Thanks in large part to the Age-Related Eye Disease study—a major 11-center, double-masked clinical trial sponsored by the National Eye Institute that followed 3,640 participants for a period of about six years—we now know that nutrition can play an important role in preventing progression of age-related macular degeneration in many patients. Data from the AREDS trial, which has been evaluated in a series of 21 published reports, demonstrated that high levels of antioxidants and zinc significantly reduce the risk of advanced AMD and its associated vision loss in certain patients. That group includes those with extensive intermediate-size drusen, at least one large druse, noncentral geographic atrophy in one or both eyes, or advanced AMD—or vision loss due to AMD—in one eye. (The report that focused most directly on this aspect of the trial was report number 8.1)

The supplement formulation tested in AREDS, and a large number of variations on that formula, are now available in products sold in stores and over the Internet. Broad access to this treatment is no small matter; another of the AREDS reports (number 112) noted that if all of the people in the United States who are candidates for this supplementation were to receive it, more than 300,000 individuals could have avoided advanced AMD and its associated vision loss during the five years after the report was published. Aside from the savings in terms of human suffering, a change of this magnitude would have a huge positive impact on our health system.

The fact remains, however, that there are a host of obstacles preventing many patients from taking advantage of this simple, effective preventive option. These obstacles include poor communication with doctors, misinformation in the marketplace and compliance problems (often age-related). To find out more about the current situation and what ophthalmologists can do to improve matters, we spoke to several doctors who participated in AREDS.

Patients and Misinformation

Susan Bressler, MD, the Julia G. Levy, PhD Professor of Ophthalmology at the Johns Hopkins University School of Medicine, described a study she participated in that was presented at ARVO in 2005 (Charkoudian LD, et al. IOVS  2005; 46: ARVO E-Abstract 1569). In the study, adult patients with a diagnosis of AMD who were examined at the Retinal Division of the Wilmer Eye Institute in July and August 2004 were surveyed about their use of supplements. The survey found that nearly half of the patients who were candidates for AREDS-type supplements were not using them, or were using an incorrect dose. At the same time, about 20 percent of study participants were taking high-dose supplements without any data to support their doing so. (However, they also found that patients who had previously been seen at the clinic were three times more likely to use supplements in accordance with AREDS guidelines than new patients.)

Other research has confirmed the miscommunication problem. A study of 100 patients with advanced AMD conducted at the University of Adelaide in Australia found that only 53 percent of them were aware that the AREDS formula was available. Thirty-eight percent were taking the supplement; however, only a single patient was taking the correct dosage.3 A study in Germany investigated the advice being given to AMD patients by pharmacists; out of 60 pharmacies, 36 recommended specific products for dietary supplementation, but the dosage never complied with the AREDS formulation, and in 24 pharmacies the need for a consultation with an ophthalmologist was never mentioned.4

“Our study confirmed that there’s a lot of misinformation out there,” comments Dr. Bressler. “People who would not benefit from the use of supplements were using them—sometimes because of something they read in the lay press, sometimes because a well-intentioned family member or neighbor recommended it to them. This means spending up to $250 a year needlessly. Some people not only didn’t stand to gain any benefit from taking them but had something to lose, such as being a smoker and using a formulation with high doses of beta carotene, which can increase the risk of lung cancer and mortality. We also found people who should have been on an AREDS-type supplement but were not. Sometimes this was because the supplement hadn’t been recommended to them, but more often the patient didn’t fully understand the recommendation, let alone the specific formula or the correct dosage.”

“Physicians still need to be educated,” says Emily Y. Chew, MD, deputy director, Division of Epidemiology and Clinical Research at the National Eye Institute. “I see patients whose doctor hasn’t recommended or even spoken to them about vitamins. It doesn’t mean the ophthalmologist doesn’t know about AREDS, but we need to get physicians to understand that nutrition is important—especially for those patients who are at risk.”

Too Many Options

Dr. Bressler observes that part of the problem comes from the plethora of formulations that are available. “Many companies produce three to seven products with the same name,” she points out. “For example, Bausch & Lomb now offers more than a half-dozen different eye-related vitamins [six versions of Ocuvite and three versions of PreserVision]. I understand the differences between them, but your average geriatric patient thinks they’re all the same. You can tell your patient to look for the PreserVision formula in the blue and white box, but that still leaves you with three choices! And they may still opt for the version with lutein simply because ‘it has something extra, so it must be better.’ Adding to the confusion, the supplements come in different forms which may require different dosing. And these are not the only pills these people are taking.”

Dr. Bressler notes that even when doctors make a specific recommendation, the patient may not “get it.” “Sometimes it’s just too much information for the patient to absorb and retain,” she says. To compensate for this, her practice gives patients a piece of paper with the name of the recommended product. “We tell them, ‘Take the paper with you when you go shopping, and don’t let anyone talk you into purchasing something other than what’s written here,’ ” she says. “That helps, but it’s still not a perfect system.”

