Download New technologies and drugs in the management of diabetic

Review
New technologies and drugs in the management
of diabetic retinopathy
Hamish MA Towler
Abstract
MD, FRCPEd, FRCSEd, FRCOphth, Consultant
Ophthalmologist, NELEEA Ltd, Spire Roding Hospital,
Ilford, UK
Diabetic retinopathy remains one of the most common and most feared causes of blindness
and visual impairment in adults of working age despite the availability of effective treatment
for more than 30 years. Sight-threatening diabetic retinopathy consists of two distinct clinical
entities: proliferative diabetic retinopathy (PDR) and diabetic macular oedema (DMO or
maculopathy) which may coexist, both of which can be detected by clinical or photographic
screening before vision is affected, thereby allowing treatment to be offered before visual
impairment has developed. Laser photocoagulation has been the mainstay of treatment of
PDR and DMO since landmark studies in the 1980s proved its effectiveness. The more recent
elucidation of the role of vascular endothelial growth factor (VEGF) in the pathogenesis of
both types of diabetic retinopathy, and the ability to specifically inhibit VEGF effects by the
intraocular injection of blocking agents offer new options of non-destructive treatment with
better visual outcomes than laser. Diabetic macular oedema may also respond to intraocular
steroid therapy, and the development of slow-release delivery systems can now provide drug
delivery for three years from a single injection. The assessment of DMO has been
revolutionised by non-invasive imaging with ocular coherence tomography (OCT) which
allows microscopic visualisation of macular detail and serial quantitative measurement of the
structural response to treatment. These new therapeutic options are improving visual
outcomes for DMO, but are also creating enormous logistical problems for both patients and
eye clinics as they are much more demanding in terms of frequent clinic visits and use of
ophthalmology imaging services than conventional but less effective laser treatment.
Copyright © 2014 John Wiley & Sons.
Practical Diabetes 2014; 31(7): 275–280
Correspondence to:
Hamish MA Towler, MD, FRCPEd, FRCSEd, FRCOphth,
Consultant Ophthalmologist, NELEEA Ltd, Spire
Roding Hospital, Roding Lane South, Ilford IG4 5PZ,
UK; email: [email protected]
Received: 2 May 2014
Accepted in revised form: 12 June 2014
Key words
anti-VEGF; intravitreal fluocinolone; ocular coherence tomography; diabetic maculopathy
Introduction
Diabetic retinopathy (DR) is a
chronic progressive and potentially
sight-threatening disease of the
retinal microcirculation associated
with prolonged hyperglycaemia
resulting from diabetes mellitus,
which may be aggravated by other
associated conditions such as hypertension and hyperlipidaemia.
This retinal microvascular damage manifests in two non-exclusive
ways: breakdown of the blood-retina
barrier resulting in retinal oedema,
and capillary occlusion which leads
to retinal ischaemia, hypoxia, and
subsequent neovascularisation. The
concept of a growth factor released
by hypoxic retina was first postulated
by Michaelson in 19481 and eventually characterised as a family of
vascular endothelial growth factors
(VEGF) in the 1990s.2 VEGF plays a
crucial role in DR by stimulating
the growth of new blood vessels
but also increases vascular permeability, resulting in retinal oedema
which is highly detrimental to visual
PRACTICAL DIABETES VOL. 31 NO. 7
function when the macula and fovea
are affected.
The recognition of the importance
of VEGF in both proliferative retinopathy and macular oedema has led to
treatment with intravitreal injection of
agents which block the effects of
VEGF. Anti-VEGF therapy was first
applied in the eye for the treatment of
neovascular (or ‘wet’) age-related macular degeneration (AMD) where the
clinical impact has been almost miraculous,3,4 and current options include
ranibizumab, bevacizumab and, more
recently, aflibercept. The experience
with anti-VEGF therapy for AMD has
confirmed the safety and effectiveness
of repeated intravitreal injections, with
low rates of endophthalmitis (less than
1:1000 injections), with no significant
risk of inducing cataract or increasing
intraocular pressure, but the need for
regular and continuing treatment has
created enormous logistical problems
in treatment delivery.
