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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 potential 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 lacking. However, there is high quality evidence to support the use of an Age-related Eye-disease Study (AREDS) supplement containing antioxidants (β-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 β-carotene could be replaced with lutein and zeaxanthin on the based on improved safety without compromising efficacy. Although there is currently insufficient evidence to recommend the routine use of any of the commercially available supplements 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.
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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 [3]. 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 [4]. 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 [5]. 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 [8]. 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 [9] 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:
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
is 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 [4]. 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 [10]. 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.
Although in global terms, AMD ranks third as the leading
causes of visual impairment [12], 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 [13] and with an ageing population the prevalence of
the disease is predicted to increase substantially [14]. 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 [15]. 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
18-/15 $58.00+.00 © 2015 Bentham Science Publishers
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 [16]. 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 [17]. 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)
[17]. 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 [18] 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
[21]. Two of these reviews focussed on the role of antioxidant vi-
tamin and mineral supplements in the prevention [19] and progres-
sion [20] of AMD and one review investigated on the role of
omega-3 fatty acid supplementation [21].
The review on ‘antioxidant vitamin and mineral supplements
for preventing age-related macular degeneration’ [19] 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” [20] 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 [22]. 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 [20]). 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.
Bad outcome
Good outcome
Beer with treatment
Nutritional Supplements in Ophthalmology Current Pharmaceutical Design, 2015, Vol. 21, No. 3 2 4669
creased risk of developing AMD [23]. 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 [24].
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)
[22]. 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
[25]. 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%. [26].
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 [28], 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 [29] 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 [30]. This study also highlighted serious meth-
odological flaws in the sub-group analysis used in the previous
study [29] 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 [31]. 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 [31]. 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 [37]. The re-
cently updated Cochrane review ‘Omega 3 fatty acids for prevent-
ing or slowing the progression of age-related macular degeneration’
[21] included two relevant RCTs [22, 38]. In one of the treatment
arms of AREDS2 [22], 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 [38],
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 [21].
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 [39].
Oxidative stress has been implicated in the pathogenesis of all cata-
ract sub-types [39]. 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 [39]. 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 [12]. 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 [40] 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 [41] 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 [42]. 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 [43].
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 [44]. This finding was consistent with the
results of a RCT conducted in Italy [45] 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 [46]. 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 [47], 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 (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 [48]. 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
[49]. 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)
Cyclooxygenase (COX)
Lipoxygenase (LOX)
2-Series Prostaglandins (PGE2)
4- Series Leukotrienes (LTB4)
-Linolenic Acid (ALA)
Eicosapentaenoic Acid
3-Series Prostaglandins (PGE3)
1-Series Prostaglandins (PGE1)
Cyclooxygenase (COX)
Lipoxygenase (LOX)
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 [53]. By contrast, data from intervention
studies on the benefit of supplementation with EFA are sparse. A
recent systematic review [54] 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 [55]. 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
future research.
The authors confirm that this article content has no conflict of
Declared none.
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Received: July 6, 2015 Accepted: September 4, 2015
... Finally, the utility of the contribution of certain nutrients in the prevention and management of this syndrome has been the subject of numerous studies and the interest of the pharmaceutical industry [9,10]. The main nutritional deficiency which has been associated to DES is the lack of vitamin A. Many case series have added bibliographic support to this idea and should be taken in to account in people having very restrictive dietetic habits [11][12][13]. ...
... The main nutritional deficiency which has been associated to DES is the lack of vitamin A. Many case series have added bibliographic support to this idea and should be taken in to account in people having very restrictive dietetic habits [11][12][13]. It has been reported in numerous publications that the use of dietary supplements containing polyunsaturated omega-3 or omega-6 fatty acids can improve the quality of the tear film and represent a protective factor against DE and its consequences [2,9,10,[14][15][16][17][18][19][20][21][22][23][24][25]. The lack of well-defined protocols to regulate the use of these substances reflects the important gaps existing in the knowledge of the effectiveness of these products and justifies, in our opinion, the performance of this study. ...
