Interview December 05, 2013
Stuart P Richer OD, PhD Kathy F Freeman OD, FAAO
Full Story: http://www.practiceupdate.com/expertopinion/651
Dr. Stuart Richer speaks with Dr. Kathy Freeman of PracticeUpdate about the effects of supplements on the prevention of ocular disease. In Part 1, Dr. Richer discusses the results of the AREDS trials. In Part 2, he goes into the benefits of the red wine extract resveratrol, particularly Longevinex; and, in Part 3, the benefits associated with meso-zeaxanthin and vitamin D.
The AREDS studies: design
Dr. Freeman: Dr. Richer, will you tell us about the AREDS2 study in general, and what were the most important actionable messages from the study?
Dr. Richer: The primary purpose of the AREDS2 study was to evaluate the efficacy and safety of lutein plus zeaxanthin and/or omega-3 long-chain polyunsaturated fatty acid supplements in reducing the risk of developing advanced macular degeneration (AMD). The study also assessed the effect of reducing the amount of zinc and of omitting beta carotene from the original AREDS formula.
The patients who participated in this 81-site multicenter study were older and sicker, but well-nourished. In fact, they had three to four times the average lutein and zeaxanthin intake of average Americans. They also had double the prevalence of diabetes, compared with the patients in the original—AREDS1—study, and more of these patients were on Centrum Silver (89% vs 67% in AREDS1) or a multivitamin in addition to the AREDS formula. Few Hispanics were represented (only about 2% percent of the study population).
The statistical bar was set very high in this study, as it employed 97.6% confidence intervals. The study was powered to detect an additional 25% reduction in the progression to AMD beyond the AREDS 1 results published in 2001.
AREDS2 results: Data on Lutein and Zeaxanthin
The results for the primary endpoints were negative and made public in early May 2013.1 The average patient in the study achieved results that were about 10% better. However, information on the effect of lutein plus zeaxanthin by tertiles of intake only appeared in the JAMA online supplement (E-Figure 1a). These results were not presented to the media for communication to the public, so the public and general practitioner in optometry and ophthalmology were unaware of the public health impact of this study. The AREDS2 results for the average American with a suboptimal daily intake of lutein/zeaxanthin showed a statistically significant prevention of catastrophic vision loss, primarily neovascularization. That was an incredible result, favoring a new AREDS2 formulation minus beta carotene but with lutein plus zeaxanthin. Surprisingly, the result was statistically negative for geographic atrophy, despite the fact that post hoc AREDS1 data had suggested that lutein plus zeaxanthin and/or omega-3 would have an outsized effect in this disease.
The net result of AREDS2 was an approximate 34% reduction overall in the profound risk of loss of vision. That means that several hundred thousand Americans would be able to drive and wouldn’t need expensive and invasive injections, if they were on an AREDS2 formulation that substituted lutein plus zeaxanthin for beta carotene. Significantly, these data imply that approximately 66 % of high-risk patients fail to benefit from an AREDS2 formulation.
The most practical advice for clinicians would be to prevent macular degeneration in the first place in low-risk patients when successful intervention is more likely biological. This can be done, first, by using lower doses in low- and medium-risk patients while examining the patients’ children and siblings.
Secondly, clinicians can promote visual performance by recognizing that carotenoids improve multiple aspects of it (eg, better contrast sensitivity and shortened glare recovery), providing individualized care, following the National Eye Institute’s high-risk patient recommendations, and educating patients. The fourth AREDS publication2 presented the cataract results. Once again, patients in the lowest quintile, or 20% of intake, had a statistically significant decreased risk of having any cataract, any severe cataract, or needing cataract surgery. Lutein plus zeaxanthin tends to mitigate nuclear cataracts, as opposed to the other forms of age-related cataracts. For patients in the lowest quintile of dietary lutein plus zeaxanthin intake, there was a 32% reduction in progression to cataract surgery, a 30% reduction in development of any cataract, and a 36% reduction in development of any severe cataract.
Safety
In terms of safety, although it is well-established from multiple prior studies that high-dose beta carotene should not be provided to smokers because it presumably raises the risk of lung cancer, we now know that the real issue is that excess beta carotene–derived vitamin A competes with vitamin D in the liver, and it is this resultant lack of vitamin D that is associated with the higher risk of lung cancer3 Nonetheless, in AREDS2, lutein plus zeaxanthin had no effect on lung cancer in former smokers or present smokers. No other safety issues arose in AREDS2.
