section 2: Animal Models and Routes for Retinal Drug Delivery

Vitamins and supplements for age-related macular degeneration

Hanna R. Coleman, MD and Emily Y. Chew, MD

CHAPTER

8

INTRODUCTION

Age-related macular degeneration (AMD) is the leading cause of visual loss in the USA among persons over 65 years of age.1,2 The incidence is projected to grow at a considerable rate because of the increasing longevity of the US population.3 The treatment of advanced AMD has progressed significantly over the years, but there is still no effective cure and unfortunately visual impairment continues to be high.4–7

HISTORY

A variety of risk factors have been found to be associated with both earlyand late-stage AMD,1,7–15 the most consistent of which are advanced age and smoking. Other risk factors include female gender, light iris color, heredity, cardiovascular health, nutrition status, high body mass index, and lifetime exposure to sunlight. Prevention of modifiable risk factors is a promising approach to reducing the individual’s and society’s burden of this condition.16–18

The possibility that the antioxidant balance can be positively altered by diet or vitamin supplementation has created much interest. Oxidative stress is thought to play a significant role in the pathogenesis of AMD because smoking is known to deplete the body’s antioxidative potential.19 Certain diets and nutritional supplements have already been shown to affect the progression of AMD. Oxidative processes occur in, and are essential to, most biological functions. As such, multiple pathways have evolved to maintain the balance between the necessary free radicals that serve as regulatory molecules and the unchecked highly reactive molecules that can initiate devastating cytotoxic reactions.20 The retina is extremely susceptible to oxidative stress due to its high oxygen use and its chronic exposure to light. Photoreceptor outer segments in particular are very vulnerable to oxidative damage because of their high content of polyunsaturated fatty acids.21,22

The Age-Related Eye Disease Study (AREDS), conducted by the National Eye Institute, was a multicenter randomized, controlled clinical trial of oral supplements. It demonstrated that high doses of antioxidant vitamins, C, E and beta-carotene and zinc can be effective in slowing the progression to advanced AMD by about 25% in participants with intermediate AMD (AREDS category 3: extensive intermediate or large drusen in both eyes) or advanced AMD in one eye (AREDS category 4). The overall risk of moderate vision loss (≥15 letters on the ETDRS chart) was reduced by 19% at 5 years.23

In this study, the rate of development of advanced AMD in participants with either no AMD (category 1) or early AMD (AREDS category 2) was exceedingly low, 1.3% in 5 years, and no beneficial effects of the combination treatment were seen. For this reason, the AREDS supplements are only recommended for persons with moderate to severe AMD.

KEY CONCEPTS AND PHARMACOLOGY OF CURRENT DIETARY SUPPLEMENTS

Continuing evidence is accumulating regarding the role of oxidative stress in the pathogenesis of AMD and the mechanisms involved in the process.24–27 Of particular interest is the occurrence and significance of macular pigment. Macular pigment is composed primarily of lutein and zeaxanthin, both of which are macular xanthophylls and members of the carotenoid family. They are found mostly in green leafy vegetables such as spinach, collard greens, and kale.28–30 The concentration of macular pigment is greatest at the inner retinal layers of the fovea and the small amounts that are present in the peripheral retina are found in rod outer segments.17,31 Studies suggest that an inverse relation exists between the risk of AMD and the amounts of lutein and zeaxanthin in the retina.32–34 A high intake of green leafy vegetables containing lutein and zeaxanthin has also been associated with a reduction in the risk of neovascular AMD.35–37

The mechanism of protection of lutein and zeaxanthin is thought to relate to their ability to reflect short-wavelength light. The reduced exposure to these wavelengths may reduce both photochemical and oxidant damage to cellular lipids, proteins, and nuclear material. It has also been postulated that the carotenoids may guard the retina from oxidative stress by modulating light and oxidant exposure via two mechanisms: by absorbing the blue light that may be associated with photochemical damage, and by quenching reactive oxygen species (antioxidative potential).36,38–42

At the beginning of the AREDS trial, lutein and zeaxanthin were not commercially available and beta-carotene, although not present in the retina, was used for its antioxidative potential. During the trial, supplementation of beta-carotene was shown to increase the risk of lung cancer and its associated mortality in smokers.43,44 It also benignly increased the yellowing of the skin. An amendment was made to the AREDS protocol to offer all smokers in the study the chance to stop the medication and consider randomization to placebo or zinc only. The current AREDS formulation with beta-carotene is thus not recommended for smokers. A follow-up clinical trial, AREDS2 (http://www. areds2.org), is currently under way to assess whether lutein and zeaxanthin and/or omega-3 polyunsaturated fatty acids can reduce the risk of developing advanced AMD. AREDS2 will also study the effect of eliminating beta-carotene from the original vitamin formulation on the development and progression of AMD.

Zinc was tested in the original AREDS formulation at high doses of 80 mg and copper was added to offset the common side-effect of cop- per-deficient anemia. The outcome in the zinc-treated group showed a few letters gained but this was considered to be of questionable clinical significance. The Blue Mountain Eye Study however recently confirmed the AREDS finding of protective influences from zinc against AMD.45 Zinc treatment was associated with decreased mortality in AREDS (relative risk, 0.73; 95% confidence interval (CI), 0.60–0.89) but the import of this is unknown given the population consisted of motivated volunteers.46,47 In AREDS, zinc also increased hospitalizations due