Review

1.

Introduction

2.

DME pathophysiology

3.

Mechanism of action for DME pharmacotherapy

4.

Triamcinolone acetonide

5.

DEX implant

6.

FA implant

7.

Complications of intraocular steroid therapy

8.

Expert opinion

Treatment of diabetic macular edema with sustained-release glucocorticoids: intravitreal triamcinolone acetonide, dexamethasone implant, and fluocinolone acetonide implant Thomas A Ciulla, Alon Harris†, Nathaniel McIntyre & Christian Jonescu-Cuypers †

Indiana University, Eugene and Marilyn Glick Eye Institute, School of Medicine, Department of Ophthalmology, Indianapolis, IN, USA

Introduction: Diabetic macular edema (DME) can be treated with intravitreal glucocorticoids, particularly triamcinolone acetonide, dexamethasone (DEX), and fluocinolone acetonide (FA). Areas covered: The pathophysiology of DME includes multiple growth factors such as VEGF and also inflammatory mediators. Glucocorticoids act on DME through multiple pathways, and current research into their efficacy, safety, and therapeutic potential when administered intravitreally is discussed. Conclusion: The intravitreal route of administration minimizes systemic side effects of glucocorticoids. Furthermore, sustained-release low-dose delivery via the DEX implant or the FA implant will limit frequent intravitreal injection and possibly some cost associated with intravitreal anti-VEGF therapy. In addition, the durable action of these treatments facilitates combination therapy. Patients can receive these implants as foundational therapy, and then receive additional treatment with laser or intravitreal anti-VEGF agents as combination therapy, which may conceivably provide some synergistic benefit. While the FA implant lasts much longer than the DEX implant, potentially decreasing the visit and treatment burden on patients and their families, the FA implant appears to have a greater risk of inducing ocular hypertension and cataract. However, these modalities have not been directly compared in a clinical trial and there is insufficient evidence to draw more elaborate conclusions. Keywords: dexamethasone, diabetes, fluocinolone acetonide, macular edema Expert Opin. Pharmacother. (2014) 15(7):953-959

1.

Introduction

Diabetic retinopathy is the leading cause of irreversible blindness in the working-age population throughout the industrialized world. It poses a significant burden on patients and society as a whole, and is expected to rise significantly worldwide [1]. The Wisconsin Epidemiologic Study of Diabetic Retinopathy revealed that the 10-year rate of developing diabetic macular edema (DME) in the United States was 20.1% among type 1 diabetics, 25.4% among type 2 diabetics using insulin, and 13.9% for type 2 diabetics not using insulin [2]. Further demonstrating the significance of this issue, nearly half of those developing DME will lose two or more lines of visual acuity (VA) within 2 years [3]. The incidence of DME increases 10.1517/14656566.2014.896899 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted

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Article highlights. .

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The pathophysiology of diabetic macular edema (DME) includes not only growth factors such as VEGF, but also inflammatory pathways. Glucocorticoids act on DME through multiple pathways, including an anti-inflammatory effect. Sustained-release low-dose delivery glucocorticoid implants will decrease the burden of therapy compared with intravitreal anti-VEGF injections. The differences, benefits, and risks of the FA and DEX implants are examined and discussed.

This box summarizes key points contained in the article.

with the duration of diabetes, the severity of retinopathy, and with increasing levels of glycosylated hemoglobin. 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. Clinically significant macular edema (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 [4]. The Wisconsin Epidemiologic Study of Diabetic Retinopathy found that over a 10-year period, CSME and non-CSME will develop in 10 and 14%, respectively, of Americans with known diabetes [2]. 2.

DME pathophysiology

DME involves macular thickening, dilated capillaries, loss of pericytes, microaneurysms, and breakdown in the blood-retinal barrier (BRB). The BRB is composed of the retinal vasculature and the retinal pigmented epithelium. Tight junctions between the endothelial cells create a selective barrier to control water and solute flux between adjacent cells and to maintain the BRB. Many interrelated pathways are linked to the cellular damage from hyperglycemia and hypoxia affecting the BRB, including angiogenic growth factors and inflammatory cytokines. Glucocorticoids modulate these pathways to exert a therapeutic effect in DME. VEGF plays a key role in angiogenesis and vascular permeability [5]. There are at least nine different VEGF isoforms due to alternative splicing that include VEGF-A, VEGF-B, VEGF-C, VEGF-D and VEGF-E. The actions of VEGF family members are mediated by the activation of tyrosine kinase receptors. VEGF receptors (VEGFRs) can signal via the MAPK signaling pathway or through elevation in intracellular calcium concentration in endothelial cells forming the vessel walls. Activation of both pathways has been suggested to increase vascular permeability. VEGF-A is a critical regulator of ocular angiogenesis and vascular permeability. VEGF-A 954

