Disease prevention and treatment may be aided by consideration of cumulative data on patients’ diets and other lifestyle factors.
Ophthalmologists are often bombarded with questions about the benefits of supplements in treating and preventing age-related macular degeneration. This is due to the great number and variety of nutritional supplements in the market that are purported to benefit eye health. To date, data from several small and one large study provide evidence about the benefit of treating AMD, but there is a lack of evidence about means to prevent AMD at earlier stages by taking supplements.
AREDS, AREDS 2
The Age-Related Eye Disease Study is the largest study of nutritional supplements to date. The randomized, placebo-controlled, double-masked AREDS was conducted at 11 centers and enrolled 3,640 participants aged 55 to 80 years. The average follow-up was 6.3 years, and 2.4% of patients were lost to follow-up. The trial demonstrated a statistically significant odds reduction for development of advanced AMD using a formula of antioxidants plus zinc.
Emily Y. Chew
The original AREDS formula consisted of 500 mg vitamin C, 400 IU vitamin E, 15 mg beta-carotene, 80 mg zinc oxide and 2 mg cupric oxide given daily. According to Emily Y. Chew, MD, one of the study investigators, this formula should not be given to patients with nonexistent or small drusen.
“The AREDS formulation is the only proven nutritional therapy for the treatment of AMD for persons who are not smokers and who are at least at intermediate risk for AMD or advanced AMD in one eye,” she said. “The supplement’s ability to retard geographic atrophy is minimal, but it is given to patients with geographic atrophy because the risk of neovascular AMD is still fairly significant, roughly 30% in 5 years.”
According to Julie A. Mares, PhD, “The fact that the AREDS trial confirmed the benefit of antioxidants in slowing vision loss with AMD was a huge leap in understanding that indicated that antioxidants could slow AMD, which is thought to be promoted by oxidative stress that can be high in this region of the retina.”
In a more recent report, people who were at high genetic risk for developing AMD had a lower risk for developing early AMD if their diets were in the highest compared with the lowest third for levels of dietary lutein, omega-3 fatty acids, beta-carotene and zinc, according to Julie A. Mares, PhD, shown above.
Source: Mares JA
Further support of the idea that supplements lowered oxidative stress came from a pilot case series recently published online in the American Journal of Ophthalmology, which suggested that short-term digestion of the AREDS supplement may alter plasma levels of the oxidative stress biomarker cystine, which could help clinicians predict how probable it is that an individual would benefit from the formula. The prospective, interventional series included 19 patients and demonstrated a significant reduction for biomarker cystine (P = .034) but not cysteine, glutathione, isoprostane or isofuran.
Despite the evidence from the original AREDS, many questions remain: Which dose of nutrients contained in supplements is optimal? Would adding other ingredients provide additional benefit? Would lowering the dose of some nutrients provide benefit without exposing individuals to potential harmful effects suggested by other trials in the literature? For example, in the recent Selenium and Vitamin E Cancer Prevention Trial, 400 IU vitamin E taken for 7 to 12 years increased the risk of prostate cancer in 34,887 healthy men from the United States, Canada and Puerto Rico over 50 years by 17%. Answers to these questions about dose and formulation are not available from the original AREDS study, which tested only one formulation, according to Dr. Mares.
The National Eye Institute is funding additional studies that test different doses and nutrient formulations. AREDS 2 data, which Dr. Chew predicts will be available during the second quarter of 2013, should demonstrate effects of high-dose xanthophylls (lutein and zeaxanthin) and omega-3 long-chain polyunsaturated fatty acids on progression of advanced AMD.
“The rationale [for the modified formula] comes from AREDS observational data, as well as a number of other studies evaluating the association between reduced AMD risk and dietary intake of lutein — found in green, leafy vegetables, such as spinach, collard greens and kale — and fish,” Dr. Chew said.
AREDS 2 also seeks to determine the effects of eliminating beta-carotene, which is said to increase the risk of lung cancer in patients who smoke, and reducing zinc levels.
