What AREDS2 means in the clinic

Study leaders provide insights into how they apply the landmark findings in practice.

By James Knaub

What do the results from the AREDS2 study mean to clinical practice?

Emily Chew, MD, PhD, the lead study author, has her answer. She advises her patients to eat a healthy diet with plenty of spinach and fish and take a quality daily multivitamin. If her examination shows evidence of early or moderate AMD, Dr. Chew recommends they take an additional supplement that was evaluated in the AREDS2¹ trial and contains 500 mg of vitamin C, 400 IU of vitamin E, 80 mg of zinc, 2 mg of copper, 10 mg of lutein and 2 mg of zeaxanthin. She believes that the approach provides consistent, clear guidance — supported by the available AREDS2 evidence — to all her patients.

“I think it simplifies things,” says Dr. Chew, deputy director of the Division of Epidemiology and Clinical Applications at the National Eye Institute (NEI) in Bethesda, Md.

AREDS2: 16 FORMULATIONS

Different combinations evaluated

Simplicity isn't exactly the hallmark of AREDS2. The specific formulation Dr. Chew now recommends is one of 16 evaluated in AREDS2. Four study arms (each with four subgroups) evaluated different combinations including or excluding beta-carotene, lutein, zeaxanthin and omega-3 fatty acids.

AREDS2 also evaluated formulations containing different levels of zinc. AREDS2 sought to improve the performance and safety of the formula the original Age-Related Eye Disease Study (AREDS) evaluated. Patients taking that original AREDS formulation were 25% less likely to progress to advanced AMD than patients who received a placebo over the original five-year study period between 2001 and 2006.

Parsing the emerging findings of AREDS even further, a more recent analysis of one arm of AREDS2 found that zinc,² which was in both the AREDS and AREDS2 formulations, may have had a negative effect in AMD patients with specific genetic factors — specifically one or two complement factor H (CFH) risk alleles.

This analysis concluded that study subjects with no CFH risk alleles but with one or two ARMS2 (age-related maculopathy sensitivity 2) risk alleles derived maximum benefit from zinc-only supplements, but those with one or two CFH risk alleles but no ARMS2 risk alleles were at risk of increased progression to advanced AMD with zinc supplementation and derived maximum benefit from antioxidant-only supplementation. At least two AREDS2-based supplement formulations have dropped zinc, based on a recently published study arm.

Questions AREDS2 studied

AREDS2 researchers subsequently studied the additional supplement formulations to investigate these questions:

• Whether adding omega-3 fatty acids, specifically 350 mg of docosahexaenoic acid (DHA) and 650 mg of eicosapentaenoic acid (EPA), might further reduce progression to advanced AMD.
• Whether removing beta-carotene, which has been associated with an increased lung cancer risk in smokers and former smokers, would affect the rate of AMD progression.
• Whether adding lutein and zeaxanthin to the formulation might reduce progression.
• Whether the amount of zinc, which has been reported to cause side effects such as stomach upset, could be reduced without reducing its protective effect.

The newer AREDS2 formulations were compared to results from a group of patients who received the original AREDS formula: 500 mg of vitamin C, 400 IU of vitamin E, 15 mg of beta-carotene, 80 mg of zinc and 2 mg of copper (Table 1). AREDS2 had no true placebo control group because the researchers did not want patients to give up the protective benefit of the original formula.

Table 1. AREDS and AREDS2 formulations

What AREDS2 found

AREDS2, published in the Journal of the American Medical Association, found no overall extra benefit from adding omega-3 fatty acids or the mixture of lutein and zeaxanthin to the formulations. Reducing the zinc in the formulation also had no significant effect on AMD progression in the study.

In a separate study also reported in May, the AREDS2 researchers found that none of the AREDS2 formulations helped reduce the risk of cataract, a question not directly studied in the original AREDS.

While the overall results of AREDS2 did not show a significant change in protection against AMD progression in the overall study population, results from two subgroups suggested that altering the formulations could improve results as well as streamline care.

ROLE OF CAROTENOIDS

Does beta carotene mask effects?

“When we looked at just those participants in the study who took an AREDS formulation with lutein and zeaxanthin but no beta carotene, their risk of developing advanced AMD over the five years of the study was reduced by about 18% compared with participants who took an AREDS formulation with beta carotene but no lutein or zeaxanthin,” Dr. Chew said at the press conference discussing AREDS2 during the ARVO meeting last May.

“Further analysis showed that participants with low dietary intake of lutein and zeaxanthin at the start of the study, but who took an AREDS formulation with lutein and zeaxanthin during the study, were about 25% less likely to develop advanced AMD compared with participants with similar dietary intake who did not take lutein and zeaxanthin.”

AREDS2 did not address the reason why, but researchers offered a theory. Lutein, zeaxanthin and beta carotene are all carotenoids. Because carotenoids compete with each other for absorption in the body, the beta carotene might have masked the beneficial effects of lutein and zeaxanthin, Dr. Chew notes.

