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Saudi Journal of Ophthalmology logoLink to Saudi Journal of Ophthalmology
. 2011 Jan 31;25(2):123–129. doi: 10.1016/j.sjopt.2011.01.011

The management of diabetic macular oedema

Adam H Ross 1,⁎, C Clare Bailey 1
PMCID: PMC3729702  PMID: 23960913

Abstract

Diabetic macular oedema (DMO) is a significant cause of visual loss in the working population. Focal/grid photocoagulation remains an effective treatment for DMO and the benchmark to which clinicians compare other newer treatment modalities. There are, however, patients who do not respond adequately or who are refractory to laser photocoagulation. This has led to the development of newer treatments such as the intravitreal injection of vascular endothelial growth factor (VEGF) inhibitors as well as intravitreal corticosteroid releasing delivery systems. Cataract formation and raised intraocular pressure remain the major disadvantages of corticosteroid use. There is mounting evidence that intravitreal VEGF inhibitors with or without combined laser photocoagulation will become the gold standard treatment for DMO.

Keywords: Diabetic macular oedema, Laser photocoagulation, Intravitreal steroids, VEGF inhibitors

1. Introduction

The global prevalence of people with diabetes is projected to rise from 171 million in 2000 to 366 million in 2030. (Wild et al., 2004) Much of this rise is due to changes in lifestyle and the ageing population.

Using published prevalence data of visually threatening diabetic retinopathy, Saaddine et al. projected that the latter would increase from 1.2 million in 2005 to 3.4 million in the United States by 2050 (Saaddine et al., 2008).

Diabetic macular oedema (DMO) as a consequence of diabetes is a significant cause of visual loss in the working population (Bunce et al., 2008). The Wisconsin Epidemiological Study of Diabetic Retinopathy looked at the twenty-five year incidence of macular oedema in persons with type 1 diabetes. They concluded that the 25 year cumulative incidence of macular oedema was 29% and was related mainly to glycemic control and blood pressure. (Klein et al., 2009).

Diagnosis of DMO has been facilitated with the advent of investigations such as optical coherence tomography (OCT). Panozzo et al. proposed a new classification of diabetic macular oedema (DMO) based on OCT findings. This classification takes into account 5 parameters: retinal thickness, extension of retinal thickening, macular volume, retinal morphology and vitreo-retinal relationship. (Panozzo et al., 2004) OCT thickness measurements are increasingly being used in the management and monitoring of DMO.

The rationale for treating diabetic macular oedema is to prevent lipids accumulating at the fovea, minimise permanent structural damage secondary to clinically significant macular oedema and stabilise visual acuity.

Before considering the current and future treatments for DMO, it is useful to consider the inflammatory mediators that could potentially be targeted. Poulaki et al. demonstrated the involvement of IGF-1 in the pathogenesis of diabetic retinopathy and its downstream signalling pathways which involve the stimulation of Vascular Endothelial Growth Factor (VEGF) gene expression (Poulaki et al., 2004).

Aiello et al. previously demonstrated that protein kinase C (PKC) is an important intracellular signalling pathway following activation of VEGF. Studies in rats illustrated that there was reduction in VEGF induced permeability by PKC inhibitors (Aiello et al., 2006). Other groups have confirmed that inhibition of classical PKC isoforms, such as PKC β, reduced VEGF induced permeability by approximately half (Harhaj et al., 2006).

Mammalian target of rapamycin (mTOR) is a further protein kinase that maintains multiple cellular pathways, including those involved in inflammation and angiogenesis. The development of mTOR inhibitors has proven to be effective in the down-regulation of VEGF and thus angiogenesis in DMO.

