Closing the chapter on omega-3 fatty acids and age-related macular degeneration may be premature

Professor Eric Souied, Head of the Department of Ophthalmology, Hôpital Intercommunal de Créteil & Hôpital Henri Mondor, France

Professor Eric Souied, Head of the Department of Ophthalmology at both the Hôpital Intercommunal de Créteil and the Hôpital Henri Mondor in France, is the lead author of a new review paper that has looked again at the results of the Age-Related Disease Study 2 (AREDS2), a multicenter study which failed to show any benefits from marine omega-3 consumption in relation to the onset and/or progression of ARMD (1). He points out that although “one interpretation of the AREDS2 results is that omega-3 supplementation does not protect against AMD progression […] an alternative analysis suggests that the design, setting and intake or subjects of the AREDS2 study may not have permitted the prophylactic potential of omega-3 to be demonstrated.”

Professor Souied has shown that epidemiological studies have consistently suggested a protective effect of omega-3 fatty acids against the onset of ARMD. However, he does recognize that only one study by Merle et al. (2) measured actual levels of omega-3 in the blood plasma of the cohort rather than using the notoriously inaccurate food frequency questionnaires.

AREDS2 was a large (n=4,203), double-blinded, randomized, placebo-controlled study using subjects who were at risk of progression to advanced ARMD. An important feature was that all the participants received the original AREDS formulation (500 mg vitamin C, 400 IU vitamin E, 15 mg beta carotene, 80 mg zinc and 2 mg copper) which had been shown to achieve a 25% risk reduction in the original AREDS trial. This meant that there was no true placebo group in the normally accepted sense. The cohort was also highly educated, highly health-conscious, and with a much lower proportion of smokers than more typical populations of the same age. Participants in the placebo arm who consumed non-defined omega-3 supplements during the study still had their results included in the final analysis.

Professor Souied made comparisons between AREDS2 and another recent intervention study, NATS2 (3). This study demonstrated poor compliance with regard to consumption of the intervention, and at first sight appears to indicate a similar result to AREDS2. However, if the subjects are defined by having consistently high EPA/DHA levels in their blood cells, then this group can be shown to have significant protection against ARMD when compared with the subjects who had consistently low EPA/DHA levels. It was noted that consumption of oily fish was much lower in ARMD patients than in the control. Overall they found that serum red blood EPA and DHA levels “were correlated ociated with substantial and significantly lower risk of neovascular ARMD.”

Though both AREDS2 and NATS2 used the same 1 g total dose of omega-3s, the DHA:EPA ratios were 1:2 and 3:1 respectively. This means that the dose of DHA was over twice as high in the NATS2 trial. This is very important, as DHA is the dominant fatty acid in the retina.

Professor Souied believes that there may have been a ceiling effect in the AREDS2 study. It seems very possible that the suboptimal AREDS2 omega-3 formulation would not have been able to provide any additional protection to a well-nourished and well-motivated cohort already consuming the original AREDS basket of fat-soluble vitamins and minerals.

1. Souied EH, Aslam T, Garcia-Layana A, Holz FG, Leys A, Silva R. & Delcourt C; “Omega-3 Fatty Acids and Age-Related Macular Degeneration”. Ophthalmic Research 2015, 55: 62–69. doi.org/10.1159/000441359
2. Merle BM, Delyfer MN, Koroenmik JF; Rougier MB et al.; “High concentrations of plasma 3 fatty acids are associated with decreased risk of late age-related macular degeneration”; J Nutr 2013; 143:505-511.
3. Souied EH, Delcourt C, Querques G., Bassols A et al. ; “Nutritonal AMD treatment 2 Study Group: Oral docosahexaenoic acid in the prevention of exudative age-related macular degeneration: the Nutritional AMD treatment study”; Ophthalmology 2013: 120: 1619-1631