acts at VEGFR 1 and 2. VEGF mediates angiogenesis by promoting endothelial cell migration, proliferation, and survival. VEGF also possesses inflammatory properties through its capacity to mediate microvascular permeability and increase adhesion of leukocytes, thus incorporating the inflammatory cascade, initiating early diabetic retinal leukocyte adhesion, and aiding the development of diabetic vasculopathy. Inflammation also plays an important role in diabetic retinopathy and diabetic macular edema. Leukostasis, adhesion molecules, prostaglandin upregulation, and retinal accumulation of macrophages occur in diabetes. Numerous inflammatory mediators have been involved in diabetic retinopathy; including TNF-a, a pro-inflammatory cytokine, and IL-6.

Mechanism of action for DME pharmacotherapy

3.

Recently, intravitreal anti-VEGF agents, bevacizumab, and ranubizumab, have been used to treat DME, while another anti-VEGF agent, aflibercept, will likely be approved soon. These three intravitreal agents bind VEGF, thereby decreasing angiogenesis and vascular permeability, causing regression of diabetic neovascularization and reduction in DME, respectively. Several recent clinical trials suggest that these therapies are more effective than laser therapy [6]. However, anti-VEGF therapy requires repeated intravitreal injection, sometimes monthly or even indefinitely. Furthermore, anti-VEGF therapy is not effective in all patients. Glucocorticoids have been the mainstay for the treatment of macular edema for many years. High-dose systemic and periocular glucocorticoids were used decades ago to suppress choroidal neovascularization due to presumed ocular histoplasmosis syndrome, because of their ability to inhibit angiogenesis independently of their hormonal activities [7]. However, therapy for macular edema and neovascular retinal disease moved away from steroids years ago as their systemic side effects like immunosuppression became known [8]. With the potential for an intravitreal route to avoid some of these systemic side effects, glucocorticoids have recently been revisited [8]. Glucocorticoids have enjoyed a resurgence after the use of periocular and intravitreal triamcinolone acetonide (TA) for posterior segment disorders [9]. In particular, unlike anti-VEGF proteins, glucocorticoids can be utilized in sustained-release forms to potentially limit the need for repeated injections common with anti-VEGF therapies. Current intravitreal glucocorticoids used for sustained-release macular applications include TA, dexamethasone (DEX), and fluocinolone acetonide (FA) [9]. Glucocorticoids inhibit macrophages that release angiogenic growth factors, downregulate ICAM-1 which mediates leukocyte adhesion and transmigration, and have been noted to decrease MHC-II expression in the subretina where AMD-associated neovessels form [10-12]. In addition to this anti-inflammatory mechanism, glucocorticoids alter the

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Treatment of diabetic macular edema with sustained-release glucocorticoids

composition of endothelial basal membrane by changing the local ratio of two laminin isoforms, suppressing basement membrane dissolution, and strengthening tight junctions to limit permeability and leakage that cause macular edema [10,12]. Study of TA has shown that it inhibits the degradation of capillary basal membrane as well as limiting the expression of VEGF and TGF-b, which downregulates the preliminary angiogenic stimulus [7]. Matrix metalloproteinases, which become activated in choroidal endothelial cells, are involved in the breakdown of basement membrane, which is so crucial to choroidal angiogenesis in vivo [7]. Downregulation of these metalloproteinases can be achieved through treatment of the cells with TA, inhibiting endothelial cell migration and tube formation [13]. 4.

