and II- the Sum is Greater Than its Parts
From an Industry Insider
L. GIERHART, PHD
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
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
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
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.
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 email@example.com.
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:
Retinal Physician, Issue: July 2005