Dr Margaret A. Greven

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	Reviewed by Professor Pavel Kuchynka, MUDr, CSc, FCMA

Steroids are an important second-line treatment for the treatment of diabetic macular oedema. While side effects remain a concern, modern formulations of intravitreal steroid allow the treatment to be tailored to the individual patient.

	Diabetic macular oedema (DME) is the leading cause of visual impairment in patients with diabetes. It has been estimated that approximately 93 million people in developed nations are affected with diabetic retinopathy, 21 million of whom have DME. A study showed that the prevalence of DME in the US is 3.8%, with risk factors being elevated haemoglobin A1c levels and longer duration of diabetes.

The increasing number of patients with diabetes worldwide suggests that the impact of DME on vision loss as well as functional impairment will continue to grow over the coming years.

	DME results from breakdown of the blood–retinal barrier and increased vascular permeability mediated by inflammatory cells, cytokines and other inflammatory mediators including vascular endothelial growth factor (VEGF). This increased permeability results in accumulation of intraretinal fluid and macular thickening.

	The most commonly used treatments for DME target the VEGF molecule; however, we have recently become more aware of other mediators of this condition to target, especially in cases refractory to anti-VEGF therapy.

	The efficacy of corticosteroids in DME has been shown in multiple clinical trials. The effectiveness of steroids in the treatment of DME results from multiple mechanisms. Recruitment of leukocytes, production of adhesion molecules, up-regulation of prostaglandins and accumulation of macrophages within the retina occur in diabetes, and steroids are nonspecific anti-inflammatory agents that inhibit these processes.

	Steroids also stabilise the blood–retinal barrier and reduce capillary permeability by inhibiting leukocyte recruitment and enhancing the activity of endothelial cell tight junctions.

 Furthermore, steroids inhibit the action of VEGF and regulate its expression, thereby directly affecting permeability and angiogenesis,

 in addition to regulating a number of other peptides involved in the inflammatory processes leading to DME.

	The side effects of steroids are a concern, especially in the era of anti-VEGF medications that have few ocular side effects. The main side effects of intravitreal corticosteroids for DME are cataract progression and glaucoma. For this reason, steroids are typically considered relatively contraindicated in patients with glaucoma or ocular hypertension.

	The question remains: How do today’s steroid options fit into the treatment of patients with DME?

	Intravitreal triamcinolone acetonide (IVTA) is more effective than placebo at improving vision in patients with refractory DME;

 its efficacy has been studied in multiple clinical trials.

 The Diabetic Retinopathy Clinical Research Network protocol I reported IVTA plus laser to have equivalent efficacy to ranibizumab plus laser in pseudophakic patients at two years.

	More recently, combination therapy with IVTA plus anti-VEGF injections has been shown to have more benefit than anti-VEGF injections alone for some patients with DME.

	IVTA is available in four preparations: Triesence, Trivaris, Kenalog and preservative-free triamcinolone acetonide prepared by compounding pharmacies. All of these formulations are off-label for DME. Kenalog, which contains preservatives, is not FDA-approved for intraocular use, but is commonly used off-label.

	Triesence and Trivaris have been approved by the US FDA for intravitreal injection and are pre-packaged and preservative free, thus avoiding the potential for sterile inflammatory reaction to preservative found with Kenalog, or potential contaminants in the compounded triamcinolone acetonide. Triesence and Trivaris are much more costly than Kenalog and compounded TA.

	IVTA must be repeated every two to four months to sustain effect. To address this need for frequent retreatment, sustained-release preparations of intravitreal corticosteroid have been developed.

	            Ozurdex (Allergan, Irvine, CA) is a sustained-release biodegradable 0.7 mg dexamethasone (DEX) implant with duration of action of four to six months, which is approved by the FDA for the treatment of DME in pseudophakes and patients scheduled for cataract surgery.

	In two three-year parallel phase III randomised clinical trials in which patients were given either DEX 0.7 mg implant, DEX 0.35 mg implant or sham procedure, 22.2%, 18.4% and 12% of patients, respectively, met the primary end point of at least a 15-letter visual acuity gain from baseline.

	Although there were high rates of cataract development in both DEX groups compared with sham, only two patients in the 0.7 mg group and one in the 0.35 mg group required incisional glaucoma surgery.

	A subgroup analysis of patients who had previously been treated for DME found that 21.5% of patients who received DEX 0.7 mg, compared with 11.1% of sham, met the primary endpoint.

	These trials demonstrated the efficacy of Ozurdex for DME treated primarily, as well as refractory to previous treatment or in vitrectomised patients. The advantages to using this strategy for DME are a longer duration of action, up to six months, and clinical efficacy in patients unresponsive to other treatments.

	The disadvantage of Ozurdex use is that, like other intraocular corticosteroid treatments, it leads to cataract in most patients and, in some, to elevated IOP.

