Treatment of DMO
Diabetic macular oedema (DMO) is a complication of a systemic disease (diabetes), and therefore should be approached both locally, by treating the retina, and systemically, by optimizing overall diabetes management. Before considering local intervention, HbA1c, blood pressure, and lipids should be as well controlled as possible, and good communication between ophthalmologists and diabetologists is essential. Some cases of mild DMO may resolve with improved control of glycaemia and blood pressure. It should be also noted that in about one third of patients, DMO may resolve spontaneously within six months of diagnosis.  In the UK, once it is decided that specific retinal treatment is necessary, the modality chosen is now based on thickness of the central retina as determined by optical coherence tomography (OCT). Current guidelines from the UK National Institute for Health and Care Excellence (NICE) recommend laser treatment for patients with a central retinal thickness of <400 microns; and intra-ocular injection of anti-vascular endothelial growth factor (anti-VEGF), currently ranibizumab, for those with central retinal thickness >400 microns. For non-responders, a long-acting intraocular steroid, fluocinolone, can be used provided that the eye involved has an artificial intra-ocular lens. 
Traditionally argon laser photocoagulation was used to treat DMO in an attempt to stabilise vision and prevent further visual loss. The Early Treatment of Diabetic Retinopathy Study (ETDRS) showed that laser treatment reduced the risk of moderate visual loss by 50% during three years of follow-up; however, only a small proportion of patients (<3%) experienced visual improvement of ≥ 15 letters. Interestingly, recent randomised trials have shown that a much higher proportion of patients with DMO can experience a clinically relevant improvement in visual acuity following laser treatment. Thus, in a study conducted by the (US-Canadian) Diabetic Retinopathy Clinical Research network (DRCR.net), laser treatment for ‘centre-involving DMO’ achieved gains of ≥ 10 letters in 32% of patients at 2 years.  The probability of improvement was similar in naïve eyes and those that had previously received ≥ 3 laser treatments. Similarly, in a more recently conducted study by DRCR.net, an improvement in visual acuity of ≥ 10 letters was observed in 28% of patients that had received laser treatment after one year.  Thus, it is clear that laser treatment can actually improve, not just stabilize, vision in some patients. As reflected in the NICE guidelines, people with “thinner” retinas respond better to laser treatment that those with “thicker” retinas. There may be other factors that modulate clinical response; and ability to identify the “responders” in advance would be of great benefit to patients and to health services. Laser treatment to areas of peripheral retinal ischaemia, as determined by wide angle fluorescein angiography, has been evaluated in small studies with good preliminary success. 
Several clinical trials have assessed the effectiveness of anti–VEGF therapies, including bevacizumab, ranibizumab, and aflibercept, for the treatment of DMO.  Anti-VEGFs are administered by intraocular (intra-vitreal) injection. A summary of the evidence available from the largest trials on these therapies is provided below.
Ranibizumab (Lucentis, Novartis Europharm Limited, Camberley, UK.) is a recombinant humanized IgG1 kappa isotype monoclonal antibody fragment (Fab) designed for intraocular use. It binds to and inhibits the biological activity of human vascular endothelial growth factor A (VEGF-A). It has a half-life of approximately 9 days.
In a randomised trial conducted by the DRCR.net, patients with ‘centre-involving DMO’ were randomised to one of four arms: sham injection + prompt laser; ranibizumab (0.5mg) + prompt (3-10 days after injection) laser; triamcinolone (intra-ocular) + prompt laser; or ranibizumab (0.5mg) + deferred (≥ 24 weeks after injection) laser. The study included 691 patients (854 eyes). Intravitreal injections of ranimizumab (or sham) were given monthly through the first 12 weeks of the study; from Week 16 onwards a complex algorithm for retreatment was used.
The primary outcome was the mean change in best corrected visual acuity (BCVA) at 1 year. At 1 year a significant gain in VA was achieved in the ranibizumab + prompt and deferred laser arms vs. the non-ranibizumab groups (p<0.001), with ~50% of patients experiencing ≥ 10 letter gain and ~30% of patients achieving gains of ≥ 15 letter after a median of 8-9 injections. This occurred even though a high proportion of cases (72% of eyes) in the deferred laser group did not receive any laser. In a subgroup analysis, it was shown, however, that for pseudophakic patients (those with an artificial implanted lens) triamcinolone + laser was comparable to ranibizumab + prompt/deferred laser. It was observed that eyes treated with ranibizumab or triamcinolone had less retinopathy progression.