Diabetic retinopathy is classified
according to its clinical features
as either proliferative (PDR) or
COPYRIGHT © 2014 JOHN WILEY & SONS
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New technologies and drugs in the management of diabetic retinopathy
non-proliferative (NPDR).5,6 NPDR in
the presence of a healthy macula and
normal visual acuity is commonly
called background diabetic retinopathy (BDR). Macular involvement is
classified separately and with greater
difficulty since the clinical features
may be much less apparent than
expected for the degree of visual loss.
The detailed photographic grading
systems which underpinned the landmark clinical trials proving the effectiveness of laser photocoagulation
(such as the DRS and ETDRS)6–8 have
evolved into simpler classifications9–13
used in population screening to identify eyes at risk from DR which require
further ophthalmic assessment and
possible treatment. No single standardised international grading system for
DR screening has been universally
adopted and, even within the UK,
there are variations in the screening
methodology, terminology, grading
levels, and referral criteria used in the
English, Northern Ireland, Scottish
and Welsh grading systems.10–13
Although all the UK screening systems
specify the use of non-mydriatic digital
cameras, pupil dilation practice varies
between regions. Pupil dilation is, however, mandatory for the assessment
and treatment of DR in eye clinics.
Ocular coherence tomography
Ocular coherence tomography
(OCT) utilises non-invasive laser interferometry to provide high resolution
cross-sectional or topographic images
of the retina in microscopic detail.
This allows serial, quantitative analysis
of retinal structural changes and
has transformed the understanding
and management of macular diseases
in general and the vitreoretinal
interface. The third generation of
Figure 1a. Focal leakage near fovea,
visual acuity (VA) 6/6
276
PRACTICAL DIABETES VOL. 31 NO. 7
OCT scanners and software provide
faster image acquisition, wider field of
view, better imaging of the choroid,
and visualisation of the retinal
capillaries without the need for intravenous dye injection.14 Fundus fluorescein angiography (FFA) remains a
very valuable investigational tool for
retinal vascular disease as it can reveal
neovascularisation and retinal capillary occlusion as well as leakage, but it
does not provide the same exquisite
structural detail and quantitative
analysis as OCT. FFA is more labour
intensive and requires an intravenous
injection of fluorescein, the administration of which carries some associated morbidity.
Foveal thickness can now be measured with such unparalleled precision
that it is likely that OCT will be utilised
in screening for diabetic macular
oedema (DMO) as an adjunct to digital retinal photography. Central foveal
thickness (FTH) as measured by OCT
is now routinely used to determine
when to undertake further treatment.
Wide field retinal imaging
Advances in digital retinal imaging
using wide field scanning laser ophthalmoscopes provides a much more
extensive view of the retina with
sensitivity and specificity similar to
standard screening employing central
one or two field protocols,15 but with a
higher technical failure rate of around
11% compared with around 6% for
standard imaging. This is too high for
routine community screening but the
ability to undertake wide field fluorescein angiography may be helpful in
predicting and managing retinal
ischaemia and neovascularisation.16
Wide field imaging can be undertaken
through a normal undilated pupil.
Figure 1b. Normal ocular coherence tomography (OCT)
with no retinal oedema
Prevention of diabetic
retinopathy
DR develops approximately 5–10 years
after the onset of diabetes and potentially can be prevented or retarded in
type 1 diabetes by ensuring tight diabetes control.17–21 The insidious development of type 2 diabetes often
results in DR being detectable at diagnosis, and in this group good blood
pressure control appears to be more
effective than tightening diabetes control in retarding progression of
DR.20,21 Good early glycaemic control
also appears to have long-term legacy
benefits even where subsequent control is less stringent.
Improving diabetes control, blood
pressure, and hyperlipidaemia may
result in the regression or amelioration of DR without the need for
specific ophthalmic treatment (Figure
1). Rapid tightening of diabetes
control may paradoxically result in
an initial worsening of retinopathy
features,22,23 thus necessitating close
ophthalmic surveillance, although
ultimately the long-term visual prognosis is improved in these patients.
Pioglitazone has been associated
with an increased risk of DMO and
this should be avoided or used with
caution in patients with more severe
background changes,24 who should
have OCT undertaken to identify
early macular thickening and oedema
which may not be clinically evident.
Laser developments
Panretinal laser photocoagulation
(PRP) remains the standard first-line
treatment for PDR. Gas lasers (argon
green and krypton red/yellow) have
largely been superseded by solid state
diode lasers including 810nm
infrared, 577nm yellow, and 647nm
Figure 1c. Resolution of lipid exudates
one year later
COPYRIGHT © 2014 JOHN WILEY & SONS
Review
New technologies and drugs in the management of diabetic retinopathy
red, as well as 532nm green frequency doubled Nd:YAG lasers.
