What is the recommended Age‑Related Eye Disease Study 2 (AREDS2) supplement formulation and dosing for a patient with intermediate dry age‑related macular degeneration, and how should smoking status affect its use?

AREDS2 Supplementation for Intermediate Dry AMD

For patients with intermediate dry age-related macular degeneration, prescribe the AREDS2 formulation containing vitamin C, vitamin E, zinc 25mg, copper, lutein 10mg, and zeaxanthin 2mg daily, which reduces progression to advanced AMD by up to 36% over 10 years. 1

Recommended AREDS2 Formulation Components

The evidence-based AREDS2 supplement contains the following specific doses: 1, 2

• Vitamin C: 500mg
• Vitamin E: 400 IU
• Zinc: 25mg (reduced from original 80mg dose)
• Copper: 2mg (essential to prevent copper-deficiency anemia from zinc)
• Lutein: 10mg
• Zeaxanthin: 2mg

The original AREDS trial demonstrated that antioxidant multivitamins combined with zinc reduced progression to late AMD (OR 0.72) and visual acuity loss of more than 3 lines (OR 0.77), with the combination reducing risk of progression to advanced AMD and visual acuity loss of at least 15 letters (OR 0.73). 1

Critical Modifications Based on Smoking Status

Current and former smokers must receive AREDS2 formulations WITHOUT beta-carotene due to an 18% increased cumulative incidence of lung cancer (relative risk 1.28), with 23 lung cancers in the beta-carotene group versus 11 in the no beta-carotene group. 1 Lutein and zeaxanthin serve as appropriate carotenoid substitutes for beta-carotene, particularly for smokers. 3, 1

Secondary analyses from AREDS2 showed that direct comparison of lutein/zeaxanthin versus beta-carotene demonstrated hazard ratios of 0.82 for development of late AMD and 0.78 for neovascular AMD, supporting this substitution. 4

Indications for AREDS2 Supplementation

Initiate AREDS2 supplements immediately for patients with: 5, 2

• Bilateral large drusen (≥125 μm)
• Confluent drusen with RPE changes (clumping, atrophy, or hyperpigmentation)
• Advanced AMD in one eye with intermediate AMD in the fellow eye
• Intermediate AMD with high-risk features including family history

The American Academy of Ophthalmology notes that if all at-risk patients received supplements, more than 300,000 could delay disease progression and associated vision loss. 1

Mandatory Smoking Cessation Counseling

Cigarette smoking is the only proven modifiable risk factor for AMD and must be addressed aggressively at every clinical encounter. 5 Current smokers face 2-3 times higher risk of AMD compared to non-smokers, with risk increasing proportionally to pack-years smoked. 5, 2 Smoking cessation is non-negotiable as it represents the key modifiable risk factor beyond supplementation. 1

Safety Considerations and Coordination with Primary Care

Coordinate with the patient's primary care physician before initiating long-term AREDS2 supplementation due to potential adverse effects. 1 The original AREDS trial reported increased risk of hospitalization due to genitourinary causes with zinc supplementation, particularly at the 80mg dose. 3, 1 The AREDS2 formulation uses 25mg zinc, which shows equivalent efficacy to 80mg with improved safety profile. 1

Copper supplementation at 2mg is mandatory to prevent copper-deficiency anemia from zinc. 1 The AREDS2 trial found that antioxidants were associated with increased risk of yellowing skin, though this was generally well-tolerated. 3

Common Pitfalls to Avoid

• Never prescribe beta-carotene-containing formulations to current or former smokers due to documented lung cancer risk 1
• Avoid 80mg zinc formulations when 25mg provides equivalent efficacy with better safety 1
• Do not use AREDS2 supplements as substitute for anti-VEGF therapy in wet AMD—these are complementary treatments 1
• Ensure copper is included in any zinc-containing formulation to prevent anemia 1

Patient Education and Monitoring

Provide patients with an Amsler grid for daily home monitoring of metamorphopsia (distorted vision), instructing them to look at the central dot and evaluate if any grid lines appear wavy or distorted. 1, 2 Patients must return immediately for any new visual symptoms, as the fellow eye remains at exceptionally high risk in unilateral disease. 1

Counsel patients that AREDS2 supplements slow progression but do not restore lost vision, and that peripheral vision is typically preserved even with central vision loss. 1 Regular comprehensive eye examinations remain crucial for early detection, as early AMD is typically asymptomatic. 5, 2