Zinc
The effect of zinc was inconclusive. Previous studies, such as those by Klein et al,4 and also the Awh study,5 suggest that certain genetic haplotypes might benefit from individualized AREDS supplements. For example, high-risk AMD patients who are heterozygous or homogeneous for the complement factor receptor 1 gene may benefit from having less or even no zinc in the formulation. The National Eye Institute has not weighed in on this issue. Also zinc was shown to be protective in terms of gene–nutrient interactions in the Rotterdam Study.6
Omega-3
The omega-3 results were surprising because the predominance of scientific evidence looking at the early incidence of AMD and the development of catastrophic vision loss suggests that patients who are provided omega-3 have a decreased risk of developing macular degeneration or the catastrophic effects are mitigated.
AREDS2 is in contradistinction to the results from approximately 20 studies that had shown the opposite. One explanation may be the confounding high degree of habitual omega-3 intake in the placebo group. Another explanation is that the dose of fish oil was simply insufficient. My colleagues at Scripps Mericos in La Jolla, California, are using the Holman RBC fatty acid index to properly characterize the dose issue. I hope to have more to say about this at the ARVO 2014 meeting.
Role of DHA and EPA
Dr. Freeman: You mentioned before that the study subjects were well-nourished.
Dr. Richer: Yes, they were extremely well-nourished. Some researchers have criticized the AREDS2 formula for insufficient docosahexaenoic acid (DHA), as opposed to eicosapentaenoic acid (EPA). A study from France, the NAT-2 study, published by Souied and colleagues in Ophthalmology in February 2013, showed that patients who had the highest levels of DHA in the blood had a significant 70% decreased risk of developing catastrophic vision loss over 3 years.7 We may need to provide more DHA in our ocular supplements to high-risk AMD patients. DHA is the major essential fatty acid, more in the retina and brain. This issue has not been addressed yet in the AREDS2 study.
How to handle geographic atrophy
We have no real guidance on how to manage patients with geographic atrophy, who make up to one-third of AMD patients who, as well, eventually develop catastrophic loss of vision. I believe that, as with Alzheimer’s disease, in which we are looking at the incredible shrinking brain, with geographic atrophy, we are looking at the incredible shrinking retina. Both diseases have a neurodegenerative component. If we search for the common nutrients that are involved in both pathologies, we may be able to address two diseases at one time. Researchers should look more closely at vitamin D, sulphurated nutrients, and copper and iron chelators that can pass the blood–retina and blood–brain barrier. In addition, most B vitamins are associated with both diseases. Magnesium and selenium also deserve our attention, as do more sophisticated forms of vitamin E, the tocotrienols. There are additional nutrients, such as resveratrol and Longevinex, to study beyond the six or so that have been assiduously studied over the last 25 to 30 years by the National Eye Institute in the AREDS1 and 2 studies. We’ve been looking for our “keys” under the brightest light, but the keys are likely under dimly lit light posts.
References
- The Age-Related Eye Disease Study 2 (AREDS 2) Research Group. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration. JAMA. 2013;309(19):2005-2015.
- Age-Related Eye Disease Study 2 (AREDS2) Research Group, Chew EY, San Giovanni JP, Ferris FL, Wong WT, et al. Lutein/zeaxanthin for the treatment of age-related cataract: AREDS2 randomized trial report no. 4. JAMA Ophthalmol. 2013;131(7):843-850.
- Cheng TY, Neuhouser ML. Serum 25-hydroxyvitamin D, vitamin A, and lung cancer mortality in the US population: a potential nutrient-nutrient interaction. Cancer Causes Control. 2012;23(9):1557-1565.
- Klein ML, Francis PJ, Rosner B, et al.CFH and LOC387715/ARMS2 genotypes and treatment with antioxidants and zinc for age-related macular degeneration. Ophthalmology. 115(6):1019-1925, 2008.
- Awh CC, Lane AM, Hawken S, et al. CFH and ARMS2 Genetic Polymorphisms Predict Response to Antioxidants and Zinc in Patients with Age-Related Macular Degeneration.Ophthalmology. 2013;120(11):2317-2323.
- Ho L, van Leeuwen R, Witteman JC, et al. Reducing the genetic risk of age-related macular degeneration with dietary antioxidants, zinc, and ω-3 fatty acids: the Rotterdam study. Arch Ophthalmol. 2011;129(6):758-766.
- Souied EH, Delcourt C, Querques G, et al. Nutritional AMD Treatment 2 Study Group. Oral docosahexaenoic acid in the prevention of exudative age-related macular degeneration: the Nutritional AMD Treatment 2 Study. Ophthalmology. 2013. 2013;120(8):1619-1631.