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Kansagara D, Gleitsmann K, Gillingham M, et al. Nutritional Supplements for Age-Related Macular Degeneration: A Systematic Review [Internet]. Washington (DC): Department of Veterans Affairs (US); 2012 Jan.

DISCUSSION

We conducted a systematic review of the benefits and harms of nutritional supplements for treatment of AMD. We found good evidence mainly from one large RCT that supplementation with carotenoids and antioxidants decreased the risk of functional vision loss among patients with Category 3 or 4 AMD. One smaller RCT also found zinc supplementation may decrease the risk of clinically significant visual loss among patients with Category 3 or 4 AMD, but six other RCTs found no clinically significant benefit from nutritional supplements in AMD patients. The effects of carotenoids or omega-3-fatty acids alone have not been well-studied.

It is likely that the discrepant findings reflect, at least in part, the size, length of follow-up, and patient characteristics in these six studies not finding benefit. These studies all included fewer than 200 patients each, were conducted over a relatively short time frame, and included large proportions of patients with mild AMD.

We also found evidence of significant potential harm from some nutritional supplements. Carotenoids such as beta carotene have been associated with an estimated 24 percent increased risk of lung cancer among smokers. Similar to the studies of potential benefits, the evidence for harms is driven primarily by two large trials, ATBC and CARET. The release of the results regarding beta-carotene and lung cancer risk from ATBC in 199427 and CARET in 199628 caused an amendment to be made to the ongoing AREDS study, in which smokers were offered a chance to change their randomization of treatment supplements category to one which included either zinc alone or placebo. This concern also has been addressed in the subsequent AREDS II study, now underway, which is discussed below under Future Studies.48

Higher doses of vitamin E (>400 IU per day) have been associated with an estimated four percent increase in mortality; a 13 to 17 percent increase in risk of prostate cancer; and a 13 to 50 percent increase in risk of congestive heart failure among those with existing CVD risk factors such as left ventricular dysfunction, diabetes mellitus, recent myocardial infarction, or renal insufficiency.

Whether the balance of benefits and harms favors supplementation in AMD patients likely depends on the population being considered. There is strong evidence for benefit in patients with more advanced AMD; and in these patients, the very small risk of harm is likely to be outweighed by the potential benefit. Using the AREDS data, one can calculate the number needed to treat with supplements to prevent one patient from developing clinically significant visual loss, as 33 over five years. In a population of patients with comorbid cardiovascular disease, 256 would need to be treated with supplements (which include vitamin E) to cause one excess death.19

The role of nutritional supplementation in patients with mild AMD is unclear. The natural history of mild AMD is one of slow progression. Among 1,117 participants with Category 1 AMD at baseline in the AREDS study, only five (0.45%) participants developed advanced AMD during 6.3 mean years of follow-up. Among 1,063 subjects with Category 2 AMD at baseline, only 13 (1.2%) subjects had significant vision loss related to AMD, and 28 (2.6%) participants progressed to Category 3 or 4.10 There was no detectable effect on vision loss in any of the treatment arms among these subjects, given the very slow rate of disease progression in mild AMD. It is unclear, however, whether the rate of progression from mild to advanced AMD increases with age. It is possible that nutritional supplementation for mild AMD may yield more detectable benefit to those over age 85 compared with younger individuals. These aged individuals make up the fastest growing demographic in the United States. The natural progression of AMD in this age group warrants further study.

Since AMD patients are likely to be older and have additional medical comorbidities, many would be at risk for some of the potential harms associated with supplementation. Because of the very slow rate of disease progression in patients with mild AMD, the lack of evidence of benefit in these patients and the potential for harm – especially amongst those with baseline medical comorbidities – the current literature does not support widespread use of these supplements for mild AMD. The balance of benefits and harms in patients with Category 3 or 4 AMD and limited life expectancy is unclear. Because the benefits of nutritional supplements do take several years to accrue, it is unclear that their use in patients with limited life expectancy is indicated.

