Pharmacologic Management of Age-Related Macular Degeneration
Aimee V. Chappelow
Age-related macular degeneration (AMD) is the leading cause of severe, irreversible vision loss in individuals older than 50 years of age in Western societies. Advanced AMD compromises the vision of over 15% of white women older than 80 years of age in the United States and approximately 14 million people worldwide.1 As the population ages, the number of individuals with early AMD in the United States is expected to double by 2050, approaching 18 million.2 Although recent advances in pharmacotherapy have increased the direct cost for treatment of AMD, treatment utilization has the potential to offset future disease burden.2 Herein we introduce important pharmacotherapies for AMD that are either in current use or under investigation in clinical trials.
RISK FACTORS FOR AMD
The current body of evidence characterizing AMD suggests a multifactorial and polygenic etiology. Risk factors associated with development of AMD include white race, cigarette smoking,3,4,5 hypertension,3,6 elevated serum cholesterol,7 low serum carotenoids,8 and prior history of ischemic stroke.9 The prevalence of AMD increases with age, from 14.4% in persons aged 55 to 64 years to 36.8% in those older than 75 years.10 Smokers, white persons, and persons with greater body mass index (BMI) experience increased risk for progression from intermediate to advanced AMD.11 Diet represents an important modifiable risk factor given its role in risk factor modification; furthermore, intake of omega-3 fatty acids and olive oil is inversely related to risk for AMD.12 Cigarette smoking remains the most important modifiable risk factor for both the development and progression of AMD.
Twin studies13,14 have established AMD as a heritable disease, but specific genetic studies have been difficult to perform because AMD presents so late in life. More recently, studies reported that homozygosity for a specific polymorphism in the gene for complement factor H increases the risk for the development of AMD sevenfold15 and may account for up to 50% of the attributable risk of AMD.16,17 An association has also been observed between a specific variant of the functional toll-like receptor 3 gene (TLR3) and protection against geographic atrophy through suppression of RPE apoptosis.18 Other single-nucleotide polymorphisms portend not only an increased risk of AMD progression but also a lower likelihood of response to treatment.19
PATHOGENESIS AND NATURAL HISTORY OF AMD
AMD has traditionally been divided into two subtypes: wet, exudative, or neovascular; or dry, atrophic, or nonneovascular. The designation of AMD as advanced may refer to the presence of either central geographic atrophy or choroidal neovascularization (CNV). CNV characterizes neovascular AMD, the subtype that is responsible for approximately 90% of cases of severe vision loss in patients with AMD.
Cumulative oxidative injury and chronic local inflammation have been proposed as the major pathogenetic mechanisms that contribute to age-related macular degeneration and drusen biogenesis. Often the first finding in early AMD, drusen are collections of cellular debris that are deposited between the RPE and Bruch membrane as the eye ages. A druse is characterized based on size (small, ≤63 μm; medium, 63–124 μm; large, ≥125 μm) and appearance of its margins (hard, distinct; soft, indistinct). The presence of multiple medium drusen or retinal pigment epithelium (RPE) abnormalities is diagnostic of early AMD. The accumulation of larger and more numerous drusen damages adjacent RPE, leading to a chronic inflammatory response. Decreased visual acuity and central scotoma may then result due to atrophy of the overlying retina (geographic atrophy).
It is thought that the same inflammatory processes that lead to geographic atrophy also help promote the growth of choroidal neovascularization.20 Furthermore, drusen themselves serve as a chronic inflammatory stimulus. Inflammatory mediators, including neutrophils, macrophages, mast cells, and activated microglia, produce and release proangiogenic factors. Either a net increase in proangiogenic molecules (TGF-alpha, TGF-beta, the angiopoietins, and members of the vascular endothelial growth factor [VEGF] family) or a net decrease in antiangiogenic molecules (pigment epithelium-derived factor (PEDF), thrombospondin, and angiostatin) will stimulate neovascularization. Local hypoxia may also play a role in up-regulating VEGF.21
The VEGF family of proangiogenic factors includes VEGF-A (often referred to simply as VEGF), VEGF-B, VEGF-C, VEGF-D, and placental growth factor (PlGF)-1 and -2. Multiple biologically active forms of VEGF-A are generated by alternative messenger RNA splicing and proteolytic cleavage. The secreted form of VEGF-A is a homodimer that binds VEGF receptor (VEGFR)-1 and VEGFR-2 on vascular endothelial cells, inducing intracellular tyrosine kinase pathways. VEGF-A has been detected in elevated levels in both the excised CNV membranes22 and vitreous of patients with CNV23 and is integral to the growth and maintenance of CNV. As such, it has become a popular and effective target for pharmacotherapy in AMD.
