Annals of Pharmacotherapy
Benefits, Potential Harms, and Optimal Use of Nutritional Supplementation for Preventing Progression of Age-Related Macular Degeneration
Carlos H. Rojas-Fernandez, BSc (Pharm), PharmD1,2, and Kevin Tyber, BSc, OD3
Objective: To briefly review age-related macular degeneration (AMD), the main findings from the Age Related Eye Disease Study (AREDS) report number 8 on the use of nutritional supplements for AMD, and to focus on data suggesting that supplement use should be guided using genetic testing of AMD risk genes. Data Sources: A literature search
(January 2001 through October 26, 2016) was conducted using MEDLINE and the following MeSH terms: Antioxidants/ therapeutic use, Genotype, Macular Degeneration/drug therapy, Macular degeneration/genetics, Dietary Supplements, Proteins/ genetics, and Zinc Compounds/therapeutic use. Bibliographies of publications identified were also reviewed. Study Selection
and Data Extraction: English-language studies assessing AREDS supplement response in patients with AMD in relation to complement factor H gene (CFH) and age-related maculopathy susceptibility 2 gene (ARMS2) risk alleles were evaluated. Data Synthesis: Three of the 4 studies demonstrated a treatment interaction between ARMS2 and CFH genotypes and a differential response to supplements. The fourth study documented an interaction for the CFH genotype only. Reported response interactions included attenuated response, no response, and good response, whereas a subset showed increased progression of AMD. Conversely, one study reported no interactions between CFH and ARMS2 risk alleles and response to
supplements. Conclusions: The weight of the evidence supports using genetic testing to guide selection of ocular vitamin use. This approach will avoid using supplements that could speed the progression of AMD in vulnerable patients, avoid using supplements that will have little to no effect in others, and result in appropriately using supplements in those that are likely to derive meaningful benefits.
gout, therapeutic monitoring, rheumatology, quality assurance, adherence
Age-related macular degeneration (AMD) is a progressive eye disease affecting the clear central vision necessary for activities of daily living such as reading or driving and is the
leading cause of legal blindness for those 55 years or older in the Western World. The first clinical sign of AMD is the finding of drusen, which are focal, acellular deposits of
polymorphous debris between the retinal pigment and Bruch’s membrane.1 Most commonly, AMD is classified using the system from the Age-Related Eye Disease Study
(AREDS) study, whereby AMD is categorized as group 1 (no AMD: no drusen or <10 small drusen without pigment abnormalities), group 2 (early AMD), group 3 (intermediate
AMD), group 4 (advanced AMD; geographic atrophy), and group 5 (neovascular AMD).2 Advanced AMD may be nonvascular (dry, atrophic, or nonexudative) or neovascular
(wet or exudative) in nature. The incidence of AMD is increasing rapidly, with more than 2 million incident cases each year in North America, largely attributable to an ageing population. In terms of prevalence, 9% of those aged >40 years have any form of AMD, which increases to 30% for those aged >75 years.
Risk factors for AMD include smoking, body mass index, and age, which collectively compose 40% of the AMD risk, whereas genetic factors such as polymorphisms in the complement
factor H gene (CFH) and age-related maculopathy susceptibility 2 gene (ARMS2) genes and others collectively constitute about 60% of the risk for AMD.1
1CRF Consulting, Waterloo, ON, Canada
2McMaster University, Hamilton, ON, Canada
3Optometrist, Ajax, ON, Canada
Carlos H. Rojas-Fernandez, CRF Consulting, Waterloo, ON, Canada.