RESTORE randomised 354 patients with ‘centre-involving DMO’ to receive one of the three following treatments: ranibizumab (0.5mg) + sham laser, ranibizumab (0.5mg) + laser, or sham injection + laser. Participants in the ranibizumab arms had a minimum of three monthly injections, after which injections were continued until stable BCVA or BCVA of 6/6 was achieved on two consecutive visits. Treatment was re-initiated if VA decreased due to recurrence of DMO. The primary outcome was mean average change in VA from baseline to months 1-12. After one year, there was a greater gain in VA in the ranibizumab groups [37% and 23% of patients with > 10 and > 15 letter gain, respectively, in the ranibizumab + sham laser arm; and 43% and 23% of patients with ≥ 10 and ≥ 15 letter gain, respectively, in the ranibizumab + laser arm) than in those receiving laser only. The median number of injections was seven.
In the RISE and RIDE trials, patients were randomised to one of three arms: ranibizumab 0.3 mg monthly, ranibizumab 0.5 mg monthly, or sham injection. Monthly treatments with ranibizumab were given for the whole duration of the study (24 months). “Rescue” laser was allowed, but there was not an active laser arm, despite the fact that laser was the standard of care for eligible patients when the studies were initiated. In RISE and RIDE 377 and 382 patients were randomised and the primary outcome of both trials was the percentage of patients with a ≥ 15 letters gain at 24 months.  The trial showed that ~ 45%, 40% and 18% of patients in the 0.3mg ranibizumab, 0.5 mg ranibizumab, and sham arms, respectively, gained ≥ 15 letters. Also, in patients receiving ranibizumab, there was less retinopathy progression. Interestingly, “rescue” laser was required in ~40% of patients in the 0.3mg ranibizumab arm and ~35% in the 0.5 mg ranibizumab arm, suggesting that in these patients, monthly ranibizumab injections were not sufficient to control DMO. Laser treatment was also given to 74% of patients in the sham group; thus, 26% of patients appear not to have received any treatment. The reason for this is not clear, but the possibility of spontaneous resolution of the DMO may be considered (with the potential for a similar phenomenon in the ranibizumab groups).
A meta-analysis of these studies undertaken by Ford et al. concluded that ranibizumab improved results obtained with laser alone, considering both mean change in BCVA and the proportion of patients with ≥15 letter gain,. Surprisingly, there was no benefit of adding laser to ranibizumab by either of these outcome measures. 
Bevacizumab (Avastin, Genetech Inc., San Francisco, CA) is a full-length humanised antibody that binds to all types of VEGF and is used successfully in cancer therapy as a systemic drug. Its potential usefulness in DMO led to the BOLT trial, in which patients were randomised to receive bevacizumab or laser. BOLT was a small trial which included 80 patients; people with macular ischemia were excluded because they were considered unsuitable for laser treatment. Laser was performed according to the modified ETDRS criteria; focal or grid laser treatment for diabetic macular oedema is applied to treat all leaking microaneurysms in areas of retinal thickening or to areas of oedema or non-perfusion (based on fluorescein angiography) located at least at 500 microns from the fovea (only rarely is treatment applied closer) in order to obtain mild ‘grey’ burns. Bevacizumab was given every 6 weeks until week 18, after which it was continued until retinal status was considered stable if the central retinal thickness was > 270 μm. The main outcome measure was BCVA at 1 year.  A greater gain in BCVA was observed in the bevacizumab vs. laser arm, with 31% and 12% of patients having a ≥ 10 letter and ≥ 15 letter gain, respectively, following bevacizumab, compared with 5% and 8% following laser. The median number of injections required was nine. Interestingly, in this trial, success of laser treatment was much lower than that observed in the ranibizumab studies described above.
Aflibercept (Eylea, Regeneron-Bayer HealthCare) is the most recent addition to the anti-VEGF family of drugs. It is a fully human recombinant fusion protein designed to bind all isoforms of VEGF-A as well as placental growth factor (PlGF), thereby inhibiting the activation of VEGF receptors. Its suitability and efficacy in treating DMO was assessed in the Da Vinci trial, and in the combined VISTA and VIVID trials.