Modern lasers can be programmed to deliver multiple spots in
variable patterns with shorter pulse
duration (20ms rather than the conventional 100ms) which produces
less ocular discomfort for the patient
and more rapid and even laser application.25 Consideration of the laser
spot diameter is very important in
planning the total amount of treatment applied, as smaller spots may
result in significant under-treatment
and failure to control neovascularisation. 1200 x 500mm diameter spots
will treat an area of retina of 236mm2
(area treated = 1200 x ¼π x 0.52) and
this is often sufficient to induce new
vessel regression in mild to moderate
PDR, whereas use of a 400mm spot
would require 1875 applications to
treat the same area of retina.
Reducing the pulse duration from
100ms single spot delivery to 20ms
multi-spot pattern delivery also
requires a commensurate increase in
power or area treated to ensure adequate clinical treatment. PRP treatment is continued until new vessel
regression is achieved.
Macular laser treatment has also
benefited from modulation of the
laser pulse duration of the diode
laser to multiple short bursts of 100ms
(compared with a conventional
100ms burst) which reduces collateral damage to the retina. This
‘micropulse’ delivery26 is as effective
as conventional macular laser but
produces no clinically visible scarring
or retinal pigment epithelial disturbance and minimises the risk of inadvertent foveal burns which can have a
devastating impact on visual acuity.
Although macular laser treatment
is effective at stabilising visual acuity, it
is less successful in improving visual
acuity which has already deteriorated.
Intravitreal drug therapy of macular
oedema is better than laser in improving visual acuity, but adjuvant macular
laser may still have a role in providing
long-term stability with reduced need
for repeated intravitreal injections.
The DRCR.net study27 has shown no
additional visual benefit of immediate
laser compared with deferred laser
over three years’ ranibizumab treatment although the laser treated
group had three fewer injections
(median 11 vs 14 injections).
PRACTICAL DIABETES VOL. 31 NO. 7
Intravitreal drug delivery
Drug delivery into the eye by direct
intravitreal drug injection was for
many years considered an act of desperation. This dramatically changed
during the HIV/AIDS era when the
treatment of cytomegalovirus retinitis
(CMVR) with intravitreal ganciclovir28
showed the route to be remarkably
effective, safe, and repeatable.
The need for regular injections to
maintain control of CMVR led to the
development of a sustained-release
intravitreal device29 (Vitrasert®)
which delivered adequate therapeutic drug levels for about 30 weeks,
and which could then be replaced if
necessary. The need for continuous
intravitreal therapy for CMVR has
since diminished with improvements
in systemic HIV treatment and
restoration of immune competence,
but the safety and effectiveness of
sustained release intravitreal drug
delivery had been established.
Ozurdex® is a polylactic-co-glycolic
acid biodegradable polymer injected
through a 22G applicator needle
which releases dexamethasone for
about four to six months. It has been
shown to be effective in treating macular oedema secondary to retinal vein
occlusion40 and uveitis, and more
recently DMO.41
Iluvien® is a non-erodible intravitreal device releasing 0.2mg fluocinolone acetonide daily for about 36
months,42,43 which is injected into the
vitreous cavity through a 25G applicator. It has recently been approved in
England for the treatment of refractory DMO by NICE44 but only for use
in eyes which have already undergone cataract surgery because
cataract is an otherwise inevitable
consequence. Like other intravitreal
steroids, raised intraocular pressure
may occur and nearly 5% of Iluvien
treated eyes may need glaucoma surgery over three years.43
Intravitreal steroids for diabetic
macular oedema
The safety of intravitreal injection of
the crystalline long-acting steroid
triamcinolone acetonide was recognised in the early 1980s,30 but it was
nearly 15 years before clinical studies
of its use for macular disease were
reported. Intravitreal triamcinolone
acetonide (IVTA) use was first investigated in neovascular age-related
macular degeneration31 where it
showed modest benefits before being
eclipsed by anti-VEGF therapy.
