Are AREDS2 Supplements Recommended in Macular Degeneration?


Age-related macular degeneration (AMD) is a progressive eye disease with a worldwide prevalence of approximately 170 million1. It is considered to be the leading cause of blindness in those over 50 years old and to date, there is no treatment that is able to cure it or reverse its sight-damaging effects. Anti-vascular endothelial growth factor (anti-VEGF) injections are applicable only to the late, neovascular form of AMD and seeks to slow or halt its progression. No such therapy is available for the dry, atrophic form of the disease, but research into the role of nutritional supplements for macular support has yielded promising results.

The Macula

The human retina is comprised of ten layers. Pertinent to the development and blinding effects of AMD are the photoreceptor layer (made of the outer segments of rods and cones receptors) and the supporting retinal pigment epithelium (RPE) layer.

diagram of retinal laters

(source: https://basicmedicalkey.com/the-special-senses-2/)

The macula of the retina contains the highest density of cone photoreceptors, particularly at its central point, the fovea, allowing for high resolution of fine detail and colour vision. Outside of the macular area, the concentration of cone receptors drops dramatically. Crucial to the health and function of the photoreceptor layer is the RPE, which regulates the transportation of nutrients and removal of metabolic waste products from the retina, as well as protecting it from excessive high-energy radiation and damaging reactive oxygen species2.

Age-related Macular Degeneration

The exact pathogenesis behind the development of AMD remains under investigation but the disease is known to be subject to both genetic and environmental factors3. Degenerative changes to the RPE layer with age is thought to play a role in AMD as it becomes increasingly less capable of supporting the light-sensing photoreceptor layer2.

The disease is typically categorised into a dry (atrophic) form and a wet (exudative or neovascular) form. The terms “early’, “intermediate”, and “advanced” are also often applied to various stages of AMD.

Early AMD is diagnosed with the presence of drusen, an accumulation of waste material within the retina at the level of the RPE. The size of drusen helps with categorisation of the specific stage of dry AMD, with larger diameters of drusen falling into the intermediate stage, often accompanied by hyper- or hypopigmentary changes of the RPE. Advanced AMD is diagnosed by the presence of geographic atrophy of the RPE and overlying retinal layers, including the photoreceptor layer, in dry AMD, or the development of abnormal neovascular vessels in the case of wet AMD4. Only approximately 10 to 15% of AMD cases are of the neovascular form5 but the loss of vision and quality of life from wet AMD can be devastating.

In the early and intermediate stages of AMD, a patient may be asymptomatic or perhaps aware of a mild blur or distortion of their central vision. By the time AMD has progressed to the late stage, vision loss in the central part of the visual field is significant and more or less permanent. Though peripheral vision largely remains unaffected, daily tasks such as reading, watching TV, and driving, are made substantially more difficult due to the deterioration of the central vision.

(source: https://www.healthplexus.net/article/classification-age-related-macular-degeneration-vs-age-related-maculopathy)

While research is inconclusive as to the loss of cellular density at the RPE layer with age and the part it may play in AMD, a significant decline of melanin pigment is noted across the entire retina after 40 years of age2. This is hypothesised to lead to a reduced protective capacity of the RPE layer as it is less able to absorb damaging light radiation and moderate the production of free oxygen radicals2. The accumulation of toxic pigment granules known as lipofuscin increases within the RPE with age and is thought to contribute directly to RPE dysfunction and cell death2, which subsequently leads to photoreceptor death and vision loss. In addition to the effects of lipofuscin, another theory postulates the development of drusen interrupts blood supply to the RPE from the underlying choroid, potentially leading to hypoxia. The role of inflammation and activation of the complement cascade of the immune system in AMD should also not be overlooked1.

The AREDS2 Trial

In 2001, the results of the first Age-Related Eye Disease Study (AREDS) were released. A major clinical trial funded by the federal USA government’s National Eye Institute, its purpose was to investigate the effects of certain nutrients on the progression of AMD and cataract. The original AREDS formulation was comprised of:

  • 500mg of vitamin C
  • 400 IU of vitamin E
  • 15mg of beta-carotene
  • 80mg of zinc as zinc oxide
  • 2mg of copper as cupric oxide in order to prevent copper deficiency subsequent to zinc supplementation

The AREDS results reported that patients at a high risk of advanced AMD were able to lower their risk of progressing to the advanced stage by 25% when taking the AREDS treatment of antioxidants and zinc. Similarly, the risk of vision loss from advanced AMD was reduced by 19% in patients with intermediate AMD or unilateral advanced AMD when taking the AREDS nutritional supplementation. The AREDS design also included a treatment arm of participants taking zinc only and a group taking high-dose antioxidants only; both these groups were found to have a reduced risk of developing advanced AMD when compared to the placebo group but with inferior effects to the antioxidants and zinc combination treatment arm6. No beneficial effect of the AREDS formulation was noted regarding the development or progression of age-related cataract.