Due to marked success with VEGF inhibitors in the management of neovascular age related macular degeneration and the known elevated intravitreal VEGF levels in patients with diabetic retinopathy (Adamis et al., 1994), researches and clinicians turned their attention to the use of these agents in the management of leakage and/or neovascularisation in diabetic eye disease. It has been well established that VEGF 165 is linked to retinal intercellular adhesion molecule (ICAM) -1, which in turn induces retinal leukostasis and blood retinal barrier breakdown, thus resulting in retinal angiogenesis and increased vascular permeability (Ishida et al., 2003).

Within this article, we shall discuss current treatments in the management of DMO. In addition, we shall review newer emerging therapies in combating this disabling condition.

2. Laser photocoagulation

The mainstay and benchmark to which newer treatments are compared is laser photocoagulation.

The Early Treatment Diabetic Retinopathy Study (ETDRS) was a landmark trial that established laser photocoagulation as a treatment for clinically significant diabetic macular oedema, defined as one or more of the following: (1) Retinal thickening at or within 500 μm of the fovea. (2) Hard exudates at or within 500 μm of the fovea if associated with adjacent retinal thickening. (3) An area of retinal thickening one disc area in size, at least part of which is within one disc diameter of the fovea. 2244 patients were randomly assigned to receive either early treatment with focal and grid photocoagulation or deferral of photocoagulation Data from this trial demonstrated that focal photocoagulation of clinically significant diabetic macular oedema substantially reduced the risk of future visual loss.

Nevertheless, visual recovery within patients with clinically significant diabetic macular oedema is harder to achieve and the ETDRS demonstrated that despite successful treatment and reduction in central retinal thickness, only 17% of patients recovered 3 or more lines (Anon, 1985).

In 2007, the DRCRnet group carried out a randomised control trial on 323 eyes comparing mild macular grid laser and conventional modified ETDRS direct/grid laser for DMO. Mild macular grid laser involved delivering barely visible 50 μm diameter burns to the whole macula, regardless of localized thickening or microaneurysms. At 12 months, only 22% of eyes receiving mild macular grid treatment showed a reduction over 0.6 disc diameters of retinal thickening, compared to 31% in the conventional treatment group (p = 0.03). The visual acuity outcome between the two groups was not substantially different (Fong et al., 2007).

Micropulse diode laser was developed as a treatment that theoretically avoids damaging the inner neurosensory retina. This potentially may reduce complications, such as paracentral scotomas and scarring post treatment (Akduman and Olk, 1999). Figueira et al. carried out a prospective randomised controlled trial comparing sub-threshold micropulse diode laser photocoagulation and conventional green argon laser in 84 eyes. This group demonstrated that at 12 months there was no statistically significant difference in visual acuity (p = 0.88), macular thickness (p = 0.81) or contrast sensitivity (p = 0.87) between the study groups (Figueira et al., 2009).

Vujosevic et al. carried out a prospective randomised trial on 62 eyes of 50 patients undergoing either subthreshold micropulse diode or modified ETDRS photocoagulation for DMO, evaluating microperimetry and fundus autofluorescence (FAF) pre and post treatment. At 12 months follow-up, this study demonstrated no clinical difference between the two groups with regard to best corrected visual acuity and mean central retinal thickness. However, micropulse diode laser treatment did not determine any change on FAF. The group concluded that microperimetry data encouraged the use of a new, less aggressive laser therapeutic approach in the treatment of clinically significant DMO (Vujosevic et al., 2010).

However, the precise optimum treatment parameters of micropulse diode have not yet been established and its use has not been adopted in a widespread manner.