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Objective: To identify the clinical evidence in the literature about the relationship between nutrition or dietary supplements and dry eye syndrome. Methods: A systematic review was performed after selecting descriptors (DECS and MeSH) using electronic data base (Pubmed, Cochrane and Embase) for the words “diet”, “food”, “nutrition” and “dry eye syndrome” appearing in the title, abstract or key words. Papers published in any language during the last ten years were selected. A scoring system regarding the scientific evidence (GRADE) was applied for all chosen manuscripts. Results: Only 17 papers were considered as relevant for our review taking into account our search criteria. The main features of the studies published have been summarized in two tables. Conclusion: The use of omega-3 poly unsaturated fatty acids, taken in the diet or as dietary supplements, appears as the most analyzed element. Omega-3 provides the greatest degree of scientific evidence regarding its usefulness as a coadjuvant in the management of dry eye. It can be said that moderate scientific evidence supports its use as a helpful tool in the treatment of dry eye syndrome. However, it is not possible to define the exact dosage to achieve a clinical benefit.
... Pathogenesis of AMD is multifactorial involving complex interplay between environmental and genetic factors Abstract leading to oxidative stress and chronic inflammation, eventually resulting in neovascularization and fibrosis. 5 Retina is especially liable to oxidative stress due to its high vascularization resulting in high oxygen tension, light induced stress in the fovea and its high content of unsaturated fatty acids and photosensitizing compounds. 6 Action of light on retina generates free radicals or reactive oxygen species (ROS) which act as proxidants and lead to chain reactions with cellular and molecular damage. ...
... Role of these vitamins and micronutrients in preventing or delaying the progression of AMD has been reported by several epidemiological studies, but results were not consistent. 2,5,6 Given the lack of hard clinical data from a randomized interventional trial and the growing concern of widespread use of unproven, high dose supplements, US National Eye institute initiated the age related eye disease D O J study (AREDS). AREDS 1 was the first large multicentric placebo controlled randomized clinical trial done to investigate the benefit of high dose supplementation with vitamin C, E, beta-carotene and zinc or its combination in preventing the progression of AMD. ...
... In the case of cataracts, this failure may be due to the inability of oral antioxidants to adequately cross the blood-aqueous barrier to achieve therapeutic levels in the avascular lens and/ or because the antioxidant activity of these compounds may not be sufficiently potent to prevent cataract formation. Both possibilities are supported by the mixed results from the Age-Related Eye Disease Study; in this study, limited retinal benefit was found, whereas there was no protection of the lens (24,26,65). Similarly, in promising pre-clinical studies of hearing loss with NAC (17,63), randomized human clinical trials found that NAC was no better than placebo in the prevention of NIHL (62). ...
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Significance: Oxidative stress contributes to vision, hearing and neurodegenerative disorders. Currently, no treatments prevent these disorders; therefore, there is an urgent need for redox modulator that can prevent these disorders. Recent Advances: Oxidative stress is associated with the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), metal dyshomeostasis, and mitochondrial dysfunction. Here we review the role oxidative stress and metal dyshomeostasis play in hearing loss, visual impairments, and neurodegeneration and discuss the benefits of a new class of multifunctional redox modulators (MFRMs) that suppress sensory and neural degeneration. MFRM not only reduce free radicals but also independently bind transition metals associated with the generation of hydroxyl radicals. MFRMs redistribute zinc from neurotoxic amyloid beta zinc (Aβ:Zn) complexes to the cytoplasm facilitating the degradation of Aβ plaques by MMP-2. Although MFRMs bind copper (Cu1+, Cu2+), iron (Fe2+, Fe3+), zinc (Zn2+) and manganese (Mn2+) they do not deplete free cytoplasmic Zn+2 and they protect mitochondria from Mn+2-induced dysfunction. Oral administration of MFRMs reduce ROS-induced cataracts, protect the retina from light-induced degeneration, reduce neurotoxic Aβ:Zn plaque formation, and protect auditory hair cells from noise-induced hearing loss (NIHL). Critical issues: Regulation of redox balance is essential for clinical efficacy in maintaining sensory functions. Future directions: Future use of these MFRMs requires additional pharmacokinetic, pharmacodynamics and toxicological data to bring them into widespread clinical use. Additional animal studies are also needed to determine if MFRMs can prevent neurodegeneration, dementia, and other forms of vision and hearing loss.
