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In the news: Dietary Nitrates & AMD; Overview of Vital Study

Green Leafy Vegetables & Early AMD Risk

Australian medical researchers report a link between intake of dietary nitrate, a precursor of nitric oxide, and risk of AMD (1). While a previous Harvard study found that greater nitrate intake was associated with risk reduction of POAG, this is the first time that the effects of dietary nitrate on AMD risk has been measured. [See also EduFacts archives at SBH.com: Vol. 18, Intake of Dietary Nitrate Associated with Lower POAG Risk].

The researchers analyzed data from 2,037 participants of the longitudinal population-based The Blue Mountains Eye Study for which complete dietary data and AMD information was available. The participants were re-examined 15 years later and included in the analysis.

Incidence of AMD (the main outcome measure) was determined by color retinal photographs of the macula which were graded for the presence of early and late AMD. Dietary data were collected using a food frequency questionnaire, and nitrate intake calculated based on a comprehensive nitrate database of foods.

After adjusting for age, sex, smoking, energy intake, fish consumption, and AMD risk alleles (CFH and ARMS-2 polymorphisms), those who consumed 100-142 mg of vegetable-sourced nitrates each day had a 35% risk reduction of developing early AMD vs. those eating less than 69 mg vegetable nitrates daily.

No additional risk reduction was seen at the highest vegetable nitrate intake level (>142 mg per day), suggesting a non-linear association or possible threshold effect.  In this study, the largest benefit was seen with moderate nitrate intake. This observation is consistent with the results of a previous study which also showed a non-linear association between dietary nitrate and, in that case, vascular disease mortality.

If these findings are confirmed, dietary nitrates may be another good reason to eat leafy vegetables in addition to the lutein and antioxidants they contain. Beet root too, is a rich source of nitrates.

Overview of the VITAL Trial

Results from The Vitamin D and Omega-3 Trial (VITAL) were published in the Nov. 10th issue of the New England Journal of Medicine (2), (3). Neither vitamin D nor omega-3 supplementation lowered the incidence of major cardiovascular events (a composite of heart attack, stroke or death from CVD causes) or invasive cancer of any type, the primary endpoints evaluated in the trial.

However a number of secondary findings appear to be encouraging: a lower incidence of heart attack (nominal 28% reduction in risk) and death from heart attack (nominal 50% reduction in risk) with fish oil vs. placebo, and a lower mortality from cancer with vitamin D (nominal 17% reduction in risk) vs. placebo. These secondary findings must be interpreted with caution, but raise the possibility that supplements might be of benefit in preventing CHD or cancer death for some.

It’s worth noting that subgroup analyses showed a lower incidence of the primary cardiovascular endpoint with fish oil supplementation vs. placebo for those with low fish intake. Baseline dietary fish intake modified the fish oil intervention’s effect on major cardiovascular events (nominally significant reduction in risk of 19%) in participants consuming < 1 ½ servings weekly, while no risk reduction was observed for those with higher intake. These apparent findings could shape the designs of future trials, as poor fish intake was common in VITAL and is common in the US.

VITAL is a randomized, double-blind, placebo-controlled trial (with a two-by-two factorial design) assessing the effects of vitamin D (2,000 IU daily) and fish oil (1,000 mg daily, 460 mg EPA/380 mg DHA, Lovaza) on the primary prevention of CVD and cancer in 25,871 men (> 50 yrs) and women (> 55 yrs). The participants, with no history of cancer or CVD at baseline, were assigned to one of four regimens: both vitamin D and fish oil, vitamin D and placebo, fish oil and placebo, or two placebos daily. Participants were followed for about 5.3 years.

The strengths of the trial include the large number of people enrolled and the applicability of the findings to many in the population as African Americans, men and women, and those with normal as well as low blood levels of vitamin D were included. Importantly, no adverse effects were seen for vitamin D or omega-3 supplementation in VITAL, including no excess bleeding or high blood levels of calcium.

An accompanying editorial (4) emphasized that the positive secondary results should be interpreted cautiously because there was no statistical correction for the multiple comparisons conducted (partly due to the number of secondary end points evaluated). Also for fish oil, the secondary effects (less heart attacks or fatal heart attacks) have not been consistently seen in all large, well-controlled trials.

For vitamin D and cancer, however, experimental studies consistently demonstrate an anti-cancer mechanism, and a recent meta-analysis reported a significant benefit with vitamin D and cancer mortality5.

References

1. Gopinath B, et al. Association of dietary nitrate intake with 15-year incidence of age-related macular degeneration. J Acad Nutr Dietetics. Epub Oct. 17, 2018.
2. Manson JE, et al. Marine n-3 fatty acids and prevention of cardiovascular disease and cancer. NEJM. Published online 11-10-18. 
3. Manson JE, et al. Vitamin D supplements and prevention of cancer and cardiovascular disease. NEJM. Published online 11-10-18.
4. Keaney JF and Rosen CJ. Vital signs for dietary supplementation to prevent cancer and heart disease. NEJM. Published online 11-10-18. 
5. Vaughn-Shaw PG, et al. The impact of vitamin D pathway genetic variation and circulating 25-hydroxy- vitamin D on cancer outcome: Systematic review and meta-analysis. Br J Cancer. 116:1092-110, 2017.