3. Intravitreal steroids

In 2008, DRCRnet carried out a multi-centre randomised controlled trial involving 840 eyes, comparing modified ETDRS laser photocoagulation with either 1 mg or 4 mg of preservative-free intravitreal triamcinolone. All patients were eligible for re-treatment at 4 monthly intervals if oedema persisted. At 4 months, mean visual acuity was better in the 4 mg group compared to both the 1 mg triamcinolone and laser groups (p < 0.001). Interestingly, at 1 year, there were no significant differences in mean visual acuity between the groups. At 16 months (and extending to 2 years), mean visual acuity was better in the laser group than in the other 2 groups. The OCT results paralleled the visual acuity results, with the 4 mg traimcinolone group demonstrating a greater beneficial effect at the 4 month visit compared to the other two groups. During the second year, there was a greater beneficial effect in the laser group, compared with the other two groups. This study further demonstrated with subanalysis of pseudophakic patients that cataract was not a confounding factor, confirming a beneficial effect in the laser group despite lens status (Anon, 2008). Three-year follow-up of 306 eyes was reported in 2009. Change in visual acuity letter score from baseline to 3 years was +5 in the laser group and 0 in each trimcinolone group. The 3 year cumulative probability of having cataract surgery was 31% in the laser group, 46% in the 1 mg group and 83% in the 4 mg group (p < 0.001 for all pairwise comparisons). It should be noted that a limitation to this study was the completeness to longer-term follow-up with only a cohort of 36% of patients being able to achieve the 3 year follow-up (Beck et al., 2009).

In 2009, Gillies carried out a study in 69 eyes comparing the 5 year outcomes of intravitreal triamcinolone with placebo for diabetic macular oedema. Five year data was only available for 66% of the group. Improvement of ⩾5 letters after 5 years was found in 42% initially treated with intravitreal triamcinolone compared to 32% initially treated with placebo., but this finding was not statistically significant (p = 0.4). There was also no difference in the mean central macular thickness reduction between the two groups (Gillies et al., 2009).

Various studies have looked at the role of intravitreal triamcinolone (IVTA) as an adjunct to focal macular laser (Lam et al., 2007; Gillies et al., 2010). Gillies et al. carried out a prospective, double-masked placebo controlled trial comparing 4 mg IVTA versus placebo 6 weeks prior to laser photocoagulation for DMO. Improvement in ⩾5 letters of BCVA was no different between the two groups (p = 0.807) despite a mean 50 μm reduction in central macular thickness in the IVTA group compared to the control group at 6 months (p = 0.016) (Gillies et al., 2010). The DRCRnet compared focal macular photocoagulation 4 weeks after sub-tenon’s injection of 40 mg triamcinolone to laser alone. There were no statistical differences between any group in terms of visual acuity (p = 0.94) or central retinal thickness (p = 0.46) (Chew et al., 2007).

Recently, the advent of intravitreal biodegradable drug delivery systems has proved of interest in the management of DMO. Haller et al. (2010) compared the use of a 700 μg dexamethasone intravitreal drug delivery system, 350 μg dexamethasone intravitreal drug delivery system and observation (171 eyes, 57 in each group, 180 day follow-up) for the treatment of DMO. At 90 day follow-up, a statistically significant difference in the proportion of eyes achieving at least a 10-letter improvement in BCVA was evident between the 700 μg dexamethasone group and the observation group (33% vs. 12%; p = 0.007). This difference was not statistically significant at day 180. At 60 day follow-up, a statistically significant difference in the proportion of eyes achieving at least a 10-letter improvement in BCVA was evident between the 350 μg dexamethasone DDS group and the observation group (23% vs. 9%; p = 0.04). This difference was not statistically significant at day 90 or day 180. At day 90, there was a statistically significant improvement in both central retinal thickness (p < 0.01) and fluorescein leakage (p < 0.001) in eyes that received the 700 μg dexamethasone DDS compared with eyes in the observation group. The 350 μg dexamethasone DDS group also demonstrated an improvement in fluorescein leakage compared to observation at day 90 (p = 0.03). This group did not show a statistically significant improvement in central retinal thickness at day 90 (Haller et al., 2010).

Fluocinolone acetonide has been recently developed as a non-biodegradable intravitreal insert (IluvienTM) with sustained release of fluocinolone for up to 36 months for treatment of DMO. The ongoing FAME study includes 956 patients randomised to receive either a low dose fluocinolone insert, a high dose fluocinolone insert or a sham injection. At 24 months, preliminary results demonstrate an improvement in the best corrected visual acuity (BCVA) of 15 or more letters of 26.8% and 26.0% in the low and high dose patients respectively (Figueira, 2010).