... 25 The main nutritional deficiency which has been associated to DED is the lack of vitamin A and D, and of essential fatty acids. [26][27][28][29][30][31][32] Subjects suffering from, or at risk of dry eye, must pay attention to maintain adequate levels of these two vitamins in their diet. It is essential to note that since lockdown is related with disruption of the work routine, this could lead to boredom. ...
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The pandemic of coronavirus disease 2019 (COVID-19) has led many countries of the world to impose a series of containment measures such as lockdowns (mass quarantines), curfews or similar restrictions (eg, stay-at-home orders, or shelter-in-place orders). All these restrictions were established in order to limit spread of COVID-19. Thus, approximately 3.9 billion people worldwide were under lockdown by early April 2020. During this time (home confinement), some solutions have been proposed by experts to improve work and school productivity, including smart working and online school lessons. However, many of the restrictive measures are likely to act as predisposing factors for dry eye disease (DED), directly or related to sick building syndrome (SBS). Herein, we discuss the implications of quarantine measures on eye health, in particular on DED associated with SBS, and introduce some potential preventive strategies for lockdown-related ocular surface disorders. Several risk factors are implicated in their pathogenesis, including environmental changes (eg, air quality) and modifications in personal behaviors (eg, the abuse of digital devices, malnutrition , and sleep/psychiatric disorders). Considering a number of predisposing factors for DED, it is possible to state that patients under lockdown are at risk of ocular surface alterations. Accordingly, the COVID-19 pandemic era is expected to determine an increase in dry eye patients all around the world (a new phenomenon that we propose to name the "quarantine dry eye") in the event that the restrictive measures will be recursively extended over time.
... -Los suplementos nutricionales destinados a sujetos con DMAE presentan formulaciones con concentraciones superiores a las de la ingesta dietética media, pero inferiores a las dosis utilizadas en los estudios AREDS [3,8,19] y en otros estudios [21]. Aunque la ingesta de luteína sugerida para la disminución de riesgo de enfermedad ocular está en torno los 6 -10 mg/día (a partir de dieta o de complementos alimenticios) [3,6,19], se necesitan más estudios clínicos bien definidos, en grupos homogéneos de sujetos y con la utilización de biomarcadores adecuados (de estatus nutricional y de objetivos clínicos), para definir con más precisión el tipo de sujetos que se beneficiarían con su ingesta (ej. ...
Introducción: Las principales causas de deficiencia visual a nivel mundial, según la Organización Mundial de la Salud (OMS) en su vigente plan de acción para la salud ocular, son los errores refractivos no corregidos (42%) y las cataratas (33%), que en su mayoría son prevenibles o curables. Asimismo, la OMS constata la tendencia al aumento en la incidencia de enfermedades oculares relacionadas con el envejecimiento, por lo que se espera que esas sean las causas más prevalentes de deficiencias visuales evitables en las próximas décadas [1], entre las que destaca la degeneración macular asociada a la edad (DMAE) como la principal causa de ceguera en personas mayores de 65 años. Entre los factores de riesgo de diversas enfermedades oculares crónicas, en su origen o en el desarrollo, se encuentran algunos componentes de los alimentos como son las vitaminas E y C, algunos minerales, varios carotenoides (luteína, zeaxantina y β-caroteno) y dos ácidos grasos omega-3 [eicosapentanoico (EPA) y el decosahexaenoico (DHA)] [2]. La ingesta dietética elevada de los alimentos que los contienen se ha asociado con un menor riesgo de DMAE, cataratas, etc., y el aporte de esos compuestos en cantidades superiores a las habitualmente consumidas con la dieta pueden lograr lentificar la progresión de la enfermedad [3].
... Alternatively, the antioxidant activity may not be potent enough. These possibilities are supported by results from the AREDS trials where retinal but no lens efficacy was observed [24][25][26]. However, retinal efficacy by the AREDS formulations is very limited. ...
