AREDS 2: Primary Results & Beyond

AREDS 2: Primary Results & Beyond

For those who have read about the primary findings in the abstract of the AREDS2 paper, the trial’s instructive secondary and sub-group findings may have gone unnoticed. Those findings are highlighted here, and help explain the current recommendation of the National Eye Institute:

 

Patients with at least moderate AMD should consider taking – or continue to take – the original AREDS formula, with beta-carotene replaced by 10 mg of lutein and 2 mg of zeaxanthin.

 

Synopsis: AREDS2 Study Design & Methods

AREDS2 (1) enrolled 4203 patients with bilateral moderate AMD (large drusen with or without pigment changes) or advanced AMD in one eye.

The primary objective was to determine whether the addition of lutein/zeaxanthin (L+Z) or omega-3 fatty acids (omega-3s ) to the AREDS formula would be more effective in reducing the 5-year risk of advanced AMD or cataract (results of the cataract portion of the trial were published separately) (2).

Another goal was to assess whether eliminating beta-carotene or changing zinc levels in the original AREDS formula would affect risk of progression.

To accomplish these goals, all participants were randomly assigned to receive daily: L+Z (10 mg, 2 mg), omega-3s (1,000 mg), both, or placebo. The placebo group served as controls.

Patients also received either the original AREDS formula or a modified AREDS formula with no beta-carotene and/or lower zinc.

Results

A description of participants’ baseline characteristics can be found in EduFacts Vol. 13, No. 9. Fifty-nine percent (59%) had bilateral large drusen, and 32% had advanced AMD in one eye and mean visual acuity of 20/32 in non-advanced eyes.

About 50% of AREDS2 participants were former smokers, and another 7% were current smokers. Those who smoked and those who had stopped less than a year prior to enrolment were excluded from receiving beta-carotene.

Serum Levels of Lutein & Zeaxanthin:

After 5 years, serum levels of lutein and zeaxanthin in those receiving L+Z and getting a beta carotene-containing AREDS formula were significantly lower than those getting L+Z and no beta-carotene. The three carotenoids compete with each other for absorption, and this finding indicates that high dose beta-carotene interferes with the absorption of lutein and zeaxanthin.

Primary analyses:

Compared to taking only the AREDS formula (controls), neither L+Z nor omega-3s co-supplemented with an AREDS formula met the 25% additional decrease in risk required to show effectiveness.

Main Effects Analyses:

Comparing participants who received L+Z to those who did not, showed a 9% reduction in risk of progression for the L+Z group.

Secondary Randomization Analyses:

Participants in the secondary randomization who were assigned to formulas with no beta-carotene were compared to those receiving formulas that contained beta-carotene.

Eliminating this carotenoid did not curb the protective effect of the AREDS formula against developing advanced AMD, as the removal of beta-carotene had no significant effect on risk of progression.

Similarly, comparing formulas modified with low dose zinc (25 mg) vs. the original zinc dose (80 mg) showed no statistical difference for risk of progression. However a trend favoring better protection was observed for the higher dose of zinc.

When participants were stratified by dietary intake of lutein and zeaxanthin, those with the lowest intake of these carotenoids at baseline who received L+Z had a 26% reduction in risk for progression compared to those who did not get L+Z.

Further Sub-group Analysis:

To investigate relative treatment effects, those taking L+Z and modified AREDS formulas without beta-carotene were compared to those taking no L+Z, plus an AREDS formula with beta-carotene.

An 18% lower risk of advanced AMD was seen for participants taking no beta-carotene plus L+Z. Essentially, this analysis addressed the question ‘what would happen if you replaced beta-carotene with L+Z in the original AREDS formula?

Safety

Lung cancers were observed in 2% of participants who took AREDS containing beta-carotene compared to 0.9% who received no beta-carotene, and about 91% of those who developed lung cancer were former smokers. Lutein/zeaxanthin was not associated with lung cancer risk. Thus, lutein and zeaxanthin appears to be a safer choice for former smokers.

No clinically or statistically significant differences in adverse events were seen when comparing the low versus high dose zinc groups.

Comments

The preponderance of evidence from AREDS2 suggests that lutein and zeaxanthin offer some protection against AMD advancement. Though subgroup analyses are rigorously interpreted with a measure of caution, many of the secondary and sub group analyses were pre-specified to be evaluated in the study’s design.

The apparent competitive absorption between high dose beta-carotene and lutein/zeaxanthin may have reduced the ability of the study to detect a significant impact of L+Z on progression to advanced AMD compared to controls.

Importantly, L+Z appeared to benefit those with inadequate intake of these carotenoids. While AREDS2 patients were generally well nourished, their intake of lutein and zeaxanthin is not representative of the general US population, where low consumption is common. The authors suggest that a greater reduction in risk may have been seen if the subjects’ diets had more closely resembled that of the overall population.

Though not discussed above, results from the age-related cataract portion of AREDS2 indicate that those consuming insufficient levels of lutein and zeaxanthin also gained some protection.

While L+Z plus an AREDS formula did not help reduce the risk of progression to cataract surgery, there was a 32% reduction in the subsequent need for surgery for those consuming the least dietary lutein and zeaxanthin. A 30% lower risk of developing any cataract – and a 36% reduction in risk of developing any severe cataract – was also noted in this group.

Omega-3 fatty acids demonstrated no benefit above and beyond that conferred by the AREDS formula to those with at least moderate AMD. Whether or not the omega-3s have a role in the primary prevention of AMD awaits further investigation.

References

1. The AREDS2 Research Group. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration. JAMA Ophthalmol Epub ahead of print, May 5, 2013.
2. The AREDS2 Research Group. Lutein/Zeaxanthin for the treatment of age-related cataract. AREDS2 randomized trial report No. 4. JAMA Opthalmol Epubm ahead of print May 5, 2013.