Triamcinolone acetonide

TA has been studied in numerous clinical trials for DME as far back as the late 1990s [14-18]. In one early prospective series of 26 eyes (20 patients) that received a single 25 mg intravitreal injection, VA improved significantly (p < 0.001) from 0.12 ± 0.08 at baseline to a maximum of 0.19 ± 0.14 during mean follow-up of 6.64 ± 6.10 months, whereas there was no significant change in a matched, but not randomized, control group of 16 patients who underwent macular grid laser photocoagulation. Predictably, about 35% of treated patients experienced elevated intraocular pressure (IOP) that was controlled with topical anti-glaucoma medication [15]. In a study of 16 eyes with CSME that failed to respond to laser photocoagulation, an intravitreal injection of TA resulted in mean improvement VA of 2.4, 2.4 and 1.3 Snellen lines at 1-, 3- and 6-month follow-up, respectively. Central macular thickness (CMT), as measured by optical coherence tomography (OCT), decreased by 55, 58 and 38% at 1-, 3- and 6-month follow-up [17]. Reinjection was performed in the above study in three of eight patients after 6 months because of macular edema recurrence. Furthermore, a prospective controlled study of 15 patients (30 eyes consisting of one study and one control eye from each patient) with bilateral diffuse DME revealed that the eye receiving a single 4 mg TA injection had a statistically significant reduction in retinal thickness versus the paired control eye, but the VA did not improve significantly [18]. In one 2006 clinical study, Audren and colleagues examined DME refractory to photocoagulation in 17 patients with bilateral DME. One eye of each patient received a single 4 mg TA injection and the other eye served as the control. CMT as measured by OCT was their main outcome, and it was measured before injection and at 4, 12 and 24 weeks. The mean CMT improved in injected eyes from 566 ± 182 µm at baseline to 359 ± 161 µm at 24 weeks [19]. More recently, the Diabetic Retinopathy Clinical Research Network (DRCR) has studied both posterior subtenon and intravitreal TA for DME. The DRCR protocol I represented

a pivotal clinical trial assessing three different treatment schemes: intravitreal 0.5 mg ranibizumab plus prompt or deferred focal/grid laser, or 4 mg intravitreal TA combined with focal/grid laser compared with focal/grid laser alone [20]. At the 2-year visit, compared with the sham plus prompt laser group, the mean change from baseline in the VA letter score was 3.7 letters greater in the ranibizumab plus prompt laser group, 5.8 letters greater in the ranibizumab plus deferred laser group, and 1.5 letters worse in the TA plus prompt laser group. When analysis was confined to the pseudophakic group of patients, TA showed similar VA results to the ranibizumab, indicating that decreased acuity could be at least in part attributed to cataract formation. At the 2-year visit, the percentages of eyes with central subfield thickness ‡ 250 µm were 59% in the sham plus prompt laser group, 43% in the ranibizumab plus prompt laser group, 42% in the ranibizumab plus deferred laser group, and 52% in the TA plus prompt laser group. These results show the potential of TA to serve as a less expensive but comparable therapy to anti-VEGF injections. Anti-VEGF therapy has become first line therapy in DME patients, especially those that are phakic, but intravitreal TA is often utilized in phakic patients who do not have access to ranibizumab. Intravitreal TA has a half-life of 18.6 days and may persist at levels sufficient to exert clinical effect for up to 3 days [21]. Consequently, repeat injections are required. Instead of intermittent bolus therapy, it is thought that sustained release of a lower-dose glucocorticoid may lead to greater efficacy with fewer complications of cataract or glaucoma. This has led to the development of the DEX and FA implants. 5.

DEX implant

In June 2009, the US FDA approved a 0.7 mg DEX implant contained in a solid bioerodable polymer for the treatment of macular edema following retinal vein occlusion. It can exert a clinical effect for 3 -- 6 months. In September 2010, the 0.7 mg implant was approved for treatment of noninfectious intermediate and posterior uveitis. It has been studied for use in DME and is currently undergoing registration trials for a DME indication. In a clinical trial known as the PLACID study, Callanan and colleagues studied 253 eyes with diffuse DME, comparing the DEX implant combined with macular laser treatment versus macular laser treatment alone. They compared eyes treated with a 0.7 mg DEX implant at baseline and laser treatment at 1 month or sham implant at baseline and laser treatment at 1 month. They found no significant difference in the percentage of patients gaining 10 letters or more of best-corrected VA (BCVA) between the treatment groups at 12 months, while the percentage of patients in the combination treatment group was greater at 1 month (p < 0.001) and at 9 months (p = 0.007). Patients with angiographically verified diffuse DME showed greater BCVA improvement

