The NIH AREDS2 Study: Age-Related Macular Degeneration (AMD) Treatment

The NIH AREDS2 Study: Comprehensive Results and Implications for Age-Related Macular Degeneration Treatment

Introduction

The Age-Related Eye Disease Study 2 (AREDS2) represents one of the most significant clinical trials in ophthalmology, conducted by the National Eye Institute (NEI) from 2006 to 2012, with long-term follow-up extending to 2018. This landmark study built upon the original AREDS findings and fundamentally changed how clinicians approach nutritional supplementation for age-related macular degeneration (AMD).

Study Design and Methodology

AREDS2 was designed as a multicenter, randomized, double-masked, placebo-controlled clinical trial with a 2x2 factorial design. The study aimed to test whether adding omega-3 fatty acids (DHA and EPA) or lutein plus zeaxanthin would enhance the effectiveness of the original AREDS formulation, while also evaluating the safety and efficacy of removing beta-carotene.

Primary Objectives

• Evaluate the effects of omega-3 fatty acids and lutein/zeaxanthin supplementation on AMD progression
• Assess the safety of eliminating beta-carotene from the original AREDS formula
• Test the impact of reducing zinc dosage from 80mg to 25mg

Study Population and Demographics

AREDS2 enrolled 4,203 participants aged 50-85 years across 82 clinical sites throughout the United States between October 2006 and September 2008. The study population had the following characteristics:

• Mean age: 74 years (range: 50-85 years)
• Gender distribution: 57% female, 43% male
• Race: 97% Caucasian, with small representations of other ethnic groups
• Education: 65% had more than a high school education
• Smoking status: 44% never smoked, 49% former smokers, 7% current smokers

Inclusion Criteria

Participants were required to have intermediate AMD in both eyes or intermediate AMD in one eye with advanced AMD in the fellow eye. The study excluded individuals with early AMD or no AMD, as the original AREDS data showed no benefit for these populations.

AREDS2 Supplement Formulations

The study tested various combinations of the following supplements:

Original AREDS Formula

• Vitamin C: 500 mg
• Vitamin E: 400 IU
• Beta-carotene: 15 mg
• Zinc (as zinc oxide): 80 mg
• Copper (as cupric oxide): 2 mg

AREDS2 Formula (Final Recommended)

• Vitamin C: 500 mg
• Vitamin E: 400 IU
• Lutein: 10 mg
• Zeaxanthin: 2 mg
• Zinc: 80 mg
• Copper: 2 mg
• Beta-carotene removed

Primary Study Results

AMD Progression Outcomes

The AREDS2 study confirmed that nutritional supplementation continues to provide significant protection against AMD progression:

• Overall risk reduction: AREDS and AREDS2 formulations reduce the risk of progression from intermediate to advanced AMD by approximately 25%
• Vision preservation: The supplements reduced vision loss by 19% in high-risk individuals
• No effect on AMD onset: The supplements do not prevent the initial development of AMD

Key Findings on Supplement Components

Lutein and Zeaxanthin vs Beta-Carotene

One of the most significant findings was the superiority of lutein and zeaxanthin over beta-carotene:

• Participants taking AREDS formulation with lutein/zeaxanthin but without beta-carotene had an 18% lower risk of progressing to advanced AMD compared to those taking the original formula with beta-carotene
• Among participants with the lowest dietary intake of lutein and zeaxanthin, those supplemented showed a 26% lower risk of AMD progression

Omega-3 Fatty Acids

Despite initial optimism, omega-3 fatty acids (DHA and EPA) showed no significant benefit:

• Adding omega-3 fatty acids to the AREDS formulation had no additional overall effect on AMD progression risk
• No beneficial impact on cataract development was observed

Zinc Dosage

The study found no significant difference in efficacy when zinc was reduced from 80mg to 25mg, suggesting the higher dose provides no additional benefit.

Safety Results: The Beta-Carotene Concern

Lung Cancer Risk

One of the most critical safety findings concerned beta-carotene supplementation:

• Former smokers taking beta-carotene experienced a nearly doubled risk of lung cancer (OR: 1.82, 95% CI: 1.06-3.12)
• No increased lung cancer risk was observed with lutein/zeaxanthin supplementation (OR: 1.15, 95% CI: 0.79-1.66)
• Current smokers were excluded from receiving beta-carotene during the trial due to known risks

Long-Term Safety Profile

The 10-year follow-up study confirmed these safety findings:

• Beta-carotene continued to show elevated lung cancer risk beyond the trial period
• Lutein/zeaxanthin demonstrated excellent long-term safety with no cancer associations
• The majority of lung cancer cases occurred in former smokers

Geographic Atrophy Outcomes

Recent analysis of AREDS2 data revealed important findings about geographic atrophy (GA), the advanced form of dry AMD:

GA Progression Rates

• Incidence: 17.3% of at-risk eyes developed incident GA during mean follow-up of 4.4 years
• Central involvement risk: Eyes with non-central GA had a 57% risk of central involvement within 4 years
• Enlargement rates: GA enlarged at approximately 0.28-0.29 mm/year following square root transformation

AREDS2 Supplements and GA

A 2024 analysis found that AREDS2 supplements may slow GA progression by up to 55% over three years, particularly when GA is located outside the central fovea.

