AREDS Eye Supplements

Helpful or Harmful?

Patients with intermediate dry AMD have historically been treated with a fixed formulation of high-dose eye supplements and zinc (AREDS) as standard of care since the pivotal placebo controlled AREDS [8] study was published by the National Eye Institute (NEI) in 2001. This formulation was modified slightly following a second AREDS2 study published in 2013 by the NEI [10].

AREDS has been shown to reduce AMD progression risk for vision loss by 25% for patients with intermediate Dry AMD. However, it was not known who would benefit and who would not. Researchers [5,9] analyzed outcomes of these AREDS compounds on 989 AREDS study patients who donated their DNA and were followed for 7 years. The AREDS study is the only placebo-controlled study with patient DNA that is suitable for this analysis. The data demonstrated that approximately 35% of patients had a genetic profile, which did best on the AREDS formulation including Zinc. It also showed that for 13% of patients with a different genetic profile (2 high-risk CFH alleles and 0 ARMS2 risk alleles) the standard AREDS formula was detrimental and accelerated vision loss much faster than placebo.

These studies along with the body of related literature led Arctic Medical Diagnostics to provide eye doctors with genetic testing for all patients taking AREDS Eye Supplements.

In 2014 Dr. Chew et al[18] at the NEI published their own analysis of the AREDS study DNA. Their conclusions were contrary; they concluded that ‘AREDS supplements reduced the rate of AMD progression in all genotypes’. Their data however, did not support that conclusion. The genotype group for CFH/ARMS2 = 2/0 had a deleterious response to Zinc and to the AREDS formulation with Zinc. The group treated with zinc had a 96% increase in progression to vision loss vs. placebo. The group treated with antioxidants and zinc (AREDS) had a 78% increase in progression to vision loss versus placebo. Two independent biostatistical reviews of this data (AREDS Report #38) have demonstrated that the study conclusions are not supported by the data and in fact demonstrate a deleterious effect in these patients. [Read Kustra and Rosner reviews]

In 2016 an additional independent study also evaluated the role of genetic variants in modifying the relationship between supplementation and progression to advanced AMD among 4124 eyes (2317 subjects with a genetic specimen), This study published in the British Journal of Ophthalmology demonstrated a statistically significant relationship between genotype and the efficacy of the AREDS formulation.[17] Some patients benefitted, while others did not. This study did not analyze the effect of AREDS in the separate genotype that has been found to demonstrate detrimental outcomes.

The use of AREDS to prevent the progression of AMD in all patients is controversial. It seems to help some patients and harm others. We recommend caution for the indiscriminate use of AREDS. Testing is available through eye care professionals across the USA and Canada.

 

FAQ

Is the design of these genetic studies retrospective?

The AREDS study was a prospective placebo controlled study. The decision to collect and analyze DNA was in the original AREDS study protocol and the DNA was collected prospectively. AREDS DNA has repeatedly been analyzed prospectively by Drs Awh and Kim, by Dr. Chew et al and now by Dr. Seddon et al [9,18,17]. One can’t analyze the DNA until the clinical outcomes are observed, but the analysis of the DNA is done prospectively. The FDA accepts these study designs as prospective genetic analyses; they are not retrospective genetic analyses.

These gene studies focus on one cohort from the AREDS study. Shouldn’t there be another study in a different patient cohort?

It is valid scientific and regulatory practice to repeat claims made on the basis of a single study cohort. The FDA, for example, does not accept a medical claim without data supporting the claim from at least two independent cohorts. There is one significant exception to that principle. There is never a requirement to repeat a study claiming toxicity. Phase 1 drug safety studies are not repeated if the compound is not safe. Calls to repeat an AREDS study asking patients with the suspect genotype to enroll under informed consent might not meet any regulatory or ethical standard now.

Should companies promoting AREDS provide a warning to doctors and patients?

There are FDA defined regulatory processes for making medical claims on a compound intended for the treatment of a disease. People promoting nutritional products are not permitted to make medical claims (ie treatment of a disease). In this instance, however it is the NEI and the AAO that are promoting AREDS for the treatment of AMD. There is no FDA approval for their claim. The NEI/NIH have been sharing the ownership of the AREDS/AREDS2 commercial patent and they have been sharing the revenues from the sale of AREDS/AREDS2 products with the manufacturers. Are they not both AREDS/AREDS2 commercial partners promoting the compounds for the treatment of intermediate AMD? FDA inquiry might provide an appropriate answer to this question including the need for appropriate warnings and approved medical claims.

Dr. Chew et al claim that their study did not demonstrate a statistically significant interaction between the genes and the AREDS supplements. Should doctors and patients continue to use the AREDS/AREDS2 products regardless of genetic profile?

Dr. Chew’s analysis in AREDS #38 reported a 78% increase in progression to advanced AMD with vision loss for patients with the suspect genotype[18]. Her statistical model suggested that this was not statistically significant. Other biostatisticians claim it is significant and there is a deleterious effect. 78% more patients with this genetic profile lost vision while on AREDS vs. placebo. There does not seem to be any data published, including AREDS report #38 that shows the treatment is safe in patients with 2 high-risk CFH alleles and 0 high-risk ARMS2 alleles. It all shows negative outcomes. The frequency of this genetic profile is between 13% and 19% of patients. Until proven safe and effective, the body of literature suggests that the compound is detrimental to these patients. The concept of ‘Do No Harm’ might be considered.

 

 

Literature Review:

 

 

Background on the major supplement studies

In 2001 the NEI publish the AREDS[8] study, which demonstrates that the AREDS eye supplement reduced the risk of AMD progression by 25% in patients with Intermediate Dry AMD.

In 2013 the NEI published the AREDS2[10] study that demonstrated that the AREDS formula could be improved by replacing beta carotene with lutein and zeaxanthin.


Background on the genetics of AMD and supplements

In 2007 and again in 2014, Lengyel[11,12] et al published that high dose zinc aggregates complement proteins into drusen causing dry macular degeneration in patients with high-risk CFH genotypes.  According to Lengyel, this occurs in AMD and in Alzheimer’s as well. This was one of the first discoveries that zinc may be harmful to patients with a certain genetic profile.

In 2008/2009 M. Klein[13] and J.Seddon[3] showed that AREDS was not effective in high-risk CFH genotypes. Klein found that the high-risk CFH patients showed no benefit over placebo.

In 2012 Perkins[15] et al then separately in 2013 Nan et al[16] described the biologic process between high dose zinc and high-risk CFH genotypes, which promotes a pro-inflammatory state leading to macular degeneration. The mechanism for the development of AMD in patients with high-risk CFH genetic profiles is now published.

In 2013 and 2014, Awh et al publish their findings that AMD patients with high-risk CFH and low risk ARMS2 genetic profiles (13%) should not take AREDS eye supplements because they may experience an increased progression to vision loss from AMD.

In 2014, Dr. Chew at the National Eye Institute published her own analysis of the AREDS patients and concluded that the AREDS supplements reduced the rate of AMD progression in all patients. Her data, however, shows that 19.2% of her patients had a genotype demonstrating an increased rate of progression to vision loss while on the AREDS treatment vs. placebo. The treatment was actually detrimental for these patients.

In 2016, Dr. Seddon’s independent study also evaluated the role of genetic variants in modifying the relationship between supplementation and progression to advanced AMD. This large study confirmed the prior observations of Awh et al that AREDS supplementation appears to differ by genotype.