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in the combination therapy group compared with the group receiving laser therapy alone (7.9 vs 2.3 letters, p < 0.0.13). As expected, increased IOP was more common among those receiving the combination therapy. No surgeries for elevated IOP were required [22]. Pacella and colleagues studied 20 eyes in 17 patients who received a 0.7 mg DEX implant monotherapy for DME. Mean ETDRS value improved from 19 letters at baseline to 26 letters at 1 month, 28 letters at 3 months, 26 letters at 4 months, and 21 letters at 6 months. The mean CMT improved from 519 µm at baseline, 413 µm on day 3, 292 µm at 1 month, and 347 µm at 3 months; it then increased to 477 and 494 µm at 4 and 6 months, respectively [23]. One potential role for the DEX implant involves pharmacotherapy of DME in vitrectomized eyes, as it is thought that these eyes have more rapid drug clearance resulting in lowered half-lives of intravitreal drugs administered as intermittent intravitreal bolus therapy. A clinical trial known as the CHAMPLAIN study evaluated 55 patients with treatmentresistant DME and a history of previous pars plana vitrectomy. The study eyes received a single 0.7 mg DEX intravitreal implant and were followed for 26 weeks. These eyes showed statistically and clinically significant improvements in both VA and vascular leakage from DME at 26 weeks. At week 8, 30.4% of patients had gained ‡ 10 letters in BCVA [24]. A large registration trial is currently underway, and the retina community eagerly awaits a potential new therapy for DME.

6.

FA implant

The FA intravitreal implant is administered in the clinic using a 25-gauge inserter, and it leads to sustained drug release for up to 36 months. Unlike the DEX implant, it is not bioerodable. In 2005, an FA intravitreal implant containing 0.59 mg FA was approved in the US for the treatment of noninfectious uveitis. Pearson and colleagues studied 196 eyes with refractory or persistent DME and evaluated the efficacy and safety of an FA intravitreal implant. Eyes were randomized 2:1 to receive a 0.59 mg implant (n = 127) or current stand of care (SOC, n = 69) of laser therapy or observation. The primary outcome evaluated was ‡ 15 letter improvement in VA at 6 months, with secondary outcomes of resolution of macular thickness and Diabetic Retinopathy Severity Score. At 6 months, 16.8% of implanted eyes showed ‡ 3 lines of improvement in VA (p = 0.0012) compared with 1.4% of SOC eyes, at 1 year 16.4% of implanted eyes (p = 0.1191) compared with 8.1% in SOC eyes, at 2 years 31.8% of implanted eyes (p = 0.0016) compared with 9.3% in SOC eyes, and at 3 years 31.1% of implanted eyes (p = 0.1566) compared with 20.0% in SOC eyes. The number of implanted eyes showing no evidence of central retinal thickening was greater than SOC eyes at 6 months (p < 0.0001), at 1 year (p < 0.0001, 956

72 compared to 22%), at 2 years (p = 0.016), and at 3 years (p = 0.0207) [25]. In a clinical trial known as the FAMOUS study, 37 patients with persistent DME despite prior focal/grid laser therapy were randomized 1:1 to receive an experimental intravitreal injection of a 0.2 or a 0.5 µg per day insert [26]. After administration of a 0.2 µg per day insert, the mean change from baseline in BCVA was 5.1, 2.7 and 1.3 letters at months 3, 6, and 12, respectively. The mean change from baseline after administration of a 0.5 µg per day insert was 7.5, 6.9 and 5.7 letters at months 3, 6 and 12, respectively. Aqueous humor sampling revealed sustained intraocular release of FA for > 1 year. Campochiaro and colleagues reported the 3-year results of the FA for DME Studies [27]. They studied 953 eyes of patients with persistent DME after one or more laser therapy treatments, randomized 1:2:2 for sham injection (n = 185), low-dose FA insert (0.2 µg per day, n = 375), or high-dose FA insert (0.5 µg per day, n = 393). At 36 months, 27.8% (high dose) and 28.7% (low dose) of implant-treated eyes versus 18.9% of sham eyes demonstrated an improvement of 15 or more letters (p = 0.018). A subgroup analysis showed particular benefit among patients with DME for ‡ 3 years. Glucocorticoid-related side effects were noted; up to 8.1% required incisional glaucoma surgery, and cataracts progressed in nearly all phakic eyes. This FA implant was approved in Europe (Austria, France, Germany, and Portugal) for the treatment of DME unresponsive to other therapies. However, it was recently denied approval for this use by the US FDA, due to concerns centering on ocular hypertension. However, there are ongoing discussions with the FDA regarding approval with more restricted indications.