About 15% to 20% of patients with early/intermediate AMD will progress to advanced AMD and experience a gradual and insidious visual loss over months to years.3
Although most persons with AMD will not become completely blind, visual loss will result in functional impairment, loss of driving ability, depressive illness in up to
one-third of patients, and lower quality of life for most patients.4 In addition, 1 in 5 patients with dry AMD will progress to neovascular AMD, which accounts for 90% of
AMD-related blindness. Finally, there is a high (43%) risk of developing neovascular AMD in a/the second eye within 5 years of wet AMD developing in the other/one eye.1
Management of AMD consists of appropriate blood pressure control and lifestyle modifications, such as smoking cessation, ensuring and maintaining a healthy weight, a
diet low in fat, and rich in green, leafy vegetables, brightly colored fruit, eggs, and fish.1 Use of ocular vitamin and mineral supplements has played a role in managing AMD
since the early 2000s based on the landmark AREDS substudy (ie, AREDS Report Number 8).5 In recent years, data have emerged suggesting that genetic testing based on CFH
and ARMS2 risk alleles might be of use in guiding supplement use in patients with AMD, based on observed differential response patterns across CFH and ARMS2 risk alleles,
though this has been a matter of controversy.6-10 Given that pharmacogenetic testing is becoming more common and that ocular supplements are widely available, it is important
that pharmacists be able to educate patients with AMD in the safe and appropriate use of these supplements. The objective of this article is to assess the role of genetic testing
to guide the appropriate use of ocular supplements.
A comprehensive literature search (January 2001 through October 26, 2016) was conducted using MEDLINE and the MeSH terms Antioxidants/therapeutic use, Genotype,
Macular Degeneration/drug therapy, Macular degeneration/ genetics, Dietary Supplements, Proteins/genetics, and
Zinc Compounds/therapeutic use. Bibliographies of publications identified were also reviewed for citations of possible relevance.
Study Selection and Data Extraction
Studies were selected if they met the following criteria: (1) the studies were published since January 2001 (the year the AREDS study was published, because no such data existed
prior to 2001); (2) the study’s objective was to assess response to AREDS supplement use in patients with AMD in relation to CFH and ARMS2 risk alleles; (3) the studies
were in English; and (4) the studies were conducted using human subjects. The initial search yielded 7 citations, 3 of which were relevant per the aforementioned criteria. The
search was expanded using the “similar articles” function in PubMed, yielding 220 citations, which decreased to 183 after applying restrictions of English, humans, and date of
publication. Review of the 183 citations resulted in identification of 2 additional citations for a total of 5 articles. Finally, an additional article was identified that was a non–peer-reviewed article, but because it was ostensibly an additional analysis of relevance, it was included, bringing the number of citations to 6.
Current Management and Early Evidence of Efficacy of Vitamin and Mineral Supplementation In 1988, zinc supplementation was found to be associated
with a reduction in visual acuity loss in AMD.11 Soon thereafter, vitamin formulations containing zinc and antioxidants began to be utilized for AMD, despite the lack of controlled
evidence of benefit.12 In the setting of a disease with no treatment options, use of nutritional supplements was likely considered a benign intervention, yet investigators and representatives
from the National Eye Institute were explicit in stating that such products should not be used without more definite data.12 Fortunately, the AREDS study (1992-2001, n = 3640)
evaluated the effect of high-dose vitamins C and E (500 mg and 400 IU), β-carotene (15 mg), and zinc supplementation (80 mg) on the progression of AMD and loss of visual acuity as coprimary end points in a primarily Caucasian population (AMD is rare in those of African origin).5 This study demonstrated that the risk of AMD progression was significantly reduced in patients with
AMD categories 2, 3, and 4 (odds ratio [OR] = 0.68; 95% CI = 0.49, 0.93) and in those with AMD categories 3 and 4 (OR = 0.66; 95% CI = 0.47, 0.93), but there was no significant
effect on the risk of visual acuity loss, thus failing to demonstrate efficacy in the primary study end point. Nevertheless, considering the lack of treatment options and the positive findings regarding AMD progression, it was suggested that supplementation with antioxidants and zinc be considered for those with category 3 and 4 AMD. It was also recommended that supplements should only be used by nonsmokers because subsequent analyses of other studies showed an increased incidence of cancer in smokers or recent ex-smokers who took β-carotene.5,8 Subsequently
the AREDS-2 study was conducted to determine whether adding lutein, zeaxanthin, DHA+EPA (docosahexaenoic acid+eicosapentaenoic acid), or both to the original AREDS
