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Nutritional Supplements In Age-Related Macular Degeneration

2 CPD in Australia | TBA in New Zealand | 8 December 2018

By Inez Hsing

Nutritional supplements play a role in slowing the progression of dry age-related macular degeneration (AMD) to late stage AMD. Eye care practitioners are perfectly positioned to educate patients with AMD, with particular emphasis on lifestyle and dietary modifications. Recommending the appropriate time to start supplements and encouraging adherence is vital.

LEARNING OBJECTIVES

1. Understand the general pathogenesis and risk factors for development of AMD
2. Classify the different stages of AMD according to the AREDS Grading System
3. Know the history of how nutritional supplements were developed
4. Identify the key constituents of the current AREDS2 antioxidant formulation
5. Understand at what stages of AMD AREDS2 antioxidant supplements are indicated
6. Identify ways to improve patient adherence to use of ARED S2 antioxidant supplements

Age-related macular degeneration is one of the leading causes of blindness and visual impairment in Australia and the Western world.1-3 The recently conducted Australian National Eye Health Survey found that 0.96 per cent of non-indigenous Australians over 50 years of age have late stage AMD, and 10.5 per cent have intermediate stage AMD.1 This is fairly comparable with previous studies such as the Blue Mountains Eye Study (BMES).3 The prevalence of AMD increases significantly with age, and this is of particular concern given the aging population and longer life expectancy in Australia.1

Age-related macular degeneration (AMD) is an acquired neuro-degenerative condition affecting the photoreceptors and retinal pigment epithelium (RPE). The RPE is responsible for maintaining the health of the overlying photoreceptors.4 In AMD, however, the RPE progressively loses its ability to express metabolic waste material and this leads to an accumulation of lipid-rich and protenacious deposits under the RPE.4-6 This extracellular material gives rise to the clinical drusen that is observed on ophthalmoscopy in patients with AMD. Drusen in turn can act as a barrier against blood supply from the underlying chorocapillaris into the RPE and photoreceptors5,6 and can also trigger inflammatory cascades within the macula.5-7 As the natural history of AMD progresses, the result is death of the overlying RPE and photoreceptors (advanced dry AMD is characterised by centre-involving geographic atrophy) or development of abnormal vessels (neovascular AMD).4,6,8

The exact mechanism by which this process occurs is not fully known but is largely thought to be multifactorial and due to a combination of age, genetics and exposure to both endogenous and environmental oxidative stress.4 The retina is known to have high oxygen demand – age-related metabolic dysfunction and the accumulation of exposure to visible light (photo-oxidative stress) over an individual’s lifetime causes the RPE significant injury.7,9 Additionally, family history is known to be a risk factor for AMD – as many as 52 gene variants have been identified that influence the immune and inflammatory responses thought to be associated with AMD.4 Exogenous oxidative stress, such as smoking, can contribute further to RPE insult and decompensation,4,6,10 and a sedentary lifestyle without sufficient physical activity likely increases overall inflammation within the body.11

Given the aging population in Australia and the developed world, it is critical to develop and adopt interventions which could slow or lower the risk of progression to advanced AMD and vision impairment. There has been significant progress in the treatment of neovascular AMD over the last few years following the development of anti-vascular endothelial growth factor (anti-VEGF) injections,4 however to date there is still no proven treatment for dry AMD. With our current knowledge and understanding of the role that oxidative stress and inflammation plays in the pathogenesis of AMD, attention has turned to the potential benefits of antioxidant supplements.


DEVELOPMENT OF THE AREDS2 FORMULATION

The original AREDS formula was developed in 2001 following a large, randomised, multicentre, double-masked and placebo-controlled clinical trial of 4,757 patients over a mean follow-up period of 6.3 years.12 The formula consisted of antioxidants (500mg Vitamin C, 400IU Vitamin E, and 15mg beta-carotene), 80mg zinc (as zinc oxide) and 2mg copper (as cupric oxide). Both Vitamin C and Vitamin E play an important role in minimising oxidative damage in the eye.11 Beta-carotene is a carotenoid agent not normally found in the eye,7 however it does share a similar molecular structure to xanthophyll agents (lutein and zeaxanthin) within the macula and was therefore thought to have fairly similar properties.13 Additionally, at the time of the AREDS study, only betacarotene was readily available.12

Zinc is an essential trace element that is involved in numerous physiological processes within the body, including modulation of metabolic and oxidative reactions.14,15 It is found in high concentrations in the photoreceptors and RPE.11 The inclusion of copper was primarily for prevention of neutropenia and anaemia caused by copper deficiency, which is a potential adverse effect of high dose zinc.12,16 The severity of AMD was categorised according to Table 1 and this was used by the AREDS group to standardise grading of AMD in practice and to more accurately assess progression of disease.

