Dietary Nitrate Intake May Modify Age-Related Macular Degeneration Risk

Emily Y. Chew, MD

New research suggests that dietary nitrate intake may be a modifiable risk factor for progression of age-related macular degeneration (AMD), with increased nitrate intake associated with decreased risk of late AMD.

However, when dietary patterns were adjusted to include a Mediterranean diet, the findings indicated that dietary nitrate intake was no longer associated with AMD progression independently.

“These results are from post-hoc analyses and are therefore hypothesis-generating in nature,” wrote study author Emily Y. Chew, MD, Division of Epidemiology and Clinical Applications, National Eye Institute, National Institutes of Health. “Much of the outcome associated with nitrate intake can be attributed to plant-based dietary patterns in general, such as a Mediterranean diet.”

Previous investigations have cited an association between narrower retinal microvasculature caliber and lower dietary nitrate intake, which may explain how nitrate intake can influence AMD development. Other evidence suggests increased dietary intake of nitrates may be associated with reduced risks of early AMD, but the findings have not been replicated in other cohorts.

Chew and colleagues investigated the association of dietary nitrate intake and the progression to intermediate and late AMD within the large, prospective Age-Related Eye Disease Study (AREDS) and AREDS2 randomized clinical trial cohorts and their extended follow-up studies. Individuals in each trial had non-late AMD in at least one eye.

Individuals in AREDS were randomized to placebo, zinc, antioxidants, or a combination of zinc and antioxidants for 5 years. AREDS2 participants were randomized to an AREDS supplement that reduced AMD risk with lutein and zeaxanthin, with docosahexaenoic acid and eicosapentaenoic acid, with a combination of both of these substance combinations, or alone for 5 years.

The main study outcomes were the association between dietary nitrate intake and the development of late AMD (neovascular AMD [nAMD] or geographic atrophy [GA]) or large drusen. Data were analyzed from March 2020 to September 2022.

Within the combined AREDS/AREDS2 cohort of 7788 participants (4288 AREDS participants and 3610 AREDS2 participants; 110 participated in both studies), there were 13,511 eligible eyes. The cohort comprised 4396 women (56%) and 3392 men (44%), with a combined mean age of 71.1 years.

The findings suggest dietary nitrate intake was associated with a decreased risk of progression to late AMD in the combined AREDS/AREDS2 cohort (hazard ratio [HR], 0.77; 95% CI, 0.69 - 0.86 for quartile 4 vs. quartile 1 of intake). It was additionally associated with a decreased risk of GA (HR, 0.71; 95% CI, 0.61 - 0.83) and nAMD (HR, 0.85; 95% CI, 0.73 - 0.99).

For the AREDS cohort alone, increased nitrate intake (quartile 4 vs. quartile 1) was associated with a decreased risk of late AMD (HR, 0.77; 95% CI, 0.65 - 0.91) and GA (HR, 0.80; 95% CI, 0.65 - 0.97), but not nAMD. In contrast, the AREDS2 cohort had no association between nitrate intake (quartile 4 vs. quartile 1) and late AMD (HR, 0.90; 95% CI, 0.80 - 1.02) or nAMD (HR, 0.93; 95% CI, 0.78 - 1.11).

Investigators noted that individuals with high nitrate intakes were likely to have diets that were denser in vitamins, minerals, and healthy fats. The Pearson correlation coefficient between nitrates (mg/d) and diet index in the combined cohort was r = .52 (P <.001).

Moreover, when the Mediterranean diet index tertiles were added to the model, the associations of dietary nitrate with late AMD were attenuated and were no longer statistically significant for nAMD, but remained significant for late AMD and GA. This may suggest that dietary nitrate is not an entirely independent estimator of late AMD in these cohorts, according to investigators.

Further, after adjustments for diet index tertiles in both the AREDS and AREDS2 cohorts, investigators noted there were no protective associations between nitrate intake and late AMD.

The study, “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,” was published in JAMA Ophthalmology.