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Background: Oral nutraceutical antioxidants have shown disappointing clinical results in reducing oxidation-induced age-related cataract and other ocular diseases. Based on the hypothesis that nutraceuticals do not adequately reach the lens by oral administration, we have developed a unique topical antioxidant formulation whose active ingredients have the reported ability to reduce oxidative stress through free radical scavenging and chelating activity. This topical nutraceutical formulation was designed to mimic the in vivo activity of multifunctional antioxidants, compounds which are being developed in our laboratory to independently scavenge free radicals and selectively bind redox metals. A comparison of the efficacy of this topical nutraceutical to multifunctional antioxidants in laboratory animal models of oxidation-induced lens changes, retinal changes, and dry eye is reviewed. Although it is less potent than the small molecule multifunctional antioxidants that will require FDA approval, the topical nutraceutical formulation beneficially reduces ocular oxidative stress. These studies suggest that this topical antioxidant may fill an unmet therapeutic need by providing a nutraceutical that beneficially reduces the effects of oxidation on age-related ocular diseases.
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Sight is often considered to be the most valuable sense. However, the way in which senses are defined, considered and researched in science and society has changed over time. Increasingly, definitions of the senses move beyond the five ‘traditional’ senses of sight, hearing, smell, taste and touch to include functions such as balance, temperature and pain perception. Our senses also interact substantially, and while neural reorganisation in the brain can help to compensate for the loss of one sensory modality, dual or multisensory impairments are a growing issue in the ageing population. This article reports the results of a UK-based cross-sectional online survey, where members of the public were surveyed in March–April 2016 to explore which sense they considered to be most valuable. Participants were first asked to rank the five traditional senses (sight, hearing, touch, smell and taste) plus three other ‘non-traditional’ senses (balance, temperature and pain) in order of most valuable to least valuable. Sight was indeed ranked by participants as the most valuable sense, followed by hearing and then balance. Overall, these findings substantiate the idea of sight being the most valuable sense among a cross-section of the UK public. This provides a further argument for promotion of eye health as a key priority for public health. However, the broader research on the senses helps to caveat and contextualise such findings. Notably, the importance of sight may be socially and culturally relative, and results could be different if the study were conducted in other contexts, for example in different countries or among people living with sensory loss. It is argued that optometrists have a key role to play in responding to anxieties regarding sight loss, dispelling stigma and fear, and promoting ways to adapt to sight loss.
Three groups of proteins are actively involved in the control of intracellular zinc, consisting of ZIP channels (SLC39A), ZnT transporters (SLC30A), and metallothioneins. Malfunctions of many zinc transport proteins, especially those belonging to the ZIP family which increase cytosolic zinc availability, have been associated with cancer. Importantly, post-translational modifications have been reported to play an increasing role in the functional control of ZIP channels. In this chapter, we therefore detail the established role of zinc signalling in cancer, with an emphasis on breast cancer, as well as demonstrate effects of post-translational modifications by phosphorylation and proteolytic cleavage.
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FFHD Print Issue for February 2017.
