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Current Pharmaceutical Design, 2015, 21, 4667-4672 4667
Controversies in the Use of Nutritional Supplements in Ophthalmology
John G. Lawrenson1,* and Andrzej Grzybowski2
1Centre for Public Health Research, School of Health Sciences, City University London, London UK; 2University
of Warmia and Mazury, Olsztyn, Poland
Abstract: Nutritional supplements are widely taken by the general population and several of these products are
marketed specifically to improve eye health. The aim of this review is to summarise the evidence for the benefit of
supplementation with antioxidant vitamins and other micronutrients for three of the most common eye diseases of
the elderly: age-related macular degeneration (AMD), cataract and dry eye syndrome (DES). Although the poten-
tial importance of diet and nutrition in these conditions is strongly supported by data from observational studies,
evidence from randomised controlled trials (RCTs) on the benefit of nutritional supplementation is generally lack-
ing. However, there is high quality evidence to support the use of an Age-Related Eye-Disease Study (AREDS)
supplement containing antioxidants (-carotene, vitamin C and vitamin E) and zinc to slow progression in those at
moderate to high risk of developing advanced AMD. Recent data from the AREDS2 trial provided data to suggest
that -carotene could be replaced with lutein and zeaxanthin on the basis of improved safety without compromising
efficacy. Although there is currently insufficient evidence to recommend the routine use of any of the commercially available supple-
ments in cataract and DES, given the public health importance of these conditions further research into the benefit of dietary modification
or nutritional supplementation should be a priority.
Keywords: Age-related macular degeneration, cataract, dry eye, nutritional supplements, antioxidants, essential fatty acids.
Based on data from large cross-sectional surveys, it has been
estimated that up to two thirds of the adult population of the US
regularly takes one or more nutritional supplements [1, 2]. These
are most often combinations of vitamins and minerals, but products
containing essential fatty acids (EFA) or other micronutrients are
also commonly used. Nutritional supplement use tends to be more
common among women than men and the likelihood of taking sup-
plements generally increases with age . The most frequen tly
reported motivation for taking these products is to maintain or im-
prove overall health and supplement users tend to be better edu-
cated and more likely to adopt healthy lifestyle behaviours than
non-users . Despite their widesp read use, high quality evid ence
that vitamin and mineral supplements improve general health out-
comes or prolong life is lacking and it is possible that high doses of
certain micronutrients may be harmful . Systematic reviews of
randomised controlled trials (RCT) for primary prevention have
shown that antioxidant supplements do not seem to prevent cancer,
cardiovascular diseases, or death [6, 7]. A meta-analysis combined
with trial sequential analysis of 53 trials with a low risk of bias
found that supplements containing beta-carotene and vitamin E in
doses higher than the recommended daily allowance (RDA) were
associated with a significant increase in mortality . It is impor-
tant to note that most placebo controlled trials of supplements for
primary and secondary prevention are conducted in industrialised
countries in generally well-nourished populations. It is therefore not
possible to rule out a benefit of supplementation in nutritionally
compromised individuals. However, for the general population
current evidence suggests that the case for vitamin supplementation
to improve health outcomes is poor. In 2013, an Editorial in Annals
of Internal Medicine  concluded:
‘Although available evidence does not rule out small benefits or
harms or large benefits or harms in a small subgroup of the popu-
lation, we believe that the case is closed- supplementing the
*Address correspondence to this author at the Centre for Public Health
Research, School of Health Sciences, City University London, London UK,
EC1V 0HB; Tel: +44 2070404310; E-mail: email@example.com
diet of well-nourished adults with (most) mineral or vitamin sup-
plements has no clear benefit and might even be harmful. These
vitamins should not be used for chronic disease prevention. Enough
The potential value of specific combinations of micronutrients
to improve eye health is frequently promoted by micronutrient
manufacturers as ‘eye nutrients’ and approximately 4% of supple-
ment usage is reported to be specifically for this purpose . The
well-publicised results of large National Eye Institute (NEI)-funded
trials in the US (Age-Related Eye Disease Study (AREDS) and
AREDS2), demonstrating the value of antioxidant supplements in
reducing the risk of developing advanced age-related macular de-
generation (AMD), may have further contributed to their wide-
spread use and promotion in the elderly. Recent surveys of optome-
trists and ophthalmologists have revealed that nutritional supple-
mentation is now part of routine clinical practice for patients with
or at risk of AMD [10, 11] although these recommendations are
frequently not evidence-based . The aim of this mini-review is
to consider evidence for the value of nutritional supplementation in
three common age-related eye diseases: AMD, cataract and dry eye.
