The pathogenesis of diabetic retinopathy (DR) and diabetic macular edema (DME) is complex. Chronic hyperglycemia affects a variety of metabolic pathways, including advanced glycation end-product generation, increased reactive oxygen species production, and abnormal activation of signaling cascades.1 These metabolic changes then lead to pathologic cytokine shifts, including proangiogenic growth factors and inflammatory cytokines.2 A primary cytokine that is upregulated in both DR and DME is vascular endothelial growth factor (VEGF). Both aqueous and vitreous concentrations of VEGF have been shown to correlate with DR severity.3,4 Vascular endothelial growth factor can induce intercellular adhesion molecule-1 (ICAM-1) expression, leukocyte adhesion, and monocyte migration, all of which trigger inflammation in the retina.5,6 Aqueous studies have shown alterations in numerous other cytokines, including interleukin (IL)-1β, IL-6, and IL-8, as well as interferon gamma-induced protein 10 and monocyte chemoattractant protein-1.7,8 An early effect of cytokine shift includes leukostasis in retinal capillaries, which begins to occur prior to any clinical signs of DR.9,10 The net effect of these pathologic shifts in cytokines as well as leukostasis is endothelial dysfunction, resulting in capillary basement membrane thickening, endothelial cell loss, pericyte loss, blood–retinal barrier insufficiency, and neovascularization.11,12
Current Treatment Strategies
Given that VEGF is a major player in the pathogenesis of DME, inhibition of VEGF has been a natural and effective therapeutic target in the treatment of DME. Currently, 3 VEGF inhibitors are utilized in clinical practice: bevacizumab (Avastin; Genentech), ranibizumab (Lucentis; Genentech), and aflibercept (Eylea; Regeneron). Robust phase 3 DME data support the use of both ranibizumab and aflibercept for the treatment of center-involving DME with significant visual acuity and anatomic benefits demonstrated.13,14 Bevacizumab has also shown efficacy in numerous DME trials and is used in an off-label fashion.15-19 Regression of DR is an additional desirable effect of VEGF suppression, and recent trials demonstrate efficacy both in the presence or absence of DME.20,21
Currently, for most providers, the initial treatment choice for center involving DME is typically 1 of the 3 anti-VEGF agents available.22 Clinical trial data demonstrate that despite positive effects for many patients, there are patients who do not respond or only partially respond from an anatomic or visual acuity standpoint. Two such trials that have explored response to anti-VEGF agents in DME are the Diabetic Retinopathy Clinical Research Network (DRCR.net ) Protocols I and T. In Protocol I, at 24 weeks, approximately 40% of eyes receiving monthly ranibizumab had persistent DME. Furthermore, visual acuity outcomes among these eyes with persistent DME were less favorable than the mean response in the trial.23 Protocol T was a comparative effectiveness study of aflibercept, bevacizumab, and ranibizumab for the treatment of DME. All 3 agents, on average, improved vision, though in patients with vision worse than 20/40, bevacizumab did not fare as well. An exploratory analysis evaluated rates of persistent DME at 24 weeks and found the highest rate in the bevacizumab group (65.6%) followed by ranibizumab (41.5%), with aflibercept having the lowest rate (31.6%). Notably, few eyes lost substantial vision in this analysis regardless of persistent edema in the follow-up period.24
The ideal and structured treatment regimens of clinical trials unfortunately do not represent real-world outcomes for DME treatment. Several real-world retrospective analyses have been performed with the consistent conclusion that real-world treatment frequency is less than clinical trials and has poorer outcomes.25,26 One such retrospective claims analysis indicated that the mean annual number of DME visits with anti-VEGF injection was 3, far fewer than clinical trials.26 As a group, patients with DME have follow-up rates that are poor and are higher than follow-up rates for patients with age-related macular degeneration and retinal vein occlusion.27
Anti-VEGF agents as a class have a relatively favorable side-effect profile and can be an effective treatment strategy for a majority of patients. However, some proportion of DME patients are nonresponders or suboptimal responders, the treatment paradigm of the many retina specialists typically will include intravitreal corticosteroids which can result in added anatomic and visual acuity benefit. Increased durability relative to anti-VEGF agents may also provide additional benefit in select patients given the known adherence issues with this group of patients. The well-described side-effect profile of the steroid class must always be considered for the individual patient.
