Antioxidants May Slow Age-Related Macular Degeneration

Miriam E. Tucker

December 31, 2012

Oral antioxidant supplementation, including with lutein and zeaxanthin, was associated with some benefits in macular function and morphologic features among patients at high risk for progression to advanced age-related macular degeneration (AMD), according to results from a new study.

The results were published online December 7 in Ophthalmology by Stephen Beatty, MD, from the Macular Pigment Research Group, Waterford Institute of Technology, Waterford City, Waterford, Republic of Ireland, and colleagues.

The 2-site double-masked, randomized, placebo-controlled Carotenoids With Coantioxidants in Age-Related Maculopathy (CARMA) study did not reach significance in its primary endpoint, best-corrected visual acuity (BCVA) at 1 year. Those results are to be published separately in early 2013. The current article reports on the secondary endpoints.

"This trial and several others indicate benefits to functional vision with lutein supplementation. What this trial has demonstrated over and above is the marginal slowing down of progression along the early AMD severity scale," coauthor Usha Chakravarthy, MD, PhD, from the Center for Vascular and Vision Sciences, Institute of Clinical Science, Royal Victoria Hospital, Belfast, Northern Ireland, told Medscape Medical News.

Participants in the supplement arm took a tablet twice daily to provide a daily dose of 12 mg lutein, 0.6 mg zeaxanthin, 15 mg d-α-tocopherol (vitamin E), 150 mg ascorbic acid (vitamin C), 20 mg zinc oxide, and 0.4 mg copper gluconate. The product is currently sold in the United States as a supplement under the name Ocuvite (Bausch and Lomb Inc). US versions of Ocuvite have formulations differing from the one used in this study. The placebo was an identical cellulose-based pill.

Study participants all had early AMD in at least 1 eye. Of a total 433 eligible participants, 252 contributed 1 study eye and 181 contributed 2 study eyes to the analysis. The investigators randomly assigned 216 participants to the supplement group and 217 to the placebo group.

By study design, the minimum follow-up period was 1 year. Secondary endpoints were assessed at 6-month intervals through 36 months. The actual follow-up averaged 18.3 months, or 7908 person-months.

The mean change in BCVA at 1 year, the primary endpoint, favored the supplemented group, but the difference did not reach statistical significance. However, there were significant improvements in some of the secondary endpoints, Dr. Beatty and colleagues report in the current article.

At 24 months, there was a 1.4-letter difference in BCVA favoring the active treatment (79.2 vs 78.7; P = .04) and slightly improved contrast sensitivity that did not reach statistical significance. At 36 months, the difference in BCVA had increased to approximately 4.8 letters in favor of the supplement (83.1 vs. 79.5; P = .04).

However, there was considerable drop-off in the study, with just 125 study eyes in the supplemented group and 135 in the placebo group remaining at 24 months and 30 and 28 eyes, respectively, at 36 months.

Progression to a higher-severity stage was slower in the group on active treatment. At 12 months, for example, 47.4% of 228 eyes in the placebo group had progressed compared with 41.7% of 230 eyes in the supplement group. Progression to late AMD (either central geographic atrophy or choroidal neovascularization) occurred in 39 placebo and 33 active treatment groups, which was an insignificant difference.

Macular pigment (MP), assessed by Raman counts, differed significantly between the 2 groups at each point except at 36 months, when the numbers became too small. Raman counts increased slightly over time in the supplement group while dropping steadily in the placebo group, with P values of .006 at 12 months, 0.000 at 24 months, and 0.454 at 36 months.

"This prospectively observed decline in MP over time in eyes with AMD has not been reported previously and is consistent with loss of photoreceptors in association with this disease, because MP is housed in the photoreceptors and their axons," the authors write.

Among the individual analytes in the supplement, lutein was the only one for which a significant relationship with visual acuity was found, with 10-fold rise in serum concentration associated with a 1.4-letter benefit (95% confidence interval, 0.3 - 2.5; P = .01). However, removal of a single outlier reduced this effect to 0.9 letters and eliminated the significance (95% confidence interval, −0.2 to 1.9).

There was a significantly slower progression along the AMD severity scale with the supplement of about 0.2 of an AMD stage (P = .014), Dr. Beatty and colleagues report.

Longer Follow-up Needed

"What the findings indicate are that persons with marked features of early AMD at risk of progression to late AMD may benefit from higher intake of lutein either through improved diet or through supplementation," Dr. Chakravarthy told Medscape Medical News.

Lutein and zeaxanthin, used in the CARMA supplement, were not included in the antioxidant formulation used in the large, placebo-controlled Age-Related Eye Disease Study (AREDS). That study did demonstrate slowing of AMD progression after a mean of 6 years' follow-up with high doses of vitamins C and E, beta-carotene, and zinc.

A second phase of AREDS, the AREDS2 trial, is investigating the use of high doses of both lutein and zeaxanthin along with the original AREDS formula, which is now the standard of care.

One of the AREDS2 investigators, retina specialist John W. Kitchens, MD, from Lexington, Kentucky, told Medscape Medical News that the small numbers and relatively short follow-up are among CARMA's limitations.

"Studies have shown that carotenoid supplementation can increase [MP] density, but what is not known is whether this has an impact on progression of AMD or visual acuity change. Unfortunately, this study is not powered properly, nor is the follow-up sufficient to determine either of these results. The forthcoming AREDS2 study with over 4000 participants and 5 years of follow-up should give us some solid data in this regard."

Dr. Chakravarthy acknowledged that the duration of follow-up in CARMA was insufficient, noting that it was the sponsor's decision not to extend the trial.

As for the role of lutein in particular, Dr. Kitchens said, "As of yet we do not have firm evidence to support the use of the individual antioxidants other than those recommended by the original AREDS study."

However, regarding CARMA, Larry Benjamin, MBBS, DO, vice president of the United Kingdom's Royal College of Ophthalmologists, London, told Medscape Medical News, "The secondary outcomes are statistically significant, and therefore it is probably reasonable to believe them. They show a better visual outcome after 12 months follow-up."

Dr. Benjamin said CARMA suggests that "screening for the earlier stages of the disease may be worthwhile in order to implement this oral supplementation and reduce the rate of progression of the disease in an earlier stage.... It would do no harm to promote this supplement in appropriate patients at suggested doses, but longer-term data on side effects and disease progression is not available."

Of course, he added, "The cost implications of screening and treatment need to be born in mind, as do other factors such as smoking and diet."

Dr. Chakravarthy, Dr. Kitchens, and Dr. Benjamin all pointed to the upcoming AREDS2 findings as potentially providing conclusive data regarding the benefits of antioxidant supplementation in AMD. Those results are expected in 2013.

The CARMA study was supported by a grant from Bausch and Lomb, Dr. Mann Pharma. The authors, Dr. Kitchens, and Dr. Benjamin have disclosed no relevant financial relationships.

Ophthalmology. Published online December 7, 2012. Abstract