Setting the Record Straight on Nutritional Therapy and AMD

An overview on AREDS, AREDS2 and observational studies supporting new approaches to nutritional therapy.

By David Boyer, MD

Nothing sets off a debate among retinal specialists like vitamins and nutrition. Nearly 10 years have passed since the Age-Related Eye Disease Study (AREDS) confirmed that high levels of antioxidants and zinc significantly reduce the risk of progression to advanced AMD and its associated vision loss.¹ Nonetheless, conjecture over impending results from AREDS2, along with studies on genetics, diet and risk factors, have divided us into purists, theorists and the ponderous ones in between.

Is it good practice to tell patients to consume concentrated supplements of macular xanthophylls and omega-3 long-chain polyunsaturated fatty acids more than a year before a complete evaluation of these supplements has been concluded by AREDS2? Is it good practice not to recommend these formulations, based on the information we already know?

Which patients diagnosed with or at risk for AMD should be taking vitamins and using nutritional therapy? Which risk factors, such as obesity and cigarette smoking, should form the basis for stepped-up counseling, aimed at urging patients to change behaviors? What should our patients eat? What foods should they avoid? What are the best ways to identify increased risk during examinations?

These are but some of the questions that arise in our daily experience, defining our styles of patient care by the answers we embrace. In this special report, we use expert opinion and the latest evidence to update you and lay a strong foundation for future practice. I will begin by providing an updated overview.

EXPANDING OPTIONS

The number of U.S. citizens who will develop AMD is expected to increase by 50% to 2.9 million by 2020.² Fortunately, therapeutic options are expanding.

The pioneering research of Johanna Seddon, MD, and her colleagues,³ found that a higher dietary intake of carotenoids—specifically green, leafy vegetables containing lutein and zeaxanthin—could decrease the risk of developing advanced or exudative AMD, the most visually disabling form of macular degeneration among older people. Such findings supported the need for trials,⁴ including AREDS,⁴ a landmark study of the clinical course of age-related lens opacity and AMD.

AREDS was a prospective, randomized, multicenter, double-masked, placebo-controlled clinical trial that evaluated the use of high-dose antioxidants and zinc as possible treatments to reduce progression of eye diseases in the elderly.

AREDS involved 3,640 subjects, 55 to 80 years of age, at 11 centers between 1992 and 2001. Follow-up of subjects continued until December 2005. Subjects were categorized according to these following risk examination findings:

■ No macular changes (category 1)
■ Small and few intermediate drusen (category 2)
■ Extensive intermediate drusen, large drusen or noncentral geographic atrophy (category 3)
■ Advanced AMD in one eye; either geographic atrophy in the center or neovascular AMD (category 4)

The subjects were randomized to receive:

■ Antioxidants, including vitamin C, 500 mg/d; vitamin E, 400 IU/d; and betacarotene, 15 mg/d (N=945) Lutein and zeaxanthin were not commercially available at this time.
■ Zinc, 80 mg/d; cupric oxide (copper), 2 mg/d (N=904)
■ Zinc, 80 mg/d; cupric oxide (copper), 2 mg; and antioxidants, including vitamin C, 500 mg/d; vitamin E, 400 IU; and betacarotene, 15 mg/d (N=888)
■ Placebo (N=903)

The results of AREDS showed that a combination of high-dose antioxidant vitamins and zinc demonstrated a 25% reduction of risk for the development of advanced AMD over a median of 6.3 years of follow-up in subjects at high risk (categories 3 or 4). After the study terminated in 2001, follow-up showed that the beneficial effects of the AREDS supplements persisted at a similar level of protection.

ROLE OF LUTEIN AND ZEAXANTHIN

AREDS gave us a confirmed formulation that is used to this day. However, accumulating evidence suggests that dietary carotenoids lutein and zeaxanthin and dietary omega-3 fatty acids may also play a protective role.

Lutein and zeaxanthin may help through antioxidant and light screening mechanisms, including a process that increases macular pigment optical density that is lost with age, especially among cigarette smokers.^5-6 When ingested, these xanthophylls accumulate in the macula, helping to respond to life-long oxidative stress that can lead to photoreceptor death.⁷ Increased risk of AMD may result from low levels of lutein and zeaxanthin in the diet, serum or retina. Risk is also believed by some to be raised by excessive exposure to blue light.⁸ Through its light-screening capacity and antioxidant activity, macular pigment may reduce photo-oxidation in the central retina.