RATIONALE FOR CORTICOSTEROIDS
The mechanism of steroids is multifactorial. Steroids nonspecifically inhibit a variety of cytokines that are involved in the inflammatory response that ultimately leads to breakdown of the blood–retinal barrier. Steroids inhibit leukocyte recruitment and improve endothelial cell tight junctions.28,29 The role of cytokines other than VEGF may become more important as retinopathy progresses. Aqueous humor studies have shown exponential increases in several cytokines with worsening DR, although VEGF concentrations remain relatively stable with increasing DR.8 Furthermore, the differential cytokine response to steroids vs anti-VEGF agents has been evaluated and reveals significant inhibition of cytokines implicated in the pathogenesis of DR. Proinflammatory mediators of DME including IL-6, IL-8, MCP-1, ICAM-1, and TNF-α are downregulated.30 Interestingly, steroids also significantly inhibit VEGF, albeit to a substantially lower degree than anti-VEGF agents.31 Corticosteroids also inhibit the arachidonic acid pathway, which results in decreased production of leukotrienes, thromboxanes, and prostaglandins.6 Ultimately, the beneficial effects of corticosteroids result in blood–retinal barrier permeability improvements, which can lead to the clinical effects of reduced DME and possibly DR.
CURRENT STEROIDS OPTIONS IN CLINICAL PRACTICE
Intravitreal triamcinolone acetonide (IVTA) is available commercially in 4 preparations: triamcinolone acetonide injectable suspension 40 mg/mL or 10 mg/mL (Kenalog; Bristol Myers Squibb), preservative-free triamcinolone acetonide injectable suspension 40 mg/mL (Triescence; Alcon), and preservative-free triamcinolone acetonide 80 mg/mL (Trivaris; Allergan). All preparations are utilized in an off-label fashion for DME, with several clinical trials supporting the efficacy and use of triamcinolone acetonide.32-36 In the DRCR protocol I, when limiting the patient analysis to pseudophakic patients, patients treated with triamcinolone with focal/grid laser did as well as the ranibizumab treated patients, with a mean gain of 9 letters seen in the former group.35
Dexamethasone 0.7-mg implant
Dexamethasone intravitreal implant 0.7 mg (Ozurdex; Allergan) is approved for the treatment of DME as well as retinal vein occlusion and posterior uveitis. The implant is a biodegradable poly (D, L-lactide-co-glycolide) polymer matrix that is injected intravitreally via a 22-gauge needle. Dexamethasone is released up to 6 months.
The efficacy of the dexamethasone implant and subsequent approval of the implant for DME was demonstrated by 2 parallel phase 3 trials, MEAD 1 and 2. In total, 1,048 patients were randomized in a 1:1:1 fashion to receive either dexamethasone 0.7-mg implant, dexamethasone 0.35 mg implant, or sham. The primary endpoint was the proportion of patients achieving 3-line visual acuity improvement or greater. A greater proportion of patients in the dexamethasone 0.7-mg group (22.2%) achieved the primary endpoint than the sham group (12%; P≤.018). The mean improvement in central retinal thickness (CRT) was also greater in the dexamethasone 0.7-mg group (−111.6 μm) than the sham (−41.9 μm; P<.001). Rates of cataract development were high but consistent with other medications in the steroid class. Sixty-eight percent of patients in the dexamethasone group and 21% in the sham group developed cataract. Intraocular pressure (IOP) events were also consistent with other medications in the steroid class. Forty-two percent of patients in the dexamethasone 0.7-mg group and 10% of sham patients required an IOP-lowering medication. Intraocular pressure-lowering incisional surgery was required in 2 patients in the dexamethasone 0.7 mg group.37
A recent prospective, observational registry study, REINFORCE, provides valuable information regarding the use of the dexamethasone 0.7-mg implant in the real world. In this study, 177 patients received dexamethasone at baseline and were followed for 1 year. The dexamethasone 0.7-mg implant was used as monotherapy in 55% of eyes and the mean reinjection interval was 5 months. Safety data were consistent with clinical trial data. No patients required incisional IOP-lowering surgery, and 22.8% of patients required IOP lowering medications. Visual acuity results were favorable, with patients improving from 7 to 9.1 letters from baseline after receiving up to 3 dexamethasone implants, respectively.