The 221 patents in the Da Vinci trial were randomised either to laser only, or to one of four regimens of intra-vitreal aflibercept; 0.5 mg every 4 weeks; 2 mg every 4 weeks; 2 mg every 4 weeks for 3 months then every 8 weeks; 2 mg every 4 weeks for 3 months, then PRN. The mean change in BCVA at 6 months (primary outcome) demonstrated superior visual gain in all aflibercept arms compared to laser. The ≥10 letters gain was highest in the 2 mg every 4 weeks subgroup, at 64 %, whereas the 0.5 mg every 4 weeks group demonstrated 34% of patients gaining ≥15 letters. After one year, data from 79% of patients were available and showed that the 6-month gain of ≥10 letters in the 2 mg every 4 weeks group had risen to 71 %. This group also had the highest percentage of patients with ≥15 letters gain; 45 %. 20 This gain compared to 30 % and 11 % gain of ≥10 letters and ≥15 letters, respectively in the laser arm at this time point.
VISTA and VIVID are two studies that were combined to provide an international head-to-head comparison between aflibercept and laser for the treatment of DMO. In these studies, 872 patients (eyes) with type 1 or type 2 DM and ‘centre-involving DMO’ were randomized - to intravitreal aflibercept injection (IAI) 2 mg every 4 weeks (2q4), IAI 2 mg every 8 weeks after 5 initial monthly doses (2q8), or to macular laser photocoagulation. The primary endpoint was the change from baseline in best-corrected visual acuity (BCVA) at one year. The proportion of eyes gaining ≥15 letters were 41.6% and 31.1% versus 7.8% in VISTA, and 32.4% and 33.3% versus 9.1% in VIVID in the 2q4, 2q8 vs laser arms respectively. Mean reduction in central macular thickness was also significantly greater in the two IAI arms. The study concluded that IAI demonstrated significant superiority in functional and anatomic endpoints over laser, with similar efficacy in the 2q4 and 2q8 groups.
Another therapeutic option for DMO treatment is represented by steroids, administered as intra-vitreal injections or sustained release implants in order to obtain high local concentrations, maximizing their anti-inflammatory, angiostatic, and anti-permeability effects while minimizing systemic toxicity.  Several randomized trials have evaluated the use of Fluocinolone, Dexamethasone and Triamcinolone in patients with DMO, as summarised below.
Fluocinolone acetonide is delivered intra-vitreally as a sustained release 3.5 x 0.37mm implant using a (25g needle) (ILUVIEN, Alimera Sciences, UK). The use of fluocinolone was assessed in two randomised, multicentre, double-masked, parallel, 36-month clinical trials in patients with DMO. There were 956 patients in the ‘Fluocinolone Acetonide for Diabetic Macular Edema’ studies which compared fluocinolone vs sham.  As in RISE and RIDE, despite the fact that the standard treatment at the time was laser, the fluocinolone comparator arm was sham. “Rescue laser” was allowed after week 6 and re-treatments could be performed after month 12. At 2 years, 28% had ≥ 15 letter gain in the fluocinolone group versus 16% in sham group. Repeated treatments after month 12 were required in some, with 21% of patients receiving two implants; 1.9% receiving three implants and 0.3% receiving four fluocinolone implants. Rescue laser was required in ~37% of patients in the fluocinolone group and 59% in the sham. As anticipated, in phakic eyes cataract surgery rates were found to be 75% in the fluocinolone group vs. 23% in the sham group. In the overall clinical trials population (excluding subjects with baseline IOP>21 mmHg), the proportion of fluocinolone treated subjects requiring treatment with IOP-lowering medication was 38% compared to 14% in the sham treated group.
Fluocinolone requires fewer treatments compared with anti-VEGFs but no head-to-head comparison of the two has been conducted. As stated above, NICE has recommended the use of Fluocinolone in a selected group of patients. 
Dexamethasone has the highest relative strength of any corticosteroid used in ophthalmic practice. Dexamethasone (OZURDEX; dexamethasone 700mcg intravitreal implant, Allergan, UK), is a commercially available implant which can be delivered to the vitreous cavity by means of an injectable device .
There were two initial studies assessing the efficacy of dexamethasone implants. The first compared two doses of dexamethasone with no treatment, and the other compared an unspecified dose of dexamethasone vs. dexamethasone-plus-laser or laser alone.  Both studies found dexamethasone gave an improvement in visual acuity, regressing to baseline after three months. Cataract and raised intra-ocular pressure were the main side effects.
