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Update on treatments of diabetic macular edema

YANG, Xiao-lu; LIU, Kun; XU, Xun

doi: 10.3760/cma.j.issn.0366-6999.2009.22.021
Review article
Free
SDC

Objective To review the update research progress about the treatment of diabetic macular edema and to give helpful guidelines in the treatment of diabetic macular edema based on available evidence to date.

Data sources A literature search of all English articles was performed on the online electronic PubMed database dated 1984 to 2009. The keywords searched included: macular edema, therapy, laser coagulation, intravitreal triamcinolone acetonide, vascular endothelial growth factor inhibitor, protein kinase C inhibitor and Pars plana vitrectomy. After finding relevant articles within these search limits, a manual search was conducted through the references from these articles.

Study selection Original articles and critical reviews were reviewed and selected to address the stated purpose.

Results To date, demonstrated means to reduce the risk of vision loss from diabetic macular edema include focal/grid laser photocoagulation and improved metabolic control. Emerging pharmacologic therapies (intravitreal triamcinolone acetonide, vascular endothelial growth factor inhibitors and protein kinase C beta-isoform inhibitors) and Pars plana vitrectomy have shown early promise in the treatment of diabetic macular edema.

Conclusions As there has been extensive development in multiple treatments of diabetic macular edema, choice of the most suitable treatment for specific patients becomes important. Combination therapy of laser, pharmacological and surgical treatment modalities may offer an alternative to treatment of diabetic macular edema.

Department of Ophthalmology, Shanghai Jiao Tong University Affiliated First People's Hospital, Shanghai 200080, China (Yang XL, Liu K and Xu X)

Correspondence to: Dr. LIU Kun, Department of Ophthalmology, Shanghai Jiao Tong University Affiliated First People's Hospital, Shanghai 200080, China (Tel: 86-21-63240090. Email: drliukun@gmail.com)

(Received September 29, 2009)

Edited by GUO Li-shao

Diabetic macular edema (DME) is one of the commonest causes of impaired vision in patients with diabetes.1 In the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR),2 the 10-year cumulative incidence of macular edema was 20.1% among those with type 1 diabetes and 25.4% among people with type 2 diabetes treated with insulin. In China, a large incidence survey was done based on data from 108 132 residents living in the Beixinjing District, Shanghai, China.3 The prevalence of DME in patients with type 2 diabetes was estimated to be 30.46% (46 of the 151 eyes). Approximately 50% of patients with DME would experience a loss of ≥2 lines of best-corrected visual acuity (BCVA) after 2 years of follow-up.4

If diabetic retinopathy is not recognized and treated early, the resulting vision loss from DME can not only have considerable healthcare and social costs, but also a devastating effect on the quality of life.

Over the past 30 years, our knowledge and understanding of the pathogenesis of diabetic retinopathy have evolved.

There has been extensive development in multiple treatments beginning with the use of laser and culminating with the use of intravitreal injections either alone or in combination with traditional treatments. With so much information available, the clinician is now faced with the task of deciphering which treatment is most suitable for a specific patient based on available evidence. In this review, we discuss the evolution of the treatment of diabetic macular edema and give helpful guidelines in the treatment of DME based on available evidence to date.

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DEFINITION OF DIABETIC MACULAR EDEMA

The Early Treatment Diabetic Retinopathy Study (ETDRS) defined macular edema as thickening of the retina and/or hard exudates within 1 disc diameter of the center of the macula. To characterize the severity of macular edema and for treatment guidelines, the term clinically significant macular edema (CSME) was used. CSME was defined as one or more of the following: retinal thickening at or within 500 μm of the center of the macula; hard exudates at or within 500 μm of the center of the macula if associated with adjacent retinal thickening; or a zone or zones of retinal thickening 1 disc area in size, at least part of which is within 1 disc diameter of the center of the macula.5

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CURRENT TREATMENT OF DIABETIC MACULAR EDEMA

The goal of any treatment modality is to reduce the amount of the macular edema, thus leading to improved visual acuity (VA). The treatment should start with medical control of metabolic abnormalities. Patients should achieve excellent glycemic control, normalize blood pressure, and reduce serum lipids. For those who failed to achieve or maintain the optimal level of metabolic control, the ocular treatments should include laser photocoagulation, pharmacological therapies (corticosteroids, vascular endothelial growth factor antagonists, and protein kinase C (PKC) beta-isoform inhibitors) and vitrectomy.

