Treatment of diabetic macular edema- the current perspective
Dr Dhanashree Ratra, Dr Vineet Ratra
Prevalence of diabetes WHO figures. India leading with maximum number of patients with diabetes in the country
Macular edema is a leading cause of vision loss in about 15% of diabetic patients
| Macular edema - leakage seen in fluorescein angiogram despite prior laser treatment. |
Macular edema (ME) is one of the main
vision-threatening complications associated with diabetic retinopathy. Till recently the gold standard for treatment
of diabetic macular edema (DME) was
laser photocoagulation . But we know that
laser was not always effective for the treatment of ME especially in the
presence of ischemia and the only option available was observation. The past
decade has seen introduction of various new drugs and drug delivery systems
which have revolutionized the treatment of ME. Recently published clinical
trials have shown that intravitreal dexamethasone (Ozurdex®; Allergan, Irvine,
Calif., USA) and ranibizumab (Lucentis®; Novartis Pharma) are effective in the
treatment of DME. In this
article we review the recent developments in this field.
Emerging pharmacotherapies for the treatment of DME-
In India, the
prevalence of diabetic retinopathy varies from 18-20.8% in known diabetics and
0.27 to 17.6% in general population.1,2,3,4 The incidence of ME
varies from 10- 25% in these studies. Reported risk factors for diabetic
retinopathy and DME include duration of diabetes, as well as the severity of
hyperglycemia, hypertension, and hyperlipidemia. Apart from these
microalbiminuria, anemia are also considered responsible.5 Intensive
control of the systemic factors and macular photocoagulation have been shown to
be effective in treating DME. In the recent times new pharmacotherapies have
emerged for the treatment of DME.
Corticosteroids-
Triamcinolone acetonide
In addition to
their anti-inflammatory properties, corticosteroids have been reported to
reduce the activity of VEGF. Currently
various formulations and delivery systems are being evaluated. The Diabetic
Retinopathy Clinical Research Network (DRCR) protocol B compared two doses (1
and 4 mg) of intravitreal triamcinolone acetonide( IVTA) versus
photocoagulation for DME.6 For most patients, photocoagulation
produced more favorable outcomes than did IVTA at 24 months of follow up.
Similar results were reported at 3-year follow-up.7 The most common
complications of IVTA are cataract formation
and increased intraocular pressure (IOP). Pseudoendophthalmitis and
infectious endophthalmitis occur much less commonly. The rate of infectious
endophthalmitis after IVTA is low in reported series. For example, in an
analysis of two large randomized controlled trials (RCT) (from the DRCR network
and the Standard Care Versus Corticosteroid for Retinal Vein Occlusion (SCORE)
trials), the rate of endophthalmitis after IVTA was 0.05%.8 A
triamcinolone-eluting intravitreal implant (I-vation, SurModics, Inc., MN, USA)
for the treatment of DME was suspended in a phase 2b RCT after the publication
of the DRCR network results showing a benefit of laser photocoagulation over
IVTA in treatment of DME
Fluocinolone acetonide
To reduce the
need for repeated intravitreal injections, several extended-release
corticosteroid delivery systems have been studied. A fluocinolone-acetonide-
(FA-) eluting intravitreal implant (Retisert, Bausch and Lomb, NY, USA) a
nonbiodegradable device that releases 0.59 μg/day of FA into the vitreous
cavity has been studied. It must be implanted in an operating room or similar
setting. In an RCT, the effects of the device versus photocoagulation for DME
were studied. At one year, DME was resolved in 57% of patients with the FA
implant versus 20% of patients with photocoagulation. There were no
statistically significant differences in final visual acuity between the two
groups.9 At 3 years, patients randomized to receive the FA implant
had persistent treatment of macular edema, but 95% of phakic eyes developed
significant cataract, and about one-third of eyes had IOP above 30 mm Hg.10
A smaller
fluocinolone acetonide-eluting device (Iluvien, Alimera Sciences, Alpharetta,
GA, USA) may be administered through a 25-gauge device in a clinic setting. The
Fluocinolone Acetonide for Macular Edema (FAME) study comprised 2 phase 3 RCTs
assessing the efficacy and safety of 0.2 μg/day (low dose) and 0.5 μg/day (high
dose) inserts in patients with DME with persistent edema despite at least one
macular laser treatment.11 The primary study endpoint was defined as
improvement in visual acuity by 15 or more letters at 2 years. At 24 months,
the primary endpoint was achieved in 28.7% and 28.6% of low- and high- dose
insert groups compared with 16.2% in the sham group. Elevated intraocular
pressure requiring incisional surgery occurred in 3.7%, 7.6%, and 0.5% of the
low-dose, high-dose, and sham groups, respectively.
