AREDS2 explores nutritional management of AMD progression

The addition of omega-3 fatty acids, with or without lutein and zeaxanthin, had an insignificant impact on age-related macular degeneration progression beyond the preventive effect of the original AREDS formulation, according to the lead author of AREDS2. On the other hand, a combination of lutein/zeaxanthin had a positive impact on slowing AMD progression.

Results of the seminal 5-year study cast new light on the effects of nutritional supplements on the progression of AMD. Through rigorous randomization and subgroup analyses, the study built upon the design and study population of the original Age-Related Eye Disease Study (AREDS), which resulted in the recommendation of a vitamin and mineral supplementation formula for maintaining aging eye health.

Results of the second AREDS, known as AREDS2, were published in the Journal of the American 
Medical Association and reported at the Association for Research in Vision and Ophthalmology meeting in Seattle in May.

The study was designed specifically to determine whether adding the carotenoids lutein (10 mg) and zeaxanthin (2 mg), the omega-3 fatty acids docosahexaenoic acid (DHA) (350 mg) and eicosapentaenoic acid (EPA) (650 mg), or the combination of carotenoids and omega-3 fatty acids to the existing AREDS formulation would further reduce patients’ risk for development of advanced AMD. The effect of eliminating beta carotene, lowering zinc dose or both in the AREDS formulation was also evaluated.

“That the omega-3s had no significant impact was somewhat surprising for many people,” Emily Y. Chew, MD, said. “The basic science would suggest that they should be important.”

Chew was lead author of the National Eye Institute study. She said it is unlikely that another such large trial would be done again to investigate the role of omega-3s in this population; consequently, researchers may not find out the reason for the unimpressive result.

“Was there truly a lack of efficacy, or did we not get the right dose? Are we starting too late? Are the ratios of the different types of omega-3s, the DHA/EPA, incorrect?” Chew asked. “We may never know.”

Despite the lack of ophthalmic benefit found in this study, omega-3s should be part of a healthy diet, according to G. Baker Hubbard, MD, one of the study authors.

“It’s very important to be clear. The study does not say that you shouldn’t have omega-3 fatty acids in your diet,” Hubbard said. “We do think it’s important to have fish in your diet, but for whatever reason, these particular supplements in this particular population didn’t result in a reduced risk of advanced AMD.”

“We need to eat well,” Chew said. “I tell my patients that all of the time. Despite the fact that omega-3 did not work in our study, so many observational data are so compelling that fish is important. I still say, ‘Eat your diet replete with fish. Eat lots of greens and leafy vegetables.’ That’s the first line of advice for anybody.”

Overall, the results showed that supplementation is just one way to manage AMD progression, according to Glenn J. Jaffe, MD, OSN Retina/Vitreous Board Member.

“I would say that the rate of progression, which was about 30% or 31%, occurred despite people being on supplements,” Jaffe said. “So, we still have a ways to go to figure out how to prevent [AMD] progression. Supplements are not the only answer. We’re going to have to do other things to decrease that rate.”

Formulations and study design

The original AREDS formulation is 500 mg of vitamin C, 400 IU of vitamin E, 15 mg of beta carotene, 80 mg of zinc and 2 mg of copper.

AREDS2 involved the randomization of patients to receive the AREDS supplement with various combinations of DHA/EPA, lutein/zeaxanthin and a low dose of zinc.

AREDS2 researchers recommended adding lutein/zeaxanthin to and subtracting beta carotene from the AREDS formulation. Beta carotene has been associated with an increased risk for lung cancer in current and former smokers. The researchers did not recommend the addition of omega-3s because they had no effect on AMD progression.

The recommended AREDS2 supplement is 500 mg of vitamin C, 400 IU of vitamin E, 10 mg of lutein, 2 mg zeaxanthin, 80 mg zinc and 2 mg of copper.

AREDS2, conducted at 82 centers from 2006 to 2012, included 4,203 patients between the ages of 50 years and 85 years who were at risk for progression to advanced AMD with bilateral large drusen or large drusen in one eye and advanced AMD in the fellow eye. Mean patient age was 73.1 years.

In the primary randomization of those 4,203 patients, 1,012 patients received the original AREDS supplementation as placebo, 1,044 patients received the original AREDS supplementation with 10 mg of lutein and 2 mg of zeaxanthin, 1,068 patients received the original AREDS supplementation with 350 mg of DHA and 650 mg of EPA, and 1,079 patients received the original AREDS supplementation with lutein, zeaxanthin, DHA and EPA.

The study did not use a placebo in the conventional sense; the placebo group for the primary randomization comprised patients who took the AREDS formulation.

“I think that’s going to be confusing to some people,” Jaffe said. “One of the things that people should realize looking at the randomization and the groups is that this is not a study to validate what the original study showed, which really was a placebo-controlled study where you’re comparing the drug to a placebo. In this case, placebo really meant, for all intents and purposes, the original AREDS formula.”

