What is the recommended formulation for individuals at risk of age-related macular degeneration (AMD) using AREDS 2 (Age-Related Eye Disease Study 2)?

AREDS 2 Formulation for Age-Related Macular Degeneration

The recommended AREDS2 formulation consists of vitamin C, vitamin E, zinc (25mg), copper, lutein (10mg), and zeaxanthin (2mg), which should be prescribed to patients with intermediate AMD or advanced AMD in one eye to reduce progression risk by up to 36% over 10 years. 1

Who Should Receive AREDS2 Supplements

Prescribe AREDS2 formulation to:

• Patients with intermediate AMD (bilateral large drusen) 1
• Patients with advanced AMD in one eye 1
• Patients with large drusen and RPE changes 1

Do not prescribe for:

• Early AMD without significant drusen 1
• Patients without AMD as primary prevention 2

Specific AREDS2 Formulation Components

The evidence-based formulation includes: 1

• Vitamin C (dose per original AREDS)
• Vitamin E (dose per original AREDS)
• Zinc 25mg (AREDS2 demonstrated equivalence to 80mg, with lower genitourinary hospitalization risk) 1
• Copper (necessary to prevent copper-deficiency anemia from zinc supplementation) 3, 1
• Lutein 10mg 1, 4, 5
• Zeaxanthin 2mg 1, 4, 5

Critical Formulation Changes from Original AREDS

Beta-carotene was eliminated from AREDS2 due to an 18% increased cumulative incidence of lung cancer in current and former smokers (95% CI, 3%-36%; P=0.01), with relative risk of 1.28 (95% CI, 1.04-1.57; P=0.02). 3 Lutein and zeaxanthin serve as the appropriate carotenoid substitute, particularly for former smokers. 1, 4, 5

Zinc dose was reduced from 80mg to 25mg because AREDS2 showed no significant difference in AMD progression between these doses, while the higher dose increased hospitalizations for genitourinary causes (7.5% vs 4.9%; P=0.001). 3, 1

Evidence Supporting Lutein/Zeaxanthin Substitution

Secondary analyses from AREDS2 demonstrated that lutein/zeaxanthin versus beta-carotene showed: 4

• Hazard ratio 0.82 (95% CI, 0.69-0.96; P=0.02) for development of late AMD
• Hazard ratio 0.78 (95% CI, 0.64-0.94; P=0.01) for neovascular AMD
• In eyes with bilateral large drusen specifically: HR 0.76 (95% CI, 0.61-0.96; P=0.02) for late AMD progression 4

While primary AREDS2 analysis did not show statistically significant benefit for lutein/zeaxanthin supplementation (HR 0.90,98.7% CI 0.76-1.07; P=0.12), exploratory analyses comparing lutein/zeaxanthin directly to beta-carotene demonstrated superiority, and the totality of evidence supports this substitution. 4, 5

Important Safety Considerations and Counseling Points

Mandatory smoking cessation counseling must accompany AREDS2 prescription, as smoking is the key modifiable risk factor for AMD progression. 1

Coordinate with primary care physician before initiating long-term supplementation due to potential adverse effects, particularly the increased rate of genitourinary conditions requiring hospitalization with zinc supplementation. 3

Advise patients that:

• AREDS2 slows progression but does not reverse existing damage 1
• Central vision loss may still occur despite supplementation 1
• Total blindness is extremely rare, as peripheral vision remains preserved 1
• If over 300,000 at-risk patients received supplements, disease progression and vision loss could be delayed 1

Clinical Pitfalls to Avoid

Do not prescribe beta-carotene-containing formulations to current or former smokers due to documented lung cancer risk. 3, 5 The AREDS2 study noted 23 lung cancers (2.0%) in the beta-carotene group versus 11 (0.9%) in the no beta-carotene group (P=0.04), predominantly in former smokers. 5

Do not use 80mg zinc formulations when 25mg provides equivalent efficacy with better safety profile. 3, 1

Do not delay anti-VEGF therapy in wet AMD patients while initiating AREDS2 supplements—these are complementary treatments, not alternatives. 1 Anti-VEGF therapy must be initiated immediately upon diagnosis of neovascular AMD with three loading doses at 4-week intervals. 1