Dexamethasone
The
dexamethasone drug delivery system (DDS) [Ozurdex, Allergan, Irvine,
California] is a biodegradable, sustained-release device approved by the US FDA
for the treatment of macular edema associated with retinal vein occlusion and
noninfectious posterior segment uveitis. A phase 2 RCT in patients with
persistent macular edema secondary to various etiologies, including DME, showed
that the dexamethasone DDS produced improvements in visual acuity, macular
thickness, and fluorescein leakage that were sustained for up to 6 months.12
In an RCT, the safety and efficacy
of the dexamethasone DDS in the treatment of DME was studied.13 Patients with persistent macular edema (at least
90-day duration) were randomized to treatment with 700 μg or 350 μg of
dexamethasone DDS or observation. At 3 months, visual acuity improved by 10
letters or more in 30% of eyes in the 700 μg group, 20% of eyes in the 350 μg
group, and 12% of eyes in the observation group. A more recent study reported
that the dexamethasone DDS improved visual acuity and macular edema in
previously vitrectomized eyes with diffuse DME.14
Vascular Endothelial Growth Factor Antagonists-
Four
intravitreal anti-VEGF agents are currently available commercially.
Pegaptanib
Pegaptanib
(Macugen, Eyetech Pharmaceuticals, Palm Beach Gardens, FL, USA) is a pegylated
aptamer that targets the VEGF165 isoform and was the first anti-VEGF medication
reported to have efficacy in the treatment of DME. The Macugen Diabetic
Retinopathy Study Group conducted a phase 2 RCT of pegaptanib for
fovea-involving DME.15 After 36 weeks of followup, the
pegaptanib-treated eyes had better visual acuity, more reduction in central
retinal thickness, and less need for laser photocoagulation compared to the
sham group. More recently, a phase 2/3 RCT reported that pegaptanib therapy was
associated with improved visual outcomes in patients with DME for up to 2 years.16
Bevacizumab
Bevacizumab
(Avastin, Genentech, Inc., South San Francisco, CA, US) is a full-length
recombinant humanized antibody against all isoforms of VEGF-A. The agent is
used commonly as an off-label intravitreal injection. The DRCR network
conducted a randomized study of 121 eyes with DME over a 12-week period.17
There were five treatment arms: focal photocoagulation, 2 consecutive 1.25 mg
bevacizumab injections, 2 consecutive 2.5 mg bevacizumab injections, 1.25 mg
bevacizumab followed by sham injection, and combination of photocoagulation
with 2 consecutive 1.25 mg bevacizumab injections. The groups that received two
bevacizumab injections without laser had a significant improvement in visual
acuity over the laser-only group. There were no detectable differences between
the 1.25 mg and 2.5 mg doses. The single injection group had no advantage over
the laser-only group. The combination of laser and bevacizumab had comparable
results to the laser-only group with a trend toward worse short-term vision
than eyes that received two bevacizumab injections. In the BOLT (Bevacizumab Or Laser Therapy in
the Management of DME) study, repeated intravitreal bevacizumab injections were
compared with modified ETDRS photocoagulation in patients with persistent DME.18
A total of 80 patients with center-involving DME and at least one prior
photocoagulation without evidence of advanced macular ischemia were included.
Patients were randomized to 2 arms: intravitreal bevacizumab (injections at
baseline, 6- and 12-week follow up with subsequent injections every 6 weeks
based on OCT-guided retreatment protocol) or photocoagulation (at baseline with
subsequent retreatment every 4 months if clinically indicated by ETDRS
guidelines). At 12 months, bevacizumab had a greater treatment effect than did
photocoagulation. The bevacizumab arm gained a median of 8 ETDRS letters,
whereas the photocoagulation group lost a median of 0.5 ETDRS letters.
Approximately 31% of patients in the bevacizumab arm versus 7.9% of patients in
the laser arm gained ≥10 ETDRS letters (p=0.01). The decrease in central macular
thickness was significantly more in the bevacizumab group compared to the
photocoagulation group.
