Data from AREDS demonstrate that treatment with zinc alone or in combination with antioxidants reduced the risk of progression to advanced AMD in participants in Categories 3 and 4. These categories are defined by extensive intermediate drusen, large drusen, or noncentral GA in 1 or both eyes, or advanced AMD or visual acuity <20/32 attributable to AMD in 1 eye. Estimates of RR derived from ORs suggest risk reductions for those taking antioxidants alone or zinc alone of 17% and 21%, respectively. The risk reduction for those taking antioxidants plus zinc was 25%. The probability of developing advanced AMD by 5 years among participants assigned to receive placebo varied within Category 3 from about 27% for those with large drusen in both eyes or with GA not involving the center of the macula in at least 1 eye, to about 6% for the remaining participants in that category. Participants in Category 4 had the highest probability of progression, with an estimated probability of 43% at 5 years.
Too few advanced AMD events occurred in Category 2 participants to assess whether any treatment tested in this study could slow the progression to advanced AMD for participants with milder drusen and retinal pigment epithelial abnormalities. This predefined group of participants adds virtually no information to the treatment comparisons. Removing this group provides more appropriate estimates of odds reductions within participants at risk for development of advanced AMD. There was no statistically significant evidence of a benefit in delaying the progression of Category 2 eyes to more severe drusen pathology (eg, moving from Category 2 at baseline to Categories 3 or 4 during follow-up). One of the original and continuing goals of AREDS is to develop severity scales for AMD similar to those for diabetic retinopathy, and to use such scales to assess whether treatment slows the progression from earlier to more advanced stages of AMD.
The apparent treatment benefit of antioxidants plus zinc and zinc alone was present for each of the events predefined in the study protocol to be signs of advanced AMD (development of signs of neovascular AMD, accounting for 70%–80% of events, and development of central GA). There was a nonstatistically significant trend for an increase in the risk of developing GA away from the center of the macula in the zinc and antioxidant plus zinc treatment groups compared with the placebo-treated group. Because the increase is not statistically significant and is contrary to the primary outcome of development of GA at the center, its explanation and importance are unclear.
The clinical importance of the reduction in the development of advanced AMD is enhanced by a corroborating effect on visual acuity. Compared with the placebo group, only the participants in Categories 3 and 4 assigned to antioxidants plus zinc had a statistically significant reduction in the odds of a 15-letter or greater visual acuity decrease (P=.008). Findings of AREDS suggest that the estimated 27% odds reduction in the visual acuity outcome for the combination arm may be the combined benefit of the zinc component (odds reduction of 17%) and the antioxidant component (odds reduction of 15%). The visual acuity benefit observed for the combination arm remains consistent for other, more severe, visual acuity outcomes, such as visual acuity worse than 20/100 or a decrease in visual acuity of 6 lines or more.
Although not a predefined outcome, a composite event was created to estimate risk reduction when advanced AMD and a loss of at least 15 letters in visual acuity were observed concurrently. This event definition resulted in estimates of odds reductions of about 25% for zinc and 37% for zinc plus antioxidants for participants in Categories 3 and 4 combined. Odds reductions for the antioxidants plus zinc treatment were 24% for Category 3 participants and 48% for Category 4 participants. This analysis suggests that the reduction in risk of visual acuity loss observed with the antioxidant plus zinc formulation may be a result of the reduction in risk of progression to advanced AMD. The AREDS clinical trial of cataract found no effect of treatment on the development of lens opacity,46
and the proportion of participants with cataract surgery in 1 or both eyes during the study was balanced across treatment groups. It is unlikely that differential treatment effects on lens opacity are affecting this visual acuity result.
Two other trials assessed supplementation for patients with AMD. A small randomized trial, completed before AREDS began, suggested a benefit of large doses of zinc on visual acuity in persons with AMD.27
For zinc alone, AREDS did not find a statistically significant reduction in the odds of a 15-letter visual acuity loss. The proportion of participants in the zinc arm with a visual acuity loss of at least 15 letters draws closer to the placebo arm by 7 years. Results from another randomized trial reported that after 4 years of supplementation, 500 IU per day of vitamin E had little benefit in reducing the risk of development or progression of AMD in a population of 1193 volunteers.47
There were few advanced AMD events in the latter study. Their results may be consistent with the AREDS finding of little or no treatment effect in slowing the progression of AMD in Category 2 participants.
