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Ocular Vitamins and AMD Progression

SEENU M. HARIPRASAD, MD

Dismayed by the failure of attempts to arrest the progression of nonexudative age-related macular degeneration (AMD), such as the now-terminated Anecortave Acetate Risk-Reduction Trial, retinal specialists are reconsidering the potential of ocular vitamins to forestall AMD progression. As we await new data from clinical trials under way, it's worthwhile to review the insights gleaned from prior studies as well as ponder the breakthroughs we hope to achieve in the future.

IMPACT OF AREDS

The Age-Related Eye Disease Study (AREDS), completed in 2001, gave us a better understanding of the genetic and environmental factors at work in the natural history of AMD and cataract, revealing potential opportunities for intervention. Previously identified risk factors for progression from dry to wet AMD include age,¹ race,¹ smoking,² family history of AMD,³ and a variation in the complement factor H gene,^4-6 as well as other genetic predispositions. AREDS assessed the impact of zinc and anti oxidant supplementation on AMD progression and helped to identify the subset of patients who stand to benefit the most from routine use of nutritional supplements.

The AREDS formulation is comprised of vitamin C (500 mg), vitamin E (400 IU), beta-carotene (15 mg), zinc (80 mg zinc oxide) and copper (2 mg cupric oxide). This combination was found to reduce the risk of developing advanced AMD by about 25% in high-risk individuals, defined in the study as those with intermediate-sized, soft, confluent drusen.⁸ To date, this combination is the only formulation of vitamin supplementation validated in a clinical trial to decrease the progression from dry to wet AMD. Interestingly, these same nutrients had no significant effect in halting the development or progression of crystalline lens opacity. Results of the study suggest that the AREDS formulation may play a key role in helping those AMD patients at high risk for developing advanced disease to maintain their remaining vision.

WHY DO ANOTHER STUDY?

Encouraged by AREDS results showing a role for dietary supplementation in AMD, the NIH is now undertaking a follow-up study known as AREDS 2. The primary objective is to determine if oral supplementation with xanthophylls and/or omega-3 long-chain polyunsaturated fatty acids (LCPUFAs) will decrease the risk of progression to advanced AMD. The study uses the xanthophylls lutein (at 10 mg/day) and zeaxanthin (at 2 mg/day), plus the LCPUFAs docosahexaenoic acid and eicosapentaenoic acid at a total of 1 g/day. Epidemiologic studies have previously shown an association between these agents and a reduced risk of advanced AMD.

AREDS 2 is a 2×2, factorial, placebo-controlled study in which participants are randomized to 1 of 4 groups: (1) lutein/zeaxanthin, (2) omega-3 LCPUFAs, (3) combined lutein/zeaxanthin and omega-3 LCPUFAs, and (4) placebo.⁹ The study recently completed enrollment of roughly 4,000 participants aged 50 to 85 with large drusen, either bilaterally or in 1 eye with advanced AMD in the fellow eye. Patients will be followed for 5 to 6 years.

A secondary goal of the study is to determine if modifications to the original AREDS formulation can maintain the documented 25% risk reduction while lowering the adverse effect profile. The high dose of zinc (80mg) used in AREDS was associated with prostate enlargement in men. In AREDS 2, that level has been halved to 40 mg per day. Researchers hope to achieve comparable reduction in AMD progression without impacting the risk of prostate enlargement. The beta-carotene component of the original AREDS formulation has also been eliminated due to concerns over its potential adverse effect profile.

Three comparisons will be made at each interim analysis of AREDS 2:

► progression to advanced AMD for lutein/zeaxanthin alone vs placebo

► progression to advanced AMD for DHA/EPA alone vs placebo

► progression to advanced AMD for lutein/zeaxanthin and DHA/EPA vs placebo.

VITAMIN USAGE

While many ocular vitamins are currently available, the literature currently supports only the use of vitamins containing the AREDS I supplementation for dry AMD characterized by soft, confluent, moderate-sized, drusen. While we currently favor the use of ocular vitamins, retinal physicians anxiously await the AREDS 2 results, as this will drive our treatment decisions in the future. RP

REFERENCES

1. Friedman DS, O'Colmain BJ, Muñoz B, et al. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol. 2004;122:564-572.
2. Khan JC, Thurlby DA, Shahid H, et al. Smoking and age related macular degeneration: the number of pack years of cigarette smoking is a major determinant of risk for both geographic atrophy and choroidal neovascularisation. Br J Ophthalmol. 2006;90:75-80.
3. Buch H, Vinding T, la Cour M, et al. Risk factors for age-related maculopathy in a 14-year follow-up study: the Copenhagen City Eye Study. Acta Ophthalmol Scand. 2005;83:409–418.
4. Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in age-related macular degeneration. Science. 2005;308:385-389.
5. Haines JL, Hauser MA, Schmidt S, et al. Complement factor H variant increases the risk of age-related macular degeneration. Science. 2005;208:419-421.
6. Sepp T, Khan JC, Thurlby DA, et al. Complement Factor H variant Y402H is a major risk determinant for geographic atrophy and choroidal neovascularization in smokers and nonsmokers. Invest Ophthalmol Vis Sci. 2006;47:536-540.
7. Haines JL, Schnetz-Boutard N, Schmidt S, et al. Functional candidate genes in age-related macular degeneration: significant association with VEGF, VLDLR, and LRP6. Invest Ophthalmol Vis Sci. 2006;47:329-335.
8. The 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;119:1417-1436.
9. Chu EY. Dietary supplements: what we should and should not be recommending for our patients. Retinal Physician. 2005;2(3):45-47.