Ranibizumab
Ranibizumab
(Lucentis, Genentech, Inc. South San Francisco, CA, USA) is a recombinant
humanized monoclonal antibody fragment that binds all isoforms of VEGF-A with
high affinity. Various clinical trials have been conducted to assess the
efficacy and safety in DME. The Ranibizumab for Edema of the Macula in Diabetes
(READ-2) study randomized 126 eyes with DME to 3 groups: ranibizumab only (injection
at baseline, months 1, 3, and 5); photocoagulation (at baseline and at 3 months
if needed); combined ranibizumab and photocoagulation (photocoagulation and
ranibizumab at baseline, and ranibizumab at 3 months if needed).19
Patients randomized to ranibizumab only showed a significantly better visual
outcome at 6 months compared with the other 2 groups. For patients with data
available at 6 months, improvement of 3 lines or more in vision occurred in 22%
of patients in the ranibizumab-only arm, none in the photocoagulation-only arm,
and 8% in combined arm. At 24 months, the study reported that intravitreal
ranibizumab provided persistent treatment benefits.20 DRCR protocol
I evaluated ranibizumab and IVTA in combination with photocoagulation by
randomizing patients into four arms: ranibizumab with prompt (within one week)
photocoagulation, IVTA with prompt photocoagulation, sham injection with prompt
photocoagulation, and ranibizumab with photocoagulation deferred for at least
24 weeks.21 The treatment protocol included a baseline treatment
followed by intravitreal study medication or sham injection retreatments every
4 weeks through the 12-week visit. After the 16-week visit, retreatment was at
the investigator’s discretion according to web-based predetermined criteria.
Ranibizumab with prompt or deferred photocoagulation resulted in more favorable
visual acuity and central macular thickness outcomes compared with
photocoagulation alone at 1 and 2 years of follow up. In ranibizumab-treated
eyes, the results were similar whether photocoagulation was given with the
first injection or deferred for at least 24 weeks. IVTA combined with
photocoagulation did not result in better visual outcomes compared with
photocoagulation alone. However, in pseudophakic eyes, the IVTA with prompt
photocoagulation group had similar visual outcomes to the 2 ranibizumab groups,
suggesting that cataract formation may have affected the visual acuity outcomes
in phakic eyes treated with IVTA. Two-year visual outcomes were similar to
1-year results and reinforced the conclusion that ranibizumab with prompt or
deferred photocoagulation should be considered for patients with vision
impairment of worse than 20/32 secondary to DME.22 The RESTORE phase
3 study also reported that ranibizumab monotherapy or combined with laser
photocoagulation provided superior visual acuity gain over standard
photocoagulation in the treatment of DME.23 Two additional phase 3
RCTs (RISE and RIDE) were conducted to evaluate the efficacy, durability, and
long-term safety of monthly ranibizumab injections in patients with
center-involving DME. The safety and
efficacy of double dose of ranibizumab was compared in the RESOLVE phase 2 trial. The
incidence and severity of systemic and ocular adverse events that are
associated with repeated intravitreal injections of two doses of ranibizumab
(0.5 mg versus 2.0 mg) in subjects with DME are being investigated in READ-3
study.
Aflibercept
Aflibercept, or
VEGF trap-eye, (Eylea, Regeneron, Tarrytown, NY, USA), is a recombinant fusion
protein with activity against all VEGF-A isoforms and PlGF that is FDA-approved
for the treatment of neovascular AMD and has been shown to have short-term
efficacy in the treatment of DME.24
The DA-VINCI study assessed the efficacy and safety of intravitreal
aflibercept versus laser photocoagulation in the treatment of DME. Patients
were randomized to one of the following treatment arms: 0.5 mg aflibercept
every 4 weeks, 2 mg aflibercept every 4 weeks, 2 mg aflibercept every 8 weeks,
2 mg aflibercept as needed, or photocoagulation. At 24 weeks, the mean change
in BCVA for aflibercept arms ranged from +8.5 to +11.4 letters compared to the
mean change of +2.5 letters in the laser-treated eyes (p<0.01). There was no
statistical significant difference between the aflibercept arms. Anatomic
effects (mean change in central retinal thickness) ranged from −127 μm to
−195 μm in aflibercept arms compared to −68 μm in laser-treated eyes at 24
weeks (p<0.01). At 52 weeks, the mean
change in BCVA for aflibercept arms ranged from +9.7 to +13.1 letters compared
to the mean change of −1.3 letters in the laser-treated eyes (p<0.01).25 In this study population, intravitreal
aflibercept produced significant improvements in visual acuity and retinal
thickness as compared to laser photocoagulation at both 24 and 52 weeks. At
this time, aflibercept is not approved by the US FDA for the treatment of DME.