Table 1. The Age-Related Eye Disease Study (AREDS) grading system for AMD (adapted from Al-Zamil & Yassin, 2017)4

The results of the AREDS study were very promising – in patients who had AREDS Category 3 AMD, or where one eye had AREDS Category 4 AMD, the risk of progression to AREDS category four was reduced by 25 per cent over a five year period compared to placebo.12 There was also a corresponding 27 per cent reduction in the risk of losing greater than 15 letters on a standard ETDRS logMAR chart.12 The risk of progression to late stage AMD was low in AREDS Category 1 and AREDS Category 2 (1 per cent and 1.3 per cent, respectively, over a five year period) and therefore it was not possible to draw any meaningful conclusions as to whether the use of AREDS antioxidants are indicated in this cohort.12 Pleasingly, a follow up observation study showed that the protective effect of AREDS antioxidant supplements persisted out to 10 years – those patients who had initially received the AREDS formula continued to demonstrate lower rates of progression to advanced AMD (particularly choroidal neovascularisation) and lower rates of both moderate and severe vision loss.17

There was, however, concern regarding the use of beta-carotene in current and past smokers – studies have shown that daily supplementation with beta-carotene in this group resulted in higher rates of lung cancer and associated mortality.18 Some of these studies were published during the course of the AREDS study. Subsequently, the 8 per cent of the AREDS group who were smokers at the time of initial enrolment were offered the chance to withdraw from the study or to be reassigned to a treatment arm not containing beta-carotene. This may have influenced why the rate of lung cancer in the AREDS cohort was overall low (0.8 per cent over the five years)12 but nonetheless raised the question of whether alternate carotenoid agents with a better safety profile could be used.

Additionally, the recommended dosage of 80mg zinc oxide in the AREDS formula exceeded both the tolerable upper intake level (UL) of 40mg/day established by the US Institute of Medicine19 and the TGA maximum recommended daily dose (MRDD) of 50mg.20 Increased consumption of zinc has been shown to be affiliated with nausea and gastrointestinal upset such as vomiting, epigastric pain, abdominal cramps and diarrhoea.13,15 Long term high-dose zinc can even potentially increase the risk of prostate cancer,21 copper-deficiency (which in turn can result in anaemia and neutropenia)16,22 and result in dysregulation of zinc homeostasis in the brain that could contribute to development and progression of Alzheimer’s Disease.15

Subsequently, the AREDS2 Research Group was formed, which followed 4,203 patients as part of a multicentre, randomised, double-masked clinical and placebo controlled trial conducted over a five year period.23 By this stage, alternate carotenoid agents (lutein and zeaxanthin) had become commercially available. Both lutein and zeaxanthin are xanthophyll carotenoids found naturally concentrated within the macula. Collectively, they are known as ‘macular pigments’ and give the macula its characteristic yellow appearance.13 Lutein and zeaxanthin have both antioxidative and anti-inflammatory properties and are responsible for filtering out short wavelength blue light before it can reach the photoreceptors.7,24 Animal studies have also shown that these macular pigments may help regulate normal function of the blood vessels within the retina and choroid.25

Given their pivotal role in the macula, it had been postulated that increased intake of lutein, in both healthy eyes and eyes affected by AMD, could improve visual function and protect against development of late stage AMD.26,27 Humans are incapable of synthesising lutein and zeaxanthin and instead rely on dietary or supplementary intake to obtain required levels.11 A meta analysis conducted by Ma and colleagues24 found that increased dietary intake of lutein and zeaxanthin may be protective against development of late AMD but not early AMD. Similarly, Huang et al28 established that supplementation with lutein and zeaxanthin increased macular pigment density within the macula and also increased central retinal sensitivity as measured by both multifocal electroretinogram (mERG) and microperimetry.28

