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In the news: Genotype Doesn’t Modify Response to AREDS2 Supplements; Aspirin Use Not Linked to AMD Progression

AREDS2 Supplement Benefits Do Not Differ by Genotype

A new post hoc analysis of the Age-Related Eye Disease Study 2 (AREDS2) concludes that two major risk alleles for AMD, complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2), do not modify the response to AREDS2 supplements for the treatment of AMD (1). Genotype made no difference in the benefits derived from AREDS2 supplements.

Whether or not genotyping should be considered for AMD patients who meet the criteria for AREDS supplementation has been controversial. When there is an interaction between genotype and treatment, it means that the response to the treatment differs depending on an individual’s genotype.

Several post hoc analyses have suggested that there are genetic subgroups who may respond differently to nutrient components (e.g. zinc vs. antioxidants) in AREDS supplements, while other analyses haven’t found any significant interactions. Recently, independent groups from three different academic centers each evaluated the available evidence and concluded that genotyping of CFH and ARMS2 to guide supplement choice for slowing AMD progression is unwarranted.

Since all previous analyses have used data from the original AREDS1 trial, and no other intervention study as large as AREDS is available to independently replicate previous findings, investigators decided to evaluate AREDS2 for any interaction between these risk alleles and response to AREDS2 supplements.

AREDS2 evaluated the following additions to the original AREDS formula (vitamins C, E, beta-carotene, zinc and copper): lutein/zeaxanthin, EPA + DHA, both or placebo. A secondary randomization tested further modifications of the original formula: lower zinc dose, no beta-carotene, both or no modification. Most of the participants also received the original AREDS formula.

The current analyses used 2775 eyes without late AMD at baseline of participants with complete data who were followed for a median of 5 years.

Genotype did not significantly modify the response to any of the AREDS2 supplements in respect to the progression of late AMD, including geographic atrophy (GA) and wet AMD. Subgroups based on CFH or ARMS2 did not respond differently to supplements with either lutein/ zeaxanthin, EPA/DHA, beta-carotene or high or low zinc doses. This was also true for groupings based on both CFH and ARMS2 genotypes.

The ARMS2 risk allele was significantly associated with progression to late AMD and wet AMD, but not with GA. No association between the CFH risk allele and AMD progression was seen.

The results suggest that AREDS2 supplements can be recommended to those with at least intermediate AMD who carry risk alleles CFH or ARMS2.

Aspirin Use not Associated with AMD Progression

In addition to analyzing for genetic interactions with AREDS2 supplements, AREDS researchers have also looked at interactions between the risk of AMD progression and taking aspirin – one of the most widely used drugs worldwide. Some observational studies have reported a link between regular aspirin use and increased risk of wet AMD (2).

Matching by propensity score (propensity for aspirin use) showed that the characteristics of the users and non-users were similar in both AREDS and AREDS2, so both studies were analyzed. Participants were stratified by quintiles, with quintile 5 being the highest propensity for aspirin use and quintile 1 the reference.

No significant association with progression to late AMD, geographic atrophy or wet AMD was observed for any quintile 2-5. The authors conclude that “patients with AMD need not avoid aspirin for this reason, when its use is medically indicated.”

References

1. Van Asten F, et al. and the Age-Related Eye Disease Study 2 Research Group. No CFH/ARMS2 interaction with omega-3 fatty acids, low vs high zinc, or beta-carotene vs lutein/ zeaxanthin on progression of age-related macular degeneration in the Age-Related Eye Disease Study 2 (AREDS2). AREDS2 Report No. 18. Ophthalmol. Epub June 12, 2019.
2. Keenan TD, et al. and the Age-Related Eye Disease Study 2 Research Group. The association of aspirin use with age-related macular degeneration progression in the Age-Related Eye Disease Studies: AREDS2 Report No. 19. Opthalmol. Epub June 26, 2019.