Our findings concur with and add to the findings of similar reviews. A recent Cochrane collaborative review found evidence for modest benefit of antioxidant, vitamin and mineral supplementation reducing the progression of AMD in people with moderate to severe signs of the disease, and no evidence that subjects with early signs of the disease show a treatment benefit.18 Our findings add to prior reviews in that we looked at a broader group of studies to examine the potential harms of supplements because the potential risks are not limited to only those with AMD, making studies including all older adults relevant to the question of harms.

FUTURE STUDIES

Based on the progression observed in AREDS among subjects with Category 2 AMD, we estimate a study enrolling 17,000 subjects followed over five years would be needed to detect a clinically significant difference in visual loss between subjects treated with antioxidants + zinc versus a placebo. Such a study is unlikely to be funded and completed in the near future. The natural history of AMD is a very slow and lengthy progression from retinal evidence of disease to functional vision loss. Not all patients with evidence of retinal disease have vision impairment that interferes with functional status. In other words, subtle changes in retinal function due to AMD may cause visual disability that is not well reflected on the basis of visual acuity measurements alone. Well-validated intermediate markers of functional vision loss would be useful. Well-designed prospective cohort studies of patients with mild AMD could elucidate the types of intermediate findings that could accurately predict future clinically significant vision loss. In addition, studies would need to confirm that these findings are consistent when measured across large groups of patients.

Given the relative lack of information about the effects of xanthophylls, carotenoids, and omega-3 fatty acids, future trials should be considered to assess the effects of these supplements in AMD patients. The results of the ongoing AREDS II trial should help to address the current gaps in evidence about the effects of the xanthophyll and omega-3-fatty acids. In addition, the AREDS II trial interventions will include four variations of the original AREDS formula for randomization. However, smokers in the study will be randomized to only groups 2 or 3 since neither of these two groups’ supplements includes beta carotene. The only variation between these two groups is the high or low Zinc content. This comprises a “smokers” subset of AREDS II.48

Previous and current studies, including the ongoing AREDS II trial, have focused on functional vision loss and AMD progression as the principal outcomes of interest. The large majority of patients with AMD, however, may suffer from more subtle visual disabilities that may, nevertheless, profoundly alter their visual functioning, such as losing their ability to safely operate a motor vehicle. It is important to emphasize that these patients, while visually impaired, may still record less than clinically significant visual loss as measured by visual acuity. Evidence is lacking as to whether quality of life outcomes and activities of daily living benefit from treatment, and further study of these outcome measures is warranted.

CONCLUSIONS

Evidence of benefit from supplementation with carotenoids and antioxidants on functional vision loss in patients with AMD is based mainly on the results of one large trial. The observed benefit occurred only among subjects with Category 3 or 4 AMD. There is evidence for a low risk of harm from some nutritional supplements at high doses. As with any clinical intervention, the balance of benefits and harms regarding supplementation in AMD patients depends upon the population being considered. Given that AMD patients are older and have additional medical comorbidities, many would be at risk for some of the potential harms associated with supplementation. The precautionary principle should be observed while further evidence evolves. Table 2 summarizes the evidence regarding the benefits and harms of oral supplements for AMD.

Table 2. Summary of the evidence on the effects of nutritional supplements for age-related macular degeneration.

Table 2

Summary of the evidence on the effects of nutritional supplements for age-related macular degeneration.

While our report notes the uncertainty in the conclusions of many of the included studies, reasonable recommendations can be extended:

  • Carotenoid and antioxidants supplements significantly decrease visual loss and can be recommended for patients with Categories 3 and 4 AMD.
  • Current literature does not support the use of these supplements for patients with mild AMD.
  • Certain nutritional supplements have significant potential harms:
Cover of Nutritional Supplements for Age-Related Macular Degeneration: A Systematic Review
Nutritional Supplements for Age-Related Macular Degeneration: A Systematic Review [Internet].
Kansagara D, Gleitsmann K, Gillingham M, et al.
Washington (DC): Department of Veterans Affairs (US); 2012 Jan.

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