The DRCR evaluated the role of the dexamethasone 0.7-mg implant in patients with persistent edema despite anti-VEGF treatment in its Protocol U study. Although 236 patients were enrolled in this study, after receiving the required 3 consecutive monthly ranibizumab doses, several patients had too great an anatomic or visual acuity improvement to meet randomization criteria. Ultimately, a total of 129 patients were randomized to receive either a combination of the dexamethasone 0.7-mg implant and ranibizumab or to continue with ranibizumab monotherapy. An average of 5.6 ranibizumab injections were received by patients over the next 24 weeks. The combination group received almost 2 dexamethasone 0.7-mg implants on average over this period. No overall difference in visual acuity between the monotherapy ranibizumab group and the combination ranibizumab/dexamethasone 0.7-mg implant group was found at 24 weeks. The combination group did have favorable anatomic results compared to the ranibizumab monotherapy group (110 µm in the combination group and 62 µm in the monotherapy group, P<.001), although this did not translate into visual acuity differences in the 24-week follow-up period. It is unknown if longer follow-up would have resulted in visual acuity differences that favored the anatomically drier combination group. Safety data from this study were consistent with prior steroid trials, with 29% of subjects in the combination group requiring treatment for increased IOP.38
FLUOCINOLONE ACETONIDE 0.19-MG IMPLANT
The fluocinolone acetonide (FA) 0.19-mg implant (Iluvien; Alimera) is a nonbioerodible polyimide tube that is designed to release fluocinolone at a steady state concentration of 0.5 to 1.0 ng/mL for a period of 3 years.39 The implant is injected via 25-gauge needle into the intravitreal space.
Two parallel phase 3 studies support the efficacy of the FA 0.19-mg implant for the treatment of DME. The FAME A and B trials enrolled 956 patients with a history of at least 1 prior laser treatment and center-involving DME to be randomized to sham control or 0.2 µg/day insert, or 0.5 µg/day insert in a 1:2:2 fashion. The primary endpoint was the percentage of patients with ≥15-letter improvement in BCVA at 24 months. Both treatment groups had approximately 28% of patients achieve the primary endpoint compared to 16% of patients in the sham. More than one FA injection was required in only 25% of patients. At 36 months, there were sustained vision improvements, which were most significant for patients with chronic DME, defined as duration of at least 3 years.40
Almost all of the phakic patients in FAME developed cataracts. Following cataract surgery, visual acuity improvements in these patients were similar to patients who were pseudophakic at baseline. The incisional glaucoma surgery rate was 4.8% in the low-dose group and 8.1% in the high-dose group.40 For patients with a history of prior corticosteroid challenge without a clinically significant rise in IOP (N=72), the incisional glaucoma surgery rate in was 0%.41 These data ultimately played a role in forming the US label for this drug and has helped mitigate IOP issues with this product.
The FAME trial was initiated when anti-VEGF therapy was not yet approved for the treatment of DME. Subsequent trials have provided valuable information regarding the use of the FA 0.19-mg implant in the current treatment era. The USER trial was a retrospective trial of 160 eyes of 130 patients treated at 4 centers in the United States. Patient data were collected up to 3 years before and up to 2 years after FA 0.19-mg implant administration. On average, prior to FA 0.19-mg implantation, patients received 1 treatment every 2.9 months. Treatments consisted primarily of anti-VEGF (77%), steroid injection (56%), and focal laser (50%). Following administration of the FA 0.19-mg implant, patients received 1 treatment every 14.3 months while maintaining similar visual acuity. The durability benefit was most evident in patients with better vision, meaning visual acuity ≥20/40 (1 treatment every 22 months) following FA 0.19-mg implant.
Fluctuations in retinal thickness during the periods before and after the FA 0.19-mg implant were also measured (maximum to minimum central retinal thickness) and those fluctionations were given the relatively new term “mean retinal thickness amplitude” (RTA). The mean RTA prior to fluocinolone 0.19-mg implant was 231 µm, and mean RTA after the implant was 96 µm (P<.001).42,43 The clinical significance of reduction in RTA needs to be explored further, although the impact to patient vision and quality of life make minimizing RTA a reasonable goal. The steady-state delivery of FA also has desirable qualities for patients with potential adherence issues.