Additionally, there was growing interest in the potential benefits of omega-3 long-chain polyunsaturated fatty acids (LCPUFA) on reducing the risk progression to advanced AMD.11,29-32 Docosahexaonic acid (DHA) is a major structural lipid found within the retina, and eicospentaenoic acid (EPA) is the precursor to DHA. These LCPUFAs are found primarily within the photoreceptor outer segments and play a role in modulating permeability of the photoreceptor membranes.11,33 In the diet, they can be found in high concentrations in oily fish.11,32 It is has been hypothesised that both DHA and EPA have anti-inflammatory and anti-atherosclerotic properties for the body, including the brain, cardiovascular system, inflammatory arthritic disease, and the retina.32,34 Sneddon and colleagues, in 2001,31 were one of the first to describe a possible protective effect of omega-3 and fish intake against AMD. In 2006, as part of the US Twin Study of Age-Related Macular Degeneration Studies, subjects underwent a food frequency questionnaire (FFQ) and this also found that higher levels of omega-3 in the diet reduced the risk of AMD.30 This same effect was seen in the 10-year longitudinal Blue Mountains Eye Study (BMES), where one serving of fish per week and one to two servings of nuts per week reduced the risk of progression of early-to-intermediate AMD.32

Thus, the primary aim of the ARED2 study was to determine whether the addition of lutein and zeaxanthin and/or DHA and EPA to the original AREDS formula would help to further reduce the risk of progression to advanced AMD.17 Patients were randomly assigned to one of four groups: (1) placebo; (2), lutein/zeaxanthin only [L+Z]; (3) docosahexaonic acid and eicospentaenoic acid [DHA+EPA] only; and (4) a combination of this [L+Z+DHA+EPA]. A secondary goal was to see if modification to the original AREDS formulation (specifically, eliminating beta-carotene and lowering the dose of zinc) affected efficacy. The distribution of patients in the AREDS2 study is shown in Figure 1. Note that participants within the ‘control’ group did not receive a true placebo but rather the original AREDS1 formulation.

Figure 1. The AREDS2 Study Design. DHA = docosahexanoic acid; EPA = eicosapentaenoic acid; AREDS = 500mg Vitamin C, 400IU Vitamin E, 15mg beta-carotene, 80mg zinc oxide and 2mg cupric oxide. Note in the secondary randomisation, patients may have received variations of the AREDS formula (i.e. no beta-carotene, low zinc, or no beta-carotene and low zinc). Patients who were current smokers or had ceased smoking <1 year ago were randomised to treatments with no beta-carotene. (from The AREDS2 Research Group)23


The results of the AREDS2 study were somewhat surprising. It was found, in primary analyses, that neither DHA/EPA supplementation nor lutein/zeaxanthin supplementation added any additional protective benefit above and beyond the original AREDS formulation.17 In further sub-analyses, the use of omega-3 supplements still did not demonstrate any significant impact on progression of AMD or visual acuity. This was contradictory to the previously presented data that high dose DHA and EPA lowers the risk of AMD progression. However, the results from the AREDS2 study may have been impacted by the lack of a true ‘placebo” group; that is, the concurrent use of the AREDS supplements may have masked any protective effect from omega-3.9,17 Additionally, incorrect dosage of DHA and EPA and/or insufficient duration of use may have influenced results.17

The AREDS2 study did show that eliminating beta-carotene and lowering the dose of zinc from 80mg daily to 25mg daily had no statistically significant impact on progression to late stage AMD.17 The AREDS2 study precluded anyone who was a current smoker or had stopped smoking less than a year before the start of the study from receiving beta-carotene. Despite this, there was still a notably higher incidence of lung cancer in former smokers who received beta-carotene.17 On the other hand, there appeared to be no increased risk of lung cancer in former smokers who received lutein and zeaxanthin.17

To further investigate the potential benefit of lutein/zeaxanthin, a prespecified secondary analysis of data was performed in which the AREDS2 study cohort simply split into two subgroups – those who received lutein and zeaxanthin in conjunction with the AREDS formulation minus beta-carotene, versus those who received the original AREDS formula and no lutein/zeaxanthin. The results of this were published in 2013 in the AREDS2 Report number three35 and showed a favourable effect for the use of lutein/zeaxanthin instead of beta-carotene (reduction of hazard ratio by 18 per cent). Additionally, the use of lutein/zeaxanthin supplements in patients with the lowest dietary intake of lutein and zeaxanthin showed a greater protective effect against late stage AMD.17,35 There was also some thought that patients who received multiple carotenoids as part of the AREDS2 study could have been subject to competitive binding and absorption between lutein/zeaxanthin versus beta-carotene – specifically, serum levels of lutein and zeaxanthin were lower in subjects who also received beta-carotene as part of their randomisation.23