In October 2014, members of the MEAD study group published the results of their three year, randomized, sham controlled trial of dexamethasone intravitreal implant (DEX) in patients with DMO.  The mean number of treatments given over 3 years was 4.1, 4.4, and 3.3 with DEX implant 0.7 mg, DEX implant 0.35 mg, and sham, respectively. The percentage of patients with ≥15-letter improvement in BCVA from baseline at study end was greater with DEX implant 0.7 mg (22.2%) and DEX implant 0.35 mg (18.4%) than sham (12.0%; P ≤ 0.018). The study also reported a greater mean average reduction in central retinal thickness (CRT) from baseline in both the 0.7 mg and 0.35 mg dexamethasone implant compared to sham. As with all steroid compounds, the rates of cataract-related adverse events in phakic eyes were higher in the dexamethasone groups (three-fold) when compared to those in the sham arm. The investigators stated that increases in IOP were usually controllable with medication or no therapy within the three years. The UK National Institute for Health Care Excellence (NICE) recently approved the use of the dexamethasone intra-vitreal implant for DMO in eyes with an artificial lens (pseudophakic) and where other treatments were ineffective or not suitable. 
Triamcinolone is a corticosteroid which can be delivered by intra-vitreal bolus injection. There have been several randomised trials on the comparing triamcinolone with laser; and none showed benefit of triamcinolone. However, as stated above (see anti-VEGF section, Ranibizumab, above) subgroup analysis of the DRCR.net demonstrated similar gains in pseudophakic eyes in patients with DMO receiving triamcinolone and those receiving ranibizumab . Furthermore, in this group, triamcinolone appeared to be cost-effective when compared with ranibizumab. The use of currently available Triamcinolone formulations, however, has not been licenced for intraocular use.
POTENTIAL FUTURE THERAPIES
There are several active areas of investigation in the DMO research field. These include novel therapies and potential new biological targets. Examples include a phase 1, open label safety and pharmacodynamic study on the use of RV 001, an Insulin-Like Growth Factor-1 (IGF-1) Receptor antagonist, given by IV infusion in patients with center-involved DMO. Refinement of treatment regimens and the effect of switching from bevacizumab to dexamethasone implant (Ozurdex) and vice versa are being tested in a phase 2 study in eyes with DMO with no or incomplete response to one of these therapies. Characterisation of sub-groups of responders and non-responders to various treatment regimens is an important goal of ongoing trials. One important area of research, described elsewhere in detail, describes the importance of fenofibrate as an oral agent, which has been shown to retard significantly the rate of diabetic retinopathy (DR) progression in adults with Type 2 diabetes (T2D), including macular oedema. 
DMO can potentially lead to blindness in people with diabetes. Treatment options for DMO have expanded considerably over the last few years. Besides laser treatment for people with thin retinas (< 400 microns in central retinal thickness) the anti-VEGFs ranibizumab, bevacizumab and aflibercept have consistently shown good clinical effectiveness in the short term without major unwanted side effects. Treatment with long-acting steroids may be considered in selected patients but their side effects, including cataract formation (which limits them to eyes with artificial lenses) and raised intra-ocular pressure, must be carefully taken into account.
In the near future, NICE is expected to recommend use of a second anti-VEGF agent, aflibercept, for DMO; recommendations will likely follow those for ranibizumab (i.e. people with DMO and central retinal thickness >400 microns). Patients in whom vitreoretinal traction from a partially detached posterior hyaloid body or an epiretinal membrane are present may benefit from vitreoretinal surgery.
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^ Diabetic Retinopathy Clinical Research Network, Elman MJ, Aiello LP, et al. Randomized Trial Evaluating Ranibizumab Plus Prompt or Deferred Laser or Triamcinolone Plus Prompt Laser for Diabetic Macular Edema. Ophthalmology. 2010;117(6):1064-1077.
^ Mitchell P et al, The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology. 2011;118:615-625
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^ Korobelnik JF et al, Intravitreal aflibercept for diabetic macular edema. Ophthalmology. 2014;121:2247-2254.
^ Kuppermann BD et al. Intravitreous dexamethasone effects on different patterns of diabetic macular edema. Archives of Ophthalmology. 2010;128:642-643.
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^ Callanan DG et al., Ozurdex PLACID Study Group. Dexamethasone intravitreal implant in combination with laser photocoagulation for the treatment of diffuse diabetic macular edema, Ophthalmology, 2013;120:1843-1851.
^ Boyer DS et al. Three-Year, Randomized, Sham-Controlled Trial of Dexamethasone Intravitreal Implant in Patients with Diabetic Macular Edema. Ophthalmology, 2014;121(10):1904-1914.
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^ Keech AC et al. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomized controlled trial. Lancet 2007;370(9600):1687-97.
^ ACCORD Study Group; ACCORD Eye Study Group, Chew EY et al. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med 2010;363(3):233-44.
^ National Institute for Health and Care Excellence. Macular oedema (diabetic) - aflibercept [ID717]. London: NICE; anticipated publication date June 2015.