Fifty-seven percent of AREDS participants were using a multivitamin or at least 1 ingredient found in the AREDS formulation at the time of their AREDS screening examination. About half of those supplementing were taking RDA doses rather than the 5- to about 15-fold higher doses of the AREDS ingredients. To accommodate these persons within the AREDS clinical trial and to standardize the use of nonstudy supplements, Centrum without lutein, a widely available multivitamin/mineral preparation with RDA-level dosages, was provided to each participant who wanted to take or continue to take a daily multivitamin. Approximately 67% of participants chose to take Centrum (about 13% of the AREDS participants who were not taking vitamins at the start of the study decided to take a multivitamin along with the study medication, perhaps because they were enrolling in this long-term study assessing the effects of vitamins and minerals). Thus, in addition to their dietary intake of vitamins C and E, beta carotene, and zinc, these persons had an increase in their intake by approximately 100% of the RDA for each of the study ingredients whether assigned to placebo or active intervention. Any increase in serum levels resulting from this intake was negligible compared with serum increases from the use of the study supplements. The statistical power of the study to test its primary hypothesis about high doses of the study ingredients might have been reduced to the extent that prior use or the continued use of RDA doses of these nutrients or other nutrients in the Centrum formulation affect the risk of AMD development. The treatment effect of the study formulations was in the beneficial direction for both AMD and visual acuity outcomes both in the group of participants choosing to supplement with Centrum at baseline and in the group not choosing Centrum at baseline (data not shown). However, these comparisons are underpowered and the choice to use Centrum was confounded by the presence of AMD at study entry.
Estimated pill counts showed that most patients took 75% or more of the assigned medications and adherence was balanced by treatment. These estimates suggest good adherence to the medication regimens, and this is supported by data showing that serum levels of each of the vitamins or minerals in the assigned study formulations in participants enrolled in the 3 AREDS clinics collecting specimens were elevated throughout the study. Tissue levels of the vitamins and minerals studied were not measured.
Possible differences between treatment groups and the placebo group were assessed for approximately 100 adverse events. The limited number of imbalances in the incidence of adverse events that were observed could be real or due to chance. The following 3 imbalances are notable (P<.01): an increase in hospitalization for genitourinary symptoms and an increase in self-reported anemia in persons assigned to receive zinc formulations; and an increase in yellowing of skin in persons assigned to receive antioxidants. A subset of participants was monitored for lipid and copper levels and the entire cohort was monitored for hematocrit because of potential concerns about the high doses of zinc given. Although there was an increase in self-reported anemia, no statistically significant effect of zinc supplements on hematocrit or serum levels of lipids or copper was observed. We have followed participants for an average of 6.3 years and have observed no serious consequence but we do not know the longer-term health effects of supplementation with these high doses of vitamins and minerals. Following the unmasking of study participants, all consenting participants will be followed for at least another 5 years.
Mortality in AREDS is about half that of the comparable general population.48
Early in the trial, a nonstatistically significant increase in mortality was observed among participants assigned to the antioxidants-alone arm. Results from 2 other randomized clinical trials suggested increased risk of mortality among smokers supplementing with beta carotene. The data and safety monitoring committee recommended that smokers discontinue study medications containing beta carotene. At the time of study enrollment, only 8% of AREDS participants were smokers and 49% were former smokers. Early imbalances in mortality were observed regardless of smoking status. Results to date find no statistically significant deleterious effect of antioxidants on mortality, although the RR estimate remains in the direction of harm for participants who had never smoked. Whether there is a true increase in risk cannot be confirmed by AREDS. The observation of a reduction in mortality associated with zinc arms compared with nonzinc arms may be somewhat exaggerated by the apparent nonstatistically significant increase in mortality observed for the antioxidants-alone arm. Comparison of zinc or zinc plus antioxidants with placebo was not significant (P
≥.14). Mortality risk in the antioxidants plus zinc arm was lower than in the placebo arm but this difference is also not statistically significant.