The article will summarise data from recently published systematic
reviews on nutritional supplementation published by the Cochrane
Eyes and Vision Group.
AGE-RELATED MACULAR DEGENERATION
Although in global terms, AMD ranks third as the leading
causes of visual impairment , it is the most common cause of
blindness in European-derived populations. For example in the UK,
AMD is responsible for over 50% of blind and partially sighted
registrations  and with an ageing population the prevalence of
the disease is predicted to increase substantially . In addition to
the obvious personal impact of AMD, the societal burden is also
considerable. Economic costs arise from both the direct costs of
treatmen t as well as indirect costs associated with visual impair-
ment, including the provision of social care . Although treat-
ments in the form of anti-vascular endothelial growth factor inhibi-
tors are available that can slow the progression of the neovascular
form of the disease (so called ‘wet’ AMD), there is still no effective
treatment for atrophic (‘dry’) AMD, which affects over 90% of
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4668 Current Pharmaceutical Design, 2015, Vol. 21, No. 32 Lawrenson and Grzybowski
sufferers. It is likely that the pathogenesis of AMD is multi-
factorial, arising from the complex interplay between genetic and
environmental factors . Oxidative stress has been implicated as
a causativ e factor in the developm ent of AMD, since the action of
light on retinal photoreceptors generates potentially damaging free
radicals . Although the presence of macular pigment is thought
to limit cellular damage by absorbing incoming blue light and/or
quenching free radicals, it has been proposed that AMD could occur
due to the cumulative effects of oxidative damage on macular pho-
toreceptors and the underlying retinal pigment epithelium (RPE)
. Consequently, increased consumption of antioxidants through
the diet has attracted significant interest as a simple, widely appli-
cable and cost-effective intervention. Observational studies have
reported that dietary components such as antioxidant vitamins and
certain carotenoids can reduce the risk of developing AMD or slow
its progression (see  for a recent review). However, results from
these non-experimental studies should be interpreted with caution,
since people with a diet rich in particular nutrients may differ in
other ways from those who do not. The highest quality evidence to
assess the benefit of nutritional supplementation comes from ran-
domised controlled trials (RCTs), where participants have been
randomly allocated to receive either a dietary supplement or a pla-
cebo/no intervention. Evidence arising from such trials has been
reviewed in two related Cochrane Systematic Reviews that were
published in 2012 [19, 20] and a recently updated review in 2015
. Two of these reviews focussed on the role of antioxidant vi-
tamin and mineral supplements in the prevention  and progres-
sion  of AMD and one review investigated on the role of
omega-3 fatty acid supplementation .
The review on ‘antioxidant vitamin and mineral supplements
for preventing age-related macular degeneration’  included data
from 4 trials, which provided high quality evidence that people
aged 40 years and above in the general population are unlikely to
prevent the development of AMD by taking supplements containing
vitamin E (data from 3 trials) or -carotene (provitamin A) (2 tri-
als). The included RCTs were large (enrolling between 1000 and 40
000 participants), conducted so as to avoid bias, and were consis-
tent with each other. The pooled risk ratio (RR) for any antioxidant
supplement in the prevention of any AMD was 0.98 (95% confi-
dence interval 0.89 to 1.08) and for advanced AMD was 1.05 (95%
CI 0.80 to 1.39). The review was unable to identify RCTs with
respect to other antioxidant supplements, such as vitamin C, lutein
and zeaxanthin, or any of the commonly marketed multivitamin
The Cochrane review “Antioxidant vitamin and mineral sup-
plements for slowing the progression of age-related macular degen-
eration”  included data from 13 trials, although these were gen-
erally small. Over half the participants were randomised in one trial
(AREDS), which found a beneficial effect of antioxidant (-
carotene, vitamin C and vitamin E) and zinc supplementation on
progression to advanced AMD (adjusted odds ratio (OR) 0.68, 95%
CI 0.53 to 0.87) over an average of 6.3 years (Fig. 1). People taking
supplements were also less likely to lose 15 or more letters of visual
acuity on a standard EDTRS chart (adjusted OR 0.77, 95% CI 0.62
to 0.96). The other 12 trials included in the review were generally
small with shorter follow-up periods (less than two years). No evi-
dence for an effect of supplementation was seen in these smaller
trials of shorter duration. Since this review was written, the results
of the AREDS2 trial have been published . The rationale for
this new study was the observational data that suggested that a high
dietary intake of omega-3 fatty acids or increased consumption of
the xanthophyll’s lutein and zeaxanthin were associated with a de-
Fig. (1). Cates plot illustrating the effect of antioxidant and mineral supplements in slowing the progression of AMD (data taken from ). In the control
group approximately 30 people in 100 had progressed to advanced AMD over 6.3 years, compared to 24 (95% CI 20 to 28) in 100 for the supplemented group.