Cyclosporine is an immunosuppressant agent approved for the treatment of dry eye disease and used off-label for other ocular pathologies. Its formulation and ocular bioavailability is a real challenge due to the large molecular weight (1.2 kDa), high lipophilicity and low water solubility. The aim of the work was to develop an aqueous micellar formulation for an efficient cyclosporine delivery to the ocular tissues, using a water soluble derivative of vitamin E (TPGS: d-alpha tocopheryl polyethylene glycol 1000 succinate) and a poloxamer (poloxamer 407) as excipients. The mixed micelles were characterized in terms of particle size, zeta potential, rheology, stability upon dilution and freeze drying. Additionally, the enzymatic-triggered release of vitamin E and vitamin E succinate from TPGS was investigated in vitro in the presence of esterase. Compared to the commercially available ophthalmic formulation, the poloxamer 407:TPGS 1:1 molar ratio micellar formulation significantly improved cyclosporine solubility, which increased proportionally to surfactants concentration reaching 0.4% (w/v) for 20 mM surfactants total concentration. Cyclosporine-loaded mixed micelles efficiently retained the drug once diluted in simulated lachrymal fluid and, in the presence of a 20 mM surfactants concentration, were stable upon freeze-drying. The drug-loaded mixed micelles were applied ex vivo on porcine cornea and compared to Ikervis®. Drug accumulation in the cornea resulted proportional to drug concentration (6.4 ± 1.9, 17.6±5.4 and 26.9±7.4 µgdrug/gcornea, after 3 h for 1, 2.5 and 4 mg/ml cyclosporine concentration respectively). The formulation containing cyclosporine 4 mg/ml (20 mM surfactant) was also evaluated on the sclera, with a view to targeting the posterior segment. The results demonstrated the capability of mixed micelles to diffuse into the sclera and sustain cyclosporine delivery (28±7, 38±10, 57±9, 145±27 µg/cm2 cyclosporine accumulated after 3, 6, 24 and 48 h respectively). Reservoir effect experiments demonstrated that the drug accumulated in the sclera can be slowly released into the underlying tissues. Finally, all the formulations developed in this work successfully passed the HET-CAM assay for the evaluation of ocular irritability.
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Purpose To evaluate ophthalmologists’ opinion of, and use of, micronutritional dietary supplements 10 years after publication of the first Age-Related Eye Disease Study (AREDS) study. Methods Participation was solicited from 4,000 European ophthalmologists. Responding physicians were screened, and those treating at least 40 patients with age-related macular degeneration (AMD) per month and prescribing nutrition supplements at least 4 times per month were admitted and completed a 40-item questionnaire. Results The surveyed sample included 112 general ophthalmologists and 104 retinal specialists. Most nutritional supplements (46%) were initiated when early/intermediate AMD was confirmed, although 18% were initiated on confirmation of neovascular AMD. Clinical studies were well known: 90% were aware of AREDS, with 88% aware of AREDS1 and 36% aware of the, as-yet-unpublished, AREDS2 studies. Respondents considered lutein, zeaxanthin, zinc, omega-3, and vitamins to be the most important components of nutritional supplements, with the results of AREDS2 already having been taken into consideration by many. Ophthalmologists anticipate more scientific studies as well as improved product quality but identify cost as a barrier to wider uptake. Conclusion Micronutrition is now part of the routine management of AMD for many ophthalmologists. Ophthalmologists choosing to use nutritional supplements are well-informed regarding current scientific studies.
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Importance Age-related cataract is a leading cause of visual impairment in the United States. The prevalence of age-related cataract is increasing, with an estimated 30.1 million Americans likely to be affected by 2020.Objective To determine whether daily oral supplementation with lutein/zeaxanthin affects the risk for cataract surgery.Design, Setting, and Patients The Age-Related Eye Disease Study 2 (AREDS2), a multicenter, double-masked clinical trial, enrolled 4203 participants, aged 50 to 85 years, at risk for progression to advanced age-related macular degeneration. Interventions Participants were randomly assigned to daily placebo; lutein/zeaxanthin, 10mg/2mg; omega-3 long-chain polyunsaturated fatty acids, 1 g; or a combination to evaluate the effects on the primary outcome of progression to advanced age-related macular degeneration. Main Outcomes and Measures Cataract surgery was documented at annual study examination with the presence of pseudophakia or aphakia, or reported during telephone calls at 6-month intervals between study visits. Annual best-corrected visual acuity testing was performed. A secondary outcome of AREDS2 was to evaluate the effects of lutein/zeaxanthin on the subsequent need for cataract surgery.Results A total of 3159 AREDS2 participants were phakic in at least 1 eye and 1389 of 6027 study eyes underwent cataract surgery during the study, with median follow-up of 4.7 years. The 5-year probability of progression to cataract surgery in the no lutein/zeaxanthin group was 24%. For lutein/zeaxanthin vs no lutein/zeaxanthin, the hazard ratios for progression to cataract surgery was 0.96 (95% CI, 0.84-1.10; P = .54). For participants in the lowest quintile of dietary intake of lutein/zeaxanthin, the hazard ratio comparing lutein/zeaxanthin vs no lutein/zeaxanthin for progression to cataract surgery was 0.68 (95% CI, 0.48-0.96; P = .03). The hazard ratio for 3 or more lines of vision loss was 1.03 (95% CI, 0.93-1.13; P = .61 for lutein/zeaxanthin vs no lutein/zeaxanthin).Conclusions and Relevance Daily supplementation with lutein/zeaxanthin had no statistically significant overall effect on rates of cataract surgery or vision loss.Trial Registration Identifier: NCT00345176.
