary DHA, a key component of omega-3 fatty acids, had a 38% lower risk of developing AMD, compared to women who consumed the lowest amount. Similar results were associated with higher intake of EPA, another important component of omega-3 fatty acids, and with higher consumption of EHA and EPA together. Consumption of one or more servings of fish a week was associated with a 42% lower risk of AMD compared to consumption of less than one serving per month.
The study’s results are compelling, Dr. Boyer notes. “It gives us further evidence of the importance of diet in modifying the risk of AMD,” he says.
Researchers at the University of Melbourne in Australia used a questionnaire to evaluate associations between past dietary fat intake and the prevalence of AMD among 6,734 participants between 1990 and 1994.9 After following up on the participants between 2003 and 2006, the researchers concluded that a diet low in transunsaturated fat and rich in omega-3 fatty acids and olive oil could reduce the risk of AMD.
Understanding the Glycemic Index
In August, researchers at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, released a summary of updated research to describe how nutrients can diminish the risk of onset or progression of AMD.10 “Preventive interventions through dietary modulation are attractive strategies because many studies suggest a benefit of micro- and macronutrients with respect to AMD, as well as other age-related debilities, and with few, if any, adverse effects,” the researchers wrote. They called for intervention trials “to better understand the full effect of these nutrients and/or combinations of nutrients on retinal health.”
In a separate Tufts study, mice ages 5 and 16 months were fed high- or low-glycemic index (GI) diets until they were 17 and 23.5 months old, respectively.11 The high-GI diets accelerated the appearance of pre-AMD retinal lesions in the mice, possibly by increasing the deposition of advanced glycation end products in the retina. “The data support the hypothesis that consuming lower GI diets, or simulation of their effects with nutraceuticals or drugs, may protect against AMD,” the researchers wrote.
| How Xanthophylls Protect the Retina |
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Researchers have looked at whether lutein and zeaxanthin protect against photooxidative damage to retinal pigment epithelial cells (RPE) and oxidation-induced changes in expression of inflammation-related genes.17 To mimic lipofuscin-mediated photooxidation in vivo, they used ARPE-19 cells that accumulated A2E, a lipofuscin fluorophore and photosensitizer, as a model system to investigate the effects of lutein and zeaxanthin supplementation. The concentrations of lutein and zeaxanthin in the RPE cells were two to 14 times the amounts detected in the medium, indicating that ARPE-19 cells actively took up the xanthophylls. When compared to untreated cells, RPE cells containing A2E responded to blue light with a 40% to 60% decrease in proteasome activity, affecting inflammation-related genes. Specifically, expression of complement factor H and membrane cofactor protein-1 decreased 50% to 80%. There was also a 20- fold increase in expression of interleukin-8. The study concluded that lutein and zeaxanthin appeared to modulate the inflammatory response by protecting proteasome from oxidative inactivation. Similar mechanisms could explain how lutein and zeaxanthin might help reduce the risk for AMD. |
Two additional studies came out of Tufts that found the glycemic index to possibly be an influential factor.
One group developed a composite scoring system to summarize the combined effect of multiple dietary nutrients on AMD risk, focusing on 4,003 participants from the AREDS population.12 They evaluated the dietary intake of vitamins C and E, zinc, lutein/zeaxanthin, DHA and EPA, and low-GI diets from baseline AREDS data. Low-GI diets and higher intake of these nutrients were associated with the greatest reduction in risk for prevalent drusen and advanced AMD.
In the second study, based on 2,924 eligible AREDS participants, researchers found an association between a diet rich in DHA with a lower progression of early AMD.13 Besides the AREDS supplement, a lower GI diet and higher DHA and EPA intake were associated with a reduced progression to advanced AMD.
Standing by the Best Evidence
Despite this increasing data, researchers at the National Institutes of Health caution that the role of nutrition – especially macular xanthophylls and omega-3 fatty acids – is still not definitive.14 NIH officials emphasize the continued use of the AREDS formulation, despite the commercial availability of AREDS2 formulations. “Observational studies have also suggested benefit from increased dietary intake of macular xanthophylls and omega-3 fatty acids,” the researchers acknowledge. They noted AREDS 2 is currently evaluating these nutrients.
Dr. Hariprasad agrees with this approach — for now. “Numerous observational studies, some completed by AREDS researchers, point to high levels of lutein and zeaxanthin decreasing the risk of AMD,”15 he says. “We have also seen evidence that omega-3 fatty acids reduce the risk of AMD.16 However, we must await the conclusions of AREDS2 before considering a change in the AREDS formulation.” OM
| Sean McKinney is a medical writer based in Philadelphia. |
References
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