	Iluvien (Alimera, Alpharetta, GA) is a new extended-release fluocinolone acetonide non-biodegradable injectable device with duration of action of three years, which is approved by the FDA for treatment of DME in patients who have been previously treated with a course of corticosteroids and did not have a significant pressure response.

	The efficacy of Iluvien in DME was established by the FAME studies, two parallel phase III randomised clinical trials in which patients were randomised 1:2:2 to sham injection, 0.2 mg/day insert and 0.5 mg/day insert. The primary endpoint of the study was the percentage of patients with an improvement of 15 or more letters from baseline.

	At two years, both the low- and the high-dose treatment groups had approximately 28% of patients achieving this endpoint, compared with 16% of patients who had received sham injection.

 At three years, there was a sustained visual acuity improvement, which was more significant for patients who had a duration of DME of at least three years compared with those with shorter duration.

	Almost all phakic patients who received the implant developed cataract; however, visual improvement in these patients after cataract surgery was the same as in those who were pseudophakic at baseline.

	After three years, incisional glaucoma surgery was needed in 4.8% of patients in the low-dose group and 8.1% of patients in the high-dose group. Importantly, in the low-dose group, visual outcomes were equivalent in patients who had and did not have glaucoma surgery.

	Iluvien offers particular promise for patients with long-standing DME refractory to other treatments, as well as difficult-to-treat vitrectomised eyes, given its long duration of action. An additional benefit is far fewer injection procedures, although frequent monitoring for pressure elevation is still required. Its disadvantages include cataract and IOP rise, as for other intraocular steroid formulations.

	Retisert (Bausch + Lomb, Rochester, NY) is a surgically implanted sustained-release fluocinolone acetonide 0.59 mg pellet with duration of action of approximately three years. The implant is placed by suturing through a scleral incision at the pars plana. Retisert is not FDA approved for DME but its use has been studied in this condition.

	In a randomised clinical trial comparing Retisert with grid laser in patients with refractory DME, 31.8% of patients who received Retisert compared with 9.3% who received grid laser met the endpoint of 15 letters’ improvement in vision at two-year follow-up.

	Although the potential efficacy of the device was demonstrated in this study, of the patients who received Retisert, 91% of phakic eyes required cataract surgery and 33.8% of patients required glaucoma surgery at four years. With these high rates of complications, the need for incisional surgery to implant the device, and its significant cost, this option is not widely used for DME.

Note: Retisert is a corticosteroid indicated for the treatment of chronic noninfectious uveitis affecting the posterior segment, however, its use has been studied for DME in the United States. The product is not licenced in the UK (

	            Although intravitreal anti-VEGF injections (with or without laser) have become the first-line treatment for DME because of excellent efficacy and low rate of complications, steroids can be used, often with excellent response, in patients with suboptimal response to anti-VEGF therapy. The longer duration of action of steroid therapies compared with anti-VEGF treatment is certainly a factor to consider, although this is somewhat offset by the need for frequent visits for IOP monitoring.

	            At our institution, we typically employ a stepwise approach for the treatment of DME, beginning with a course of three to six monthly injections of bevacizumab in patients with DME. Suboptimal responders are changed to aflibercept for at least three monthly injections. In those patients who still have suboptimal response, we next use a preservative-free formulation of IVTA to gauge response in terms of efficacy as well as IOP.

	If IOP remains within the normal range, IVTA can be repeated every three to four months, or longer-acting steroid preparations may be used. Interestingly, we have seen several patients have a poor response to IVTA but an excellent response to Ozurdex. We often move more quickly to steroid therapy in vitrectomised patients.

	            A newer therapy that offers significant promise is the fluocinolone acetonide implant. At our institution, we are beginning to use this formulation in select patients and to determine where it fits into our treatment algorithm. Most likely, those patients with excellent response to bevacizumab or aflibercept who are able to be seen every one or two months will remain on anti-VEGF therapy, but those patients who have transportation issues, a strong preference for reduced injections or with minimal pressure response to IVTA or Ozurdex will be the most likely candidates for fluocinolone acetonide.

	When considering the three-year efficacy of fluocinolone acetonide, it is important to remember that patients still need frequent follow-up to check IOP.

	            With regard to side effects, we largely discount cataract formation, given that most DME patients will have early visually significant cataracts regardless of treatment with steroid and that modern cataract surgery is very safe and effective. Glaucoma, however, is an important consideration in any patient for whom corticosteroid treatment for DME is considered.

	In conclusion, steroids are an important second-line treatment in the retinal physician’s armamentarium for DME. Today’s formulations of intravitreal steroid allow the clinician to select shorter-acting or sustained-release preparations tailored to the individual patient’s needs.

	4. J.L. Edelman, D. Lutz D and M.R. Castro. 

Author | Dr Margaret A. Greven

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