Complications of intraocular steroid therapy

7.

Since the mid-1950s, steroid-induced open angle glaucoma has been known to be associated with topical steroid application, and the studies discussed subsequently indicate that similar issues exist for intraocular steroids. Primary open-angle glaucoma, age, diabetes mellitus, genetic susceptibility, connective tissue disease, and gender have all been examined as possible risk factors contributing to this association [28]. The rise in IOP may lead to significant biomorphometric changes and subsequent visual field defects, potentially leading to blindness. Approximately three-fourths of all patients treated with intraocular steroids will need IOP-lowering therapy within 3 years of initiating therapy [28]. IOP rise begins in patients sensitive to steroid effects after ~ 2 weeks of therapy, and reaches its maximum during the fourth week of treatment. Pressure elevation ceases 6 weeks after discontinuation of steroid medication [29]. Spiers and colleagues reported a persistently high IOP level after ceasing steroid therapy [29]. The exact mechanism of steroid-induced secondary IOP rise

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Treatment of diabetic macular edema with sustained-release glucocorticoids

is not known, however, one established contributory factor is increased outflow resistance within the trabecular meshwork [28,30,31]. Pearson and colleagues reported that IOP ‡ 30 mmHg was observed in 61.4% of implanted eyes compared to 5.8% of SOC eyes at any time point and 33.8% of implanted eyes required surgery to address ocular hypertension (OHT) after 4 years [25]. Campochiaro and colleagues report that in their study there was a greater need for surgical glaucoma intervention at the 3-year point in patients receiving the FA injection group; 2.5% of the high-dose group, 1.3% of the low-dose group, and 0% of the sham injection group required laser trabeculoplasty. Incisional glaucoma surgery was needed in 8.1% of the high-dose group, 4.8% of the low-dose group, and 0.5% of the sham injection group [27]. Arcinue and colleagues compared the efficacy of FA implant to DEX implants in patients with noninfectious uveitis. No eyes in the DEX group needed additional glaucoma medications, surgery, or laser compared to 44% of eyes in the FA group. Eyes with the FA implant had a statistically higher rate of needing more glaucoma medications, surgery, or laser (p = 0.02) [32]. In a retrospective study, Bollinger and colleagues report that 19 of 42 eyes (45%) receiving FA implants over the course of the 8-year study period required glaucoma surgical intervention. They concluded that patients receiving FA implants have a significant risk of increased IOP that frequently necessitates glaucoma surgery [33]. Intracameral DEX application does not seem to cause an increased risk for glaucoma in infantile cataract surgery. Mataftsi and colleagues looked at 18 patients with a median age of 3 months at cataract removal and a median follow-up of 38 months. Four of the studied eyes require temporary IOP-lowering medication, but none of the eyes developed glaucoma during the study period [34]. A meta-analysis by Kiddee and colleagues found that 66 and 79% of individuals developed OHT following 0.59 and 2.1 mg FA implants respectively, and 11 and 15% of patients following 0.35 and 0.7 mg DEX implants, respectively. For patients with DME, 15.7 and 14.9% developed OHT following 0.35 and 0.7 mg DEX intravitreal implants. Their analysis showed that prevalence of OHT was higher in FA implant groups than DEX implant groups. Pre-existing or family history of glaucoma seemed to have an increasing risk for OHT development after intravitreal steroid application. However, various definitions for OHT limited accurate comparisons between studies [35]. Ocular steroid therapy is known to cause secondary cataract formation, a complication also associated with administration of systemic steroids. Pearson and colleagues report that implanted phakic eyes required cataract extraction at a higher rate than SOC phakic eyes by the 4-year mark; 91 compared with 20% [25]. Campochiaro and colleagues reported that cataract development rates were higher in those patients receiving FA inserts; they reported that 42.7% of the lowdose group, 51.7% of the high-dose group, and 9.7% of the