Other emerging steroid drug delivery systems in development include a triamcinolone acetonide trans-scleral helical implant (I-vation) (ClinicalTrials.gov: NCT00915837). The results of these trials are awaited.

The main drawback of intravitreal steroids are the development of cataract and elevation of intraocular pressure (Gillies et al., 2004; Quiram et al., 2006).

4. Intravitreal VEGF inhibitors

Many trials and studies have demonstrated that inhibition of VEGF using agents, such as pegaptanib, bevacizumab and ranibizumab has shown dramatic improvements in resolution of DMO and improvement in visual acuity.

Pegaptanib (macugen) has previously been investigated using a randomised control trial in 172 eyes. This latter study compared different doses of Pegaptanib (0.3 mg, 1 mg, 3 mg) versus each other and sham injection at study entry, week 6 and week 12. Additional injections and/or laser could be given as required for another 18 weeks after week 12. At week 36, all 3 Pegaptanib subgroups had better visual acuity than the sham group. At week 36, the median visual acuity was better with 0.3 mg group as compared with sham (p = 0.04). In addition, mean central retinal thickness decreased by 68 μm in the 0.3 mg group, versus an increase of 4 μm in the sham group (p = 0.02). There was no statistical difference between the Pegaptanib doses, although the authors attributed this to small numbers within the study (Cunningham et al., 2005). Further studies assessing the effect of pegaptanib are underway.

The READ-2 study compared the effect of intravitreal 0.5 mg ranibizumab versus laser photocoagulation versus combined ranibizumab and laser photocoagulation in 126 eyes. This latter study demonstrated that the mean gain in best corrected visual acuity was significantly better in the ranibizumab group compared to the laser photocoagulation group (p = 0.0001) at 6 months. There was no statistically significant difference between the ranibizumab group and the combination group (Nguyen et al., 2009).

Massin et al. (2010) recently published the RESOLVE study – a randomised controlled double masked, multicenter phase II study evaluating the safety and efficacy of ranibizumab in the treatment of DMO at 12 months. Patients were randomised to three treatment arms: 0.3 mg ranibizumab, 0.5 mg ranibizumab or sham injection and received three monthly injections. Thereafter, all patients could receive laser photocoagulation if required depending on specified treatment criteria.. After month 1, the ranibizumab dose could be doubled by increasing the injection volume from 0.05 ml to 0.1 ml if the central retinal thickness was >300 μm or was >225 μm and the reduction in retinal oedema from the previous assessment was <50 μm. At 12 months, the ranibizumab treatment arms had a mean gain of 10.3 letters compared to the sham group, which had a mean decline of 1.4 letters (p < 0.0001). In addition, the mean central retinal thickness reduced by 194.2 μm compared to 48.4 μm with sham injection (p < 0.0001) (Massin et al., 2010).

A phase III study evaluating the efficacy and safety of ranibizumab in patients with visual impairment due to DMO (RESTORE) is currently underway. This is a randomised, double-masked, multicenter trial with three treatment arms: ranibizumab 0.5 mg in addition to sham laser, ranibizumab in addition to active laser, and sham injection in addition to active laser. Over one year, patients treated with combination ranibizumab and laser were able to read a mean average additional 5.9 letters. Those who received monotherapy ranibizumab alone could read mean average 6.1 letters more than at the start of the study. This compared to a mean average gain of 0.8 letters in patients who received laser therapy alone (p < 0.0001) (Schlinge, 2010).