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Dietary supplements are used by half to two-thirds of American adults, and the evidence suggests that this usage is one component of a larger effort to develop a healthier lifestyle. Dietary supplement users tend on average to be better educated and to have somewhat higher incomes than nonusers, and these factors may contribute to their health-consciousness. Dietary supplement use also tends to be more prevalent among women than among men, and the prevalence of use increases with age in both men and women. Numerous surveys document that users of dietary supplements are significantly more likely than nonusers to have somewhat better dietary patterns, exercise regularly, maintain a healthy weight, and avoid tobacco products. While supplement users tend to have better diets than nonusers, the differences are relatively small, their diets have some substantial nutrient shortfalls, and their supplement use has been shown to improve the adequacy of nutrient intakes. Overall, the evidence suggests that users of dietary supplements are seeking wellness and are consciously adopting a variety of lifestyle habits that they consider to contribute to healthy living.
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IMPORTANCE The Age-Related Eye Disease Study (AREDS) formulation for the treatment of age-related macular degeneration (AMD) contains vitamin C, vitamin E, beta carotene, and zinc with copper. The Age-Related Eye Disease Study 2 (AREDS2) assessed the value of substituting lutein/zeaxanthin in the AREDS formulation because of the demonstrated risk for lung cancer from beta carotene in smokers and former smokers and because lutein and zeaxanthin are important components in the retina. OBJECTIVE To further examine the effect of lutein/zeaxanthin supplementation on progression to late AMD. DESIGN, SETTING, PARTICIPANTS The Age-Related Eye Disease Study 2 is a multicenter, double-masked randomized trial of 4203 participants, aged 50 to 85 years, at risk for developing late AMD; 66% of patients had bilateral large drusen and 34% had large drusen and late AMD in 1 eye. INTERVENTIONS In addition to taking the original or a variation of the AREDS supplement, participants were randomly assigned in a factorial design to 1 of the following 4 groups: placebo; lutein/zeaxanthin, 10 mg/2 mg; omega-3 long-chain polyunsaturated fatty 3 acids, 1.0 g; or the combination. MAIN OUTCOMES AND MEASURES Documented development of late AMD by central, masked grading of annual retinal photographs or by treatment history. RESULTS In exploratory analysis of lutein/zeaxanthin vs no lutein/zeaxanthin, the hazard ratio of the development of late AMD was 0.90 (95% CI, 0.82-0.99; P = .04). Exploratory analyses of direct comparison of lutein/zeaxanthin vs beta carotene showed hazard ratios of 0.82 (95% CI, 0.69-0.96; P = .02) for development of late AMD, 0.78 (95% CI, 0.64-0.94; P = .01) for development of neovascular AMD, and 0.94 (95% CI, 0.70-1.26; P = .67) for development of central geographic atrophy. In analyses restricted to eyes with bilateral large drusen at baseline, the direct comparison of lutein/zeaxanthin vs beta carotene showed hazard ratios of 0.76 (95% CI, 0.61-0.96; P = .02) for progression to late AMD, 0.65 (95% CI, 0.49-0.85; P = .002) for neovascular AMD, and 0.98 (95% CI, 0.69-1.39; P = .91) for central geographic atrophy. CONCLUSION AND RELEVANCE The totality of evidence on beneficial and adverse effects from AREDS2 and other studies suggests that lutein/zeaxanthin could be more appropriate than beta carotene in the AREDS-type supplements. TRIAL REGISTRATION Identifier: NCT00345176.