Diabetic macular edema continues to afflict a growing number of patients both domestically and globally. Fortunately, there are several treatment options available to patients. Anti-VEGF agents provide great visual acuity and anatomic results for many patients and have a relatively favorable side-effect profile. In patients with suboptimal or no response, consideration can be given to the steroid class. In patients with adherence issues or those who simply desire less frequent treatment intervals, the durability benefit of some of the available steroid agents may be of benefit. Finally, combination therapy with both anti-VEGF and steroid medication is a reasonable option to consider in patients with refractory DME. RP
- Safi SZ, Qvist R, Kumar S, Batumalaie K, Ismail IS. Molecular mechanisms of diabetic retinopathy, general preventive strategies, and novel therapeutic targets. Biomed Res Int. 2014;2014:801269.
- Das A, McGuire PG. Retinal and choroidal angiogenesis: pathophysiology and strategies for inhibition. Prog Retin Eye Res. 2003;22(6):721-748.
- Adamis AP, Miller JW, Bernal MT, et al. Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am J Ophthalmol. 1994;118(4):445-450.
- Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994;331(22):1480-1487.
- Miyamoto K, Khosrof S, Bursell SE, et al. Vascular endothelial growth factor (VEGF)-induced retinal vascular permeability is mediated by intercellular adhesion molecule-1 (ICAM-1). Am J Pathol. 2000;156(5):1733-1739.
- Zur D, Iglicki M, Loewenstein A. The Role of Steroids in the Management of Diabetic Macular Edema. Ophthalmic Res. 2019:1-6.
- Dong N, Xu B, Chu L, Tang X. Study of 27 Aqueous Humor Cytokines in Type 2 Diabetic Patients with or without Macular Edema. PLoS One. 2015;10(4):e0125329.
- Dong N, Xu B, Wang B, Chu L. Study of 27 aqueous humor cytokines in patients with type 2 diabetes with or without retinopathy. Mol Vis. 2013;19:1734-1746.
- Leal EC, Manivannan A, Hosoya K, et al. Inducible nitric oxide synthase isoform is a key mediator of leukostasis and blood-retinal barrier breakdown in diabetic retinopathy. Invest Ophthalmol Vis Sci. 2007;48(11):5257-5265.
- Miyamoto K, Khosrof S, Bursell SE, et al. Prevention of leukostasis and vascular leakage in streptozotocin-induced diabetic retinopathy via intercellular adhesion molecule-1 inhibition. Proc Natl Acad Sci USA. 1999;96(19):10836-10841.
- Abu-El-Asrar AM, Dralands L, Missotten L, Al-Jadaan IA, Geboes K. Expression of apoptosis markers in the retinas of human subjects with diabetes. Invest Ophthalmol Vis Sci. 2004;45(8):2760-2766.
- Barber AJ, Lieth E, Khin SA, Antonetti DA, Buchanan AG, Gardner TW. Neural apoptosis in the retina during experimental and human diabetes. Early onset and effect of insulin. J Clin Invest. 1998;102(4):783-791.
- Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012;119(4):789-801.
- Korobelnik JF, Do DV, Schmidt-Erfurth U, et al. Intravitreal aflibercept for diabetic macular edema. Ophthalmology. 2014;121(11):2247-2254.
- Soheilian M, Ramezani A, Obudi A, et al. Randomized trial of intravitreal bevacizumab alone or combined with triamcinolone versus macular photocoagulation in diabetic macular edema. Ophthalmology. 2009;116(6):1142-1150.
- Soheilian M, Ramezani A, Bijanzadeh B, et al. Intravitreal bevacizumab (avastin) injection alone or combined with triamcinolone versus macular photocoagulation as primary treatment of diabetic macular edema. Retina. 2007;27(9):1187-1195.
- Solaiman KA, Diab MM, Abo-Elenin M. Intravitreal bevacizumab and/or macular photocoagulation as a primary treatment for diffuse diabetic macular edema. Retina. 2010;30(10):1638-1645.
- Diabetic Retinopathy Clinical Research Network, Scott IU, Edwards AR, et al. A phase II randomized clinical trial of intravitreal bevacizumab for diabetic macular edema. Ophthalmology. 2007;114(10):1860-1867.
- Rajendram R, Fraser-Bell S, Kaines A, et al. A 2-year prospective randomized controlled trial of intravitreal bevacizumab or laser therapy (BOLT) in the management of diabetic macular edema: 24-month data: report 3. Arch Ophthalmol. 2012;130(8):972-979.
