Results from AREDS-2 clinical trial & what it means for you

Age-Related Eye Disease Study (AREDS) and Age-related Eye Diseases Study-2 (AREDS-2) were landmark studies in providing a clue to show benefit from nutritional supplements. The article below, from Retina India's newsletter from 2013, is still relevant today to patients of Age-related macular degeneration.

Age-Related Eye Disease Study (AREDS) had reported in 2001 that a nutritional supplement of daily high doses of vitamins C and E, beta-carotene, and the minerals zinc and copper—called the AREDS formulation—can help slow the progression to advanced AMD. American Academy of Ophthalmology has recommended use of the AREDS formulation to reduce the risk of advanced AMD.

However, beta-carotene use has been linked to a heightened risk of lung cancer in smokers. And there have been concerns that the high zinc dose in AREDS could cause minor side effects, such as stomach upset, in some people.

from NEI

In 2006, the National Eye Institute (NEI) launched AREDS2, a five-year study designed to test whether the original AREDS formulation could be improved by adding omega-3 fatty acids; adding lutein and zeaxanthin; removing beta-carotene; or reducing zinc. The study also examined how different combinations of the supplements performed. Omega-3 fatty acids are produced by plants, including algae, and are present in oily fish such as salmon. Lutein and zeaxanthin are carotenoids, a class of plant-derived vitamins that includes beta-carotene; both are present in leafy green vegetables and, when consumed, they accumulate in the retina. Prior studies had suggested that diets high in lutein, zeaxanthin, and omega-3 fatty acids protect vision.

Adding omega-3 fatty acids did not improve a combination of nutritional supplements commonly recommended for treating age-related macular degeneration (AMD), a major cause of vision loss among older people. The plant-derived antioxidants lutein and zeaxanthin also had no overall effect on AMD when added to the combination; however, they were safer than the related antioxidant beta-carotene. This study has been published in the Journal of the American Medical Association.

Apparently, even before the AREDS2 study was finished, manufacturers began marketing supplements based on the study design.

In AREDS2, participants took one of four AREDS formulations daily for five years. The original AREDS included 500 milligrams vitamin C, 400 international units of vitamin E, 15 milligrams beta-carotene, 80 milligrams zinc, and two milligrams copper. Other groups took AREDS with no beta-carotene, AREDS with low zinc (25 milligrams), or AREDS with no beta-carotene and low zinc. Participants in each AREDS group also took one of four additional supplements or combinations: these included lutein/zeaxanthin (10 milligrams/2 milligrams), omega-3 fatty acids (1,000 milligrams), lutein/zeaxanthin and omega-3 fatty acids, or placebo. Progression to advanced AMD was established by examination of retina photographs or treatment for advanced AMD.

AMD breaks down cells in the layer of tissue called the retina in the back of the eye that provide sharp central vision, which is necessary for tasks such as reading, driving, and recognizing faces. Advanced AMD can lead to significant vision loss.

Ed: To read more about the disease AMD, please read the article by Dr Mallika Goyal, Hyderabad, in the December issue of inSIGHT.

In the first AREDS trial, participants with AMD who took the AREDS formulation were 25 percent less likely to progress to advanced AMD over the five-year study period, compared with participants who took a placebo. In AREDS2, there was no overall additional benefit from adding omega-3 fatty acids or a 5-to-1 mixture of lutein and zeaxanthin to the formulation. However, the investigators did find some benefits when they analyzed two subgroups of participants: those not given beta-carotene, and those who had very little lutein and zeaxanthin in their diets.

Those who took an AREDS formulation with lutein and zeaxanthin but no beta-carotene were found to have a reduced risk of developing advanced AMD over the five years of the study by about 18 percent, compared with participants who took an AREDS formulation with beta-carotene but no lutein or zeaxanthin. Further analysis also showed that participants with low dietary intake of lutein and zeaxanthin at the start of the study, but who took an AREDS formulation with lutein and zeaxanthin during the study, were about 25 percent less likely to develop advanced AMD compared with participants with similar dietary intake who did not take lutein and zeaxanthin.

Removing beta-carotene from the AREDS formulation did not curb the formulation’s protective effect against developing advanced AMD, an important finding because several studies have linked taking high doses of beta-carotene with a higher risk of lung cancer in smokers. Although smokers were not given a formulation with beta-carotene in AREDS2, the study showed an association between beta-carotene and risk of lung cancer among former smokers.

Adding omega-3 fatty acids or lowering zinc to the AREDS formulation also had no effect on AMD progression.

The study included more than 4,000 subjects at 82 clinical sites around the US, aged 50 to 85 years, who were at risk for advanced AMD. Eye care professionals assess risk of developing advanced AMD in part by looking for yellow deposits called drusen in the retina. The appearance of small drusen is a normal part of aging, but the presence of larger drusen indicates AMD and a risk of associated vision loss. Over time, the retina begins to break down in areas where large drusen are present during a process called geographic atrophy. AMD can also spur the growth of new blood vessels beneath the retina, which can leak blood and fluid, resulting in sudden vision loss. These two forms of AMD are often referred to as dry AMD and wet AMD respectively.

The AREDS2 study results provide physicians and patients with new information about preventing vision loss from AMD. People over 60 years old should get a dilated eye exam at least once a year and should discuss with their doctor whether taking AREDS supplements is appropriate for them.

Who should consider taking a combination of antioxidants and zinc like those examined in AREDS and AREDS2? People at high risk for developing advanced AMD should consider taking the antioxidant-zinc combinations examined in AREDS and AREDS2. These people are defined as having either:

• Intermediate AMD in one or both eyes. It usually involves little or no vision loss.
• Advanced AMD in one eye, which may lead to significant visual loss, but not the other eye.

Note for patients: Queries pertaining to retinal disorders (along with scanned relevant copies of the medical reports) can be e-mailed to doctor@retinaindia.org. Retina India’s medical team will try to answer the queries as soon as possible.