formulation would decrease the risk of developing advanced AMD and to evaluate the effect of eliminating β-carotene, lowering the dose of zinc to 25 mg, or both.13
The AREDS-2 study demonstrated that the risk of AMD progression was not further decreased, and it was suggested that the previous formulation could be changed to include
lutein and zeaxanthin and exclude β-carotene. Since the AREDS-2 study was published, the standard of care for dry AMD has been the AREDS-2 ocular formulation
(AREDS-F) containing vitamin E (400 IU), vitamin C (500 mg), lutein (10 mg), zeaxanthin (2 mg), copper (2 mg), and zinc (80- and 25-mg formulations available). It is important to note that the AREDS2 study was not designed to address equivalency of different doses of zinc studied (25 and 80 mg) and that, currently, the only zinc dose proven to reduce AMD risk is 80 mg as studied in the original AREDS study.5
AMD is primarily influenced by genetic factors, with environmental and behavioral factors also playing important roles.1,14 Since 2005, it has been documented that a polymorphism
(Tyr402His) in the CFH gene greatly increases the risk of AMD in white people in a dose-related manner. There are additional polymorphisms (eg, complement factor B [CFB] and C2 genes), and collectively, polymorphisms in CFH, CFB, and C2 genes may explain almost 75% of AMD cases.15 CFH is a major inhibitor in the complement
pathway, which is synthesized in the macula and is present in drusen.16 In addition, there is a strong association between the Ala69Ser polymorphism of the ARMS2 gene, although its function is uncertain. Klein et al6 conducted a study using DNA from 876 AMD category 3 and 4 participants from the AREDS cohort to determine whether CFH and ARMS2 genotypes influenced
treatment response to supplementation with antioxidants and zinc. Their findings suggested that response to AREDS supplementation was likely related to the CFH genotype, thus potentially predicting treatment outcome and avoiding supplement use in those who would not benefit. Despite these findings, these investigators suggested that practice should not be changed until these results were replicated. Conversely, Awh et al9 suggested that treatment with AREDS supplements should be guided by patient’s genotypes based on their study results, which demonstrated
that CFH and ARMS2 risk alleles influenced the response to antioxidants, zinc, or both. Most recently, Awh et al8 reported a study using DNA analysis from 989 white AREDs participants with stage 3 and 4 AMD at enrolment to determine the impact, if any, of CFH and ARMS2 risk alleles on AMD progression based on the AREDS formulation components. Four genotype groups (GTG1-GTG4) were composed according to the number of CFH or ARMS2 risk alleles, and results from these analyses were striking.8 Specifically, there was an increased risk of progression to
advanced AMD for GTG group 2 participants taking zinc alone (hazard ratio [HR] = 3.07; 95% CI = 1.18, 8.00) or the AREDS F formulation (antioxidants + zinc; HR = 2.73; 95% CI = 1.04, 7.20), whereas a decreased risk of progression was observed among patients in GTG group 1 taking antioxidants alone (HR = 0.38; 95% CI = 0.16, 0.93), but not AREDS-F supplements (HR = 0.8; 95% CI = 0.39, 1.63), or zinc alone (HR = 1.03; 95% CI = 0.50, 2.14); a decreased risk of progression was also observed for GTG group 3 participants taking zinc alone (HR = 0.51; 95% CI
= 0.31, 0.86) or the AREDS-F formulation (HR = 0.57; 95% CI = 0.35, 0.93); finally, no benefit was observed for GTG group 4 participants regardless of treatment arm (see Figure 1 and Table 1).The investigators suggested GTG group– directed treatment for white patients with AREDs category 3 in 1 eye or category 4 (advanced AMD in 1 eye only).Interestingly, Chew et al7 conducted a study to replicate the findings by Awh et al using a larger sample size (n = 1237; though the source of these additional subjects is unclear) and a different analytical approach. Because CFH
and ARMS2 genotypes were not found to alter the benefits of AREDS supplements in their analyses, the investigators concluded that genetic testing should not guide treatment and argued that the suggestions of Awh et al were not clinically appropriate.7,17 Collectively, these studies have garnered significant attention and disagreement in the literature.18-22 Indeed, the 2015 report by Chew et al and its accompanying editorial argue against using genomic testing, whereas others argue that the original AREDS findings are overstated and that the 2015 study results are based on flawed analyses.23-25 Most recently, Seddon et al10 published findings further supporting the differential effectiveness of antioxidant and zinc supplementation based on CFH and
ARMS2 genotypes. The study used a larger sample (n = 4124 eyes) with the eye as the unit of analysis and appropriately excluded eyes with AMD 1 or 4, as in the original AREDS analyses. Similar to prior analyses, the use of antioxidants alone was associated with a lower hazard of developing advanced AMD (HR = 0.81; 95% CI = 0.67, 0.99).
