To treat DME, keep steroids close

Anti-VEGF therapies have their value, but some patients will be treated more effectively with a synthetic steroid.

By Stephen G. Schwartz, MD, MBA and Ingrid U. Scott, MD, MPH

Diabetic macular edema remains an important cause of vision loss worldwide.¹ Based on the results of the Early Treatment Diabetic Retinopathy Study (ETDRS),² a randomized clinical trial (RCT), focal/grid photocoagulation became the standard treatment for DME for decades. Over the past 10 years, however, pharmacotherapies have become more widely used, especially for center-involved DME.³

The reason: the development of anti-vascular endothelial growth factor (anti-VEGF) agents — including the drugs approved by the FDA, ranibizumab (Lucentis, Genentech), aflibercept (Eylea, Regeneron), and the off-label use of bevacizumab (Avastin, Genentech). These are all effective and frequently used as first-line treatments for DME.⁴

But corticosteroids are also beneficial for certain patients with DME.⁵ Their effects are thought to be multifactorial but include anti-inflammation, capillary vasoconstriction, and inhibition of VEGF expression.⁶ Three synthetic corticosteroids have been used extensively as treatments for DME: triamcinolone acetonide, dexamethasone and fluocinolone acetonide.⁷

All corticosteroids are associated with multiple ocular risks, including cataract progression⁸ and elevation of intraocular pressure.⁹ Intravitreal corticosteroids are also associated with infectious endophthalmitis and pseudo-endophthalmitis.¹⁰ A recent retrospective study of 406,380 intravitreal injections showed that intravitreal corticosteroids (triamcinolone and dexamethasone) were associated with a significantly higher rate of endophthalmitis than were anti-VEGF agents (0.13 percent vs. 0.019 percent).¹¹ Because most patients are treated with a series of injections, the cumulative rate of endophthalmitis per patient is higher than this, which highlights one benefit of extended-release preparations.¹²

Triamcinolone acetonide

Off-label use of intravitreal triamcinolone acetonide was once relatively common but declined as anti-VEGF agents became available. In a nonvitrectomized eye, intravitreal triamcinolone acetonide is typically effective for about three months.¹³ A single-dose preparation of triamcinolone acetonide, while not approved for DME, is FDA-approved for visualization during pars plana vitrectomy¹⁴ and for certain inflammatory conditions.

The Diabetic Retinopathy Clinical Research (DRCR) network conducted an RCT (protocol B) comparing triamcinolone acetonide to photocoagulation and reported that triamcinolone acetonide was associated with generally less favorable outcomes at two years follow-up. However, among patients with poor visual acuity at baseline (about 20/200 – 20/320), when compared to photocoagulation, triamcinolone 4 mg was associated with a greater median change in visual acuity (21 versus 7 letters), a lower rate of >10-letter worsening (0 percent vs. 17 percent), and a higher rate of >10-letter improvement (77 percent vs. 42 percent).¹⁵ Generally similar results, favoring photocoagulation over triamcinolone for most eyes, were also reported at three years follow-up.¹⁶

The DRCR network conducted another RCT (protocol I) comparing ranibizumab plus prompt or deferred photocoagulation versus triamcinolone plus prompt photocoagulation versus sham injection plus prompt photocoagulation and reported that ranibizumab was associated with the most favorable outcomes. At one-year follow-up, when compared to patients randomized to receive sham injection plus photocoagulation, the mean visual improvement was significantly greater in patients receiving ranibizumab plus prompt or deferred photocoagulation, but not in patients receiving triamcinolone acetonide plus photocoagulation. Among pseudophakic eyes, triamcinolone plus photocoagulation was associated with similar visual outcomes compared with ranibizumab plus photocoagulation, suggesting that the apparent advantage of ranibizumab may have been related to cataract formation in phakic eyes treated with triamcinolone.¹⁷ Similar results were reported at 218 and 519 years follow-up.