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Laser photocoagulation

The principal treatment of DME remains macular laser photocoagulation.1 The exact mechanism of action of laser photocoagulation-induced resolution of DME is unknown. One explanation involved laser-induced destruction of oxygen-consuming photoreceptors. Oxygen that normally diffused from the choriocapillaries into the outer retina could diffuse through the laser scar to the inner retina, thus relieving inner retinal hypoxia.6 Another theory proposed that laser photocoagulation was thought to induce proliferation of both the endothelial cells in retinal capillaries and pigment epithelial cells, thereby improving the integrity of both inner and outer blood-retina barriers by replacing damaged cells.

The ETDRS trial,5 undertaken in 1985, was the first properly conducted randomized trial to establish the benefits of laser for both DME and proliferative diabetic retinopathy (PDR). In the study, focal photocoagulation of eyes with macular edema reduced the risk of moderate visual acuity loss (defined as a loss of 15 or more letters) by approximately 50% (from 24% to 12%) three years after randomization. Among eyes with center-involved macular edema and baseline acuity worse than a Snellen equivalent of 20/40 that were treated with focal photocoagulation, the 15-letter improvement rate at 1 year was 11% and at 3 years was 16%.

The standard guidelines for laser photocoagulation for DME have been provided by the ETDRS.5 Direct treatment to leaking microaneurysms and grid treatment to diffuse macular edema or nonperfused thickened retina have been suggested for mild and moderate non-proliferative diabetic retinopathy (NPDR), and combination panretinal photocoagulation (PRP) and focal laser photocoagulation has been suggested for DME in selected cases of severe NPDR and in eyes with PDR. Eyes with CSME which need PRP for severe NPDR/PDR should always undergo treatment for the macular edema first followed by PRP after 2-4 weeks. As an initial panretinal coagulation may enhance the DME by increasing the inflammatory reaction or changing the centralized blood flow, thus worsening the macular edema and leading to severe visual loss.4

Complications associated with laser therapy include loss of central acuity (rare), vitreous haemorrhage (rare), decreased contrast sensitivity, scotomata in the central visual field (because of laser scars) and progressive enlargement of these with time (creeping), impaired colour vision and headaches.7

However, despite laser photocoagulation, there continues to be patients with refractory DME who continue to have visual loss. Because of this population, alternative treatments have recently been attempted. As alterations of the blood-retina interface were crucially implicated in edema development, this interface should be the target of therapeutic intervention. In particular, serum leakage from the vessels after breakdown of the blood-retina barrier(s) involved an inflow of a variety of factors into the ocular tissues. A therapeutic depression of vascular leakage could be achieved by application of nonsteroidal and steroidal anti-inflammatory drugs, e.g. of triamcinolone, of vascular endothelial growth factor (VEGF) antagonists, or of PKC inhibitor.

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Intravitreal triamcinolone acetonide (IVTA)

In the past decade, intravitreal corticosteroid injections emerged as an increasingly used treatment option for certain patients with macular edema. Compared with subtenon or peribulbar steroid injection, intravitreal delivery allowed the steroid to bypass the blood-retinal barrier, leading to a more concentrated dose of steroid for a prolonged period of time.8 IVTA was effective in the elimination of macular edema and improvement of visual acuity, especially in diabetic macular edema unresponsive to grid or focal laser therapy.9,10

The landmark study by Martidis et al10 was conducted with an intravitreal injection of 4 mg in 0.1 ml of triamcinolone acetonide into sixteen eyes with CSME that failed to respond to at least two previous sessions of laser photocoagulation. Mean improvement in visual acuity was 2.4, 2.4 and 1.3 Snellen lines at the 1, 3 and 6 months of follow-up respectively. The central macular thickness as measured by optical coherence tomography (OCT) decreased by 55.0%, 57.5% and 38.0%, respectively, over these same intervals from an initial pretreatment mean of (540.3±96.3) μm.

IVTA has also been used with PRP in patients with simultaneous DME and PDR, for its proven effect of decreasing macular edema worsened by the PRP treatment.11,12 Kang et al13 advocated that combined IVTA followed 3 weeks later by macular photocoagulation laser was more effective than isolated IVTA. Aydin et al14 also advocated that macular laser photocoagulation after IVTA improved VA, rather than laser concomitant with IVTA, and only IVTA application for CSME.