There is inconclusive evidence from observational studies to suggest that people who eat a diet rich in antioxidant vitamins (carotenoids, vitamins C and E) or minerals (selenium and zinc) may be less likely to develop age-related macular degeneration (AMD). OBJECTIVES: To examine the evidence as to whether or not taking antioxidant vitamin or mineral supplements prevents the development of AMD. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2011, Issue 12), MEDLINE (January 1950 to January 2012), EMBASE (January 1980 to January 2012), Open Grey (System for Information on Grey Literature in Europe) (, the metaRegister of Controlled Trials (mRCT) (, ( and the WHO International Clinical Trials Registry Platform (ICTRP) ( There were no date or language restrictions in the electronic searches for trials. The electronic databases were last searched on 26 January 2012. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) comparing an antioxidant vitamin and/or mineral supplement (alone or in combination) to control. DATA COLLECTION AND ANALYSIS: Both review authors independently assessed risk of bias in the included studies and extracted data. One author entered data into RevMan 5 and the other author checked the data entry. We pooled data using a fixed-effect model. MAIN RESULTS: We included four RCTs in this review; 62,520 people were included in the analyses. The trials were conducted in Australia, Finland and the USA and investigated vitamin E and beta-carotene supplements. Overall the quality of the evidence was high. People who took these supplements were not at decreased (or increased) risk of developing AMD. The pooled risk ratio for any antioxidant supplement in the prevention of any AMD was 0.98 (95% confidence interval 0.89 to 1.08) and for advanced AMD was 1.05 (95% CI 0.80 to 1.39). Similar results were seen when the analyses were restricted to beta-carotene and alpha-tocopherol alone. AUTHORS' CONCLUSIONS: There is accumulating evidence that taking vitamin E or beta-carotene supplements will not prevent or delay the onset of AMD. There is no evidence with respect to other antioxidant supplements, such as vitamin C, lutein and zeaxanthin, or any of the commonly marketed multivitamin combinations. Although generally regarded as safe, vitamin supplements may have harmful effects and clear evidence of benefit is needed before they can be recommended. People with AMD should see the related Cochrane review 'Antioxidant vitamin and mineral supplements for slowing the progression of age-related macular degeneration' written by the same review team.
Background Dry eye is a common, complex condition that can reduce ocular comfort and visual performance. The impact on quality of life has been rated as similar to the effect of moderate angina and, in more severe cases, dialysis and severe angina. This study aimed to use meta-analysis to compare omega-3 fatty acid and placebo fatty acid in the management of dry eye syndrome. Material/Methods Comparative studies published until 1 June 2014 were searched through a comprehensive search of the Medline, Embase, Web of Science, and the Cochrane Library electronic databases. A systematic review and cumulative analysis of comparative studies reporting the effect of omega-3 fatty acid on dry eye syndrome was conducted. All analyses were performed using the Review Manager (RevMan) v.5 software (Nordic Cochrane Centre, Copenhagen, Denmark). Results The trials involved a total of 790 participants in 7 independent studies. All the studies are published between 2007 and 2013. Meta-analysis of the 5 studies that reported data in mean SD values revealed that the tear break-up time (TBUT) was significantly greater by 1.58 s (WMD=1.58, 95% CI=0.60 to 2.55; P=0.007). Combination of all the Schirmer’s test data showed that omega-3 fatty acid supplementation could significantly improve the Schirmer’s test (WMD=0.74, 95% CI=0.29 to 1.19; P=0.001). However, the combination of all the OSDI test data showed that omega-3 fatty acid supplementation did not significantly improve the OSDI test results (WMD=−4.54, 95% CI=−9.85 to 0.78; P=0.09). Conclusions Based on the data included in our meta-analysis, omega-3 fatty acid was associated with better TBUT and Schirmer’s. No significant differences were detected in OSDI test results. Consequently, our findings suggest that omega-3 fatty acid offers is an effective therapy for dry eye syndrome.
