TL;DR
The Age-Related Eye Disease Study 2 (AREDS2) represents one of the most significant advances in our understanding of how to manage age-related macular degeneration (AMD).
Conducted by the National Eye Institute, this landmark research has transformed the way eye care professionals approach nutritional supplementation for people at risk of vision loss.
What even is age-related macular degeneration?
Before exploring the AREDS2 study in detail, it’s important to understand what age-related macular degeneration actually is.
AMD is the leading cause of vision loss in people aged 50 and older in the UK and developed countries worldwide. The condition affects the macula, the central part of the retina responsible for sharp, detailed vision needed for activities like reading, driving, and recognising faces.
There are two main types of AMD:
- Dry AMD (atrophic): The most common form, accounting for approximately 85-90% of cases, where the macula gradually deteriorates over time
- Wet AMD (neovascular): A more severe form where abnormal blood vessels grow beneath the retina, causing rapid vision loss.
AMD doesn’t cause complete blindness, but it severely impacts central vision, making everyday tasks increasingly difficult and significantly affecting quality of life.
Timeline of AREDS and AREDS2 milestones
Understanding the development of AREDS2 is easier when you see the key dates:
- 2022: 10-year follow-up results published, confirming long-term benefits and safety of the AREDS2 formula
- 1992: The original AREDS study begins, enrolling 3,640 participants
- 2001: AREDS results published, showing 25% reduction in AMD progression risk with the original formula
- 2006: AREDS2 launches with 4,203 participants to refine and improve the formula
- 2012: AREDS2 primary study phase completes after five years of follow-up
- 2013: AREDS2 results published, establishing the lutein and zeaxanthin formula as superior to beta-carotene
- 2017: Extended follow-up continues to track participants’ outcomes.
The origins of AREDS2
The foundation: The original AREDS study
The journey to AREDS2 began with the groundbreaking original AREDS study, launched in 1992.
This initial clinical trial investigated whether a specific combination of vitamins and minerals could slow the progression of AMD and reduce cataract formation. The original AREDS formula consisted of:
- 500 mg vitamin C
- 400 international units vitamin E
- 15 mg beta-carotene
- 80 mg zinc (as zinc oxide)
- 2 mg copper (as cupric oxide)
The results were remarkable: the formula reduced the risk of progression to advanced AMD by approximately 25% in people with intermediate or advanced AMD in one eye.
However, questions remained about how to optimise the formula, particularly concerning beta-carotene, which subsequent research linked to an increased risk of lung cancer in smokers.
Launching AREDS2
Motivated by these safety concerns and the potential benefits of other nutrients, the National Eye Institute launched AREDS2 in 2006. The study aimed to refine the original formula by testing whether omega-3 fatty acids and the carotenoids lutein and zeaxanthin could enhance effectiveness whilst eliminating the risks associated with beta-carotene.
Key objectives of the AREDS2 study
AREDS2 was designed with several critical objectives:
Adding omega-3 fatty acids
Researchers tested whether adding omega-3 fatty acids – specifically docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) – would further reduce AMD progression risk. Omega-3s are concentrated in retinal structures and possess anti-inflammatory properties, making them promising candidates for eye health.
Substituting lutein and zeaxanthin for beta-carotene
Lutein and zeaxanthin are carotenoids naturally found in green leafy vegetables and concentrated in the macula. The study investigated whether these could serve as safer, more effective alternatives to beta-carotene, particularly for current and former smokers.
Adjusting zinc and beta-carotene levels
AREDS2 also examined the effects of removing beta-carotene entirely and testing lower zinc doses to determine if the original 80 mg daily amount was necessary for effectiveness.
The AREDS2 study design
AREDS2 was meticulously designed as a multicentre, randomised, double-masked, controlled clinical trial. The study enrolled 4,203 participants aged 50 to 85 years across 82 clinical sites in the United States between 2006 and 2012.
Participant criteria
The study included only individuals with:
- Intermediate AMD in both eyes, or
- Intermediate AMD in one eye and advanced AMD in the other eye
This targeted approach focused on people most likely to benefit from nutritional intervention, as previous AREDS data showed no benefit for those without AMD or with only early-stage disease.
