AREDS2

In Review

Age-Related Eye Disease Study 2 Research Group writers. "Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial". JAMA. 2013. 309(13):2005-2015.
PubMed

Clinical Question

In patients with risk for advanced AMD, does added intake of lutein-zeaxanthin, omega-3-long-chain polyunsaturated fatty acids (DHA + EPA), or both to the established AREDS formula (antioxidant vitamins C and E, beta carotene, and zinc) reduce the risk for developing advanced AMD?

Bottom Line

The addition of lutein + zeaxanthin, DHA + EPA, or both to the AREDS formulation does not statistically reduce the risk of progression to advanced AMD. However, lutein + zeaxanthin could serve as an appropriate substitute for beta carotene due to a potential increased incidence of lung cancer in former smokers.

Major Points

The prior Age-Related Eye Disease Study (AREDS) formulation (including vitamins C and E, beta carotene, and zinc) was shown to reduce the progression to age-related macular degeneration (AMD), which was supported by a 2012 Cochrane review. However, the ATBC (1994) and CARET (1996) studies raised concerns that beta carotene may increase the risk for lung cancer mortality among smokers. The AREDS2 trial's primary intervention sought to determine if adding lutein+zeaxanthin, DHA + EPA, or both reduced this risk of progression. The study's secondary intervention evaluated the effects of eliminating beta carotene, lowering zinc doses, or both in the original AREDS formulation. The AREDS2 trial's primary analyses showed no statistically significant overall effect of lutein+zeaxanthin or DHA+EPA on progression to advanced AMD or changes in visual acuity. There was also no effect of beta carotene elimination or lower-dose zinc on progression to advanced AMD. The incidence of lung cancers was noted to be higher in former smokers who were treated with beta carotene, suggested a possible substitution of beta carotene with lutein+zeaxanthin.

Guidelines

AAO age-related macular degeneration (2015, adapted)

• Antioxidant vitamin and mineral supplementation per AREDS and AREDS2 should be considered if intermediate or advanced AMD
  • No evidence supports use of these supplements if below intermediate AMD
• Replacement of beta-carotine with lutein/zeaxanthin may reduce risk of lung cancer in smokers

Design

• Multicenter, randomized, double-masked, placebo-controlled phase 3 study with a 2x2 factorial design
• N=4203 (6916 eyes)
  • Primary Randomization (AREDS with lutein+zeaxanthin, DHA+EPA, or Both) (n=4203)
    • Placebo (n=1012), Lutein+zeaxanthin (n=1044), DHA+EPA (n=1068), Both (n=1079)
  • Secondary Randomization (AREDS with no beta carotene, with low-dose zinc, or both) (n=3036)
    • Placebo (n=659), No beta carotene (n=863), Low-dose zinc (n=689), Both (n=825)
• Setting: 82 centers in the United States
• Enrollment: October 2006 and September 2008
• Median follow-up: 5 years
• Analysis: Time to progression of AMD

Population

Inclusion Criteria

• Able and willing to consent to both the qualification and the randomization/follow-up phases of the study
• Likely, willing and able to undergo yearly examinations for at least five years
• Agreed to stop current use of supplements containing lutein, zeaxanthin, omega-3 LCPUFAs (specifically DHA+EPA), vitamin C, vitamin E, beta-carotene, zinc or copper, other than those supplied by AREDS2
• Demonstrated adherence to the run-in regimen (consumption of at least 75 percent of run-in medication as determined by pill count or pill weight)
• Had fundus photographs of adequate quality as assessed with a standardized protocol by the Reading Center (University of Wisconsin Fundus Photograph Reading Center)
• Were randomized within three months following the qualification visit.

Exclusion Criteria

• The presence of ocular disease in either eye that may have confounded evaluation of the retina
• Previous retinal or other ocular surgical procedures (other than cataract extraction) that may have complicated assessment of the progression of AMD
• A chronic requirement for any systemic or ocular medication administered for other diseases and known to be toxic to the retina or optic nerve
• Previous daily supplementation with 2mg or more of lutein and/or 500 mg or more of omega-3 LCPUFAs for a period of 1 year or more prior to the date of randomization (A participant was eligible for the study if he/she agreed to stop taking these supplements during the study run-in period)
• Intraocular pressure of 26 mm Hg or higher or some reason to believe that the participant might have glaucoma
• Cataract surgery within 3 months or capsulotomy within 6 weeks prior to the qualification visit. Other exclusion criteria included: history of lung cancer
• Any systemic disease with a poor five-year survival prognosis; hemochromatosis; Wilson’s disease, or recent diagnosis of oxalate kidney stones; any condition that would make adherence or follow-up difficult or unlikely; current participation in other studies that might affect adherence to the AREDS2 follow-up schedule; or use of systemic anti-angiogenic therapy for treatment of choroidal neovascularization or cancer.