The DRCR network also conducted a phase 2 RCT of peribulbar triamcinolone acetonide (protocol E) and concluded that peribulbar triamcinolone was not associated with improved outcomes at 34 weeks.²⁰

Despite these generally unfavorable clinical trial results, triamcinolone acetonide remains beneficial for certain patients with DME.²¹

Dexamethasone

A single injection of intravitreal dexamethasone was reported ineffective in the treatment of DME in a small pilot study,²² perhaps due to rapid clearance from the vitreous. A bioerodable, extended-release dexamethasone delivery system (Ozurdex, Allergan) is approved for the treatment of DME²³ as well as for macular edema associated with retinal vein occlusion and posterior segment noninfectious uveitis. The dexamethasone delivery system is injected in a clinical setting with a single-use 22-gauge applicator (Figure). In most patients the delivery system is effective for about 3-6 months.²⁴,²⁵ Recently, the dexamethasone delivery system was reported in a series of five pregnant patients with DME and was associated with favorable outcomes.²⁶

Figures: A 67-year-old woman with type 1 diabetes mellitus and a history of quiescent proliferative diabetic retinopathy (status-post panretinal photocoagulation) presented with recurrent diabetic macular edema OS. In the past, she responded poorly to anti-VEGF agents. At presentation (A), best-corrected visual acuity was 20/50 OS and optical coherence tomography demonstrated macular edema. The patient was treated with a dexamethasone delivery system (Ozurdex). One month later (B), best-corrected visual acuity improved to 20/40 OS and optical coherence tomography demonstrated substantial improvement of macular edema.

The dexamethasone delivery system is associated with multiple risks, some associated with intravitreal corticosteroids and some specific to the insert. In the phase 3 RCT, among patients treated with the 0.7 mg insert (which is the dose of the approved Ozurdex delivery system), 41.5 percent required IOP-lowering medication and 0.3 percent required incisional glaucoma surgery within three years.²⁷ The dexamethasone delivery system may migrate into the anterior chamber in pseudophakic eyes, resulting in corneal edema.²⁸ Use of the inserts has also been reported to be associated with endophthalmitis²⁹ and acute retinal necrosis related to varicella zoster virus.³⁰

The Diabetic Macular Edema Treated with Ozurdex (DMEO) trial was a prospective study that measured changes in pro-permeability factors in the aqueous before and after treatment of DME. The investigators recently reported that treatment with the dexamethasone delivery system was associated with decreases in aqueous angiopoietin-2, hepatocyte growth factor, endocrine gland-VEGF, and others, suggesting multiple methods of action.³¹

Fluocinolone acetonide

Fluocinolone acetonide is available in two different extended-release delivery systems. A relatively large non-bioerodable implant (Retisert, Bausch + Lomb), which is surgically implanted in an operating room under aseptic conditions, is approved by the FDA for the treatment of chronic noninfectious posterior segment uveitis³² but not for DME. The implant is generally effective for about three years, and while effective in the treatment of DME it is associated with high rates of cataract development and IOP elevation.^33-35

A smaller, non-bioerodable insert (Iluvien, Alimera), which is injected in a clinical setting with a single-use 25-gauge applicator, is FDA-approved for the treatment of DME in patients previously treated with corticosteroids without a clinically significant increase in IOP.³⁶ The insert has been reported effective for up to three years.³⁷ In the phase III RCT, among patients treated with the 0.2-µg/day insert (which is the dose of the approved Iluvien insert), 38.4 percent required IOP-lowering medication and 4.8 percent required incisional glaucoma surgery within three years.³⁸ Similar to the dexamethasone delivery system, the insert may migrate into the anterior chamber.³⁹

Summary

While there are a variety of intravitreal corticosteroids available, there is no general consensus regarding their use.⁴⁰ They are typically used as second-line agents in patients with center-involved DME who respond insufficiently to a series of anti-VEGF injections. Because of their association with cataract progression, they are relatively more beneficial in pseudophakic eyes. They may be preferable to anti-VEGF agents in pregnant patients and in patients who wish to reduce the number of required injections.

There is no current preparation of triamcinolone acetonide approved for the treatment of DME, although historically it has been used extensively for this purpose. The dexamethasone delivery system (Ozurdex) is typically effective for three to six months while the fluocinolone acetonide insert (Iluvien) is effective for up to three years; the inserts are associated with generally favorable outcomes although they have also been associated with cataract progression, IOP elevation, endophthalmitis and migration into the anterior chamber. OM

REFERENCES

About the Authors
	Stephen G. Schwartz, MD, MBA, is associate professor of Ophthalmology at University of Miami Miller School of Medicine and Medical Director of Bascom Palmer Eye Institute at Naples.
	Ingrid U. Scott, MD, MPH, is professor, Departments of Ophthalmology and Public Health Sciences, Penn State College of Medicine.
	Partially supported by NIH Center Core Grant P30EY014801 and Research to Prevent Blindness Unrestricted Grant to the University of Miami.