Beer with treatment
Nutritional Supplements in Ophthalmology Current Pharmaceutical Design, 2015, Vol. 21, No. 3 2 4669
creased risk of developing AMD . Lutein and zeaxanthin are
major constituents of the macular pigment and possess antioxidant
and UV light filtering properties and so protect the photoreceptors
and RPE from damage .
In AREDS2 participants took the original AREDS formulation
(or a variation of thereof) as ‘standard care’ and were randomly
assigned, using a factorial design, to additionally receive a placebo
or a capsule containing lutein/zeaxanthin and/or omega-3 long
chain polyunsaturated fatty acids (LCPUFA). Patients were fol-
lowed up for a median period of 5 years. The primary analysis
found that the addition of lutein and zeaxanthin to the original sup-
plement did not confer any additional benefit regarding progression
to advanced AMD (hazard ratio (HR) 0.90, 98.7% CI 0.76 to 1.07)
. However, further exploratory analyses of the trial data, which
compared those taking and not taking lutein/zeaxanthin suggested
that lutein and zeaxanthin may be a more appropriate component of
the AREDS formula than th e -carotene in th e original formula
. The secondary analyses of a direct comparison of lu-
tein/zeaxanthin vs. beta carotene showed hazard ratios of 0.82 (95%
CI, 0.69-0.96; p =0.02) for development of any late AMD, 0.78
(95% CI, 0.64-0.94; p =0.01) for the development of neovascular
AMD, and 0.94 (95% CI, 0.70-1.26; p =0.67) for development of
central geographic atrophy. Eliminating -carotene could also be
argued to be beneficial on safety grounds. The Alpha Tocopherol-
Beta-Carotene Cancer Prevention (ATBC) Study, which investi-
gated the impact of supplemental -tocopherol and -carotene on
cancer incidence in male smokers, found that -carotene increased
lung cancer incidence by 17% and overall mortality by 8%. .
Although the switch of carotenoids in the AREDS formula seems
reasonable, it should be pointed that as with -carotene 15 years
ago, the long-term safety profile of this combination is unknown.
Moreover, if lutein and zeaxanthin are th e optimal carotenoid s to be
used, further work is required to determin e the most effective dose
AMD is a complex disease in which individual susceptibility is
determined by a combination of genetic and environmental risk
factors. There has been a significant interest in whether the benefi-
cial effect of nutritional supplements is influenced by particular
AMD genotypes [28-30]. Klein and co-workers provided some
evidence for a treatment interaction in those AREDS participants
with the complement factor H (CFH) genotype , which was
specifically related to the zinc component of the formulation. A
subsequent analysis of AREDS data similarly found that the re-
sponse to supplementation was linked to specific genetic polymor-
phisms  and the study authors made the case for genotype-
directed nutritional therapy. However, these findings could not be
confirmed in a recent retrospective analysis of a larger cohort of
AREDS participants . This study also highlighted serious meth-
odological flaws in the sub-group analysis used in the previous
study  and concluded that the AREDS supplement reduced the
rate of progression of AMD across all genotype groups.
