The AREDS2 dietary supplement reduces the risk of age-related macular degeneration progression


The Age-Related Eye Disease Studies (AREDS and AREDS2) established that dietary supplements can slow progression of age-related macular degeneration (AMD), the most common cause of blindness in older Americans. In a new report, scientists analyzed 10 years of AREDS2 data.

They show that the AREDS2 formula, which substituted antioxidants lutein and zeaxanthin for beta-carotene, not only reduces risk of lung cancer due to beta-carotene, but is also more effective at reducing risk of AMD progression, compared to the original formula.

A report on the study, funded by the National Institutes of Health, published in JAMA Ophthalmology.

“Because beta-carotene increased the risk of lung cancer for current smokers in two NIH-supported studies, our goal with AREDS2 was to create an equally effective supplement formula that could be used by anyone, whether or not they smoke,” said Emily Chew, M.D., director of the Division of Epidemiology and Clinical Application at the National Eye Institute (NEI), and lead author of the study report.

“This 10-year data confirms that not only is the new formula safer, it’s actually better at slowing AMD progression.”

AMD is a degenerative disease of the retina, the light-sensitive tissue at the back of the eye. Progressive death of retinal cells in the macula, the part of the retina that provides clear central vision, eventually leads to blindness. Treatment can slow or reverse vision loss; however, no cure for AMD exists.

The original AREDS study, launched in 1996, showed that a dietary supplement formulation (500 mg vitamin C, 400 international units vitamin E, 2 mg copper, 80 mg zinc, and 15 mg beta-carotene) could significantly slow the progression of AMD from moderate to late disease.

However, two concurrent studies also revealed that people who smoked and took beta-carotene had a significantly higher risk of lung cancer than expected.

In AREDS2, begun in 2006, Chew and colleagues compared the beta-carotene formulation to one with 10 mg lutein and 2 mg zeaxanthin instead. Like beta-carotene, lutein and zeaxanthin are antioxidants with activity in the retina. The beta-carotene-containing formation was only given to participants who had never smoked or who had quit smoking.

At the end of the five-year AREDS2 study period, the researchers concluded that lutein and zeaxanthin did not increase risk for lung cancer, and that the new formation could reduce the risk of AMD progression by about 26%.

After the completion of the five-year study period, the study participants were all offered the final AREDS2 formation that included lutein and zeaxanthin instead of beta-carotene.

In this new report, the researchers followed up with 3,883 of the original 4,203 AREDS2 participants an additional five years from the end of the AREDS2 study in 2011, collecting information on whether their AMD had progressed to late disease, and whether they had been diagnosed with lung cancer.

Even though all the participants had switched to the formula containing lutein and zeaxanthin after the end of the study period, the follow up study continued to show that beta-carotene increased risk of lung cancer for people who had ever smoked by nearly double.

There was no increased risk for lung cancer in those receiving lutein/zeaxanthin.

In addition, after 10 years, the group originally assigned to receive lutein/zeaxanthin had an additional 20% reduced risk of progression to late AMD compared to those originally assigned to receive beta-carotene.

“These results confirmed that switching our formula from beta-carotene to lutein and zeaxanthin was the right choice,” said Chew.

Funding: The study was funded by the NEI Intramural program (EY000546) and through contracts (AREDS2 contract HHS-N-260-2005-00007-C; ADB contract NO1-EY-5-0007; AREDS Contract NOI-EY-0-2127, and contract HHS-N-263-2013-00005-C).

The AREDS2 contracts were supported by the NIH Office of Dietary Office of Dietary Supplements, the National Center for Complementary and Integrative Health, the National Institute on Aging, the National Heart, Lung, and Blood Institute, and the National Institute of Neurological Disorders and Stroke.

The study took place at the NIH Clinical Center.

Age-related macular degeneration (ARMD) is the most common cause of blindness prevalent in developed countries, particularly in people older than 60 years. Macular degenerative changes involve the central part of the retina that is the fovea. The central vision is affected, resulting in difficulty in reading, driving, etc. It accounts for 8.7% of all types of blindness worldwide.[1]


Several risk factors have been identified and associated with this disease.[2] Risk factors can be classified into a sociodemographic, lifestyle, cardiovascular, hormonal and reproductive, inflammatory, genetic, and ocular. Sociodemographic factors include age, gender, race, socioeconomic status. Various studies have demonstrated an increase in prevalence as well as the progression of ARMD with age.[3] Studies have found women to be at greater risk of ARMD. However, the association is not very consistent. Both early and late ARMD are known to be common among non-Hispanic whites when compared to blacks and Hispanics.[4] Socioeconomic factors like education, income, employment status, or marital status have no association with prevalence or stage of maculopathy.[5]

Smoking is an independent risk factor for ARMD.[6] Alcohol intake is not associated with the development of ARMD.[7] The role of other lifestyle factors like obesity and physical activity in the progression of ARMD is uncertain. The Age-Related Eye Disease Study (AREDS) documented that antioxidant and zinc supplementation decreases the risk of ARMD progression and vision loss.[8] A mild to moderate association between elevated blood pressure and ARMD has been described. Atherosclerotic lesions increase the risk of late ARMD.[9] No consistent relationship between cholesterol level and ARMD has been documented. Further studies are required to better define the mechanisms through which HDL mediates ARMD.[10] No significant relationship has been found between diabetes and ARMD. 

Hormone replacement therapy or estrogen therapy in women after menopause has been found to have a potential protective effect.[11] Studies have suggested that inflammation plays a role in the pathogenesis of drusen and ARMD. Various complement-related genetic variants are associated with ARMD. These include Y402H in the CFH gene and other variants in factor B /complement component 2, complement component 3, and complement Factor I.[12]


The disease is estimated to affect around 196 million people by 2020 and 288 million people by 2040.[1] Early AMD is more common in individuals of European ancestry than in Asians, whereas the prevalence of late AMD is the same between the two populations. In 2015, AMD was the fourth most common cause of blindness globally and the third most common cause for moderate to severe vision loss. This shows the increasing importance of AMD globally.[13]


The structures involved in the disease process are the photoreceptor cells in the outer retina, the retinal pigment epithelium (RPE), Bruch’s membrane, and the capillary bed in the inner choroid (choriocapillaris).

  • There is a loss of choriocapillaris in ARMD. Reduced diffusion of VEGF from RPE towards the choroid may be responsible for this loss. However, the occurrence of this damage independent of any other tissue is also a possibility.
  • Bruch’s membrane thickening due to the accumulation of lipids has been long postulated in ARMD. This, in turn, results in reduced fluid movement from RPE towards the choroid. This reduced hydraulic conductivity causes fluid accumulation beneath the RPE and causes detachment of the RPE. 
  • Accumulation of lipofuscin in RPE, resulting in altered metabolism of the degraded photoreceptors occurs in this disease. This results in the accumulation of deposits (drusen) beneath the RPE. 
  • Photoreceptor loss, as well as shortening of outer segments of the photoreceptors, has also been documented in ARMD.

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