Based on questionnaires completed by AREDS subjects, AREDS Report No. 22 found higher dietary intake of lutein and zeaxanthin was independently associated with decreased likelihood of having neovascular AMD, geographic atrophy and large or extensive intermediate drusen.⁹ In the Blue Mountain Eyes Study, a population-based trial of 2,454 subjects, higher dietary lutein and zeaxanthin intake was found to reduce the risk of long-term incident AMD.¹⁰

OMEGA-3: GROWING BODY OF EVIDENCE

Consistent evidence also points to the potential benefits of fish and omega-3 fatty acids. Fatty acids “may modulate metabolic processes and attenuate effects of environmental exposures that activate molecules implicated in pathogenesis of vasoproliferative and neuro-degenerative retinal diseases,” according to SanGiovanni and Chew.¹¹ “These processes and exposures include ischemia, chronic light exposure, oxidative stress, inflammation, cellular signaling mechanisms and aging.”

Dietary questionnaire-based reports^12-17 strengthened this hypothesis as well. “If these results are generalizable, they may guide the development of low-cost and easily implemented preventive interventions for progression to advanced AMD,” wrote AREDS researchers. Additional research has also associated protective effects to the consumption of omega-3 fatty acids to reduced risk of AMD.^18-20

Most recently, researchers evaluated 38,022 participants in the Women's Health Study, including 235 who had been diagnosed with AMD.²⁰ After adjusting for age and treatment assignment, the researchers found that women who had consumed the most dietrary docosahexaenoic acid (DHA), a key component of omega-3 fatty acids, had a 38% lower risk of developing AMD, compared to women who consumed the lowest amount. Similar results were associated with higher intake of eicosapentaenoic acid (EPA), another important component of omega-3 fatty acids, and with higher consumption of EHA and EPA together. Consumption of one or more servings of fish per week was associated with a 42% lower risk of AMD when compared to consumption of less than one serving per month.²⁰

WAITING ON AREDS2

Commercial supplements that include lutein, zeaxanthin and omega-3 fatty acids (Icaps from Alcon [not AREDS-based], and PreserVision Eye Vitamin AREDS 2 Formula from Bausch + Lomb) have already been released. However, we are still awaiting the definitive results of the evaluation of these supplements in AREDS2, a 5-year multicenter, randomized trial. The final report from the Age-Related Eye Disease Study Research Group may be available as early as the spring of 2013.

Purists are understandably concerned that physicians are recommending supplements in advance of these results. In addition, many of us question the practice of offering treatments still under study. If patients change regimens or drop out of the study because of these new commercial formulations, we will never know what we are confirming. Longitudinal studies such as AREDS2 give us tremendous information on natural history and specific responses to varying combinations of therapies, ensuring that we can make better long-term recommendations.

WHAT TO CONSIDER: AREDS & AREDS2

Despite reservations, we must keep in mind that the therapies confirmed by AREDS were created 12 years ago, when good sources of supplementary lutein and zeaxanthin were not available for consumption and measurement. Also, not much was known about the potential benefits of omega-3 fatty acids.

We have learned a great deal since then, including risk factors and recommendations for healthy living. (See “Putting Vitamin and Nutritional Therapy into Practice” article.) But is there enough independent evidence to justify recommending supplements from AREDS2 guidelines at this point? This is a question that we will continue to debate for some time.

Turning the Tide?

Some evidence shows we may be turning the tide with preventive measures for AMD. An evaluation of 5,553 members of various ethnic groups found that the prevalence of AMD decreased 6.5% between 2005 and 2008, representing a significant drop from the 9.4% prevalence estimated between 1988 and 1994 by the Third National Health and Nutrition Examination Survey.1 —David Boyer, MD 1. Klein R, Chou CF, Klein BE, Zhang X, Meuer SM, Saaddine JB. Prevalence of age-related macular degeneration in the US population. Arch Ophthalmol 2011;129:75-80.

Daily Formulations for AREDS and AREDS2
AREDS:	AREDS2:*
■ Vitamin C, 500 mg	■ Lutein 10 mg
■ Vitamin E, 400 IU	■ Zeaxanthin, 2 mg
■ Beta-Carotene, 15 mg	■ Docosahexaenoic Acid (DHA), 350 mg
■ Zinc Oxide, 80 mg	■ Eicosapentaenoic Acid (EPA), 650 mg
■ Cupric Oxide (Copper), 2 mg
*AREDS2 is also testing variations to the AREDS formula (low zinc, no beta-carotene). The research being conducted by the National Eye Institute.