There is a plausible biological rationale for supplementing with
dietary omega-3 fats to prevent or slow the progression of AMD.
The omega-3 fatty acid docosahexaenoic acid (DHA) accounts for
50% to 60% of the total fatty acid content of the outer segments of
photoreceptors . The constant turnover of outer segment mem-
branes requires a continuous dietary supply of DHA or its precur-
sors and a deficiency may therefore predispose to the development
of AMD . Further evidence comes from observational studies,
which have reported that the consumption of fish or foods rich in
omega-3 long-chain polyunsaturated fatty acids (LCPUFA) could
reduce the risk of developing AMD [32-36]. Similarly, a nested
cohort study within the Age-Related Eye Disease Study (AREDS)
found that participants at moderate to high risk of progressing to
late AMD, who reported the highest consumption of omega-3
LCPUFA, were 30% less likely to develop advanced AMD when
compared to those reporting the lowest consumption . The re-
cently updated Cochrane review ‘Omega 3 fatty acids for prevent-
ing or slowing the progression of age-related macular degeneration’
 included two relevant RCTs [22, 38]. In one of the treatment
arms of AREDS2 , subjects aged 50-85, at high risk of pro-
gressing to advanced AMD, were randomised to receive a daily
dose of the omega-3 LCPUFA, DHA and eicosapentaenoic acid
(EPA) or a control supplement. The median follow up period was 5
years. In the Nutritional AMD Treatment 2 (NAT-2) study ,
people aged 55-85 with neovascular AMD in one eye and interme-
diate AMD in the other were randomly assigned to receive a daily
supplement containing DHA and EPA or a placebo for a period of 3
years. In both trials, the main outcome measures were the develop-
ment of advanced AMD and progression to moderate or worse vi-
sion loss (defined as a loss of 15 or more letters on a standard
EDTRS letter chart). The trials, which had a low risk of bias, pro-
vided high quality evidence that people taking omega-3 LCPUFA
supplements were not at a decreased (or increased) risk of develop-
ing advanced AMD. The pooled HR for progression of AMD was
0.96, 95% CI 0.84 to 1.10 .
In summary, the lack of an effective treatment for the majority
of individuals with AMD represents a major public health problem.
Most of the available evidence on diet and nutrition comes from
cohort studies where residual confounding from other lifestyle vari-
ables is always a problem. Such confounding can be avoided in
RCTs, although such trials are expensive to conduct and are gener-
ally of short duration. The results of the landmark AREDS trial
provided high quality evidence that people with AMD may experi-
ence a modest delay in progression of the disease by supplementa-
tion with a specific combination of antioxidants (vitamins C, E and
-carotene) and zinc. AREDS2 concluded that lutein/zeaxanthin
may be more appropriate than -carotene in AREDS-type supple-
ments, given the valid safety concerns regarding this component.
There are a number of unanswered questions; patients recruited into
these trials were well nourished with an above average intake of
dietary nutrients and it is not clear whether the results can be ap-
plied to the population as a whole. There is also limited data on the
long-term safety of these supplements. In terms of primary preven-
tion, there is currently no evidence that commonly marketed micro-
nutrient formulations prevent the development of AMD.
Cataract is defined as any visible opacity within the substance
of the ocular lens and is further classified on the basis of its ana-
tomical location: cortical, nuclear or posterior sub-capsular .
