AREDS I and II- the Sum is Greater Than its Parts
Impressions From an Industry Insider
DENNIS L. GIERHART, PHD

I have been asked to comment on the Age-Related Eye Disease Study (AREDS) formula for Retinal Physician from an industry perspective. I would like to start by commending the visionary thinking of Dr. Frederick Ferris of the National Eye Institute (NEI). Dr. Ferris led the efforts to intervene in age-related macular degeneration (AMD) and cataracts with a nutritional supplement using the best science available nearly 15 years ago. His leadership has resulted in a clinical outcome and supplement formula that could save at least 300000 AMD sufferers from progressing to advanced stages of AMD or going blind over a 5-year period. The cost savings from this type of intervention is immense and suggests that this trial was money well spent by our government.

The following discusses some concerns about the original formula and describes the debate as the NEI will move forward on the new AREDS II trial.

The formula currently being sold has attracted some controversy but is also the current clinically validated "standard of treatment." During the first AREDS trial, 2 outside trials concluded that beta-carotene (BC) could increase the risks of lung cancer in smokers. The current thinking is that BC's role as a retinoid precursor is responsible and that the risks may be modifiable with a proper balance of antioxidants.

Perhaps more importantly, is the inability to detect BC in human ocular tissues and the failure in animal studies to show BC has a direct protective role. BC was a very hot carotenoid at the conception of the AREDS trial and zeaxanthin and lutein were not commercially available.

The next controversy centered on the high levels of zinc (80 mg of zinc oxide) included in the formula. This level is nearly twice the upper tolerable level established by the Institute of Medicine and the formula cannot be used in some European countries because of this. This form of zinc is not highly bioavailable and a promising recent report (AREDS report #13) has even suggested that zinc may increase survivability.

The levels of zinc in predecessor pilot trials were even higher than 80 mg/day. Reports to date have shown no serious deleterious effects from this level of zinc intake. The scientific data for a protective role for zinc has continued to amass. There remains some controversy as to whether a "zinc paradox" occurs in-vivo. While certain levels of zinc are both essential and neuro-protective, high levels of "free zinc" may be highly reactive and neurotoxic.¹ There are some high-zinc feeding animal trials suggesting decreased cognitive function in elderly animals and neuronal damage during stroke from ischemia/reperfusion. The NEI is aware of this issue and is monitoring cognition in AREDS patients.

Finally, and most recently, 2 reports have come out suggesting an increased risk of heart failure events with high levels of vitamin E or alpha-tocopherol intake. The NEI released a statement on the first report — a meta analysis of a number of other studies. The statement concluded that if the negative effects were real, they were confined to those in the sub-group consuming more than 800 IU a day. A second report in the Journal of American Medical Association this year suggested that these reports of heart events might be seen at 400 IU a day. While these 2 reports were highly publicized, they ignored numerous other reports of beneficial effects of higher doses of tocopherols. The eye contains tissue that discriminates among stereoisomers, so it might be wise to stay at 400 IU of natural tocopherol isomers as found in foods.

The NEI and AREDS steering committees have been trying to proceed with a second trial that incorporates the latest scientific and clinical findings. There are significant challenges these groups must consider. They must address the validity of the above issues, determine whether the AREDS formula remains the standard of treatment going forward, decide if they should exclude BC, lower zinc and vitamin E, and decide how to test the possible improvements.

The currently considered "new ingredients" include the macular pigments, zeaxanthin and lutein, and the constituents of fish oil or Omega-3 essential fatty acids.

The science around the macular pigments has become a hot scientific field and continues to justify their inclusion in any new formula. Scientists have begun to elucidate basic biological mechanisms beyond absorption of blue light and quenching of reactive oxygen species to explain their protective effects. This includes delayed drusen and lipofusin accumulation and toxicity. Epidemiologists have continued to link various AMD risk factors with the pharmokinetics of retinal deposition of these pigments and new etiologies related to AMD (like inflammation). Two animal models, the Japanese quail and rhesus monkeys, have demonstrated the essential nature of these compounds to retinal health and how they afford protection. The safety of both, at intakes of up to 2 mg/kg of body weight has also been established. This has been confirmed by the Food and Drug Administration (FDA) and the World Health organization (WHO). In an Archives of Ophthalmology editorial, at the two year anniversary of the AREDS release, Dr. Jampol argued that perhaps zeaxanthin, which accumulates preferentially in the center of the macula, may be the best carotenoid for a new formula. This followed a paper from England that was the first to analyze serum zeaxanthin separately from lutein and found a low blood serum level of zeaxanthin to be more predictive of the risks of AMD progression.²

In AREDS II planning meetings, the outside advisors divided into those who thought higher doses of macular pigment should be included and in a ratio of
1:1 lutein/zeaxanthin, like the macular ratio, and those that thought the ratio should be 5:1 � 10:1, like the diet and serum, and at levels reflecting high green leafy vegetable consumption.

A similar debate ensued with the Omega-3 fatty acids. Some argued for higher doses and a ratio of EPA/DHA similar to epidemiology studies and some argued about compliance issues and a higher content of DHA.

The AREDS guiding committee have important and difficult choices to make. If the scientific choices were not difficult enough, they were complicated even more by patents. In December 2003, Bausch & Lomb received a patent on the AREDS composition and promptly sued competitors for infringement. B&L had supported the AREDS trial through a government agreement, cooperative research and development agreement (CRADA), that entitled B&L to certain rights. The pending lawsuit complicated planning processes and was partially resolved in mid-March, 2005, when Alcon and B&L cross-licensed patents to each other to settle the lawsuit. It is unknown whether both will have rights to the formula that is tested in AREDS II even though they are not funding the trial.

In summary, the AREDS formula and those associated with it's implementation have been visionary and will need all their wisdom as they plan future trials.

Dennis Gierhart, Ph.D., is chairman and chief scientific officer for ZeaVision LLC. He has worked on zeaxanthin and retinal nutrition for the last 15 years, and has intellectual property around zeaxanthin compositions and sponsors significant research in this field. He can be reached by phone at (314) 628-1000 or by e-mail at dgierhart@zeavision.com.

REFERENCES

1. Ugarte, M. and Osborne, N. Zinc in the Retina. Progress In Neurobiology. 2001;64:219-249.

2. Gale, C.R. et al. Lutein and Zeaxanthin Status and Risk of AMD. Invest Ophthalmol Vis Sci. 2003;44: 2461-2465.