“Recent data suggest that humans do not necessarily need 80 mg zinc, because the body maintains tight homeostasis of zinc absorption, and no more than 25 mg will be absorbed,” Dr. Chew said. “We are testing all of these treatment strategies to see if we can further increase the beneficial effects of the AREDS formulation.”
CAREDS, ongoing analyses
The expense of long-term clinical trials often makes them less feasible for testing the benefits and potential risks over longer time periods and limits the testing of different doses and formulations. Furthermore, it is not practical to test whether supplements prevent the development of AMD in the early stages because it takes many years to accrue enough cases to compare.
“We must glean insights and make inferences from observational studies, which study the occurrence of AMD in free-living situations,” Dr. Mares said. “To date, there are no consistent data from observational studies to support the benefit of supplements. One difficulty in drawing conclusions from observational data is that the intake of high-dose supplements, such as those tested in AREDS trials, has not been used by many people for long periods of time. Another problem is that people often begin supplementing when they are diagnosed with other health conditions, which are more common in people who develop AMD. Yet another problem is that we cannot usually isolate the effect of supplements from the effect of other lifestyles that protect or promote AMD, unless we begin to separate people into groups with and without these factors. This can only be done in very large studies which pool data from a large number of observational studies, and this has not yet been done.”
However, data from several observational studies, including the Rotterdam Eye Study, suggest that healthy diets and lifestyles may prevent or slow AMD. In the Rotterdam study, people who consumed foods that provided the same nutrients as AREDS supplements, but at much lower levels, were less likely to develop AMD, mostly in early stages, Dr. Mares said.
In a more recent report, people who were at high genetic risk for developing AMD had a lower risk for developing early AMD if their diets were in the highest compared with the lowest third for levels of dietary lutein, omega-3 fatty acids, beta-carotene and zinc, according to Dr. Mares.
Dr. Mares is one of many investigators for the observational study Carotenoids in Age-Related Eye Disease Study (CAREDS). Participants included women, aged 50 to 79 years from 1994 to 1998 from Iowa, Wisconsin and Oregon, whose intake of lutein plus zeaxanthin was above the 78th percentile and below the 28th percentile at baseline in the initial Women’s Health Initiative (WHI) Observational Study. The women were recruited 4 to 7 years after the WHI baseline assessments and provided fundus photographs that permitted assignment of the presence and severity of AMD.
“We observed very different results in women who were older than 75 years of age at the time photographs were taken and those who were younger,” Dr. Mares said. “This might be due to dietary changes made late in life, as a result of having health conditions that are more common in people with AMD.”
For example, women may have adopted fruit and vegetable rich diets proven in the Dietary Approaches to Reduce Hypertension trial to lower blood pressure, which is often a risk factor for AMD, she said. Or, another reason for discrepant results in younger and older women is that more women in the oldest group might have avoided early stages of AMD until after age 75 years.
To more reliably estimate the relationship of long-term diets to odds of having AMD, Dr. Mares and colleagues focused further investigation in women younger than 75 years of age for whom the associations of diet and lifestyle to early AMD would be less biased by these factors.
“This would permit us to more reliably estimate the relationship of long-term diets to odds of having AMD,” she said. “Also, we looked at relationships after excluding women who reported large changes in dietary intake in the period immediately preceding the assessment of AMD. In this group of women younger than 75 years of age, those with diets in the highest fifth for intake of lutein and zeaxanthin had lower odds of having early stages of AMD — a stage that is roughly equivalent to ‘intermediate AMD,’ for which progression was slowed with antioxidant supplements in AREDS 1.”
However, looking across all observational studies assessing the potential benefits of lutein and zeaxanthin in preventing early AMD, the data are conflicting, Dr. Mares said.
“A remaining question is whether this association reflects the benefit of lutein per se or, rather, other protective aspects of diet and lifestyle that are more common among people with high lutein levels in their diets or blood,” she said.