In 2006, the same study group investigated whether the addition of plant-derived antioxidant carotenoids lutein and zeaxanthin, as well as omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), to the original AREDS vitamin formulation were able to further reduce the risk of progression to advanced AMD.

Lutein and zeaxanthin play a major role in macular pigmentation and are postulated to be able to filter damaging short wavelength radiation as well as provide some antioxidant activity7. Within the human body, these carotenoids are found at their greatest level in the retina, especially at the macula where they accumulate to a concentration five-fold that of the peripheral retina8. Lutein had been considered for inclusion during the original AREDS trial but was not commercially available at the time. A third carotenoid pigment is now known to play a significant role in macular health and pigment density – meso-zeaxanthin, which is synthesised by the body from dietary lutein. Although meso-zeaxanthin was first identified in the retina in 19939 it was not considered for inclusion in the AREDS2 trials, probably due to lack of sufficient understanding of its biomechanisms at the time and likely also its lack of commercial availability, similar to lutein.

During the AREDS2 clinical trials, one group of participants received 10mg lutein and 2mg zeaxanthin, another group was given 350mg DHA and 650mg EPA, and a third group given both the additional carotenoids and omega-3s. All subjects were requested to also take the original AREDS supplementation or were offered further randomisation to receive a variation, such as a reduced zinc dose of 25mg or removal of the beta-carotene.

The results of the AREDS2 study were made public in 2013 and found that the addition of neither lutein and zeaxanthin nor DHA and EPA were able to further lower the risk of progression to late stage AMD10. However, as an interesting aside, it was revealed that participants with a history of smoking were found to have a higher incidence of lung cancer in the group taking beta-carotene as part of the original AREDS formulation when compared to the group with beta-carotene removed. No effect on vision or risk of AMD was observed in the group without beta-carotene or the reduced zinc dose. Subsequently, the AREDS2 formulation contains lutein and zeaxanthin as carotenoid substitutes in place of beta-carotene to the benefit of both current and past smokers, resulting in a final formula of:

  • 500mg of vitamin C
  • 400IU of vitamin E
  • 25mg or 80mg of zinc
  • 2mg of copper
  • 10mg of lutein
  • 2mg of zeaxanthin11

The subjects given the lowered zinc dose of 25mg were found to have no statistically significant differences from those given the full dose of 80mg in the risk of AMD progression. Though both concentrations are acceptable as per the AREDS2 formula, the reduced dosage may be preferred in macular supplements due to the lower risk of adverse effects, such as anaemia and stomach disturbances10.

Further scrutiny of the AREDS2 clinical trials sought to assess the validity of the claim that omega-3 fatty acids, DHA and EPA, offered no substantial protective effect against AMD as many other clinical studies were able to demonstrate the prophylactic capability of omega-3 in AMD12. Despite the AREDS2 being a large (over four thousand participants), randomised, multicenter, placebo-controlled, double-masked trial, it has been suggested that the study protocols were not adequately designed to accurately assess the effects of omega-3 supplementation12.

Practical Applications for Healthcare Practitioners

To summarise, the AREDS2 formulation has been shown to reduce the risk of progression in age-related macular degeneration in the following situations:

  • Patients with intermediate AMD in one or both eyes
  • Patients with advanced AMD in one eye only6

It should be noted that no benefit of the AREDS2 supplement has been demonstrated for patients with no existing AMD or those with early AMD.

Diagnosis of AMD should be conducted by a qualified eyecare practitioner, whether an optometrist or ophthalmologist, to prevent any misdiagnosis of another macular condition, such as central serous chorioretinopathy or a form of macular dystrophy. A comprehensive examination of macular health includes ophthalmoscopy with or without fundus photography, measurement of visual acuity with and without refraction, and ideally optical coherence tomography to more thoroughly assess the RPE.

The patient should also be made aware that the ingestion of the AREDS2 vitamins have not been shown to reverse any existing vision loss from AMD (or any other ocular condition) and while the supplement can reduce the risk for many patients, it is not considered a cure or treatment for AMD and cannot be guaranteed to completely prevent the development or progression of macular degeneration.