Potential complications of intravitreal corticosteroid treatment are divided into steroid-related and injection-related adverse effects. Steroid-related side effects most commonly include cataract formation15 and an elevation in intraocular pressure (IOP).16 Injection-related side effects include retinal detachment, vitreous hemorrhage, and endophthalmitis.17

Intravitreal injection of triamcinolone acetonide is a promising therapy method for DME unresponsive to laser photocoagulation. But in many patients, the recurrence of macular edema approximately six months after the injection as the effect diminishes necessitates repeat injections. Repeated intravitreal injections carry risk and are inconvenient for patients and their families. A nonbiodegradable intravitreal implant, Retisert (Bausch and Lomb, Rochester, USA)18 has been developed for the sustained release of fluocinolone acetonide steroid within the posterior segment and has been Food and Drug Administration (FDA)-approved for chronic macular edema due to uveitis. There is also recent interest on dexamethasone intravitreous drug delivery system (DDS, Allergan Inc., USA) in a biodegradable polymer, which has shown favorable outcomes in the treatment of macular edema due to various etiologies, including DME, in a recent phase 2 study. A phase 3 trial is underway.19

Further studies are warranted to assess the long-term efficacy and safety of intravitreal steroid implants.

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VEGF inhibitors

VEGF also known as vascular permeability factor, has been demonstrated to play the most important role in the pathologic processes of DME.20 Up regulation of VEGF is associated with breakdown of blood-retina barrier and increased vascular permeability,21 stimulation of endothelial cell growth, and neovascularization.22 Therefore the pharmacologic inhibition of VEGF appears to be a promising treatment strategy for diabetic retinopathy, in which breakdown of the blood-retina barrier and neovascularization play an important pathogenetic role.23

Several clinical trials are currently evaluating the role of anti-VEGF agents with the hope of preventing retinal neovascularization, diabetic macular edema and other vasoproliferative retinopathies, without the retinal destruction inherent in current therapeutic regimens.24

Pegaptanib (Macugen; Eyetech Pharmaceuticals; NewYork, USA), is an anti-VEGF aptamer approved for intravitreal injection in the treatment of neovascular age-related macular degeneration (AMD). The Macugen Diabetic Retinopathy Study Group reported gains in VA of 10 letters in 34% and 15 letters in 18% of patients with DME after an intravitreal pegaptanib sodium injection in a randomized, double-masked, multicenter trial with a follow-up of 36 months.25,26

Bevacizumab (Avastin, Genentech, Inc., South San Francisco, USA), a full-length recombinant humanized antibody, is active against all isoforms of VEGF-A. Recent studies have demonstrated the usefulness of an intravitreal injection of bevacizumab in the reduction of macular edema secondary to central retinal vein occlusion, vascular permeability and fibrovascular proliferation in retinal neovascularization secondary to PDR, and choroidal neovascularization secondary to age-related macular degeneration.27-29

Diabetic Retinopathy Clinical Research Network (http://DRCR.net)30 conducted a phase 2 randomized clinical trial of intravitreal bevacizumab for diabetic macular edema demonstrating that intravitreal bevacizumab could reduce DME in some eyes (about half of eyes exceed an 11% reduction in retinal thickness compared with baseline at either the 3-week or 6-week visit). And the doses of 1.25 to 2.5 mg seemed to provide similar stability or improvement in BCVA, OCT, and fluorescein angiography (FA) in diffuse DME at 24 months. However, whether there is a clinically meaningful benefit in treating DME with intravitreal bevacizumab requires the conduct of a large phase 3 randomized clinical trial.

Ranibizumab (Lucentis, Genentech, Inc., South San Francisco, USA), is FDA-approved for the treatment of exudative AMD.31 Chun et al32 and Nguyen et al33 conducted two pilot studies of ranibizumab respectively. Although significant reduction in foveal thickness and improved visual acuity was noted in the treatment of DME with ranibizumab in the pilot study, a randomized controlled trial is needed to evaluate the long-term benefits of ranimizumab in this patient population. DRCR.net is planning two phase 3, prospective, randomized, multicenter trials.

The use of anti-VEGF drugs is becoming increasingly more prevalent; however, some unresolved issues such as the ideal regimen, duration of treatment, potential of combination treatments, and safety concerns with long-term VEGF inhibition deserve further investigations. Large multicenter randomized controlled clinical trials with longer follow-up are needed to evaluate the safety and efficacy of these new anti-VEGF treatments of DME.