AREDS2 investigators did not want to eliminate the original AREDS supplement, which was already shown to be effective, Jaffe said.

“Because of the original study, which showed that the original AREDS formulation was helpful, they didn’t want to eliminate that because that wouldn’t have been ethical. So, patients in the ‘placebo’ group really did get standard-of-care AREDS vitamins,” Jaffe said.

In a secondary randomization, 3,036 patients culled from the primary group were randomized to four more groups that received the original AREDS supplement; the original AREDS supplement with no beta carotene; the original AREDS supplement with low-dose zinc; or the original AREDS supplement with low-dose zinc and no beta carotene. Of the original patients in the primary randomization, 1,167 chose not to be included in the secondary randomization.

No smokers were assigned to the two secondary randomization groups receiving beta carotene.

Patients were directed to take AREDS supplements daily. Patients were followed annually; median follow-up was 5 years.

Considering the elaborate randomization scheme and various permutations of the AREDS supplement, the study design may have decreased the study power to detect a particular result, Jaffe said.

Results and recommendations

Study results showed that 1,940 eyes of 1,608 patients progressed to advanced AMD.

The probability of progressing to advanced AMD was 31% in the placebo group, 29% in the lutein/zeaxanthin group, 31% in the DHA/EPA group and 30% in the lutein/zeaxanthin with DHA/EPA group. The difference in probability and risk between the lutein/zeaxanthin and DHA/EPA groups and the other groups was statistically insignificant.

The elimination of beta carotene and the reduction of zinc had an insignificant effect on the risk of AMD progression.

The authors deemed lutein/zeaxanthin a suitable substitution for beta carotene for smokers and former smokers.

The risk of AMD progression was about 20% lower in patients who took AREDS with lutein/zeaxanthin than in those who took AREDS with beta carotene, Chew said.

“It’s incremental change. It’s not a huge change,” she said. “If you look at the general population of AREDS1, we had a 25% reduction in the risk of advanced disease. If you add this to lutein instead of beta carotene, how much would this be? It’s not 20% on top of the 25%. It’s not additive. It’s probably another 5% or more. It’s not a huge change, but it’s sufficient. I think it makes things simpler in one formulation. Regardless of smoking, you can take it or not take it.”

Supplement manufacturers will most likely change their AREDS formulation by eliminating beta carotene and adding lutein/zeaxanthin, Chew said. The formulation should not include omega-3s, she said.

“Obviously, you don’t want to keep taking omega-3s if they don’t do anything for you and they just increase the cost and the bulk of the drug. So, my guess is that [manufacturers] are poised to change, but it’s up to them,” she said.

Additionally, patients have been, and will continue to be, informed about these changes and the availability of lutein/zeaxanthin supplements, Chew said.

“Patients are being informed right now. They’re going to ask us what to do,” she said. “The majority of them can probably stay with what they have for the time being until we get the new formulation. But there are different supplements on the market that have some lutein in them without beta carotene. Some have only 6 mg of lutein. … Some have omega-3 with lutein/zeaxanthin. So, it’s a mixture, and my guess is that the companies would do something about that. With this data, I think they will probably go ahead and make it.”

Subgroup analyses

Investigators also conducted four subanalyses based on patients’ dietary intake of lutein and zeaxanthin, Chew said. Patients were categorized into quintiles depending on the amount of lutein and zeaxanthin they consumed, with those consuming the least being in the lowest quintile and those consuming the most being in the highest quintile.

“We did it four different ways to make sure we weren’t cherry-picking and just finding things,” she said.

The quintile analyses looking at dietary intake of lutein and zeaxanthin showed that patients with the lowest dietary intake of dietary lutein and zeaxanthin had the greatest response to supplementation.

“In every one of those analyses, we found that the lowest group had a significant improvement with lutein/zeaxanthin. So, that just means that the population who is not taking the green leafy vegetables and not eating enough lutein/zeaxanthin had an even higher rate of improvement,” Chew said.

The quintile analyses were somewhat skewed because the overall AREDS2 study population had a higher dietary intake of lutein/zeaxanthin than the general population, Chew said.

“If you compare our population, AREDS2, to the general population, we are in the top 40th percentile. So, most people who are in AREDS2 are already, compared to the general population, way above them. This is a well-educated, well-nourished group,” she said.

Hubbard said the quintile analysis underscored the importance of dietary intake of lutein/zeaxanthin through leafy green vegetables.

“That’s a very important point to make and should be one of the take-home points of the study,” Hubbard said. “Spinach and kale are the things that made a big difference in terms of the supplements. Lutein and zeaxanthin are the supplements that are derived from spinach and kale. If you never have spinach or kale in your diet, then if you take the supplement and lutein and zeaxanthin, you have a 26% reduction in your risk of progression to advanced AMD.”

The addition of lutein/zeaxanthin to the AREDS formulation had an insignificant impact on progression of lens opacity and cataract surgery. However, as in the AMD arm, patients in the lowest quintile of dietary lutein/zeaxanthin intake responded better to supplementation than those in the highest quintile.