IVTA was then shown to be very
effective in the treatment of cystoid
macular oedema due to intraocular
inflammation (uveitis),32,33 and
application of IVTA to diabetic macular oedema quickly followed.34,35
Anecdotal case reports, uncontrolled
retrospective studies and the
DRCR.net have subsequently shown
modest benefits but also confirmed
the significant complications of raised
intraocular pressure and cataract.36–38
A sustained release fluocinolone
device (Retisert®) which delivers clinically effective drug levels for approximately three years has been successfully used in uveitis,39 but like the
Vitrasert requires surgical placement
thereby engendering higher risks of
vitreous haemorrhage and retinal
detachment than a single pass injection through the pars plana.
Intravitreal anti-VEGF therapy
for DMO and PDR
Pegaptanib was the first intravitreal
anti-VEGF agent to be shown to be
effective for DMO,45 and was quickly
followed and replaced by bevacizumab,46 ranibizumab,47 and aflibercept48 as they became available and
proved to be more clinically effective.
Only ranibizumab and aflibercept
have been licensed for intraocular
injection, but bevacizumab has been
used extensively throughout the world
‘off-label’ and shown to be as clinically
effective as ranibizumab49 and significantly cheaper.50–52
Repeated treatment with these
agents is necessary because of the
shorter duration of action than
intravitreal steroids, but long-term
visual results are better than for laser
treatment alone or combined with
anti-VEGF therapy,53,54 and without
the risks of raised intraocular pressure or cataract associated with
steroids. The number of treatments
reduces over time, the DRCR.net
reporting nine, three, and two injections in the first, second, and third
years respectively in patients allocated to deferred laser treatment.50
There are no published studies to
date of ‘head to head’ randomised
clinical trials of Ozurdex® or Iluvien
with intravitreal anti-VEGF therapy,
although Ozurdex/Lucentis® and
COPYRIGHT © 2014 JOHN WILEY & SONS
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New technologies and drugs in the management of diabetic retinopathy
Ozurdex/Avastin® trials55,56 are in
progress. These trials will be essential
to determine the most appropriate
treatment for DMO, in terms of
visual recovery, complications, overall cost, and acceptability to patients.
Revascularisation of the retina:
intravitreal activated protein C
Retinal neovascularisation which
results from retinal ischaemia can currently be successfully treated by laser
photocoagulation, but this is
a destructive process which may
compromise peripheral vision. The
intriguing possibility of stimulating
retinal revascularisation using intravitreal activated protein C has been
recently reported in two cases of
central retinal vein occlusion but further evaluation is clearly required.57
Drug licensing, treatment
options, and personalised
health budgets
The modern era of intravitreally
injected drug therapy has been
plagued by the dilemma of the availability of drugs licensed to be used in
this way. Ranibizumab is licensed for
intravitreal administration whereas
bevacizumab, a much cheaper but
almost equally effective alternative,48 is
not. In the UK, doctors are obliged by
the GMC to use licensed drugs where
available and not to choose a drug
primarily because of its lower cost. As
a result, the cumulative drug cost
of these new and effective therapies
threatens to burgeon out of
control. Intravitreal therapy is more
effective in treating DMO than laser
with better visual outcomes, so who
should determine which treatment
option is selected? From October
2014, anyone receiving NHS continuing health care in England will have a
right to have a personal health budget,
and potentially the choice of therapy.
to regression of sight-threatening
retinopathy without the necessity for
specific eye treatment.
Engaging patients with OCT
images of their retinal changes and
subsequent progress has, in the
author’s experience, been very helpful in encouraging patients to
address control issues without the
need for hectoring. It is essential that
patients appreciate that their longterm contribution to the control of
their diabetes and contributory risk
factors is as important as any treatment which their ophthalmologist
can provide.
Focal DMO in eyes with good
visual acuity and no foveal thickening
on OCT should be treated with focal
laser photocoagulation which is effective, safe, economical, and with good
long-term results particularly where
improved diabetes control is achieved.
Diffuse macular oedema associated with reduced visual acuity ideally
requires intravitreal therapy, which
may be augmented by macular grid
laser to reduce the need for additional drug injections. Intravitreal
anti-VEGF therapy appears to be
slightly more clinically effective in
improving visual acuity than intravitreal steroids, without the complications of cataract or raised intraocular
Optimising the management of
PDR and macular oedema
Panretinal laser photocoagulation
remains the cornerstone of management of proliferative diabetic retinopathy, and the innovations in laser
delivery described earlier have made
this a little more comfortable for
patients although doubling the cost of
the hardware.