Objective To determine whether genotypes at 2 major loci associated with late age-related macular degeneration (AMD), complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2), influence the relative benefits of Age-Related Eye Disease Study (AREDS) supplements. Design Unplanned retrospective evaluation of a prospective, randomized, placebo-controlled clinical trial of vitamins and minerals for the treatment of AMD. Subjects AREDS participants (mean age, 69 years) who were at risk of developing late AMD and who were randomized to the 4 arms of AREDS supplement treatment. Methods Analyses were performed using the Cox proportional hazards model to predict progression to late AMD (neovascular or central geographic atrophy). Statistical models, adjusted for age, gender, smoking status, and baseline AMD severity, were used to examine the influence of genotypes on the response to therapy with 4 randomly assigned arms of AREDS supplement components: placebo, antioxidants (vitamin C, vitamin E, β-carotene), zinc or a combination. Main Outcome Measures The influence of the genotype on the relative treatment response to the randomized components of the AREDS supplement, measured as progression to late AMD. Results Of the 1237 genotyped AREDS participants of white ethnicity, late AMD developed in 385 (31.1%) during the mean follow-up of 6.6 years. As previously demonstrated, CFH genotype (P = 0.005), ARMS2 (P< 0.0001), and supplement were associated individually with progression to late AMD. An interaction analysis found no evidence that the relative benefits of AREDS supplementation varied by genotype. Analysis of (1) CFH rs1061170 and rs1410996 combined with ARMS2 rs10490924 with the 4 randomly assigned arms of AREDS supplement and (2) analysis of the combination of CFH rs412852 and rs3766405 with ARMS2 c.372_815del443ins54 with the AREDS components resulted in no interaction (P = 0.06 and P = 0.45, respectively, before multiplicity adjustment). Conclusions The AREDS supplements reduced the rate of AMD progression across all genotype groups. Furthermore, the genotypes at the CFH and ARMS2 loci did not statistically significantly alter the benefits of AREDS supplements. Genetic testing remains a valuable research tool, but these analyses suggest it provides no benefits in managing nutritional supplementation for patients at risk of late AMD.
This review provides a perspective on the Age-related Eye Disease Study 2 (AREDS2) including a summary of the goals and rationale of the study, major findings, subsequent management recommendations, and questions that remain to be answered. The primary goal of the AREDS2 was to evaluate the efficacy and safety of lutein plus zeaxanthin and/or omega-3 long-chain polyunsaturated acid supplementation in reducing the risk of developing advanced age-related macular degeneration (AMD). AREDS2 also investigated the effects of omitting β-carotene and reducing the concentration of zinc from the original AREDS formulation. Although primary analysis from the AREDS2 did not reveal a benefit of daily supplementation with lutein/zeaxanthin on AMD progression, secondary exploratory analyses suggested that lutein/zeaxanthin were helpful in reducing this risk. Comparison of low-dose to higher-dose zinc showed no significant benefit. The overall evidence on the beneficial and adverse effects from AREDS2 and other studies suggests that lutein/zeaxanthin could be more appropriate than β-carotene in AREDS-type supplements. Questions remain regarding the AREDS2 study results such as: whether the findings are generalizable to the population as a whole, what is the long-term safety profile of lutein/zeaxanthin supplementation, should other carotenoids be included in AREDS-type supplements, and at what optimal doses?
Age-related macular degeneration (AMD) is the most common cause of irreversible visual loss in the developed world. Both environmental and genetic factors contribute to the development of disease. Among environmental factors, smoking, obesity and dietary factors including antioxidants and dietary fat intake most consistently affect initiation and progression of AMD. There are also several lines of evidence that link both cardiovascular and inflammatory biomarkers to AMD. The genetic etiology of AMD has been and continues to be an intense and fruitful area of investigation. Genome-wide association studies have revealed many common variants associated with AMD and sequencing is increasing our knowledge of how rare variants impact disease. Evidence for specific interactions between environmental, therapeutic and genetic factors is emerging and elucidating the mechanisms of this interplay remains a major challenge in the field. The knowledge of non-genetic, modifiable risk factors along with information about heritability and genetic risk variants for this disease acquired over the past 25 years have greatly improved patient management and our ability to predict which patients will develop or progress to advanced forms of AMD.