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Management Brief No. 49

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Management eBriefs
Issue 49March 2012

A Synthesis of the Evidence: Nutritional Supplements for Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in the developed world. Observational studies suggest that people with dietary intakes higher in various carotenoids, antioxidants, and omega-3 fatty acids have a lower risk of developing AMD. This has led to several supplementation trials designed to examine the ability of nutritional supplementation with carotenoids, antioxidants, or omega-3 fatty acids to prevent the progression of AMD. The severity of AMD ranges from Category 1 (least severe) to Category 4 (most severe).

Investigators at the VA's Evidence-Based Practice Center in Portland, OR conducted a systematic review of the literature to examine the effects of these specific dietary supplements. To assess potential benefits, investigators evaluated trials of these supplements in patients with AMD. In order to assess potential harms, the investigators also evaluated trials of these supplements in any adult population, not limited to AMD. After reviewing the literature spanning more than 50 years up until February 2011, investigators identified seven randomized controlled clinical trials (RCTs) of nutritional supplements in AMD patients to help answer the following two key questions:

Question #1
In patients with age-related macular degeneration, do nutritional supplements containing carotenoids (zeaxanthin, lutein, beta-carotene), antioxidants (zinc, vitamin E, vitamin C), or omega-3 fatty acids alone or in combination prevent functional loss?

  • Evidence that supplementation with carotenoids and antioxidants prevents functional vision loss in patients with AMD is based mainly on the results of one large randomized controlled clinical trial.
  • This trial had multiple treatment arms and found both zinc alone and a combination of antioxidants (vitamins E and C) + beta carotene prevented functional visual loss. However, the combination of all of these supplements (vitamins E and C, beta carotene, and zinc) had the largest protective effect.
  • This benefit was only seen in patients with Category 3 or 4 AMD, while no significant protective effect was noted in patients with milder disease.
  • One much smaller trial in patients with Category 3 or 4 AMD found zinc supplementation was associated with lower rates of visual loss.

Question #2
In adult populations, what are the harms of carotenoid, antioxidant, and omega-3 fatty acid supplementation?

  • In addition to the 7 RCTs involving patients with AMD, 7 systematic reviews and 41 RCTs involving non-AMD adult populations contributed evidence to assess potential harms.
  • Vitamin E at high doses (>or=400IU/day) may be associated with increased risk of mortality, congestive heart failure, and prostate cancer.
  • Beta-carotene may be associated with an increased risk of lung cancer among active smokers. A meta-analysis combining data from four studies determined that the overall risk of lung cancer among current smokers treated with beta-carotene was significantly elevated. However, no increase in lung cancer was found among former smokers or non-smokers in these four studies.
  • In prospective cohort studies that used lower doses than those used in RCTs, a small inverse association between carotenoids and lung cancer among current smokers has been observed.
  • In one study, zinc was associated with urinary tract infections and hospital admissions due to genitourinary causes.
  • Yellowish discoloration of the skin was frequently reported in trials of beta-carotene, and has been noted in trials of lutein. Gastrointestinal symptoms also were commonly reported in trials of various supplements.

Carotenoid and antioxidant supplements significantly decrease visual loss and can be recommended for patients with Categories 3 and 4 AMD. The current literature does not support the use of these supplements for patients with mild AMD. However, certain nutritional supplements may have significant potential harms, such as increased mortality and congestive heart failure in high-risk patients with vitamin E; increased risk of prostate cancer with vitamin E; and increased risk of lung cancer among smokers with beta-carotene.

This report is a product of VA/HSR&D's Quality Enhancement Research Initiative's (QUERI) Evidence-Based Synthesis Program (ESP), which was established to provide timely and accurate syntheses of targeted healthcare topics of particular importance to VA managers and policymakers - and to disseminate these reports throughout VA.

Kansagara D, Gleitsmann K, Gillingham M. Freeman M, Quinones A. Nutritional Supplements for Age-Related Macular Degeneration: A Systematic Review. VA-ESP Project #05-225;2011.

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This Management eBrief is a product of VA/HSR&D's Quality Enhancement Research Initiative's (QUERI) Evidence-Based Synthesis Program (ESP). ESP is currently soliciting review topics from the broader VA community. Nominations will be accepted electronically using the online Topic Submission Form. If your topic is selected for a synthesis, you will be contacted by an ESP Center to refine the questions and determine a timeline for the report.

This Management e-Brief is provided to inform you about recent HSR&D findings that may be of interest. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. If you have any questions or comments about this Brief, please email CIDER. The Center for Information Dissemination and Education Resources (CIDER) is a VA HSR&D Resource Center charged with disseminating important HSR&D findings and information to policy makers, managers, clinicians, and researchers working to improve the health and care of Veterans.

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