Treatment of DMO requires a
more selective and individualised
patient approach, which has been
greatly assisted by OCT retinal imaging. All patients need to be reminded
of the importance of good diabetes,
blood pressure and lipid control,
implementation of which may lead
Generic name
(proprietary
name)
Mechanism
of action
Ranibizumab
(Lucentis)
Blocks VEGF-A Yes
Yes
Yes
4
£742.17
230µl
3
£247.39
66%
£10 390.38
(£3463.46)
Bevacizumab
(Avastin)
Blocks VEGF-A No
Yes
Yes
4
£242.66
4ml
40
£6.07
50%
£3397.24
(£84.98)
Aflibercept
(Eylea)
Blocks VEGF-A Yes
and VEGF-B
Yes
Yes
6–8
£816.00
250µl
4
£204.00
75%
£11 424.00
(£2856.00)
Triamcinolone
(Kenalog)
Steroid
No
Yes
No
16–18
£1.49
1ml
1
£1.49
90%
£13.41
Dexamethasone Steroid
(Ozurdex)
Yes
Yes
No
16–18
£870.00
solid
1
£870.00
0%
£7830.00
Fluocinolone
(Iluvien)
Yes
Yes
No
150
£5500.00
solid
1
£5500.00
0%
£5500.00
Steroid
Licensed Effective Effective Duration BNF cost/ Potential Potential Dose
Three-year
for IVT? for DMO? for PDR? of effect volume
doses
minimum wasted drug cost*
(weeks)
unit cost
*Based on 14 anti-VEGF injections from DCRC.net or 9 triamcinolone or Ozurdex injections, with potential minimal drug cost shown in parentheses.
IVT = intravitreal therapy; DMO = diabetic macular oedema; PDR = proliferative diabetic retinopathy; BNF = British National Formulary; VEGF = vascular
endothelial growth factors.
Table 1. Intravitreal drugs for treating diabetic retinopathy in the UK
278
PRACTICAL DIABETES VOL. 31 NO. 7
COPYRIGHT © 2014 JOHN WILEY & SONS
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New technologies and drugs in the management of diabetic retinopathy
pressure, but requiring more frequent injections over a period of
years. Anti-VEGF therapy has the
additional benefit of inhibiting
retinal and iris neovascularisation.
The longer duration of effect of
intravitreal steroids is, however, more
attractive to patients.
The higher affinity of aflibercept
to VEGF extends its therapeutic
effect, and the da Vinci trial48
showed that, after the first three onemonthly injections, reducing the
injection frequency to every two
months was as clinically effective as
monthly treatment, requiring seven
injections over the year compared
with 11 monthly injections. In comparison, nine ranibizumab injections
were utilised in the first year of
the DRCR.net study27 which would
appear to make aflibercept the
more cost effective although price
discounting through confidential
NHS patient access schemes makes
direct price comparisons unreliable.
Utilising BNF prices, the drug cost of
aflibercept is nearly £1000 cheaper
over one year when used in this way,
with further significant savings
accruing from fewer clinic attendances and investigations.
The specific choice of intravitreal
agent should be determined primarily by clinical effectiveness, notwithstanding licensing issues. Although
trials in neovascular AMD have
shown that bevacizumab is not inferior to ranibizumab in clinical effectiveness,49 there may be individual
patients who respond to one agent
better than another, so it is important
that clinicians can switch to an alternative agent without delays imposed
by cost considerations alone.
As in AMD treatment, the drug
costs of treating DMO are beginning
to escalate and clinicians are not
immune to the impact of this on overall health budgets. There is considerable wastage in the administration of
ranibizumab and aflibercept, whose
unit costs could be significantly
reduced (Table 1) if aliquotted
under appropriate aseptic conditions
as employed for bevacizumab.
