When dietary patterns in individuals were adjusted to follow a Mediterranean diet, nitrate intake was no longer associated with AMD progression independently. Photo: Getty Images.

Low dietary nitrate intake has previously been suggested to be a risk factor for age-related macular degeneration (AMD) progression; however, this finding has not been replicated in other cohorts or adjusted for dietary patterns. Researchers recently aimed to determine whether there is an association between dietary nitrate intake and AMD progression.

This cohort study analyzed data from the prospective Age-Related Eye Disease Study (AREDS) and AREDS2 randomized clinical trial cohorts and their extended follow-up studies. There were a total of 7,778 participants in both trials who had non-late AMD in at least one eye (56% women). The researchers reported in their paper, recently published in JAMA Ophthalmology, that a Mediterranean diet, which was associated with a lower risk of progression to late AMD in the AREDS cohort, was highly correlated with nitrate intake.

“Healthy diet patterns such as the Mediterranean diet are commonly dense in a wide variety of vitamins, minerals, fatty acids and protective bioactive molecules, which may have contributed to the protective associations observed for dietary nitrates in the present study,” the authors explained in their paper. “These include folate, pyridoxine hydrochloride (vitamin B6) and cyanocobalamin (vitamin B12). In addition, dietary patterns such as the Mediterranean diet, which appear to be protective against late AMD, may reflect the effect of healthier overall lifestyles (or to unknown or unmeasured aspects of healthy lifestyles) rather than individual components, which reduce progression to late AMD.”

Similar to the Blue Mountain Eye Study, which first identified a reduced risk of incident early AMD with increased nitrate intake, there appeared to be a threshold for the association of nitrate intake to progression to large drusen in the AREDS cohort. In that study, early AMD was not associated with increased risk beyond the third quartile. In the current study, increasing nitrate intake beyond quartile three in AREDS (nitrate median of 139mg/day) did not further lower the risk for large drusen, suggesting that it might not be necessary to consume nitrate levels of 140mg/day or greater to prevent early AMD.

The associations between nitrate intake and both late AMD phenotypes were more pronounced in the AREDS cohort than in the AREDS2 cohort. These differences might reflect the narrower distribution of dietary nitrate in the AREDS2 cohort, the authors suggested.

“In the combined cohort, the highest nitrate intake quartile compared with individuals with nitrate intakes in the lowest quartile had a 20% lower risk for progression to overall late AMD, 22% lower risk for progression to geographic atrophy and 39% lower risk for progression to nAMD. Because dietary nitrate was associated with all stages of AMD, it is possible that the cumulative lower risk over a period that is longer than the follow-up of the individuals in these cohorts could be substantially lower.”

Despite this conclusion, the authors agreed that further research is needed before dietary nitrate intake can be recommended as a therapy for AMD.

Supplement Consideration

A commentary in response to the study, also published in JAMA Ophthalmology, noted that the findings are noteworthy and may warrant new initiatives, perhaps sending a strong message that a healthy diet can provide benefits that dietary supplements do not. “After all, supplements only add trace components of vegetables, whereas whole vegetables displace alternative bulk foods that may themselves be harmful because they deliver calories, saturated fat, cholesterol and other undesirable substances, of which many people ingest more than they need,” the commentary author wrote.

He added that it will take an AREDS/AREDS2-type effort to test the effects of a nitrate-based supplement combined with an AREDS2 supplement.

“One argument is that many people have difficulty following dietary recommendations—even with the best of intentions—so they resort to dietary supplements, which have some effect on AMD, but not enough. Do we know enough to immediately recommend the use of nitrate supplements? There are strong arguments against proceeding quickly and without caution. Dietary supplementation recommendations in ophthalmology rest on a solid base of evidence and should not be undermined by a rush to act on preliminary evidence,” he concluded in his response.

1. Broadhead GK, Agron E, Peprah D, et al. Association of dietary nitrate and a Mediterranean diet with age-related macular degeneration among US adults. The Age-Related Eye Disease Study (AREDS) and AREDS2. JAMA Ophthalmol. December 22, 2022. [Epub ahead of print]. 2. Larsen M. Nitrates and age-related macular degeneration. JAMA Ophthalmol. December 22, 2022. [Epub ahead of print].