The use of nutritional supplementation does not replace a healthy, balanced diet, ideally with foods known to be natural sources of the vitamins and minerals included in the AREDS2 formulation. These include dark green vegetables such as kale and spinach, and also yellow and red fruits and vegetables, such as capsicums, oranges, and corn. Egg yolk and maize have been found to contain the highest mole percentage of both lutein and zeaxanthin8. As the role of ultraviolet radiation and subsequent retinal damage has been implicated in the pathogenesis of AMD, protection in the form of sunglasses and a hat when outdoors continues to be pertinent advice for all patients.

References

  1. Pennington, K. L., & DeAngelis, M. M. (2016). Epidemiology of age-related macular degeneration (AMD): associations with cardiovascular disease phenotypes and lipid factors. Eye and vision (London, England)3, 34. doi:10.1186/s40662-016-0063-5. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5178091/. Accessed 8/7/19]
  2. Boulton, M., Dayhaw-Barker, P. (2001). The role of the retinal pigment epithelium: topographical variation and ageing changes. Eye (Lond), 15, 384-9. DOI:10.1038/eye.2001.141. [https://www.nature.com/articles/eye2001141.pdf. Accessed 8/7/19]
  3.  Nowak J.Z. Age-related macular degeneration (AMD): Pathogenesis and therapy. Pharmacol. Rep. 2006;58:353–363. [https://www.ncbi.nlm.nih.gov/pubmed/16845209. Accessed 8/7/19]
  4. Ferris, Frederick L. et al. Clinical Classification of Age-related Macular Degeneration. Ophthalmology. 2013 Apr;120(4):844-51. doi: 10.1016/j.ophtha.2012.10.036 [https://www.ncbi.nlm.nih.gov/pubmed/23332590. Accessed 8/7/19]
  5. Ambati, J., & Fowler, B. J. (2012). Mechanisms of age-related macular degeneration. Neuron75(1), 26–39. doi:10.1016/j.neuron.2012.06.018 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404137/. Accessed 8/7/19]
  6. Age-Related Eye Disease Study Research Group (2001). A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Archives of ophthalmology (Chicago, Ill. : 1960)119(10), 1417–1436. doi:10.1001/archopht.119.10.1417 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1462955/. Accessed 8/7/19]
  7. Age-Related Eye Disease Study 2 (AREDS2) Research Group, Chew, E. Y., Clemons, T. E., Sangiovanni, J. P., Danis, R. P., Ferris, F. L., 3rd, … Sperduto, R. D. (2014). Secondary analyses of the effects of lutein/zeaxanthin on age-related macular degeneration progression: AREDS2 report No. 3. JAMA ophthalmology132(2), 142–149. doi:10.1001/jamaophthalmol.2013.7376 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4636082/. Accessed 10/7/19]
  8. Mozaffarieh, M., Sacu, S., & Wedrich, A. (2003). The role of the carotenoids, lutein and zeaxanthin, in protecting against age-related macular degeneration: a review based on controversial evidence. Nutrition journal2, 20. doi:10.1186/1475-2891-2-20 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC305368/. Accessed 15/7/19]
  9. Arunkumar, R., Calvo, C. M., Conrady, C. D., & Bernstein, P. S. (2018). What do we know about the macular pigment in AMD: the past, the present, and the future. Eye (London, England)32(5), 992–1004. doi:10.1038/s41433-018-0044-0 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5944649/. Accessed 22/7/19]
  10. The Age-Related Eye Disease Study 2 (AREDS2) 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(19):2005–2015. doi:10.1001/jama.2013.4997. [https://jamanetwork.com/journals/jama/fullarticle/1684847. Accessed 8/7/19]
  11. NIH. What the Age-Related Eye Disease Studies Mean for You. May 2018. [https://nei.nih.gov/areds2/PatientFAQ. Accessed 22/7/19]
  12. Souied E, H, Aslam T, Garcia-Layana A, Holz F, G, Leys A, Silva R, Delcourt C: Omega-3 Fatty Acids and Age-Related Macular Degeneration. Ophthalmic Res 2016;55:62-69. doi: 10.1159/000441359 [https://www.karger.com/Article/FullText/441359#. Accessed 10/7/19]

The author of this article takes full responsibility for the accuracy of this article and is not in any way affiliated or employed by Intelligent Formula – any views stated is entirely the author’s view.

About the Author:

Jane Chong, B.Optom
Jane graduated from the University of Melbourne in 2012 with a Bachelor of Optometry and therapeutic endorsement. She has worked as a clinical optometrist ever since, gaining valuable experience across ocular disease management, contact lenses prescribing, paediatric optometry, and general optometry.

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