Given these findings, and the improved safety profile of lutein/zeaxanthin, the AREDS2 study group concluded that these were suitable alternate carotenoid agents that could replace beta-carotene into the AREDS2 formulation, particularly in patients with a history of smoking and/or a low dietary intake of lutein and zeaxanthin.35 Numerous researchers have also supported the transition from beta-carotene to  lutein/zexanthin as well as using a lower dose of zinc given that this has a similar efficacy to high dose zinc with respect to slowing progression to advanced AMD.9 An example of a proposed antioxidant formulation based on the most recent evidence from the AREDS2 and other studies was given by Andreatta and Sherbiny, and is listed in Table 2.

Table 2. Proposed “Evidence-Based” Formula (adapted from Andreatta & Sherbiny, 2014)9


Finally, there has been suggestion that the use of antioxidant supplements should be guided by an individual’s genetic profile as the response to, and benefit from, these agents could vary depending on genetic variants.8,13 A study by Awh and colleagues in 2015 sub-analysed the original AREDS group based on genotypes and found that the use of antioxidant and zinc supplements may only benefit certain individuals with a specific genetic profile.36 This was promptly countered by the AREDS2 study group which identified several areas of selection bias in the methodology of Awh’s retrospective study.37 Moreover, in their own analysis the AREDS2 group was unable to establish a statistically significant link between high risk genotypes and AREDS supplements.38

They concluded that “genetic testing is not recommended for initiating or determining the appropriateness of the AREDS formulation. One should not deprive patients of a therapy that has been proven to have significant public health impact on the basis of a statistically flawed, not replicated retrospective analysis of existing data”.37 More research is being conducted in this area, however at the current time AREDS antioxidant supplements remain our most proven way of slowing progression to late stage AMD in high-risk patients.

INDICATIONS FOR USE OF AREDS2 ANTIOXIDANT SUPPLEMENTS

As previously mentioned, the original AREDS study had found that the risk of progression to late stage AMD was fairly low in AREDS Category 1 and AREDS Category 2.12 Subsequently, the cohort in AREDS2 consisted of patients who were at high risk of progression to advanced AMD – that is, those with bilateral large drusen, bilateral non-central geographic atrophy, or large drusen/non-central geographic atrophy in one eye and late stage AMD in the fellow eye.23 Essentially, this included patients with Category 3 AMD in both eyes, or Category 4 AMD in one eye only.

Thus, the benefit of AREDS2 antioxidant supplements in earlier stages of AMD remains unknown although use of these are unlikely to confer any harm.8,13 As with all AMD patients, significant emphasis should still be placed on the importance of lifestyle modification such as cessation of smoking and performing light physical activity,11 as well as increasing dietary intake of omega-3 and carotenoids. Specifically, a ‘Mediterranean diet’, which is rich in fish, nuts, vegetables, fruit and legumes, has been shown to be associated with lower incidences of AMD.11 These recommendations are particularly applicable in patients with a family history of AMD.

ADHERENCE TO USE OF AREDS2 ANTIOXIDANT SUPPLEMENTS

Adherence to the use of antioxidant supplements remains a critical factor. In the AREDS2 study, inclusion criteria included screening for patients with good adherence using a ‘run-in’ phase – subjects were provided with a placebo and only those who took more than 75 per cent of this placebo medication were allowed to participate.23

A barrier to adherence in Australia has been the misalignment between the TGA-enforced maximum recommended daily dose (MRDD) of 50mg zinc and the use of 80mg zinc daily in the original AREDS formula. In an attempt to remedy this, some formulations have historically contained lower doses of the AREDS antioxidant ingredients and relied on practitioners making ‘off-label’ recommendations to take multiple tablets daily. A study conducted by Ng and Goggin in 2006 explored compliance with the use of Blackmores Macu-Vision in 100 patients.39 The on-label dosing recommendation of Macu-Vision is one tablet daily or as prescribed. At one tablet daily however, patients received only a modified version of the AREDS supplements (no beta-carotene, and half dose of the remaining ingredients – 250mg Vitamin C, 200 IU Vitamin E, 40mg zinc and 1mg copper). Thus, there is a need for the recommending practitioner to emphasise off-label twice-daily dosing.