Study groups
Participants were randomly assigned to receive different supplement combinations, allowing researchers to compare:
- The addition of lutein/zeaxanthin
- The addition of omega-3 fatty acids
- Both additions combined
- Variations with or without beta-carotene
- Different zinc levels (80 mg versus 25 mg)
Each participant was followed for an average of five years, undergoing regular comprehensive eye examinations, detailed retinal imaging, and diagnostic tests to accurately monitor disease progression.
Major findings from AREDS2
When the study results were published, they provided clear guidance for AMD management:
Omega-3 fatty acids showed no additional benefit
Despite the biological plausibility, adding DHA and EPA to the AREDS formula did not significantly reduce the risk of AMD progression. This finding surprised many researchers but provided important clarity about which supplements actually help.
Lutein and zeaxanthin proved beneficial
The substitution of lutein and zeaxanthin for beta-carotene was highly successful. Not only did this change eliminate the lung cancer risk associated with beta-carotene in smokers, but participants who took lutein and zeaxanthin also showed somewhat better protection against AMD progression, particularly those whose diets were low in these nutrients.
Zinc levels remained effective
Reducing zinc from 80 mg to 25 mg did not significantly affect the formula’s effectiveness, but the NEI continues to recommend 80 mg zinc based on the overall study results.
The AREDS2 formula recommendation
Based on these findings, the National Eye Institute now recommends the modified AREDS2 formula containing:
Importantly, current and former smokers should take the AREDS2 formula without beta-carotene to avoid the increased lung cancer risk.
The 10-year follow-up study
In 2022, researchers published results from a 10-year follow-up analysis, extending observations five years beyond the original study period. This longer-term research confirmed that:
- The AREDS2 formula continued to reduce AMD progression risk over a decade
- The substitution of lutein and zeaxanthin for beta-carotene was not only safer but actually more effective than the original formula
- The supplements remained well-tolerated with no significant adverse effects
- The benefits persisted in participants who continued taking the supplements.
These findings provided even stronger evidence for the AREDS2 formula’s long-term effectiveness and safety.
Who should take AREDS2 supplements?
AREDS2 supplements are specifically recommended for people with:
- Intermediate AMD in one or both eyes: These individuals are at higher risk of progression to advanced disease
- Advanced AMD in one eye: Even with vision loss in one eye, protecting the other eye is crucial
Who should not take AREDS2 supplements
AREDS2 supplements are not beneficial for:
- People without AMD or with only early-stage AMD (the supplements don’t prevent AMD onset)
- Those seeking cataract prevention (AREDS2 showed no effect on cataract development or progression)
Additionally, some people should avoid high-dose supplements for medical reasons, so it’s essential to discuss supplementation with your optometrist or ophthalmologist before starting.
Understanding your AMD stage
To determine whether AREDS2 supplements might benefit you, you need to know your AMD stage. During a comprehensive eye examination, your eye care professional will:
- Dilate your pupils to examine your retina
- Look for drusen (yellow deposits under the retina)
- Assess the extent of retinal pigment changes
- Classify your AMD as early, intermediate, or advanced
Based on this assessment, they can advise whether AREDS2 supplementation is appropriate for your situation.
Impact on eye health recommendations in the UK
Whilst AREDS2 was conducted in the United States, its findings have influenced eye care recommendations worldwide, including in the UK. The Royal College of Ophthalmologists and optometrists across Britain now regularly recommend AREDS2-based supplements for appropriate patients.
NHS and private care
On the NHS, AREDS2 supplements are not typically prescribed, as they’re classified as nutritional supplements rather than medicines. However, eye care professionals will advise eligible patients to purchase appropriate supplements from pharmacies or health retailers. Many opticians and pharmacies in the UK stock AREDS2-formula products specifically designed to meet the study specifications.
A landmark in eye health research
For people with AMD, AREDS2 supplements offer hope – not as a cure, but as a scientifically proven method to slow disease progression.
Combined with regular eye care, healthy lifestyle choices, and appropriate medical treatment when needed, these supplements form part of a comprehensive strategy for preserving vision and maintaining quality of life as we age.
If you’re concerned about AMD or have been diagnosed with the condition, speak with your eye care professional about whether AREDS2 supplementation is right for you. With the right approach, many people with AMD can continue to enjoy good functional vision for years to come.