Baseline Characteristics

• Median age: 74 years
• 96% Caucasian
• Gender- 57% female, 43% male
• 7% current smokers
• 19% with prior cardiovascular disease, 44% and 50% taking statin-class cholesterol lowering drugs and aspirin, respectively. * Ocular characteristics include 59% with bilateral large drusen, 32% with advanced AMD in one eye and mean visual acuity of 20/32 in eyes without advanced AMD

Interventions

• Primary Intervention- Randomized to placebo (AREDS formula including Vitamin C (500 mg), Vitamin E (400 IU), beta carotene (15 mg), zinc (80 mg), copper (2mg) vs AREDS + lutein (10 mg), zeaxanthin (2 mg), AREDS + DHA (350 mg), EPA (650 mg), or AREDS + lutein (10 mg), zeaxanthin (2 mg), DHA (350 mg), EPA (650 mg).
• Secondary Intervention- Randomized to placebo (AREDS formula) vs AREDS without beta carotene, AREDS with reduced zinc (25 mg), or AREDS without beta carotene and reduced zinc (25 mg).
• Follow-up visits were scheduled annually, telephone contact 3 months after randomization and subsequent telephone contacts 6 months between study visits.

Outcomes

Primary Outcomes

Progression to advanced AMD by 5 years (neovascularization, geographic atrophy) with placebo vs AREDS+ lutein+zeaxanthin, AREDS + DHA +EPA, or AREDS+Both

31% (493 eyes [406 participants]) for placebo, 29% (468 eyes [399 participants]) for lutein + zeaxanthin, 31% (507 eyes [416 participants]) for DHA + EPA, and 30% (472 eyes [387 participants]) for lutein+zeaxanthin and DHA+EPA

Compared with placebo, lutein+zeaxanthin (HR 0.90, [98.7% CI, 0.76-1.07]; P-0.12); for DHA +EPA (HR 0.97 [98.7% CI, 0.82-1.16, P=0.70); for both (HR 0.29 [98.7 CI, 0.75-1.06] P=0.10)

Secondary Outcomes

Progression to advanced AMD by 5 years with placebo vs AREDS without beta carotene or AREDS with reduced zinc

Compared with placebo, eliminated beta carotene (HR 1.07 [95% CI, 0.94-1.20] P=0.31); reducing zinc (HR 1.06 [95% CI, 0.95-1.19] P=0.32)

Subgroup Analysis

With regards to evaluating treatment effects in terms of dietary intake of lutein + zeaxanthin, participants in the lowest quintile of dietary intake of lutein + zeaxanthin demonstrated a protective effect for progression to advanced AMD (HR 0.74 [95% CI 0.59-0.94] P=0.01). However, there was no trend with increasing lutein + zeaxanthin intake.

AREDS2 participants who were not active smokers or who had quit smoking more than 1 year prior to the study and were assigned to study groups receiving beta carotene showed an increased incidence of lung cancers (23 [2%] and 11 [0.9%], respectively; nominal p=0.04). Thirty-one (91%) of those participants developing lung cancer were former smokers. No increased risk in lung cancer was appreciated in those taking lutein+zeaxanthin supplementation.

Adverse Events

No clinically or statistically significant differences in reported adverse events, including developing neoplasms, were noted across treatment groups in the primary randomization group. As noted, those in the secondary randomization for beta carotene who were former smokers were noted to have a statistically significant increased incidence in lung cancers. Of note, supplementation with lutein+zeaxanthin, DHA+EPA, zinc, or beta carotene was not associated with a statistically significant impact on patient mortality.

Criticisms

Several limitations exist for this study, including: adherence to original AREDS formulation, complicated study design that may have affected true evaluation of lutein+zeaxanthin and DHA+EPA supplementation, potential interaction between 2 carotenoids (beta carotene, lutein+zeaxanthin).

Funding

Study supported by intramural program funds and contracts from the National Eye Institute (NEI), National Institutes of Health (NIH), Department of Health and Human Services, Bethesda, Maryland (contract HHS-N-260-2005-00007-C; ADB Contract N01-EY-5-0007). Funds were distributed to these contracts by the following NIH institutes: Offices of Dietary Supplements; National Center for Complementary and Alternative Medicine; National Institute on Aging; National Heart, Lung, and Blood Institute; and National Institute of Neurological Disorders and Stroke. The study medications and raw materials were provided by Alcon, Bausch & Lomb, DSM, and Pfizer.