Despite this, Ng and Goggin found that only 1 per cent of patients were compliant with twice-daily dosing, and a significant 95 per cent of patients continued to take only one tablet a day.39 At this level, they hypothesised that the effectiveness of the AREDS formulation would be reduced. They also identified that only 53 per cent of patients were even aware of antioxidant supplements. Of the patients who were aware of these supplements, only 38 per cent of patients were actually taking them, with the biggest barrier to use identified as cost.39 These results strongly highlight the important role that eye care practitioners play in educating patients on the availability of antioxidant supplements, the benefits of these when taken in the correct dose, and recommending formulations that are cost effective and lessen financial burden to the patient.

Additionally, there have been numerous studies to suggest that once daily dosing of a medication is associated with better patient adherence across a variety of ocular and systemic conditions.40,41 Robin and colleagues41 investigated the adherence of once daily prostaglandin drops for management of glaucoma versus drops requiring multiple doses. In the former, adherence was approximately 97 per cent which was significantly higher than the adherence reported with multiple medications (85.6 per cent). Thus, it stands to reason that a once-daily AREDS2 antioxidant supplement is likely to be associated with greater patient adherence and would also be more cost effective. Once-daily dosing in Australia is now very much achievable following the results of the AREDS2 study – given that there was no statistically significant daily difference in risk reduction between high-dose and low-dose zinc, the possible incorporation of 25mg zinc in an antioxidant formulation (similar to that listed in Table 2) paves the way for once daily dosing while still complying with TGA regulations.

Finally, there have been several studies regarding dispensary and reminder systems to encourage patient adherence. Although pill organisers such as Webster Paks have gained popularity, they are still reliant on the patient transferring their medications from one container to another. The Vitamins, Teachers and Longevity (VITAL) Study found that the use of calendar blister packs (where patients are provided with an entire month’s supply of designated medications that are self-contained within individually dated blisters) improved patient adherence significantly, compared to pill organisers.42 Tan and colleagues43 found a similar benefit in using calendar blister packs to encourage adherence to the use of anti-hypertensive medications. Adequate education and counselling of patients regarding the purpose of medication, drug reminder packaging and some form of reminder system (eg. phone or SMS) have also been identified as modifiable factors that can encourage patient adherence.44-46

In summary, patient adherence is likely to be greatest with a once-daily antioxidant supplement that is cost effective, complies with both the AREDS2 study findings and TGA regulations, and whose dispensary and reminder systems have been proven to encourage compliance.

CONCLUSIONS

The incidence and prevalence of AMD continues to increase in line with the aging population in Australia and the Western world. While there is no cure for dry AMD, research has shown that a combination of lifestyle changes (such as cessation of smoking and light physical activity), dietary modifications (increased consumption of fish, nut, vegetables and fruits) and antioxidant supplements may play a role in lowering the risk of progression to late stage AMD (characterised as centre involving geographic atrophy or choroidal neovascularisation).

The results of the large scale populationbased AREDS2 study strongly suggest that antioxidant and carotenoid supplements (but not necessarily omega-3 supplements) are indicated in patients at risk of progression to late stage AMD. Recent findings suggest the safety profile of these supplements is overall high. Eye care practitioners are in a unique position to educate patients on AMD and, as part of a holistic approach, recommend the use of antioxidant supplements at the appropriate time. Similarly, measures that have been proven to improve patient adherence should be implemented by both practitioner and suppliers to ensure patients are receiving the full benefit of supplementation.

 

 

       Inez Hsing graduated from Queensland University of Technology in 2008 with First Class Honours and a University Medal. She currently works as a clinical optometrist at the OKKO Eye Specialist Centre in Brisbane, Queensland. Ms. Hsing has a particular interest in macular and vitreoretinal disease, and therapeutic management of anterior segment disease and glaucoma.   


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' The results of the large scale population based AREDS2 study strongly suggest that antioxidant and carotenoid supplements (but not necessarily omega-3 supplements) are indicated in patients at risk of progression to late stage AMD... '