This effect was limited to those progressing to neovascular AMD for zinc (HR = 0.66; 95% CI = 0.50, 0.88) or antioxidant and zinc (HR = 0.73; 95% CI = 0.56, 0.97), with no significant effect of either on advanced AMD. Multivariate analyses revealed associations between low to high genetic risk groups, with significant interactions for those with 2 CFH risk alleles versus 0 risk alleles in those developing neovascular AMD (P = 0.019) and an inverse association for overall AMD (P = 0.024) and neovascular AMD (P =0.009) for the higher ARMS2 risk allele groups. Finally, and
consistent with prior work documenting a potential harmful effect of supplements and zinc according to genotypes, Seddon et al found higher hazards for progressing to overall advanced AMD (HR = 1.23; 95% CI = 0.82, 1.85) or neovascular (1.54; 95% CI = 0.85, 2.78) AMD, with significant interactions (P = 0.039 and 0.024, respectively) when comparing the effectiveness of the combination versus placebo for the high-/low-genetic-risk groups.
Figure 1. Treatment response based on CFH and ARMS2 genetic risk alleles. Graphs showing the 7-year demonstrated progression rates
to advanced age-related macular degeneration within each genotype group (GTG) as a function of treatment. Progression was determined
from AREDS outcomes using Cox proportional hazards survival estimate. The number of patients in each GTG is shown in parentheses.a
Abbreviation: AREDS-F, Age-Related Eye Diseases Study Formulation.
a Reproduced with permission from Elsevier, from Awh et al.8
Table 1. Risk of AMD Progression by Genotypes and
Genotype Group Hazard Ratio (95% CI) P Value
1 Antioxidants 0.38 (0.1.6-0.93) 0.03
Zinc 1.03 (0.50-2.14) 0.93
AF 0.80 (0.39-1.63) 0.54
2 Antioxidants 1.33 (0.48-3.96) 0.61
Zinc 3.07 (1.18-8.00) 0.02
AF 2.73 (1.04-7.20) 0.04
3 Antioxidants 0.72 (0.44-1.18) 0.19
Zinc 0.51 (0.31-0.86) 0.01
AF 0.57 (0.35-0.93) 0.03
4 Antioxidants 0.85 (0.49-1.48) 0.56
Zinc 0.93 (0.53-1.65) 0.82
AF 0.88 (0.50-1.55) 0.65
Abbreviations: AMD, age-related macular degeneration; AF (AREDS-F), age-related eye diseases study formulation (ie, antioxidants + zinc). aReproduced with permission from Elsevier, from Awh et al8 (table 5: Risk of age-related macular degeneration progression within each genotype group as a function of age-related eye diseases study-assigned treatment group compared with progression if treated with placebo).
Contextualizing the Data for Patient Care
The aforementioned data may be reconciled by considering contextually relevant clinical and statistical concepts. A cursory appraisal of the AREDS-8 report reveals this to
be a failed study based on the primary end point.5,18-21 It is concerning that the statistical analyses were changed post hoc by excluding patients with category 2 AMD after the
study results were known and that the study was marginally powered for only one of the primary end points.26
These considerations alone bring into question the appropriateness of widespread supplement use, especially considering that their use became widespread in the absence of a validating study.
