gms | German Medical Science

Introduction: The Age-Related Eye Disease Study 2 (AREDS2) was designed to evaluate the effects of lutein/zeaxanthin and omega-3 LCPUFAs on AMD [1]. Observational data from the original AREDS suggested that the increased dietary intake of lutein and zeaxanthin in green leafy vegetable such as kale, collard greens, and spinach and omega-3 long-chain polyunsaturated fatty acids (LCPUFAs), in fish were inversely associated with the risk of late AMD [2], [3]. Because the AREDS2 participants are at high risk of developing late AMD, the AREDS formulation would be recommended to them. The treatment effect of the additional nutrients, lutein/zeaxanthin and omega-3 LCPUFAs was evaluated as the effect beyond that of AREDS formula, which reduced the risk of progression to late AMD by 25% in 5 years.

AREDS2 Results: The primary analyses compared each of the treatment groups with placebo and there were no statistically significant differences [4]. However, when using the entire population in the main effects evaluation comparing lutein/zeaxanthin vs. no lutein/zeaxanthin, there was a 10% reduction in the risk developing advanced AMD, hazard ratio (HR): 0.90, 95% confidence interval (CI): 0.82-0.99, p=0.04. When the effect was evaluated stratified by the different levels of dietary intake of lutein/zeaxanthin, the HR was 0.74 with 95% CI of 0.59 to 0.94, p=0.01 for those in the lowest level of dietary intake, in favor of supplementation with lutein/zeaxanthin. When tested for the two separate outcomes of advanced AMD, the HRs were 0.89 (CI: 0.79-1.00, p=0.05) for the development of neovascular AMD and 0.92 (CI: 0.78-1.07, p=0.27) for development of central geographic atrophy. We conducted a head-to-head comparison of lutein/zeaxanthin vs. beta-carotene by comparing those randomized to lutein/zeaxanthin and the AREDS formulation minus the beta-carotene with those randomized to AREDS formulation with beta-carotene (and NO lutein/zeaxanthin). The HRs for the lutein/zeaxanthin/ and AREDS with no beta-carotene vs. the no lutein/zeaxanthin/and AREDS with beta-carotene comparisons were 0.82 (95% CI: 0.69– 0.96), p=0.02 for progression to late AMD; 0.78 (95% CI: 0.64-0.94, p=0.01) for neovascular AMD; and 0.94 (95% CI: 0.70-1.26), p=0.67 for central geographic atrophy.

In analyses restricted to those with bilateral large drusen at baseline, the HRs for lutein/zeaxanthin vs. no lutein/zeaxanthin were 0.87 (95% CI: 0.77-0.95, 45 p=0.04) for developing late AMD; 0.80 (95% CI: 0.68-0.95, p=0.01) for progression to neovascular AMD, and 0.94 (95% CI: 0.78-1.13, p=0.51) for progression to central geographic atrophy. Individuals randomized to beta-carotene had an increased incidence of lung cancer (2% vs. 0.9%), P=0.04; 91% of incident lung cancers were in former smokers.

The visual acuity results showed no statistically significant differences for visual acuity loss of 10+ or 15+ letters from baseline. However, for the more severe visual acuity loss of 30+ letters from baseline or final visual acuity of worse than 20/100, the HR were 0.84 (o5% CI: 0.69-1.01), P=0.06 and 0.83 (95% CI: 0.89-1.00), P=0.05, respectively.

AREDS2 Conclusion: The totality of evidence would suggest that substituting lutein/zeaxanthin for beta-carotene in the AREDS formulation provides a safer and more efficacious supplement for the treatment of AMD in those who are at high risk of developing advanced AMD.

What have we learned beyond the primary results of AREDS2?

Numerous analyses and presentations have been made. A summary of these additional analyses will help us understand the use of observational data to either provide evidence for other hypotheses to be tested in the future. We also used the opportunity to replicate some of the analyses conducted in AREDS.

Planned Analyses:

1.

Validation of AREDS AMD Severity Scale: We planned to validate the AMD scale progression known as the AREDS AMD classification which is a 9 point scale. We used the AREDS2 data to assess whether the baseline AMD severity could predict progression in 5 years to late AMD. WE also evaluated by the simplified AMD AREDS Scale, ranging from 0 to 4. The rates of progression were very similar in AREDS2 as in AREDS.
The final conclusion was: The AREDS severity scale for AMD is a useful measure for assessing risk of late AMD in the AREDS2 population and should be a useful tool for future clinical trials of treatments for AMD.

2.

Cognitive Function Testing: None of the nutritional supplement, omega-3 fatty acids, lutein/zeaxanthin, zinc vs. no zinc, low vs. high levels of beta-carotene, had any treatment effect on cognitive function in AREDS2 participants. (data not presented) [5].

3.

Cardiovascular Disease: Neither omega-3 fatty acids and lutein/zeaxanthin had any effect on cardiovascular disease AREDS2 participants. (data not presented) [6].

4.

Association of Statins with AMD: We found no association of statin use with AMD, neither harmful nor beneficial.

5.

Association of Aspirin with AMD. We found no association of aspirin use with AMD, neither harmful nor beneficial.

6.

Association of cataract surgery with progression to late AMD. We found no accelerated progression to late AMD following cataract surgery.

7.

Progression Rate of Geographic Atrophy. The square root transformation of the area of progression of geographic atrophy in AREDS2 is similar to that of AREDS.

8.

Genetics and AMD have been described extensively in AREDS and further analyses are ongoing for AREDS2 (Data not presented).