Eye Vitamins for Age-Related Macular Degeneration

Background

Age-related macular degeneration (AMD) is the major cause of vision loss in the elderly in industrialized countries.^1,2 At least one in ten individuals over the age of 65 years is affected.^3-5 More than ten years ago a landmark study showed the benefits of supplementation with specific vitamins on the progression of AMD. Now, another study has been published that lends more clarity to which supplements do and do not seem to slow progression of AMD. This document looks at the evidence for using vitamins in patients with AMD.

Review of AMD

Age-related macular degeneration involves damage to the retina. There are two different forms of AMD: dry and wet. The dry form, also called nonexudative AMD or geographic atrophy in its advanced form, is most common. It accounts for more than eight out of ten cases. Aging and thinning of the retina are involved in dry macular degeneration. The wet form, also called neovascular AMD or exudative AMD, is less common. It involves the growth of new blood vessels under the retina. Wet AMD is more aggressive than dry AMD and can cause rapid and severe vision loss. In addition, dry AMD can progress to wet AMD in some cases.³

There is some evidence that the effects of aging on the retina are caused by oxidative stress.⁶ Besides advanced age, risk factors for AMD may include Caucasian race, a first-degree relative with AMD, cigarette smoking, high blood pressure, exposure to sunlight, obesity, and a diet rich in some types of fats.^3,6,7 In fact, cigarette smoking appears to more than double the risk for AMD.^5,6

Vascular endothelial growth factor antagonists such as pegaptanib (Macugen) are given via intravitreal injection for the treatment of wet AMD. However, there are no known treatments for dry AMD. This makes prevention and slowing of progression of dry AMD especially important.

AREDS

Animal data and observational studies prompted the study of dietary supplements for slowing progression of AMD in clinical trials. These include two large randomized controlled trials (RCTs), AREDS and AREDS2.

The Age-Related Eye Disease Study (AREDS) included almost 4000 patients with AMD. It looked at prevention of progression of AMD with specific vitamins (vitamin C 500 mg, vitamin E 400 units, and beta-carotene 15 mg, with or without zinc 80 mg and copper 2 mg; zinc 80 mg and copper 2 mg alone; and placebo). The median age of enrolled patients was 69 years, a little over half of the patients were women, and they were followed for an average of 6.3 years.²

The group that received antioxidants plus zinc had a significant reduction in the risk for development of advanced AMD (odds ratio [OR] 0.72; 99% confidence interval [CI] 0.52 to 0.98). However, those with less severe AMD (early disease) typically have a very low rate of progression to more advanced AMD. This subgroup showed no benefit from treatment with antioxidants plus zinc. The benefit was shown mainly in those with intermediate AMD (dry) in one or both eyes or advanced AMD (dry or wet) in one eye, with a reduction in development of advanced AMD (OR 0.66, 99% CI 0.47 to 0.91) and a reduced risk for vision loss (OR 0.73, 99% CI 0.54 to 0.99 ).^2,5

From these results, it appears that treating around ten to 22 high-risk patients with the AREDS vitamin formulation for five years will prevent one from progressing to severe macular degeneration.²

There were no statistically significant increases in serious adverse events with any of the formulations used in the study.² However, cigarette smoking is now a contraindication to the use of beta-carotene because it can increase the risk for lung cancer in current or former smokers.^2,4 It is worth noting as well that about two-thirds of patients in the study took a multivitamin (Centrum) in addition to their study drug.^2,4

Based on the results of AREDS, treatment guidelines were updated to recommend the AREDS formulation for patients most likely to benefit: those with intermediate AMD in one or both eyes or advanced AMD in one eye.⁵ In addition, a number of different products with the same formulation used in AREDS hit the market: PreserVision AREDS (U.S.), ICaps AREDS, etc. There are also products available that have a similar content to the AREDS formulation, but not exactly the same. These include Vitalux AREDS (Canada), which has less beta-carotene but added lutein and zeaxanthin.