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PKC beta-isoform inhibitors

Hyperglycemia is an important factor in the development and progression of diabetic retinopathy and DME.34 Hyperglycemia activates PKC by inducing de novo synthesis of diacylglycerol, a physiologic activator of PKC.35 Substantial preclinical and clinical data suggest that the β-isoform may play an important role in regulating endothelial cell permeability and is an important signaling component for VEGF.36 Conversely, inhibition or genetic knockout of PKC β-isoform activity reduces diabetes-induced retinal permeability and ischemia-induced retinal neovascularization.37 Zhu et al38 proved that the enhanced endothelin-1 (ET-1) expression associated with the activation of PKC has occurred in early diabetes, and PKC inhibitor could reverse the up regulation of ET-1.

Ruboxistaurin (Arxxant, Eli Lilly and Company, Indianapolis, USA), a specific inhibitor of PKC-β1 and PKC-β2, has shown efficacy against DME in two separate phase 3 trials.39,40 The PKC-DRS Study Group studied 426 patients with diabetic macular edema. The primary outcome was the slowing or reversal of the progression of macular edema or the prevention of laser treatment. Patients had no prior photocoagulation (panretinal or focal) but could have macular edema at baseline. Sub analysis of the two studies showed that ruboxistaurin decreased the development of sight-threatening macular edema and the occurrence of visual loss, most efficacious at the 32-mg dose and where hemoglobin A1c was less than 10% at baseline. While a recent study conducted by PKC-DRS Study Group reported that treatment did not delay disease progression over a 30-month follow up.41 A smaller study noted that ruboxistaurin treatment was associated with a reduction in retinal vascular leakage, as measured by vitreous fluorometry, but visual acuity was not affected.42 Aiello et al43 thought that ruboxistaurin did not prevent the progression of diabetic retinopathy nor the combined outcome of DME progression or the application of laser photocoagulation.

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Vitrectomy

The biologic plausibility of vitrectomy for DME has been suggested by clinical observations that posterior vitreous detachment (PVD) is associated with a lower incidence of DME.44 Pars plana vitrectomy (PPV) became a treatment option in DME after Lewis et al45 described a reduction in edema associated with posterior hyaloidal traction in 100% of eyes treated with PPV.

Recent work suggested that factors altering vascular permeability (e.g., AGEs, VEGF) accumulated in the vitreous of hyperglycemic patients resulting in DME. Removal of vitreous gel could decrease the concentration of DME-promoting factors and also improve the fluid currents and thus oxygenation of the inner retina.

Several retrospective studies showed that vitrectomy led to reduction of CMT in most cases and improvement of visual acuity in 43%-69% of study eyes.46-48 However, vitrectomy may decrease DME, even if no vitreomacular traction or a posterior vitreous detachment is present. Gandorfer et al,49 Ikeda et al,50 and La Heij et al51 reported on the resolution of DME after vitrectomy in eyes without any evidence of vitreomacular traction.

It is not clear that internal limiting membrane (ILM) peeling is necessary for PPV to be an effective treatment for DME. ILM peeling may hinder the formation of epiretinal membranes and may aid in removing all the cortical vitreous that otherwise may be left behind even after posterior hyaloid is removed. Several reports showed that vitrectomy with ILM removal had a better anatomical as well as functional results,49,52 and its effectiveness was maintained in the long term.53 However, for eyes with chronic diffuse DME, there were concerns for further photoreceptor damage in an already damaged macula by removing ILM as well as the possible dye toxicity during the ILM removal.54,55 Yamamoto et al56 reported that the ILM does not have to be removed to treat eyes with DME.

Complications of vitrectomy include recurrent vitreous haemorrhage, retinal tears and detachment, cataract formation and glaucoma.