Beta carotene and smoking

While adding lutein and zeaxanthin did not provide additional protective benefit in the overall AREDS2 study — only in the two small subgroups described — replacing beta carotene in the original AREDS formulation with lutein and zeaxanthin in AREDS2 provided essentially the same benefit.

Table 2. AREDS2-based commercial supplements with omega-3

Thus, some of the AREDS2 data support the idea that patients can retain the same protective effect against AMD progression using lutein and zeaxanthin without exposing smokers and former smokers to the increased lung cancer risk associated with beta carotene.

“If you can reduce that risk, that is important.” Dr. Chew says. “By removing that beta-carotene and adding lutein [and] zeaxanthin you have one simple formulation that you can use for patients regardless of their smoking history.”

Many patients with AMD have a history of smoking. While the absolute risk of developing lung cancer may be small, reducing the relative risk is worthwhile, Dr. Chew says.

How to manage patients

The combination of maintaining the same protective benefit against AMD progression, avoiding beta carotene in patients with a smoking history and a clear, consistent message to give all her patients, helped lead Dr. Chew to this approach for these patients:

• No evidence of AMD on examination. Dr. Chew recommends a diet rich in spinach and fish, supplemented with a daily multivitamin.
• Evidence of early or moderate AMD. She recommends the same healthful diet and multivitamin, supplemented with the AREDS2 formulation with lutein and zeaxanthin but without beta carotene.
• Evidence of advanced AMD. Dr. Chew does not recommend adding an AREDS 2 formulation vitamin, because doing so has not been shown to prevent progression in either of the AREDS studies.

Dr. Chew also gives patients printed material that explains the AREDS research and her approach to supplements.

In short, the data suggest that replacing beta carotene with lutein and zeaxanthin makes the formulation safer without diminishing its protective benefit in reducing progression to advanced AMD. Further, that formulation appears appropriate for all patients, regardless of whether they are or were smokers.

“Removing beta carotene simplifies things,” says AREDS2 coauthor Wai T. Wong, MD, who is part of the NEI retinal disease unit. “We have identified a formulation that should be good for everyone regardless of smoking status.”

WHERE ORIGINAL AREDS FORMULATION STANDS

Nonsmokers and zinc

While Dr. Chew and others are following the approach to remove beta carotene from their patients' diets, some in the field suggest that people who have never smoked and are taking an original AREDS formulation supplement should keep taking it, based on their lower risk of lung cancer as nonsmokers and because of the longer clinical track record of the original AREDS formula.

Table 3. Commercial supplements based on AREDS2

While reducing zinc from 80 mg to 25 mg per day in the studies did not significantly affect the protective effects of those formulations, Dr. Chew notes the available data do not make clear how much zinc is necessary or optimal to prevent AMD progression. According to the NEI, there have been reports of mild side effects such as upset stomach in some people taking zinc supplements, but that problem was not reported in the AREDS studies.

Understanding role of omega-3

While the omega-3 fatty acids did not improve protection against AMD in AREDS2, other studies have proved them beneficial to cardiac health. Researchers emphasize that omega-3 fatty acids should remain part of a healthy diet (Table 2).

“Even though these [AREDS] supplements have been shown to have some value, we still need nutrients from whole food,” says Marc Levin, MD, a retina specialist and clinical assistant professor at the University of Illinois College of Medicine. “We don't want people on a poor diet thinking that taking these supplements are going to keep them in a good state of health. We don't know what else, besides the specific nutrients and antioxidants, is in whole foods that may be contributing to the beneficial affects on macular degeneration.”

Dr. Chew also calls diet the “front-line therapy” in eye health, stressing fish and dark green, leafy vegetables such as spinach and kale.

NAVIGATING SUPPLEMENTS

AREDS2 formulations evolve

While explaining the AREDS2 study and results to patients can be complicated, navigating the world of vitamin and mineral supplements can be daunting. Because the FDA regulates vitamins and supplements less vigorously than pharmaceuticals and medical devices, manufacturers can and do easily create and market new formulations.

Ocular supplements are often marketed as general eye health formulas. Vitamin manufacturers also market broader multivitamin products containing varying doses of all or some of the vitamins and minerals studied in AREDS and AREDS2 (Table 3). Dozens of such supplement products are for sale online.

Tables 2 and 3 list supplements containing formulations based on AREDS2. Supplements containing the original AREDS formulations are still available, too, as are products that include different doses of the same vitamins and minerals the AREDS research studied.

Dr. Chew recommends the specific AREDS2 formulation because it has been rigorously studied. It also helps streamline the discussion for both the ophthalmologist and the patient when so many supplement products are available.

“It makes it simpler for the patient, and you could have one formulation on the shelf,” Dr. Chew says. OM

REFERENCES

1. Age-Related Eye Disease Study 2 Research Group. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA. 2013;309:2005-2015

2. Awh CC, Lane AM, Hawken S, Zenke B, Kim IK. CFH and ARMS2 genetic polymorphisms predict response to antioxidants and zinc in patients with age-related macular degeneration. Ophthalmology. 2013;120:2317-2323.