In 2010, a landmark DRCR.net study compared 0.5 mg intravitreal ranibizumab with prompt focal/grid laser photocoagulation, 0.5 mg ranibizumab with deferred laser photocoagulation (at least 24 weeks later), 4 mg intravitreal triamcinolone with prompt laser or a sham injection with prompt laser. This study demonstrated that at 1 year, 0.5 mg intravitreal ranibizumab combined with either prompt or deferred laser photocoagulation, showed superior improvements in best corrected visual acuity (BCVA) compared with laser treatment alone. The group treated with 4 mg intravitreal triamcinolone with prompt laser did not demonstrate a significant improvement in BCVA compared with laser alone. However, this group did result in a greater reduction in retinal thickness on OCT. compared with the laser group. It should be noted that when a subgroup analysis was carried out on the pseudophakic patients in the triamcinolone group, there was an improvement in BCVA similar to that of the ranibizumab group, suggesting that the initial finding of no significant BCVA improvement in the whole triamcinolone group may have been the result of cataract formation in phakic patients (Elman et al., 2010).

Lam et al. compared the efficacy of 3 monthly injections of 1.25MG versus 2.5MG of intravitreal bevacizumab for diabetic macular oedema in 52 eyes. Significant reduction in mean central foveal thickness was observed in both groups at all follow-up visits (p < 0.013). At 6 month follow-up, the mean logMAR BCVA improved from 0.63 to 0.52 in the 1.25 mg group and 0.60 to 0.47 in the 2.5 mg group and thus no significant difference in BCVA was observed between the 2 groups at any time point (Lam et al., 2009). In 2008, Ahmadieh et al. carried out a randomised controlled trial comparing three injections of 1.25 mg intravitreal bevacizumab versus combined 1.25 mg intravitreal bevacizumab and 2 mg intravitreal triamcinolone, followed by two injections of intravitreal bevacizumab at 6-week intervals versus sham injection. A total of 115 eyes were recruited. At week 24, central macular thickness was reduced significantly in both the intravitreal bevacizumab group (p = 0.012) and the combined intravitreal bevacizumab and intravitreal triamcinolone group (p = 0.022) compared to the sham group. With regard to visual acuity change from baseline to week 24, there was a significant difference between combined intravitreal bevacizumab and intravitreal triamcinolone group and the sham group (p = 0.006) as well as a significant difference between the intravitreal bevacizumab group and the sham group (p = 0.01). There were no significant changes detected between both treatment groups, although the combination group demonstrated an earlier beneficial effect (Ahmadieh et al., 2008).

Scott et al. compared 1.25 mg intravitreal bevacizumab at baseline and 6 weeks, versus 2.5 mg bevacizumab at baseline and at 6 weeks, versus 1.25 mg bevacizumab at baseline and sham injection at 6 weeks, versus laser photocoagulation versus combination 1.25 mg bevacizumab at baseline and 6 weeks and laser photocoagulation at 3 weeks in 121 eyes. This group established the 1.25 mg intravitreal bevacizumab and the 2.5 mg bevacizumab groups both demonstrated a greater reduction in central retinal thickness at 3 weeks (p = 0.009 and < 0.001, respectively) compared with laser photocoagulation. This finding was not maintained through to 12 weeks. The latter groups also demonstrated a median one line improvement at 3 weeks which was sustained through to 12 weeks, as compared with the laser group (p = 0.01 and 0.003, respectively). The combination of bevacizumab and laser demonstrated no short term benefits (Scott et al., 2007).

A further randomised controlled trial involving 150 eyes with a follow-up of 36 weeks compared 1.25 mg intravitreal bevacizumab versus 1.25 mg intravitreal bevacizumab and 2 mg intravitreal triamcinolone versus macular laser photocoagulation. Retreatment was performed at 12-week intervals when required. Compared with baseline, visual acuity improvement was significantly better in the intravitreal bevacizumab group at all follow-up visits up to 36 weeks (p < 0.001). In the combined intravitreal bevacizumab and intravitreal triamcinolone group, visual acuity improved significantly only at weeks 6 and 12 (p = 0.002 and 0.019, respectively). In the macular photocoagulation group, visual acuity did not significantly change compared to baseline (Soheilian et al., 2009). More recently Michaelides et al. carried out a prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (BOLT Study). Patients were randomised to either intravitreal bevacizumab (6 weekly; minimum of three injections and maximum of nine injections in the first 12 months) or laser photocoagulation (four monthly; minimum of one treatment and maximum of four treatments in the first 12 months). The bevacizumab group gained a median of 8 ETDRS letters compared to the laser group which lost a median of 0.5 ETDRS letters (p = 0.0002). This correlated with the reduction in central retinal thickness at 12 months (Michaelides et al., 2010).

