A Randomized, Multicenter Interventional Study of Nutritional Supplementation in Patients With Unilateral Wet AMD

Retinal diseases are currently the leading cause of legal blindness in the developed world. Among these disorders, age-related macular degeneration (AMD) is one of the most prevalent conditions in individuals over 55 years of age. In the United States, the prevalence of AMD varies from 0.5% at 55 years to 7% in people over 75 years. These data are clearly a cause for concern, in view of the aging of the population in developed countries. In Spain, a country with one of the greatest population aging problems, AMD affects 1.7% of all people over 50 years, and the incidence increases with age, reaching 18.5% among those over 85 years. AMD is characterized by progressive destruction of the central region of the retina (macula), resulting in central vision loss. While this does not lead to complete blindness, the associated impairment of autonomy has a very strong impact upon patient quality of life. AMD is a multifactorial disease - a fact that makes it difficult to establish the underlying etiology. In this sense, although only age is accepted as the principal factor associated to the development of AMD, other factors such as smoking, diet, oxidative stress, arterial hypertension or obesity have been extensively investigated in the context of the disease.

Late AMD, the most severe presentation of the disease, clinically manifests as either geographic atrophy (dry form) or choroidal neovascularization (CNV) (wet form). Although patients with wet AMD only represent 10% of the total cases, CNV is the main and most serious cause of central vision loss. At present, the treatment of wet AMD comprises intraocular injections of certain antiangiogenic agents such as ranibizumab, bevacizumab, aflibercept, etc., which act by blocking vascular endothelial growth factor (VEGF). No effective treatment is yet available for dry AMD, though the Age-Related Eye Disease Study (AREDS) has shown that the administration of antioxidant supplements is able to slow progression of the disease. Such vitamin supplements are also indicated in patients who already have severe AMD (both exudative and atrophic) in one eye, since the risk of progression in these cases is high.

The AREDS, sponsored by the National Eye Institute, was started in 1998 with the purpose of evaluating the effect of high-dose antioxidants (vitamins C and E, and beta-carotene) and minerals (zinc) upon the course of the disease. The results of the study showed that high levels of antioxidants and zinc significantly reduced the risk of progression towards advanced stages of AMD by 25%, and of vision loss by 19%. However, due to safety reasons, the doses used in the AREDS cannot be administered in the European Union, since they exceed the Recommended Daily Allowances (RDA). Therefore, the standard clinical practice is to use these substances in patients with high risk AMD as nutritional supplements at the usual RDAs. However, no interventional studies demonstrating the effects of these supplements have been carried out.

Following publication of the AREDS I, certain dietary intake studies suggested the importance of other molecules such as omega-3 fatty acids (DHA, EPA, DPA) and lutein / zeaxanthin. The AREDS work group therefore decided to conduct a new study including both nutrients in addition to those already evaluated (antioxidants and zinc). Lutein exerts an antioxidative effect, can act as a blue light filter, and moreover has antiinflammatory properties. This latter effect is especially important, considering that AMD is a disease secondary to a low-grade chronic inflammatory process of the retinal pigment epithelium (RPE). In addition to their antioxidant and antiinflammatory effects, the omega-3 fatty acids have important antiangiogenic properties, as evidenced both by in vitro and in vivo studies.

Recent studies involving new antioxidant and antiangiogenic molecules such as resveratrol, present in grapes and wine, have also revealed great efficacy in slowing the progression of advanced AMD. Hydroxytyrosol is another polyphenol with important antioxidant and antiinflammatory effects in the RPE.