Based on their analyses showing no associations between genotypes and outcomes from supplement therapy, Chew et al7 suggested that therapy should not be guided by genetic testing and noted that a lack of power might explain their null findings. The issue of study power is valid and not surprising because 27 multiple comparisons were conducted, making it very difficult to
detect statistically significant results. In addition, the Bonferroni correction used in the study is a very conservative approach for dealing with multiplicity, and some argue that it should only be used for 5 or fewer comparisons. 27 Other authors were also highly critical of this issue, suggested that these results were not clinically interpretable, and that patients should be offered supplement therapy without regard for genotypes.26,28 In an accompanying editorial to the report by Chew et al, Wittes and Musch28 state additional concerns regarding the conduct
of subgroup analyses using groups defined post hoc,in as much as some variables might be affected by treatment allocation. Yet the findings of Awh et al illustrate a reasonable exception because genotypes were determined using baseline DNA samples, and genotypes for AMD risk would not be changed by treatment with vitamin and/ or mineral supplements. It is also ironic that supplements have been used based on benefits observed in patients with category 3 and 4 AMD in the AREDS-8 report, which were derived from post hoc subgroup analyses. Indeed, the genetic analyses are consistent with the appropriate conduct of subgroup analyses, where the test of interest is whether the subgroup(s) behave significantly differently than the overall study population.29 If AREDS supplements were beneficial for the entire study population (including those who were excluded from analyses) and were independent of genotype, there would
be no controversy regarding their use in patients with AMD. This is not the case, however, because the data of Awh et al demonstrate a robust, inverse association of AREDs with
zinc, or zinc alone, with an increased risk of AMD progression in those in the GTG2 group. The patients who received zinc or an AREDS-8 formulation had 7-year progression rates to advanced AMD of 43% (P = 0.023) and 40% (P = 0.039),respectively, compared with 17% for those receiving placebo. Conversely, there was a lack of benefit of supplement use for GTG group 4, benefits only for those receiving antioxidants in GTG group 1, and benefits for those in GTG group 3 receiving zinc or AREDS with zinc.8 It should be emphasized that association is not causation, and although some may label these findings as lowerquality evidence, context matters a great deal. For example, low-quality evidence led to recommendations to avoid aspirin use in children given its association with Reye’s syndrome because safer alternatives exist—for example, acetaminophen.30 In such a context, health care providers and patients need to be informed and supported in decision making by having access to contextually appropriate evidence summaries as well as clinical guidance based on the weight of the evidence, regardless of whether the evidence
base is complete.31-33 The current situation regarding AREDS supplements in AMD is similar, in as much as the adverse outcomes of using zinc-containing supplements in
GTG2 group patients are serious. Thus, using antioxidants without zinc or not using supplementation in the GTG2
group is ostensibly safer and consistent with doing no harm (see Figure 1). Given the aforementioned risk-benefit data, GTG-directed genetic testing to guide nutritional supplementation
for white patients with AREDS category 3 or 4 AMD represents a prudent and logical approach to optimize patient care. Avoiding unnecessary supplement use is another benefit from genetic testing because those in GTG group 4 had minimal and no efficacy attributable to use of AREDs supplements, whereas those in GTG groups 1 and 3 derived benefits from antioxidants. Avoiding unnecessary use of medications in older patients is a key tenet of proper geriatric care in order to reduce unnecessary polypharmacy, keep medication burden to a minimum, avoid adverse drug events and drug-nutrient interactions, and decrease out-of-pocket costs for patients (many of whom have limited financial resources), given that yearly costs for supplements are approximately $400.00. Along these lines, Ellingson and Ambati34 recently reported on the appropriate use of AREDS vitamins in patients presenting to an academic medical center ophthalmology clinic. The
authors noted that 73% of their patients were using supplements, yet they did not meet AREDS criteria for their use. Based on the observed use patterns, an adjusted NNT = 220 was reported, and direct cost utilities from inappropriate vitamin use ranged between $218 000 to $657 000 per quality- adjusted life year.34 It is also worth noting that the original supplement formulation