Long-Term Follow-Up Results (10 Years)

The extended follow-up study of 3,882 participants provided crucial long-term data:

AMD Progression

• Lutein/zeaxanthin showed a persistent beneficial association with reduced late AMD progression (HR: 0.91, 95% CI: 0.84-0.99)
• When directly compared to beta-carotene, lutein/zeaxanthin showed a 20% reduction in late AMD risk (HR: 0.80, 95% CI: 0.68-0.92)

Safety Confirmation

• No long-term adverse effects were associated with lutein/zeaxanthin
• Beta-carotene risk for lung cancer persisted throughout the 10-year follow-up period
• The study provided definitive evidence supporting the formula change

Clinical Implications and Recommendations

Current Formula Recommendations

Based on AREDS2 results, the current recommended formulation includes:

• Vitamin C: 500 mg
• Vitamin E: 400 IU
• Lutein: 10 mg
• Zeaxanthin: 2 mg
• Zinc: 25-80 mg (both doses shown effective)
• Copper: 2 mg
• Beta-carotene: Should be avoided, especially in current and former smokers

Target Population

AREDS2 supplements are recommended for individuals with:

• Intermediate AMD in both eyes
• Advanced AMD in one eye with intermediate AMD in the fellow eye
• Not recommended for individuals without AMD or with only early AMD

Special Considerations

• Smokers and former smokers should exclusively use the AREDS2 formula without beta-carotene
• Supplements do not prevent AMD onset but significantly slow progression
• No effect on cataract development has been demonstrated

Economic and Public Health Impact

The AREDS2 findings have substantial implications for public health:

• With an estimated 288 million people expected to be affected by AMD globally by 2040, even modest improvements in treatment effectiveness have enormous impact
• The 10-20% additional benefit from lutein/zeaxanthin over beta-carotene could prevent thousands of cases of vision loss
• The safety profile makes AREDS2 supplements suitable for long-term use in appropriate populations

Limitations and Future Directions

Study Limitations

• Participants were predominantly Caucasian (97%), limiting generalizability to other populations
• The study excluded current smokers from beta-carotene arms, potentially underestimating risks
• Long-term follow-up had some participant attrition

Future Research

Ongoing research continues to explore:

• Optimal dosing strategies for individual components
• Additional nutrients that might enhance AMD protection
• Personalized medicine approaches based on genetic risk factors
• Treatment strategies for geographic atrophy

Conclusion

The AREDS2 study represents a paradigm shift in AMD management, providing robust evidence for the current recommended supplement formulation. The replacement of beta-carotene with lutein and zeaxanthin not only improved safety profiles but also enhanced efficacy in preventing AMD progression. For individuals with intermediate AMD or advanced AMD in one eye, AREDS2 supplements offer a 25% reduction in progression risk with excellent long-term safety, making them a cornerstone of current AMD management strategies.

The study's comprehensive design, large participant population, and extended follow-up period provide confidence in these recommendations, supporting their continued use in clinical practice and their availability to patients at risk for vision loss from AMD.

References

References

**** National Eye Institute. Age-Related Eye Disease Studies (AREDS/AREDS2). https://www.nei.nih.gov/research/clinical-trials/age-related-eye-disease-studies-aredsareds2/about-areds-and-areds2

**** Macular Society. AREDS2 supplements slow sight loss in late-stage dry AMD. July 18, 2024. https://www.macularsociety.org/about/media/news/2024/july/areds2-supplements-slow-sight-loss-in-late-stage-dry-amd/

**** Chew EY, et al. Long-term Outcomes of Adding Lutein/Zeaxanthin and ω-3 Fatty Acids to the AREDS Supplements on Age-related Macular Degeneration Progression. JAMA Ophthalmology. 2022. https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2792855

**** BrightFocus Foundation. New Study Confirms the Efficacy of AREDS2 Eye Vitamin Supplement. February 25, 2025. https://www.brightfocus.org/resource/new-study-confirms-the-efficacy-of-areds2-eye-vitamin-supplement-for-slowing-age-related-macular-degeneration/

**** National Center for Biotechnology Information. Long-term Outcomes of Adding Lutein/Zeaxanthin and ω-3 Fatty Acids. PubMed. 2022. https://pubmed.ncbi.nlm.nih.gov/35653117/

**** National Eye Institute. AREDS/AREDS2 Frequently Asked Questions. November 18, 2020. https://www.nei.nih.gov/research/clinical-trials/age-related-eye-disease-studies-aredsareds2/aredsareds2-frequently-asked-questions

**** University of Michigan Health. Dietary Supplements and Age-Related Macular Degeneration. January 31, 2004. https://www.uofmhealth.org/conditions-treatments/dietary-supplements-and-age-related-macular-degeneration

**** Chew EY, et al. The Age-Related Eye Disease Study 2 (AREDS2). PMC. July 25, 2012. https://pmc.ncbi.nlm.nih.gov/articles/PMC3485447/

**** Chang JR, et al. Demographic and Dietary Characteristics of the AREDS2 Participants. Investigative Ophthalmology & Visual Science. 2010. https://iovs.arvojournals.org/article.aspx?articleid=2369340

**** Keenan TD, et al. Progression of geographic atrophy in age-related macular degeneration. PMC. July 26, 2018. https://pmc.ncbi.nlm.nih.gov/articles/PMC6246813/

**** Chew EY, et al. Long-term Outcomes of Adding Lutein/Zeaxanthin and ω-3 Fatty Acids. PMC. June 1, 2022. https://pmc.ncbi.nlm.nih.gov/articles/PMC9164119/