Many more agents
are being studied and are in various phases of clinical trials. Exciting times
are ahead when we await the results of these trials. However that does not make
laser obsolete. It still has its place in the treatment of DME.
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- Rema M, Premkumar S, Anitha B, Deepa R, Pradeepa R, Mohan V. Prevalence of Diabetic Retinopathy in Urban India: The Chennai Urban Rural Epidemiology Study (CURES) Eye Study, I. Invest Ophthalmol Vis Sci. 2005;46:2328-33
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- Krishnaiah S, Das TP, Nirmalan PK, Shamanna BR, Nutheti R, Rao GN, Thomas R. Risk factors for diabetic retinopathy: Findings from The Andhra Pradesh Eye Disease Study. Clin Ophthalmol 2007:1(4) 475–82
- Raman R, Vaitheeswaran K, Vinita K, Sharma T. Is Prevalence of Retinopathy Related to the Age of Onset of Diabetes? Sankara Nethralaya Diabetic Retinopathy Epidemiology and Molecular Genetic Report No. 5. Ophthalmic Res 2011;45:36–41
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- Beck RW, Edwards AR, Aiello LP, et al. Three-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema. Arch Ophthalmol 2009;127:245–51.
- Bhavsar AR, Ip MS, Glassman AR. The risk of endophthalmitis following intravitreal triamcinolone injection in the DRCRnet and SCORE clinical trials. Am J Ophthalmol 2007; 144:454–6.
- Fluocinolone acetonide ophthalmic- Bausch & Lomb: fluocinolone acetonide envision TD implant. Drugs RD, 2005;6:116–9.
- Montero JA and Ruiz-Moreno JM. Intravitreal inserts of steroids to treat diabetic macular edema. Current Diabetes Reviews. 2009; 5: 26–32.
- Campochiaro PA, Brown DM, Pearson A, et al. Long-term benefit of sustained-delivery fluocinolone acetonide vitreous inserts for diabetic macular edema. Ophthalmology.2011; 118: 626–35.
- Kuppermann BD, Blumenkranz MS, Haller JA, et al. Randomized controlled study of an intravitreous dexamethasone drug delivery system in patients with persistent macular edema Arch Ophthalmol. 2007;125:309–17.
- Haller JA, Kuppermann BD, Blumenkranz MS, et al. Randomized controlled trial of an intravitreous dexamethasone drug delivery system in patients with diabetic macular edema. Arch Ophthalmol. 2010;128:289–96.
- Boyer DS, Faber D, Gupta S, et al. Dexamethasone intravitreal implant for treatment of diabetic macular edema in vitrectomized patients. Retina.2011; 31:915–23.
- Cunningham Jr ET, Adamis AP, Altaweel M, et al. A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema. Ophthalmology. 2005;112:1747–57.
- Sultan MB, Zhou D, Loftus J, Dombi T, Ice KS. A phase 2/3, multicenter, randomized, double-masked, 2-year trial of pegaptanib sodium for the treatment of diabetic macular edema. Ophthalmology 2011;118:1107–18.
- Diabetic Retinopathy Clinical Research Network. A phase II randomized clinical trial of intravitreal bevacizumab for diabetic macular edema. Ophthalmology. 2007; 114:1860–7.
- Michaelides M, Kaines A, Hamilton RD, et al. A prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (BOLT study). 12-month data: report 2. Ophthalmology. 2010;117:1078–86.
- Nguyen QD, Shah SM, Heier JS, et al. Primary end point (six months) results of the ranibizumab for edema of the mAcula in diabetes (READ-2) study. Ophthalmology 2009;116:2175–81.
- Nguyen QD, Shah SM, Khwaja AM, et al. Two-year outcomes of the ranibizumab for edema of the mAcula in diabetes (READ-2) study. Ophthalmology 2010;117:2146-51.
- Elman MJ, Aiello LP, et al. Diabetic Retinopathy Clinical Research Network. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2010;117:1064–77.
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- Mitchell P, Bandello F, Schmidt-Erfurth U, et al. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology. 2011;118:615–25.
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