Macroscopically, CNV is a neovascular proliferation that breaks through Bruch’s membrane and progresses laterally either beneath the RPE (type 1) or between the RPE and Bruch membrane (type 2).24 CNV is often associated with exudates and hemorrhage due to abnormal permeability of its endothelium and general vascular fragility. CNV may be classified based on clinical (subfoveal, juxtafoveal, or extrafoveal) or angiographic (classic, occult, predominantly classic, or minimally classic) criteria. Classic CNV refers to a lesion that exhibits bright, well-defined, focal hyperfluorescence that increases in area and intensity in late phases. Occult CNV may be classified as one of two angiographic subtypes: late leakage of undetermined significance (LLUS) or fibrovascular pigment epithelial defect (FVPED). The latter is characterized by an irregular retinal pigment epithelial (RPE) elevation with or without either early hyperfluorescent stippling or late leakage. LLUS refers to late leakage without evidence of a corresponding FVPED or classic CNV in earlier frames. A lesion composed of <50% classic CNV is termed minimally classic, whereas CNV composed of >50% classic CNV is known as predominantly classic. Occult CNV by definition has no component of classic CNV. With regard to lesion location, juxtafoveal CNV is located within a 200 μm radius of the center of the foveal avascular zone (FAZ), outside the 1 μm radius subfoveal zone. Extrafoveal refers to lesions at least 200 μm from the center of the FAZ.
Neovascular AMD is a progressive disease with poor visual prognosis if untreated. The proportion of patients with visual acuity worse than 20/200 progressed from 20% at baseline to 76% at 3 years in one meta-analysis that pooled patients with all CNV subtypes.25 Untreated fellow eyes with subfoveal classic and occult with no classic CNV experienced similar rates of vision loss at 24 months (62% and 69%) in two large prospective trials.26,27 Extrafoveal lesions tend to progress to subfoveal lesions, with juxtafoveal CNV progressing to subfoveal CNV in more than 90% of patients over the course of 5 years if not treated.28 Furthermore, in patients with unilateral neovascular AMD, 27% develop CNV in the fellow eye over the course of 3 years.28 Risk factors for choroidal neovascularization in the fellow eye include the presence of large drusen (≥63 μm), five or more soft drusen, focal retinal pigment epithelial (RPE) hyperpigmentation, and definite systemic hypertension.29 The Macular Photocoagulation Study (MPS) reported a 5-year cumulative incidence rate of neovascular AMD ranging from 7% (if all aforementioned risk factors were absent) to 87% (if all four risk factors were present).30
Nonneovascular (Dry) AMD
Of the two types of AMD, options for treatment of nonneovascular AMD are more limited in scope and efficacy. Despite ongoing research exploring novel therapies, dietary/lifestyle modification, and daily antioxidant/zinc vitamin supplementation have remained the mainstay of therapy for the past decade. Investigations of nonpharmacologic therapy for dry AMD, including Rheopheresis, laser photocoagulation, and macular translocation surgery, have been plagued by either unacceptable rates of adverse events or poor outcomes. The Drusen Laser Study Group found that prophylactic laser actually promotes the development of CNV in high-risk dry AMD.31 Although it did not identify serious treatment-related adverse effects, the randomized, double-masked, placebo-controlled Multicenter Investigation of Rheopheresis for AMD (MIRA-1) trial failed to identify an effect in the intent-to-treat group.32 Furthermore, macular translocation surgery with 360° peripheral retinectomy, though promising with respect to short-term visual acuity outcomes, results in recurrent geographic atrophy in most patients.33 Here we review data that support a beneficial role for antioxidant and zinc supplementation in preventing the progression of dry AMD and outline emerging therapies currently under investigation.
Antioxidant Vitamins and Zinc
Therapy for dry AMD has consisted of daily antioxidant (vitamin C, vitamin E, and β-carotene) and zinc supplementation since results of the Age-Related Eye Disease Study (AREDS) were published in 2001. The AREDS trial enrolled 4,757 persons aged 55 to 80 years into one of four AMD categories determined by visual acuity; presence, size, and extent of drusen and RPE abnormalities; and presence of advanced AMD. Subjects were followed for an average of 6.3 years following randomization into one of four treatment groups: (i) placebo, (ii) antioxidants (500 mg vitamin C, 400 IU vitamin E, and 15 mg beta-carotene daily), (iii) antioxidants plus 80 mg zinc plus 2 mg copper daily, (iv) 80 mg zinc plus 2 mg copper daily.34 Copper was added to groups supplemented with zinc to prevent copper deficiency anemia, a condition associated with high levels of zinc intake.
Of greatest significance, the AREDS found that supplementation with antioxidants plus zinc plus copper significantly delayed the progression from intermediate to advanced AMD (neovascular disease or geographic atrophy) by 25% over 5 years.34 Intermediate AMD was specifically defined as the presence of at least one large druse ≥125 μm, extensive intermediate drusen, or noncentral geographic atrophy. AREDS patients with features of mild AMD (small or few intermediate drusen or RPE abnormalities) experienced no reduction in rate of disease progression; however, this subgroup enjoyed an extremely low 5-year risk for progression, and the study was not powered to detect a small reduction. Subsequent reports have validated the protective effect of antioxidant,35,36 carotenoid,27 and zinc37 supplementation on macular function in AMD patients. Compared with no therapy, daily therapy with antioxidants and zinc has been estimated to lower the percentage of patients with intermediate AMD who develop visual impairment in the better-seeing eye from 7% to 5.6%.27
Daily vitamin supplementation for patients with intermediate AMD has proved to be a cost-effective therapy, though one with variable compliance. On average, a 1-month supply of an AREDS-formula vitamin costs less than $10. The associated cost-effectiveness ratio reported based on stochastic computerized models ranges from $21,000 to $32,000 per quality-adjusted life year (QALY),38,39 rendering vitamin therapy for dry AMD roughly four times more cost-effective than PDT with verteporfin for subfoveal CNV.40 However, patient surveys indicate compliance rates ranging from 38% to 80%.41,42,43 Furthermore, of eligible AMD patients taking an eye health vitamin supplement, many either use a formulation not recommended by the AREDS or use the incorrect dose of an AREDS-like formulation.42,43 As such, practitioners should educate patients regarding proper use of vitamin supplements.