KEY POINTS TO REMEMBER

► Higher dietary intake of carotenoids—specifically lutein and zeaxanthin—could decrease the risk of advanced or exudative AMD.3,7,9,10 ► AREDS showed that a combination of high-dose antioxidant vitamins and zinc reduced the risk of progression of AMD by 25% over a median of 6.3 years of follow-up in subjects at high risk.1 ► Dietary intake of fish and omega-3 fatty acids has been associated with reduced risk of AMD.11-21

REFERENCES

1. 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.
2. Friedman DS, O'Colmain BJ, Muñoz B, et al. Eye Diseases Prevalence Research Group. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol. 2004;122:564-572.
3. Seddon JM, Ajani UA, Sperduto RD, et al. Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration. Eye Disease Case-Control Study Group. JAMA. 1994;272(18):1413-1420.
4. Snodderly DM. Evidence for protection against age-related macular degeneration by carotenoids and antioxidant vitamins. Am J Clin Nutr. 1995;62(6 Suppl):1448S-1461S.
5. Bernstein PS, Zhao DY, Wintch SW, et al. Resonance Raman measurement of macular carotenoids in normal subjects and in age-related macular degeneration patients. Ophthalmology. 2002;109(10):1780-1787.
6. Gale CR, Hall NF, Phillips DI, Martyn CN. Lutein and zeaxanthin status and risk of age-related macular degeneration. Invest Ophthalmol Vis Sci. 2003;44(6):2461-2465.
7. Bone RA, Landrum JT, Guerra LH, Ruiz CA. Lutein and zeaxanthin dietary supplements raise macular pigment density and serum concentrations of these carotenoids in humans. J Nutr. 2003;133(4):992-998.
8. Krinsky NI, Landrum JT, Bone RA. Biologic mechanisms of the protective role of lutein and zeaxanthin in the eye. Annu Rev Nutr. 2003;23:171-201.
9. Age-Related Eye Disease Study Research Group, SanGiovanni JP, Chew EY, Clemons TE, Ferris FL 3rd, Gensler G, Lindblad AS, Milton RC, Seddon JM, Sperduto RD. The relationship of dietary carotenoid and vitamin A, E, and C intake with age-related macular degeneration in a case-control study: AREDS Report No. 22. Arch Ophthalmol. 2007;125(9):1225-1232.
10. Tan JS, Wang JJ, Flood V, Rochtchina E, Smith W, Mitchell P. Dietary antioxidants and the long-term incidence of age-related macular degeneration: the Blue Mountains Eye Study. Ophthalmology. 2008;115(2):334-341.
11. SanGiovanni JP, Chew EY. The role of omega-3 long-chain polyunsaturated fatty acids in health and disease of the retina. Prog Retin Eye Res. 2005;24(1):87-138.
12. SanGiovanni JP, Chew EY, Clemons TE, et al. The relationship of dietary lipid intake and age-related macular degeneration in a case-control study: AREDS Report No. 20. Arch Ophthalmol. 2007;125(5):671-679.
13. SanGiovanni JP, Chew EY, Clemons TE, et al. The relationship of dietary lipid intake and age-related macular degeneration in a case-control study: AREDS Report No. 20. Arch Ophthalmol. 2007;125(5):671-679.
14. Chiu CJ, Klein R, Milton RC, Gensler G, Taylor A. Does eating particular diets alter the risk of age-related macular degeneration in users of the Age-Related Eye Disease Study supplements? Br J Ophthalmol. 2009;93(9):1241-1246.
15. Seddon J, et al. Dietary fat intake and age-related macular degeneration [ARVO abstract]. Invest Ophthalmol Vis Sci. 1994;35:#2003.
16. Seddon JM, Rosner B, Sperduto RD, et al. Dietary fat and risk for advanced age-related macular degeneration. Arch Ophthalmol. 2001;119(8):1191-1199.
17. Seddon JM, Cote J, Rosner B. Progression of age-related macular degeneration: association with dietary fat, transunsaturated fat, nuts, and fish intake. Arch Ophthalmol. 2003;121(12):1728-1737.
18. Chua B, Flood V, Rochtchina E, et al. Dietary fatty acids and the 5-year incidence of age-related maculopathy. Arch Ophthalmol. 2006;124(7):981-986.
19. Augood C, Chakravarthy U, Young I, et al. Oily fish consumption, dietary docosa-hexaenoic acid and eicosapentaenoic acid intakes, and associations with neovascular age-related macular degeneration. Am J Clin Nutr. 2008;88(2):398-406.
20. Christen WG, Schaumberg DA, Glynn RJ, Buring JE. Dietary {omega}-3 fatty acid and fish intake and incident age-related macular degeneration in women. Arch Ophthalmol. 2011;129(7):921-929.
21. Klein R, Chou CF, Klein BE, Zhang X, Meuer SM, Saaddine JB. Prevalence of age-related macular degeneration in the US population Arch Ophthalmol. 2011;129(1):75-80.

---

Dr. Boyer practices ophthalmology with Retina-Vitreous Associates Medical Group in Los Angeles and is clinical professor at the Keck School of Medicine of the University of Southern California in Los Angeles. Dr. Boyer has relationships with Alcon and Science Based Health, both makers of eye vitamins. He also reports minimal financial interest in Allergan, Genentech, Novartis, and iCo.