Oxidative stress has been implicated in the pathogenesis of all cata-
ract sub-types . With advancing age, lens proteins become in-
creasingly susceptibility to oxidative damage and post-translation
modification leading to impaired visual acuity and a reduction in
contrast sensitivity . Age-related cataracts are the leading cause
of blindness worldwide and are responsible for 51% of blindness in
the population over 50, corresponding to approximately 20 million
people . Supplementation with dietary antioxidants has been
proposed as a strategy for cataract prevention and several observa-
tional studies have found an association between consumption of
antioxidant vitamins or particular carotenoids and a reduced risk of
cataract development (see  for a recent review). However, not
all of these data are consistent and there is a risk that the reported
outcomes may be subject to bias and confounding. A Cochrane
Systematic Review ‘Antioxidant vitamin supplementation for pre-
venting and slowing the progression of age-related cataract’ was
published in 2012  and included data from 9 trials of generally
high methodological quality, in which 117,272 individuals over the
age of 35 had been randomised to receive antioxidant vitamins (-
carotene, vitamin C and vitamin E, used alone or in combination) or
placebo. In the pooled analysis, there was no evidence of effect for
-carotene in reducing risk of cataract (2 trials) (RR 0.99, 95% CI
0.91 to 1.08) or reducing rates of cataract extraction (3 trials) (RR
1.00 95% CI 0.91 to 1.10), vitamin E in reducing risk of cataract (3
4670 Current Pharmaceutical Design, 2015, Vol. 21, No. 32 Lawrenson and Grzybowski
trials) (RR 0.97, 95% CI 0.9 to 1.04) or cataract extraction (5 trials)
(RR 0.98 95% CI 0.91to 1.04). Similarly, data from one RCT com-
paring vitamin C to placebo found no difference in rate of incident
cataract (HR 0.97, 95% CI 0.85 to 1.12). The review authors con-
cluded th at ‘costs and adverse effects [of taking antioxidants to
prevent cataracts] should be weighed carefully with unproven
benefits before recommending their use’.
Cataract outcomes were also included in the AREDS and
AREDS2 trials. The original AREDS study reported that the use of
a supplement containing antioxidant vitamins (-carotene, vitamin
C, vitamin E) and zinc did not affect the development or progres-
sion of lens opacities over the trial period . Similarly, AREDS2
found that the addition of lutein/zeaxanthin to the original AREDS
formulation had no effect on the rates of cataract surgery or moder-
ate vision loss .
In summary, despite encouraging results from observational
studies, RCTs that have ev aluated the effect of particular antioxi-
dant vitamins and carotenoids on the development of cataract or
cataract extraction have failed to consistently establish a causal
association or benefit. The lack of an effect of antioxidants in these
relatively short-term trials could suggest that longer-term intake is
required or that formulations containing multiple antioxidants are
necessary to provide a clinically significant benefit. Using the
AREDS cohort and a Cox regression analysis of baseline factors
that predicted cataract, the use of multivitamin supplements (Cen-
trum, Wyeth Consumer Healthcare) was found to be associated
with a lower risk of developing nuclear cataracts over an average of
9.8±2.4 years follow up . This finding was consistent with the
results of a RCT conducted in Italy  that was not included in the
Cochrane review, although intriguingly in this study multivitamin
use was associated with an increased risk of posterior sub-capsular
cataracts. Cataract outcomes based on participant reports were also
investigated in the multivitamin arm of the Physicians’ Health
Study II (PHS II), a large-scale randomised trial of middle-aged and
older men . This study found that long-term daily multivitamin
use was associated with a 9% lower risk of cataract compared to
placebo (HR, 0.91; 95% CI, 0.83-0.99; p=0.04). Given the high
prevalen ce of cataract in the eld erly population , even a modest
reduction in risk of cataract would potentially have a large public
health impact, however potential benefits need to be balanced
against the risk o f harm.
DRY EYE SYNDROME
Dry eye syndrome (DES) is one of the most common ophthal-
mic conditions in the world with an estimated prevalence of 5-30%
of the population aged 50 and above . DES occurs where the
eye does not produce enough tears or where the tears evaporate too
quickly. The condition is associated with inflammation of the ocu-
lar surface and leads to reduced ocular comfort, varying degrees of
visual disturbance and a corresponding reduction in quality of life
. There has recently been a great deal of interest in the potential
for oral supplementation with essential fatty acids (EFAs), specifi-
cally omega-3 and omega-6 LCPUFA, as an adjunct to conven-
tional treatments in DES. Increased consumption of omega-3 fatty
acids has been advocated in evidence-based reviews and profes-
sional guidance on DES and associated conditions such as mei-
bomian gland dysfunction [50-52]. Omega-3 and omega-6 EFA,
which must be obtained from the diet, are precursors of eicosanoids
that are locally-acting signalling molecules which regulate inflam-
mation. Omega-3 LCPUFAs such as DHA and EPA are present in
certain vegetable oils (e.g. flaxseed oil) and in oils from cold water
fish and other marine animals. Omega-6 fatty LCPUFA e.g. arachi-
donic acid and linoleic acid are found in sunflower oils, evening
primrose oil and animal fats. Omega-6 fatty acids e.g. linoleic (LA)
can be metabolised into the pro-inflammatory mediators prosta-
glandin E2 (PGE2) and leukotriene B4 (LTB4) via the arachidonic
acid pathway or into less potent inflammatory mediators e.g. pros-
Fig. (2). Metabolic pathways for dietary omega-3 and omega-6 EFA in eicosanoid synthesis.