“I think patients are much more aware of the importance of nutrition than they were five or 10 years ago,” says Michael Klein, MD, a retinal specialist and professor of ophthalmology at the Casey Eye Institute of Oregon Health and Science University in Portland. “However, the large number of nutritional supplements available can be quite confusing to the patient who is at high risk for advanced AMD who has been advised to take AREDS supplements.”

Dr. Klein says he minimizes the confusion by recommending a specific product—usually Bausch & Lomb’s PreserVision. “This is the preparation that was used in the original AREDS study, and it can be administered in two capsules daily,” he explains. “We’ve made up handout sheets with the picture of the box on them and the correct dosage, which we give to our patients.”

Dr. Klein notes that getting patients to take the correct dosage is also an issue. “Taking the wrong dosage is probably more common than we realize,” he says. “Some people will take more, thinking that more is better; others will simply decide what amount they think is best. Many of them will just forget to take it. Compliance with medications isn’t nearly what we’d like it to be.”

As for the issue of patients who may not need the supplements taking them, Dr. Klein notes that there’s no information about whether they’ll benefit from them. “It’s conceivable that they might benefit in the long run,” he says, “but we have insufficient evidence to warrant their general use in this population. Supplements can be expensive, and people in this population may already be taking several medications. Adding more when it’s not really necessary wouldn’t be advisable.”

The Beta Carotene Factor

Because the original AREDS formula contained beta carotene, which is associated with a higher risk of lung cancer when taken by smokers, doctors who want to recommend the supplement have to find an alternative for patients who smoke. We asked the experts about several possible alternatives.

• Substituting lutein for beta carotene. Some of the doctors we spoke to are comfortable opting for available supplements that substitute lutein for beta carotene; others feel that this is too risky without clinical evidence that such a substitution is safe and effective.

Dr. Klein currently favors recommending the version of PreserVision that has lutein in place of beta carotene. “This altered formula was originally designed for smokers, who shouldn’t be taking beta carotene,” he notes. “We should remember, however, that we have suggestive, but not conclusive, evidence that lutein is helpful, and it is currently being evaluated in a large clinical trial.” (The AREDS 2 trial, now enrolling participants, will examine the effect of high doses of lutein and zeaxanthin, as well as omega-3 fatty acids, on AMD and cataract.)

Dr. Bressler isn’t willing to make that substitution. “Products often contain additional supplements without any concrete evidence that they’re beneficial,” she notes. “Those added ingredients may compete with the favorable things retained in the formulation. Some products take out the beta carotene and substitute lutein, but for all we know, lutein is as bad as beta carotene for a person who smokes. We have no evidence one way or the other.”

• Take the individual ingredients, minus the beta carotene. Dr. Bressler says this is easier said than done. “It’s hard to find these precise ingredients in the amounts recommended and put it together yourself,” she says. “And, you have to get your hands on the right type of copper to avoid copper deficiency anemia, which can be induced by the zinc.”

• Just take part of the formula. “The AREDS group that took only antioxidants did not show a statistically significant difference from the placebo group in terms of AMD progression or vision loss,” notes Dr. Bressler. “The group that took only zinc did show statistically reduced AMD progression, but not reduced vision loss. I’d consider recommending that option for a patient who is a smoker. However, the combination of zinc and antioxidants produced a decrease in both disease progression and vision loss. That’s why this is the primary recommendation made to patients who are good candidates to benefit.”

Dr. Bressler says that an ideal option for smokers would be a pill that had everything in the AREDS formula except beta carotene, with nothing else added. “Unfortunately,” she adds, “I haven’t found a supplement fitting that description.”

• Skip the supplements and eat a better diet. “Many experts favor a healthy diet rather than supplements,” notes Dr. Klein. “While this seems reasonable, achieving the goal of good nutrition with adequate numbers of helpings of the right foods isn’t always easy to do. Considering the results of AREDS, it makes sense that we recommend both a proper diet and AREDS supplements to best prevent advanced AMD in those at high risk for developing it.”

What About Lifestyle Changes?

Numerous studies have found a positive or negative association between AMD progression and lifestyle factors such as smoking, being overweight or eating certain food groups. (One prospective study found that a diet high in fruit—especially oranges and bananas—was inversely associated with neovascular AMD.5) Given that data, one could argue that it makes sense to recommend changes in lifestyle as a way to prevent AMD progression. However, it’s important to recognize that an association is not a cause-and-effect connection.

“Studies, including epidemiologic studies done outside of AREDS and observational studies done within AREDS, can help assess risk factors for progression of disease,” notes Dr. Bressler. “You can take that information and develop an intervention and test it. But just finding an association doesn’t mean you’ve found a treatment.