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Combination therapy

Having established a clear benefit with either laser, triamcinolone or anti-angiogenic agents, interest is now focusing on trials that evaluate combination therapy. Combination therapy with other classes of retinal therapeutics could provide clinicians with a set of power tools to treat macular edema, and may lead to a synergistic benefit that is not observed with monotherapy. The first significant trial comparing laser and IVTA was reported by Avitabile et al57 in 2005 in which they randomized patients to receive intravitreal triamcinolone alone or combined with grid laser at 3 months or grid laser alone in the treatment of cystoid macular oedema. At 45 days after treatment, the eyes of the two groups receiving triamcinolone had better visual acuity and lower central macular thickness (CMT) than those receiving photocoagulation at all time points. However, the triamcinolone effect regressed at 6 months. More recently, Lam et al58 reported a comparative randomised controlled trial. Patients were randomised to grid laser photocoagulation (37 eyes), 4 mg of IVTA (38 eyes) or 4 mg of IVTA combined with sequential grid laser about 1 month later (36 eyes). After treatment, significant central foveal thickness reductions were noted in both the IVTA and combined groups at all follow-up visits (P=0.01) but not in the laser group. The standardized reduction in macular thickening at 17 weeks was significantly greater in the combined group versus the IVTA group (P=0.007), suggesting that combined treatment might prolong the effects of IVTA.

A phase 2 trial compared the effects of laser treatment, intravitreal bevacizumab, and combined intravitreal bevacizumab and laser or sham injection.30 Random assignment to one of five groups: (A) focal photocoagulation at baseline (n=19), (B) intravitreal injection of 1.25 mg of bevacizumab at baseline and 6 weeks (n=22), (C) intravitreal injection of 2.5 mg of bevacizumab at baseline and 6 weeks (n=24), (D) intravitreal injection of 1.25 mg of bevacizumab at baseline and sham injection at 6 weeks (n=22) or (E) intravitreal injection of 1.25 mg of bevacizumab at baseline and 6 weeks with photocoagulation at 3 weeks (n=22). Compared with group A, groups B and C had a greater reduction in CMT at 3 weeks and about one line better median VA over 12 weeks. There were no meaningful differences between groups B and C in CMT reduction or VA improvement. Combining focal photocoagulation with bevacizumab resulted in no apparent short-term benefit on adverse outcomes.

To investigate the efficacy of a single intravitreal bevacizumab injection alone or in combination with intravitreal triamcinolone acetonide versus macular laser photocoagulation (MPC) as primary treatment of DME, a randomized, three-arm clinical trial was conducted by Soheilian et al.59 Intravitreal bevacizumab injection in patients with DME yielded a better visual outcome at 24 weeks compared with macular photocoagulation, although it was not associated with a significant decrease in CMT. No adjunctive effect of intravitreal triamcinolone acetonide was demonstrated. Further clinical trials with longer follow-up are required to evaluate the long-term visual outcomes and complication profiles after primary treatment with such medications.

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TREATMENT GUIDELINES FOR DIABETIC MACULAR EDEMA

Focal or grid laser is still a recommended first line treatment. As is recommended by ETDRS, small microaneurysms with focal DME may be treated by conventional focal photocoagulation. Grid laser is recommended for areas of diffuse leakage with no defined focal leakage. Diffuse DME which do not respond to grid photocoagulation may benefit from intravitreal injections using triamcinolone acetonide or novel VEGF inhibitors. In patients with cystoid macular edema, evidence would support first-line treatment with intravitreal triamcinolone followed by grid laser at 3 months.57 At this time, there are no published head-to-head comparisons of IVTA versus the anti-VEGF agents for this disease, although the pending DRCR.net trials may provide useful guidelines in this regard. A proper evaluation of the vitreous and retina is fundamental to select the appropriate treatment approach in DME. Eyes with DME and additional vitreous traction may benefit from pars plana vitrectomy with or without ILM peeling. A combination of laser, pharmacological and surgical treatment modalities may be necessary to maintain central vision in eyes with DME.

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SUMMARY

DME results from a series of biochemical and cellular changes that ultimately cause progressive leakage and exudation. Improved metabolic control and local ocular treatments (photocoagulation) is still the mainstay in treatment based on evidence. Moreover, a number of pharmacological agents that could slow the progression of DME in earlier stages are now being tested. The results from clinical trials with intravitreal steroid, anti-VEGF agents, PKC inhibitors are promising and further clinical trials are actively ongoing that may shed further light on long-term outcomes and comparisons between each of the treatment modalities. But we should be clear that this is a complicated disease which has been far than thoroughly investigated, which needs our further research on its pathogenesis thus leading to the introduction of additional pharmacological agents for the treatment and reduction of visual loss of DME.

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Keywords:

macular edema; therapy; laser coagulation; intravitreal triamcinolone acetonide; vascular endothelial; growth factor inhibitor; protein kinase C inhibitor; Pars plana vitrectomy

© 2009 Chinese Medical Association