Adoption of bevacizumab as a firstline anti-VEGF agent would have an
even greater impact in reducing
costs, although this has the potential
to lead to legal challenge by the pharmaceutical industry as a consequence
PRACTICAL DIABETES VOL. 31 NO. 7
Right eye
Figure 2a. Macula before treatment,
VA 6/36
Left eye
Figure 2b. Macula before treatment,
VA 6/30
Figure 2d. OCT after third ranibizumab
treatment
Figure 2c. OCT topographic map before
treatment
Figure 2f. OCT after first intravitreal (IVT)
triamcinolone
Figure 2e. Macula OCT before treatment
Figure 2g. OCT after third IVT ranibizumab
Figure 2i. OCT after IVT triamcinolone,
VA 6/30
Figure 2h. Fluocinolone implant in situ
Figure 2j. OCT after IVT fluocinolone,
VA 6/19
COPYRIGHT © 2014 JOHN WILEY & SONS
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New technologies and drugs in the management of diabetic retinopathy
of current drug licensing advice by
the GMC.
Illustrative cases
Case 1. (Figure 2.) A 62-year-old
woman with type 2 diabetes of 13
years duration presented to her
optometrist with reduced visual acuity of 6/30 in both eyes. Significant
diabetic retinopathy was detected
and she was immediately referred for
further management.
Retinal examination and photography showed microvascular changes
with dot haemorrhages and microaneurysms at both maculae but very
little lipid exudate (Figure). Slit lamp
biomicroscopy showed macular
oedema, confirmed by OCT scan
with central macular thickness of
>400mm (Figure). An incidental finding of shallow anterior chambers with
narrow drainage angles but normal
intraocular pressures was also made.
In view of the extensive and diffuse bilateral macular oedema, poor
visual acuity, and concerns about
glaucoma, intravitreal therapy with
ranibizumab was undertaken, with
three injections at monthly intervals
to both eyes resulting in improvement in the clinical features of
retinopathy, a 50% reduction in macular thickness but deterioration in
visual acuity to 6/48 right eye and no
improvement in the left acuity.
Treatment was then switched to
intravitreal triamcinolone in the
right eye, with further reduction
in macular thickness and improvement in acuity of two lines to 6/30.
In view of the better clinical response
to
intravitreal
steroid
than
ranibizumab, intravitreal fluocinolone (Iluvien) injection was subsequently undertaken in the left eye,
with visual acuity improving to 6/19
three months after injection. Right
intravitreal fluocinolone injection is
planned when the triamcinolone
effect has dissipated.
Lesson: a poor or modest response
to one intravitreal agent does not
preclude a good response to an alternative even if the clinical situation
appears hopeless – ‘try, try, try
again!’
Case 2. (Figure 3.) A 64-year-old man
presented with a non-ischaemic left
central retinal vein occlusion and
macular oedema reducing visual
280
PRACTICAL DIABETES VOL. 31 NO. 7
Right eye
Left eye
Figure 3a. Right macula after laser,
VA 6/15
Figure 3b. Left macula after laser,
VA 6/30
Figure 3c. Right macula OCT after laser,
VA 6/15
Figure 3d. Left macula OCT after laser,
VA 6/30
Figure 3e. Right OCT after IVT
fluocinolone, VA 6/19
Figure 3f. Left OCT after IVT
triamcinolone, VA 6/15
acuity to 6/19. The right eye was
normal with visual acuity of 6/9. Risk
factor investigations revealed hypertension and type 2 diabetes, control
of the latter proving less than ideal.
The left macular oedema was treated
successfully with intravitreal antiVEGF (bevacizumab or ranibizumab)
therapy over the next two years,
during which he was observed to
develop non-proliferative diabetic
retinopathy followed by diabetic
macular oedema in the right eye, the
latter also treated successfully with
intravitreal ranibizumab.
Laser photocoagulation was
undertaken after two years to reduce
the frequency of intravitreal injections. Visually significant cataracts
developed in both eyes, which were
treated successfully by phacoemulsification and intraocular lens implants
combined with intravitreal triamcinolone to prevent recurrence of
macular oedema.
The macular oedema in both eyes
resolved completely one month after
the intravitreal triamcinolone injections, so when the oedema recurred
intravitreal fluocinolone implants
were administered to both eyes. No
oedema has recurred yet in the right
eye but has reappeared in the left eye
one month after the fluocinolone
implant injection, which may reflect
the additional vascular damage from
the original vein occlusion.
Lesson: poor diabetes control can
confound the best attempts to arrest
the progression of the ocular
complications of diabetes despite
innovations in therapy.
Declaration of interests
There are no conflicts of interest
declared.
References
References are available online at
www.practicaldiabetes.com.
COPYRIGHT © 2014 JOHN WILEY & SONS
Review
New technologies and drugs in the management of diabetic retinopathy
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