“For example,” she continues, “people who say they eat three to seven portions of fish every day seem to have less macular degeneration than age- and gender-matched people who say they wouldn’t eat fish if you paid them. However, that doesn’t mean that eating fish protected the first group. It might mean that, but it could mean a lot of other things. All those fish eaters might take really good care of themselves in other ways and have a lower ‘factor x’ because they take such good care of themselves. That’s why you take risk-factor studies and say, ‘OK, maybe eating lots of fish lowers your risk.’ You translate that into a clinical trial like AREDS 2 and give half of the subjects a lot of fish oil supplement and the other half none, and see whether all this supplementing with fish makes a difference. That’s what AREDS 2 is doing—testing fish oil and lutein and zeaxanthin.

“My take-home message is that you can recommend altering lifestyle based on this kind of association,” she concludes, “but there’s no hard evidence that if you eat certain things, lower your weight and never smoke you’ll protect yourself from macular degeneration. There’s just evidence that suggests that these things may be related in some way.”

Dr. Chew agrees. “Observational studies we’ve conducted have found that people who ate fish more often had a decreased risk of AMD compared to people who don’t eat fish at all,” she says. “Similarly, people with the highest intake of lutein and zeaxanthin had the lowest risk of AMD. However, this type of study just looks at people as they are, which is not good for proving cause and effect.”

Nevertheless, Dr. Klein feels it’s important to recommend making lifestyle changes. “There are plenty of reasons beside macular degeneration to avoid things like smoking and obesity,” he notes. “It’s important to eat a proper diet rich in fruits and vegetables, reduce your weight, exercise and stop smoking for overall good health. So I do think we should tell our patients that lifestyle factors are important when we discuss nutrition and macular degeneration.”

Altering the Formula

Beyond the idea of substituting lutein for beta carotene, which several products do, many products offer other variations on the original AREDS formula, including increasing the amount of some ingredients on the premise that “more is better.” (A study conducted in the United Kingdom a few years ago reviewed the contents of 22 eye nutrient products; it found that although more than 75 percent contained all the ingredients used in the AREDS formula—including beta carotene—only two products matched the dosage profiles recommended in AREDS.6)

“In general, consuming more of a particular component is not necessarily better,” notes Dr. Klein. “In the case of AREDS supplements, there’s no evidence for giving increasing amounts of the recommended ingredients. On the contrary, it may be that in the case of zinc, one of the AREDS ingredients, less than the 80 mg used in AREDS would be desirable.” [Note: The AREDS 2 study includes a comparison of 25 and 80 mg of zinc.] “Vitamins C and E don’t need to be given in higher doses—the levels in the AREDS formula are considered very adequate. If a supplement lacks the major components in the AREDS formula, or if they’re given at significantly lower doses or in huge doses, I’d hesitate to recommend that product.”

Dr. Klein notes that some products add other ingredients that are touted as beneficial for macular degeneration. “We should just give what we know works,” he says. “Some supplements may combine the original formula with omega-3 or lutein or zeaxanthin, and I think those are reasonable. But with the exception of beta carotene, all of the ingredients in the AREDS formula should be included.”

Get the Word Out

According to Dr. Bressler, the AREDS 2 trial is still recruiting patients. “We’re seeking about 4,000 individuals at approximately 70 clinical centers across the country,” she says. “Once the full complement is recruited, the goal is to follow everyone for five years. So we’re at least five years away from having final results.”

In the meantime, she believes the system is not doing a good enough job of getting the word out about the benefits of the AREDS formula. “There’s a lot of room for improvement in terms of educating the population at risk,” she says. “Health-care providers need to identify the patients who would benefit from the supplement, counsel them accordingly, persistently remind them to use the supplement, and make sure they know how to do so correctly. The message needs to be put out there over and over again until we get it right.”

1. AREDS report no. 8. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss. Arch Ophthalmol. 2001;119:10:1417-36.

2. Bressler NM, et al. Potential public health impact of Age-Related Eye Disease Study results: AREDS report no. 11. Arch Ophthalmol 2003;121:11:1634-6.

3. Ng WT, Goggin M. Awareness of and compliance with recommended dietary supplement among age-related macular degeneration patients. Clin Experiment Ophthalmol. 2006;34:1:9-14.

4. Ziemssen F, Warga M, Bartz-Schmidt KU, Wilhelm H. "Do you have a remedy for macular degeneration?" A field study about the advice given on dietary supplementation in 60 German pharmacies. [Article in German] Ophthalmologe. 2005;102:7:715-25.

5. Cho E, Seddon JM, Rosner B, Willett WC, Hankinson SE. Prospective study of intake of fruits, vegetables, vitamins, and carotenoids and risk of age-related maculopathy. Arch Ophthalmol. 2004;122:6:883-92.

6. Arora S, Musadiq M, Mukherji S, Yang YC. Eye nutrient products for age-related macular degeneration: what do they contain? Eye. 2004;18:5:470-3.