Chew said that the cataract data were secondary to the AMD findings and that further study of the effect of supplementation on cataract formation is warranted.

“They were very secondary, and we didn’t do the very rigorous cataract photographs that we did in the first AREDS because we didn’t have the resources for 82 clinics,” Chew said. “Although we did get the findings for the cortical and posterior subcapsular cataracts, and nuclear cataract we did mostly by cataract surgery, we found that, overall, there’s no difference.”

Lutein/zeaxanthin was expected to have an effect on cataract formation, according to Jonathan Stein, MD.

“[Lutein/zeaxanthin] are the only naturally occurring carotenoids in the lens, so there was some speculation that maybe supplementing them will help prevent any sort of cataract formation,” he said. “But I think it was clearly elucidated that that does not at all have any effect on cataract formation. It basically didn’t change any of the rates.”

Competing carotenoids

The authors’ suggestion of replacing beta carotene with lutein/zeaxanthin was based on compelling pharmacologic findings, Chew said.

“The changes that are suggested are due to two things,” she said. “One is that we found an adverse effect of beta carotene increasing lung cancer in participants who were former smokers. In these former smokers, we don’t have all of the detailed information. These are former smokers with more than 5 years of not smoking and many years further back, probably, so we don’t know when they stopped smoking. Having smoked ever does increase your risk.”

The rate of lung cancer was 2% in the beta carotene group and 0.9% in the non-beta carotene group, mostly in former smokers.

Hubbard said that in the 1990s, beta carotene was linked to a risk of lung cancer, especially in smokers and former smokers.

“Beta carotene has always been a source of concern, definitely in smokers,” Hubbard said. “The safety of beta carotene has been a very important question and one that was addressed specifically in the study.”

A “smoker’s formula” of the AREDS supplement with lutein instead of beta carotene is available, he said.

Beta carotene was included in the original AREDS formulation because lutein/zeaxanthin was not commercially available, Hubbard said.

“There is actually no beta carotene in the retina. There is no beta carotene in the macula. However, there are other carotenoids that are similar but not exactly the same that are in the macula, and those are lutein and zeaxanthin. Lutein and zeaxanthin were not commercially available as supplements at the time the original AREDS study was designed. They had to use beta carotene because that was the only one that was available,” he said.

When present, beta carotene may play a role in the pathogenesis of lung cancer by inducing cell death in lung tissue, Stein said.

“It has to do with the localized lung environment, what the beta carotene may be broken down to in that environment,” he said. “Instead of becoming protective or antioxidant, it can become pro-oxidant and increase the oxidative stress and the oxidative damage and then the cellular death rate in those areas. Any time you have cell death and new cells are made, the new cells can be abnormal and cause cancer.”

The second reason for the change is that beta carotene blocks the systemic absorption of lutein, Chew said.

“Beta carotene and lutein are actually absorbed by the same carriers,” she said. “There is competitive absorption. So, if you give them at the same time, these carriers are going to compete for each other. We saw that in AREDS1, that when you elevated beta carotene, the lutein levels in the blood went down.”

Jaffe suggested that it would have been optimal to eliminate beta carotene in one of the primary patient groups to negate the damping effect of beta carotene on those carotenoids.

“It may have been better from the start to have, as one of the primary groups, no beta carotene but with lutein/zeaxanthin to give the best chance of having higher doses of those latter two additives,” he said. “There might have been a difference if beta carotene hadn’t reduced the tissue levels and serum levels of lutein/zeaxanthin.”

Omega-3s

Given the anti-inflammatory properties of DHA and EPA, Stein was among those who found their lack of effect a surprise.

DHA is concentrated in the photoreceptors, which are vulnerable to the inflammatory cascade and necrosis, he said.

“When the cells die in the retina … you start having cell death,” he said. “That’s what macular degeneration is. It’s the death of the photoreceptors and the loss of vision. So, the thought was to give these antioxidants that would be deposited in the macula, as well as the rest of the body, and would prevent the rate of cell death through these mechanisms.”

Stein noted that AREDS2 patients received an ethyl ester form of DHA/EPA, which is less bioavailable than the re-
esterified triglyceride form. Formerly, fish were pressed, a process that produced ample amounts of bioavailable oil but also yielded mercury and other toxins. Manufacturers then started to produce a purified ethyl ester form of fish oil, which has low bioavailability and produces side effects. To remedy this, companies re-esterified the oil into a form with higher bioavailability and fewer impurities.

“That’s really good bioavailability, even better than simply pressing the fish,” Stein said.

Also, the 1,000 mg total dose of DHA/EPA used in AREDS2 may have been suboptimal, said Stein, who typically asks his patients to take a daily 2,000 mg dose of re-esterified fish oil.

“They didn’t do that in the study,” Stein said. “For all we know, the levels of DHA and EPA actually getting into the system of these study subjects were minimal and subclinical.” – by Matt Hasson