Omega 6 FROM THE DIET Omega 3
Linoleic Acid (LA)
-Linolenic Acid (GLA)
Arachidonic Acid (AA)
2-Series Prostaglandins (PGE2)
4- Series Leukotrienes (LTB4)
-Linolenic Acid (ALA)
3-Series Prostaglandins (PGE3)
1-Series Prostaglandins (PGE1)
Nutritional Supplements in Ophthalmology Current Pharmaceutical Design, 2015, Vol. 21, No. 3 2 4671
taglandin E1 (PGE1). Similarly, omega-3 LCPUFA e.g. EPA,
which act competitively for the enzymes cyclooxygenase and
lipoxygenase, are metabolised into the less biologically active 3-
series prostaglandins (Fig. 2). The balance between intake of
omega-3 and omega-6 LCPUFA is likely to be a key factor in
modulating the bodies’ inflammatory response and it can therefore
be hypothesised that optimising the omega-3/omega-6 ratio may
mitigate against the signs and symptoms associated with DES.
There is compelling data from observational studies on the
value of increasing dietary intakes of omega-3 fats. For example, in
a subset of participants in the Women’s Eye Study in the US
(N=32,470) a higher intake of omega-3 was inversely associated
with the incidence of DES . By contrast, data from intervention
studies on the benefit of supplementation with EFA are sparse. A
recent systematic review  of RCTs investigating omega-3
LCPUFA for DES included data from 7 trials involving 720 par-
ticipants. Although pooled data found a small but statistically sig-
nificant increase in tear stability and quality, it is debatable wh ether
these differences would be clinically meaningful. Importantly no
difference was found in the Ocular Surface Disease Index (which
assessed the severity of symptoms associated w ith dry ey e). In
summary, although there is some evidence for the effectiveness of
EFA supplementation in DES, more data is needed before supple-
ments can be widely recommended.
A large percentage of the general population is taking a diverse
range of nutritional supplements to maintain or improve their over-
all health without any evidence-based justification. Supplementing
the diet of well-nourished adults with mineral or vitamin supple-
ments appear to have no clear benefit and might even be harmful. It
is important that any advice given regarding supplements is in-
formed by the best available research evidence. Howev er, there is a
dearth of high quality data from randomised trials on the effective-
ness of these preparations for common age-related eye conditions
such as AMD, cataract and DES. It should also be borne in mind
that the use of high dose micronutrient supplements also has the
potential for harm, for example several trials have reported higher
rates of lung cancer in cigarette smokers who were taking nutri-
tional supplements containing -carotene and there is also the pos-
sibility of interactions of nutrition al supplements with prescribed
medications . Currently there is insufficient evidence to rec-
ommend commercially available supplements for the prevention or
treatment of cataract or DES. However, there is high quality evi-
dence to support the use of an AREDS-formulation supplement
containing antioxidants (-carotene, vitamin C and vitamin E) and
zinc to slow progression in those patients at high risk of developing
advanced AMD, including those with intermediate AMD in one or
both eyes (AREDS category 3) or advanced AMD (AREDS cate-
gory 4) in one eye, but not the other eye. Recent data from the
AREDS2 trial provided further evidence that -carotene in the
original AREDS formula could be replaced with lutein and zeaxan-
thin on the basis of improved safety without compromising effi-
cacy. Giv en the current scale of the public health problem caused
by age-related eye disease and with increasing longevity, reducing
the risk of developing these diseases or slowing their progression
through dietary modification should remain an important area for
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Received: July 6, 2015 Accepted: September 4, 2015