AREDS2

The results of AREDS2 (n=4203), which also looked at potential benefits of supplements on progression to advanced AMD, were recently published. This study involved adding lutein 10 mg and zeaxanthin 2 mg, the omega-3 fatty acids DHA 350 mg and EPA 650 mg, both, or placebo to a variation of the AREDS formulation. The variations of the AREDS formulation included original AREDS, original AREDS minus beta-carotene, original AREDS with a lower dose of zinc, or original AREDS minus beta-carotene with a lower dose of zinc. The patient population in AREDS2 was at high risk for progression to advanced AMD, such as those who were shown to have the most benefit in AREDS (i.e., intermediate dry AMD in one or both eyes or advanced AMD in one eye). Median follow-up in AREDS2 was five years.⁴

The results of AREDS2 did not show a further reduction in the risk of progression to advanced AMD or effect on visual acuity beyond that of the original AREDS formulation in any of the treatment groups. In other words, the addition of omega-3 fatty acids or lutein/zeaxanthin provided no added benefit. However, a post hoc analysis of the AREDS2 data suggests that lutein plus zeaxanthin may be a suitable substitute for beta-carotene when given with the original AREDS formulation (minus beta carotene).⁴ This formulation can be considered for smokers, due to their contraindication to the use of beta carotene. However, the hypothesis will require further study.^1,4,8

AREDS vitamin formulations without beta-carotene and with added lutein and zeaxanthin (same as the AREDS2 formulation) are currently available, such as PreserVision AREDS 2 (U.S., currently being reformulated without omega-3’s). There are also products available that have a similar content to the AREDS2 formulation, but not exactly the same. These include Vitalux-S (Canada) and PreserVision Lutein (Canada), which have less zeaxanthin and no beta-carotene.

Conclusion

A combination of vitamin C 500 mg, vitamin E 400 units, beta-carotene 15 mg, zinc 80 mg, and copper 2 mg reduces progression of AMD in patients with intermediate AMD in one or both eyes or advanced AMD in one eye [Evidence level A; high-quality RCT].² Lutein 10 mg plus zeaxanthin 2 mg may be an appropriate replacement for the beta-carotene component for smokers, where there is an increased risk of lung cancer with beta-carotene use.⁴

Tell patients it’s okay to take eye vitamin formulations such as PreserVision AREDS along with a multivitamin. But let them know that multivitamins alone have not been shown to help with AMD.

Tell those without AMD or those with early AMD it’s too soon to recommend eye vitamins for prevention or slowing of disease progression, respectively. Instead, encourage lifestyle modifications that are likely to reduce the risk such as smoking cessation, eating a healthy diet with green leafy vegetables, and wearing good sunglasses.^6,7,9

Levels of Evidence

In accordance with the trend towards Evidence-Based Medicine, we are citing the LEVEL OF EVIDENCE for the statements we publish.

Adapted from Siwek J, et al. How to write an evidence-based clinical review article. Am Fam Physician 2002;65:251-8.

Project Leader in preparation of this PL Detail-Document: Stacy A. Hester, R.Ph., BCPS, Assistant Editor

References

1. Ma L, Dou H, Wu YQ, et al. Lutein and zeaxanthin intake and the risk of age-related macular degeneration: a systematic review and meta-analysis. Br J Nutr 2012;107:350-9.
2. AREDS 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;119:1417-36.
3. Kowluru RA, Zhong Q. Beyond AREDS: Is there a place for antioxidant therapy in the prevention/treatment of eye disease? Invest Ophthalmol Vis Sci 2011;52:8665-71.
4. AREDS2 Research Group. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA 2013;309:2005-15.
5. American Academy of Ophthalmology Retina Panel. Preferred Practice Pattern Guidelines. Age-related macular degeneration. October 2011. http://one.aao.org/CE/PracticeGuidelines/PPP_Content.aspx?cid=f413917a-8623-4746-b441-f817265eafb4. (Accessed July 15, 2013).
6. Cavallerano AA, Cummings JP, Freeman PB, et al. Care of the patient with age-related macular degeneration. 2004. http://www.aoa.org/documents/CPG-6.pdf. (Accessed July 15, 2013).
7. Cheung LK, Eaton A. Age-related macular degeneration. Pharmacotherapy 2013;doi:pii:S0161-6420(13)00313-8.10.1016/j.ophtha.2013.03.028.
8. Ma L, Dou HL, Huang YM, et al. Improvement of retinal function in early age-related macular degeneration after lutein and zeaxanthin supplementation: a randomized, double-masked, placebo-controlled trial. Am J Ophthalmol 2012;154:625-34.
9. Sin H, Liu DT, Lam DS. Lifestyle modification, nutritional and vitamins supplements for age-related macular degeneration. Acta Ophthalmol 2013;91:6-11.

Cite this document as follows: PL Detail-Document, Eye Vitamins for Age-Related Macular Degeneration. Pharmacist’s Letter/Prescriber’s Letter. August 2013.

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