Later findings for CAREDS also suggest a protective effect for diets high in monounsaturated fatty acids and vitamin D, as well as increased physical activity. One published analysis in Archives of Ophthalmology showed that having a combination of three healthy behaviors, related to healthy diet, physical activity and lack of a smoking habit, was associated with a 71% lower odds ratio for AMD compared with high-risk scores (P < .001).
“We are continuing to study lutein status in relation to AMD while considering all of these other factors jointly in order to see whether the chances of developing AMD increase when these potential preventive factors are considered together,” Dr. Mares said. “In our studies, we are currently adding genetic risk factors for AMD, and we will also include gene variants that have the potential to predict better lutein status in the eye.”
Considering all available data cumulatively, as the scientific evidence from a variety of study types grows, may be the key to better understanding how to prevent or slow the development of AMD, Dr. Mares said. – by OSN Retina Editorial Staff
- About AREDS2. Age-Related Eye Disease Study 2 website. http://www.areds2.org/. Accessed March 15, 2012.
- Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss. AREDS report no. 8. Arch Ophthalmol. 2001;119(10):1417-1436.
- Brantley MA Jr., Osborn MP, Sanders BJ, et al. The short-term effects of antioxidant and zinc supplements on oxidative stress biomarker levels in plasma: a pilot investigation [published online ahead of print March 1, 2012]. Am J Ophthalmol. doi:10.1016/j.ajo.2011.12.010.
- Ho L, van Leeuwen R, Witteman JC, et al. Reducing the genetic risk of age-related macular degeneration with dietary antioxidants, zinc, and omega-3 fatty acids: the Rotterdam study. Arch Ophthalmol. 2011;129(6):758-766.
- Klein EA, Thompson IA Jr, Tangent CM, et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2011;306(14):1549-1556.
- Mares JA, Voland RP, Sondel SA, et al. Healthy lifestyles related to subsequent prevalence of age-related macular degeneration. Arch Ophthalmol. 2011;129(4):470-480.
- Millen AE, Voland R, Sondel SA, et al; CAREDS Study Group. Vitamin D status and early age-related macular degeneration in postmenopausal women. Arch Ophthalmol. 2011;129(4):481-489.
- Moeller SM, Parekh N, Tinker L, et al; CAREDS Research Study Group. Associations between intermediate age-related macular degeneration and lutein and zeaxanthin in the Carotenoids in Age-Related Eye Disease Study (CAREDS): ancillary study of the Women’s Health Initiative. Arch Ophthalmol. 2006;124(8):1151-1162.
- Parekh N, Chappell RJ, Millen AE, Albert DM, Mares JA. Association between vitamin D and age-related macular degeneration in the Third National Health and Nutrition Examination Survey, 1988 through 1994. Arch Ophthalmol. 2007;125(5):661-669.
- Parekh N, Voland RP, Moeller SM, et al; CAREDS Research Study Group. Association between dietary fat intake and age-related macular degeneration in the Carotenoids in Age-Related Eye Disease Study (CAREDS): an ancillary study of the Women’s Health Initiative. Arch Ophthalmol. 2009;127(11):1483-1493.
- van Leeuwen R, Boekhoorn S, Vingerling JR, et al. Dietary intake of antioxidants and risk of age-related macular degeneration. JAMA. 2005;294(24):3101-3107.
For more information:
- Emily Y. Chew, MD, can be reached at the National Institutes of Health, Building 10, CRC, room 3-2531, 10 Center Drive, MSC 1204, Bethesda, MD 20892-1204; email: email@example.com.
- Julie A. Mares, PhD, can be reached at the University of Wisconsin, Department of Ophthalmology and Visual Sciences, 610 N. Walnut Street, 1063 WARF Building, Madison, Wisconsin 53726-2336; 608-262-8044; email: firstname.lastname@example.org.
- Disclosure: Dr. Chew and Dr. Mares have no relevant financial disclosures.