The antioxidant formulation included only 3 antioxidants: beta carotene, vitamin E, and vitamin C. Individual effects of each of these components cannot be evaluated. Two carotenoids, lutein and zeaxanthin, were considered for inclusion in the formulation during the planning phase because they are concentrated in the macula.49
However at AREDS initiation, neither carotenoid was readily available for manufacturing in a research formulation. Beta carotene, another carotenoid with antioxidant potential, was included because it was readily available and under investigation in clinical trials of heart disease and cancer. The dose of beta carotene used in this study was 15 mg/d. Other studies using similar doses of beta carotene in persons at high risk for lung cancer (cigarette smokers and asbestos workers) have demonstrated an increased incidence of cancer and mortality in persons assigned to beta carotene supplementation.42,43
Persons who smoke are at increased risk for both AMD50
and lung cancer. Whether the benefits of a formulation that contains beta carotene for AMD outweigh the increased risk of lung cancer cannot be determined from this study and it may be prudent for smokers to avoid taking beta carotene. Lutein and zeaxanthin may be beneficial to macular health51
but whether they can be substituted for beta carotene cannot be answered by AREDS. The dose of vitamin C (500 mg) used in the formulation is about 5 times what the general population receives from diet alone.44
The 400-IU dose of vitamin E is about 13 times the RDA and the dose of zinc as zinc oxide is about 5 times the RDA. These levels of zinc and vitamins C and E generally can be obtained only by supplementation.
When interpreting AREDS data, several factors should be considered. First, as is often the case in prevention studies, the population participating in this study may differ from the general population. The AREDS participants were relatively well-nourished compared with the general population, and the effect of this and other differences on the generalizability of AREDS findings is unknown. Second, the AREDS retinal outcomes are based on color fundus photography rather than on fluorescein angiography or clinical examinations. Using fundus photographs without fluorescein angiography to identify advanced AMD may delay the identification of advanced AMD events and may underestimate the absolute incidence. Most cases are identified with long-term follow-up and the assessment of the outcome is identical in each randomized treatment group. Third, for data in this study OR reductions are greater than estimates of RR reductions. Finally, it is not known how long someone at risk for advanced AMD should use supplements. Data from AREDS suggest that the combination therapy confers a treatment benefit for AMD and visual acuity outcomes that is maintained through 7 years of follow-up in participants at risk for progression to advanced AMD. The treatment benefit is modest and participants in all treatment arms continue to progress to advanced AMD and lose vision over time.
AREDS was designed to assess whether active treatment with antioxidants and/or zinc could reduce the risk of developing advanced AMD. The results are consistent in demonstrating that, compared with the placebo group, participants in Categories 3 and 4 assigned to receive antioxidants plus zinc had the largest reduction of the risk of developing advanced AMD or visual acuity loss. Participants assigned to receive either zinc or antioxidants seem to have a lesser benefit from the study medication. The study was not powered to assess whether there were differences between apparently effective treatments.
Who should consider long-term supplementation with zinc and antioxidants? The results of AREDS to date demonstrate no benefit of the study formulations for persons in Categories 1 or 2. For Americans older than age 70, approximately 80% fall in these low-risk groups.37
In AREDS, persons in these categories had low rates of progression to advanced AMD (1.3% in 5 years for Category 2 and <1% for Category 1) and therefore the study has very low power to assess the effect of these treatments on the development of advanced AMD. With these low rates it seems reasonable to defer consideration of supplementation until the risk of progression is higher, especially because analyses to date do not show that treatment is effective in slowing the progression of AMD from Category 2 to Categories 3 or 4. Whether supplementation benefits persons who already have advanced neovascular AMD in both eyes is not clear and this study was not designed to address this question. There is limited evidence from AREDS that supplements may delay further visual acuity loss in some of these more advanced eyes () but further study of this outcome is needed.
Although both zinc and antioxidants plus zinc significantly reduce the odds of developing advanced AMD for participants in Categories 3 and 4, the only statistically significant reduction in rates of at least moderate visual acuity loss occurred in persons assigned to antioxidants plus zinc. When considering long-term supplementation, some people may have reason to avoid 1 or more of the ingredients evaluated in AREDS. Persons who smoke cigarettes should probably avoid taking beta carotene, and they might choose to supplement with only some of the study ingredients. The effect of using zinc supplementation alone can be estimated from these data but the effect of using only some of the antioxidants or substituting other antioxidants, such as lutein, cannot be determined.
Based on data from AREDS, persons older than 55 years should have dilated eye examinations to determine their risk of developing advanced AMD. Those with extensive intermediate size drusen, at least 1 large druse, or noncentral GA in 1 or both eyes or those with advanced AMD or vision loss due to AMD in 1 eye, and without contraindications such as smoking, should consider taking a supplement of antioxidants plus zinc such as that used in this study.