5. Other potential treatments

5.1. VEGF165b

VEGF165b is an endogenous molecule expressed in human retina, vitreous and iris (Perrin et al., 2005). It inhibits VEGF165 mediated angiogenesis and is, therefore, anti-angiogenic. Konopatskaya et al demonstrated using a mouse model that a single intraocular injection of VEGF1b can significantly reduce pre-retinal neovascularisation. This group hypothesised that controlling the balance of VEGF165 and VEGF165b, by regulating the splicing between the isoforms may be a valuable method for treating diabetic eye disease in future (Konopatskaya et al., 2006). In addition, animal models have shown that VEGF165b confers no inhibition of physiological angiogenesis, permitting this process to proceed normally (Konopatskaya et al., 2006; Stitt et al., 2005).

VEGF165b is an exciting novel addition to this arena and perhaps the control of endogenous VEGF165b will provide a useful target in future.

5.2. PKC inhibitors

Davis et al. carried out a prospective randomised trial evaluating the effect of the PKC inhibitor (Ruboxistaurin) compared to placebo in treating DMO. 685 patients were recruited with follow-up to 36 months. Moderate visual loss occurred in 5.5% of ruboxistaurin treated patients compared to 9.1% of placebo treated patients (p = 0.034)). In addition, treatment with ruboxistaurin was also associated with less progression of DMO to within 100 μm of the macular centre in eyes with CSMO at baseline and with less frequent laser photocoagulation (Aiello et al., 2006). Further trial results are awaited and the drug is not currently available for use in diabetic retinopathy.

5.3. mTOR inhibitors

The mTOR inhibitor sirolimus (rapamycin) has been developed as a potential treatment for both neovascular age related macular degeneration (nAMD) as well as DMO, due to its ability to inhibit inflammation and angiogenesis. Sirolimus inhibits hypoxia-inducible factor-1 alpha (HIF-1α) involved in activating angiogenesis and hyper-permeability in addition to stimulating VEGF (Dutcher, 2004; Hudson et al., 2002). Trials using Sirolimus for both DMO and nAMD are underway.

5.4. VEGF-TRAP

VEGF-TRAP is a soluble VEGF receptor fusion protein that binds to all isoforms of VEGF-A as well as placental growth factor. It has a higher binding affinity compared to that of ranibizumab and bevacizumab and thus has a longer duration of action (Do et al., 2009; Kaiser, 2009). Interestingly, Stewart et al. demonstrated that 79 days after a single VEGF Trap (1.15 mg) injection, the intravitreal VEGF-binding activity would be comparable to ranibizumab at 30 days (Stewart and Rosenfeld, 2008). This is a key advantage due to the chronicity of DMO as well as the burden associated with regular intravitreal VEGF inhibitor injections.

A double-masked randomized controlled study evaluating the safety and efficacy of intravitreal VEGF Trap-Eye in patients with DMO is in progress (ClinicalTrials.gov: NCT00789477).

6. Conclusions

We are entering a new era with regard to the management of DMO. Until recently, laser photocoagulation has been the mainstay of treatment and the benchmark to which we compare all treatments of DMO. However, there is growing evidence that intravitreal VEGF inhibitors (with or without) in combination with laser photocoagulation will become the gold standard of therapy to add to our armamentarium when combating DMO.

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