Although the AREDS demonstrated no adverse effects in the treatment group, daily high-dose antioxidant supplementation carries some risk, especially in patients who smoke or have cardiac disease. Smokers should be advised to avoid beta-carotene supplementation owing to the potential for increased risk of lung cancer.44 Beta-carotene–free AREDS-formula vitamins designed specifically for smokers are commercially available. One meta-analysis also indicated that beta-carotene supplementation slightly increases the risk for cardiovascular death in the general population (odds ratio 1.1; p = 0.003)45; however, the beta-carotene dosage studied was three times greater than that used in the AREDS. Daily supplementation with twice the dose of vitamins C and E used in AREDS was found to be associated with worsening heart disease in women with pre-existing heart disease.46 Furthermore, a 2005 meta-analysis47 of 19 randomized controlled trials reported a significant increase in all-cause mortality associated with high (≥400 IU/d) vitamin E supplementation (either alone or with vitamin C and/or beta-carotene). Given these potential risks, in conjunction with lack of evidence for a role for antioxidant supplementation in the prevention of AMD,48 supplementation with AREDS-like vitamins in the general population is not warranted.
Lutein and Zeaxanthin
Sufficient evidence exists to suggest a possible role for supplementation with lutein, zeaxanthin, and ω-3 long-chain polyunsaturated fatty acids (LCPUFA) in slowing the progression of dry AMD. Lutein and zeaxanthin are oxygenated carotenoids (xanthophylls) that represent the major diet-based compounds of macular pigment. Studies have identified an inverse relationship between risk of neovascular AMD and dietary intake of lutein,8 lutein/zeaxanthin,49 and omega-3 fatty acids.50 Furthermore, dietary supplementation with lutein has been shown to increase the density of macular pigment,51,52 which is hypothesized to protect against AMD.53 Examination of autopsy eyes reveals lower retinal lutein and zeaxanthin in eyes with AMD compared to controls.54
The Age-Related Eye Disease Study 2 (AREDS2), a phase III multicenter randomized controlled trial that concluded enrollment in June 2008 [http://www.clinicaltrials.gov; NCT00345176], will evaluate the effect of daily supplementation with high doses of lutein, zeaxanthin, and omega-3 fatty acids (docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]) on the risk of progression to advanced AMD. Approximately 4,000 men and women aged 50 to 85 years will be followed for a minimum of 5 years following assignment to one of four study arms: (i) lutein/zeaxanthin alone, (ii) DHA/EPA alone, (iii) lutein/zeaxanthin and DHA/EPA, or (iv) placebo. Additional treatment will also be offered with either the original AREDS formulation or variations on the AREDS formulation without beta-carotene and/or lower in zinc.55 Secondary outcome measures will include adverse events, effects of DHA/EPA on cardiovascular morbidity and mortality, and incidence of cataract surgery. In prior studies, both lutein and zeaxanthin have been administered daily for up to 9 months without evidence of toxicity.56,57
Although antioxidants, zinc, and lutein/zeaxanthin represent the most efficacious pharmacotherapies for dry AMD, these therapies are not effective in preventing AMD. Despite reports that lutein and zeaxanthin reduce oxidative stress-induced apoptosis in photoreceptors,58 a large prospective study found no correlation between lutein/zeaxanthin intake and risk of self-reported early AMD.59 Furthermore, three separate randomized controlled trials60,61,62 failed to identify a relationship between antioxidant intake and incident AMD.
Vitamin B and Folic Acid
Vitamin B and folic acid supplementation may be beneficial in preventing AMD in a subset of the female population.63 The rationale is based on the proposed etiologic role for atherosclerosis and endothelial dysfunction in AMD.64 Although hyperhomocysteinemia is considered an independent risk factor for atherosclerosis, and serum homocysteine levels may be lowered by oral supplementation with folic acid, pyridoxine, and cyanocobalamin, treatment of hyperhomocysteinemia has not been shown to reduce cardiovascular events or mortality.65 However, the Women’s Antioxidant and Folic Acid Cardiovascular Study (WAFACS),63 which randomized 5,205 women older than 40 years of age with three or more cardiovascular risk factors to receive placebo or a combination of folic acid, pyridoxine, and cyanocobalamin, found that fewer women in the combination treatment group developed AMD than in the placebo group (p = 0.02) after an average follow-up of 7.3 years.63 Studies have yet to evaluate the role for folic acid, pyridoxine, and cyanocobalamin supplementation in men or in women not at increased risk of vascular disease.