sham injection group developed cataracts. These numbers represent 81.7, 88.7 and 50.7%, respectively, of the patients in each group with phakic eyes at the start of the study [27]. The DEX group studied by Arcinue and colleagues showed only 50% of eyes phakic at baseline to exhibit cataract progression and require subsequent surgery compared with 100% of FA-treated eyes. The authors concluded that FA-implanted eyes are 4.7 times more at risk of cataract progression (p = 0.04) than DEX-treated eyes [32]. As for the treatment of secondary steroid-induced glaucoma, Kiddee and colleagues reported that therapy is similar to primary open-angle glaucoma. Trabeculectomy was the most common surgical procedure for OHT after intravitreal steroid application, followed by viscocanalostomy, drainage devices, and cyclophotocoagulation [35]. Only a few studies reported use of argon laser trabeculoplasty. In eyes developing OHT following steroid implantation, elevated IOP was primarily treated with topical medication [35]. 8.

Expert opinion

Agents reviewed in this article are all glucocorticoids, which differ from the most common alternative pharmacologic category, anti-VEGF therapy. While systemic glucocorticoids have numerous systemic side effects, the intravitreal route of administration minimizes these systemic side effects, while taking advantage of multiple pathways by which glucocorticoids inhibit diabetic retinopathy and DME. Furthermore, sustained-release low-dose delivery via the DEX implant or the FA implant will limit frequent intravitreal injection, often required with intravitreal anti-VEGF therapy. Glucocorticoid implants would also likely limit the cost of repeated treatment with expensive anti-VEGF therapies such as ranibizumab or aflibercept. Corticosteroid implants may minimize the risk of endophthalmitis, given the lower number of injections. The sustained-release action of these implants represents the potential for lower risk of traumatic cataract from a smaller number of intravitreal injections, although the risk of glucocorticoid cataract is obviously greater. While the FA implant lasts much longer than the DEX implant, potentially decreasing the visit and treatment burden on patients and their families, the FA implant appears to have a greater risk of OHT and cataract. However, these modalities have not been directly compared in a clinical trial. There is insufficient evidence to draw more elaborate conclusions, especially to determine if multiple injections with the DEX implant lead to the same risks as the longer-lasting FA implant. Nevertheless, the DEX implant may have a risk profile that is easier to titrate given its shorter duration of action. If a clinician ultimately had access to these treatments, in addition to anti-VEGF therapy and laser, current standard of care would suggest anti-VEGF therapy for initial treatment of center-involved DME. For noncentered involved DME, laser treatment seems reasonable, since the risks of laser photocoagulation are minimal in these cases, compared to the

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risks, discomfort, and expense of approved anti-VEGF therapies. There are no large randomized prospective clinical trials comparing sustained-release glucocorticoid therapy to antiVEGF therapy as first-line therapy in center-involved DME; in the future, however, DEX could represent a first line therapy for center-involved DME. DEX or FA implants might be especially attractive as first-line therapies for center-involved DME in eyes that have undergone vitrectomy, since it is thought that anti-VEGF agents have shorter half-life, and presumable less efficacy in these cases. The DEX implant would be favored over the FA implant in those eyes that are pseudophakic and have low risk of glaucoma. For center-involved DME that is persistent despite periodic anti-VEGF therapy, DEX implant would represent a good option. In patients who are pseudophakic without significant risk of glaucoma, FA implant would represent a reasonable option as well. FA implant would also represent a reasonable Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

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Affiliation Thomas A Ciulla1 MD, Alon Harris†4 MS PhD FARVO, Nathaniel McIntyre2 MS & Christian Jonescu-Cuypers3,2 MD PhD † Author for correspondence 1 Midwest Eye Institute, Retina Service Indianapolis, IN, USA 2 Indiana University, School of Medicine, Department of Ophthalmology, Indianapolis, IN, USA 3 Charite´ University Hospital, Department of Ophthalmology, Campus Benjamin Franklin, Berlin, Germany 4 Lois Letzter Professor of Ophthalmology, Indiana University, Eugene and Marilyn Glick Eye Institute, School of Medicine, Department of Ophthalmology, 1160 W. Michigan Street, Indianapolis, IN 46202, USA Tel: +1 317 278 0177; Fax: +1 317 278 1007; E-mail: [email protected]

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Treatment of diabetic macular edema with sustained-release glucocorticoids: intravitreal triamcinolone acetonide, dexamethasone implant, and fluocinolone acetonide implant.

Diabetic macular edema (DME) can be treated with intravitreal glucocorticoids, particularly triamcinolone acetonide, dexamethasone (DEX), and fluocino...
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