was changed to exclude β-carotene based on observational data from 2 different studies showing an association between β-carotene and lung cancer.35,36 The point
to be made is that the current issue of whether or not to use genetic testing to guide supplement use represents a similar paradigm: although the evidence may not be perfect, the
risk of worsening progression of AMD by using supplements in the GTG2 group is unacceptable and merits appropriate action. Additional concerns to consider include what,
if any, are the long-term risks associated with long-term use supplement use as well as theoretical concerns regarding the opposing effects of zinc in early versus late AMD.19
Practice Recommendations for Pharmacists
The role of genotype-guided supplement therapy is an important consideration that has hitherto not received much attention in the pharmacy literature; hence practical suggestions
are necessary. Of particular relevance to limited treatment options, knowledge of a patients’ genetic profile is important to provide an appropriate recommendation regarding nutritional supplementation strategies. First, for patients in the GTG2 group (high CFH and low ARMS2 risk—13% of patients), supplementation with zinc or the AREDS-F is not recommended because both treatment arms fared statistically worse (Figure 1 and Table 1) than the placebo arm and demonstrated higher rates of AMD progression compared with placebo or antioxidants alone.
Second, for patients in the GTG1 group (low CFH and low ARMS2 risk—28% of patients), active therapy with antioxidants is recommended because antioxidants showed the best results with statistically significant benefits over placebo at 7 years, whereas AREDS-F therapy had a slight (nonstatistically) beneficial effect over placebo. Third,patients in the GTG3 group (low CFH and high ARMS2 risk—35% of patients) had the best 7-year outcomes with zinc or with AREDS-F supplements; thus, these patients should be offered therapy with a supplement formulation
that provides the same amounts of vitamins and zinc as the AREDS with zinc formulation. Fourth, patients in the GTG4 group (high CFH and high ARMS2 risk—24% of patients) derived no benefit with any of the treatment strategies; it could be argued that supplements should not be used, but based on the original AREDs study, the converse may also be argued. The above information is of particular importance to pharmacists when presented with questions about supplements intended for patients with AMD. With knowledge of the aforementioned response patterns, pharmacists will be able to have a meaningful dialogue with patients regarding supplement use and help determine which supplements, if any, patients should utilize. In cases where the patient has not undergone genetic testing, or is unaware of the results, the pharmacist should refer the patient back to their eye care professional to avoid patients taking supplements that will (1) be harmful to the patient (ie, those in GTG2 group) or (2) be of no benefit, contribute to increased out-of-pocket costs, and increase pill burden. Table 2 is intended to assist pharmacists
when discussing eye-targeted vitamins with patients. It is also helpful for pharmacists to understand that when discussing the AMD genetic test results with a patient, eye care professionals will consider that the results will be explained in a comprehensive manner to the patient, specifically discussing the following: (1) genetic risk loci where the patient is homozygous because this guarantees that all children will have inherited the risk allele from the tested parent, (2) the overall genetic risk score, and (3) the availability of free genetic counseling for an in-depth
review of the results with the patient (see http://www.macularisk.com).
Table 2. Selecting Supplements Based on Genotype Subgroup(GTG).
GTG Antioxidants AREDS-F Zinc
1 Y N N
2 Y N N
3 Y Y Y
4 Y/Na Y/Na Y/Na
Abbreviations: AREDS-F, Age-Related Eye Disease Study Formulation;
N, no; Y, yes. aOriginal analyses from AREDS demonstrated overall protective effect, whereas recent secondary analyses by Awh et al8 showed no benefit according to GTG.
Based on currently available evidence, use of ocular vitamin supplements in patients with AMD should be guided by genetic testing until further data suggest otherwise. This
approach will avoid use of supplements that could be harmful to some, avoid use of supplements that will have no effect on the disease, and result in appropriately using supplements
in patient groups that are likely to derive meaningful benefits.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
The authors received no financial support for the research, authorship, and/or publication of this article.
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