- Writing Committee for the Diabetic Retinopathy Clinical Research Network, Gross JG, Glassman AR, et al. Panretinal Photocoagulation vs Intravitreous Ranibizumab for Proliferative Diabetic Retinopathy: A Randomized Clinical Trial. JAMA. 2015;314(20):2137-2146.
- Wykoff CC. Intravitreal aflibercept for moderately severe to severe non-proliferative diabetic retinopathy (NPDR) The phase 3 PANORAMA Study. 2019; https://investor.regeneron.com/static-files/e7daf4ed-4b85-4ed6-9ff1-eb5f9f67a5da . Accessed July 10, 2019.
- Solomon SD, Chew E, Duh EJ, et al. Diabetic retinopathy: a position statement by the american diabetes association. Diabetes Care. 2017;40(3):412-418.
- Bressler SB, Ayala AR, Bressler NM, et al. Persistent macular thickening after ranibizumab treatment for diabetic macular edema with vision impairment. JAMA Ophthalmol. 2016;134(3):278-285.
- Bressler NM, Beaulieu WT, Glassman AR, et al. Persistent macular thickening following intravitreous aflibercept, bevacizumab, or ranibizumab for central-involved diabetic macular edema with vision impairment: a secondary analysis of a randomized clinical trial. JAMA Ophthalmol. 2018;136(3):257-269.
- Ciulla TA, Bracha P, Pollack J, Williams DF. Real-world outcomes of anti-vascular endothelial growth factor therapy in diabetic macular edema in the United States. Ophthalmol Retina. 2018;2(12):1179-1187.
- Kiss S, Liu Y, Brown J, et al. Clinical utilization of anti-vascular endothelial growth-factor agents and patient monitoring in retinal vein occlusion and diabetic macular edema. Clin Ophthalmol. 2014;8:1611-1621.
- Ehlken C, Helms M, Bohringer D, Agostini HT, Stahl A. Association of treatment adherence with real-life VA outcomes in AMD, DME, and BRVO patients. Clin Ophthalmol. 2018;12:13-20.
- Tamura H, Miyamoto K, Kiryu J, et al. Intravitreal injection of corticosteroid attenuates leukostasis and vascular leakage in experimental diabetic retina. Invest Ophthalmol Vis Sci. 2005;46(4):1440-1444.
- Felinski EA, Antonetti DA. Glucocorticoid regulation of endothelial cell tight junction gene expression: novel treatments for diabetic retinopathy. Curr Eye Res. 2005;30(11):949-957.
- Whitcup SM, Cidlowski JA, Csaky KG, Ambati J. Pharmacology of corticosteroids for diabetic macular edema. Invest Ophthalmol Vis Sci. 2018;59(1):1-12.
- Sohn HJ, Han DH, Kim IT, et al. Changes in aqueous concentrations of various cytokines after intravitreal triamcinolone versus bevacizumab for diabetic macular edema. Am J Ophthalmol. 2011;152(4):686-694.
- Gillies MC, Sutter FK, Simpson JM, Larsson J, Ali H, Zhu M. Intravitreal triamcinolone for refractory diabetic macular edema: two-year results of a double-masked, placebo-controlled, randomized clinical trial. Ophthalmology. 2006;113(9):1533-1538.
- Dehghan MH, Ahmadieh H, Ramezani A, Entezari M, Anisian A. A randomized, placebo-controlled clinical trial of intravitreal triamcinolone for refractory diabetic macular edema. Int Ophthalmol. 2008;28(1):7-17.
- Ip MS, Bressler SB, Antoszyk AN, et al. A randomized trial comparing intravitreal triamcinolone and focal/grid photocoagulation for diabetic macular edema: baseline features. Retina. 2008;28(7):919-930.
- Diabetic Retinopathy Clinical Research N, 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 e1035.
- Elman MJ, Bressler NM, Qin H, et al. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2011;118(4):609-614.
- Boyer DS, Yoon YH, Belfort R, Jr., et al. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology. 2014;121(10):1904-1914.
- Maturi RK, Glassman AR, Liu D, et al. Effect of adding dexamethasone to continued ranibizumab treatment in patients with persistent diabetic macular edema: a DRCR network phase 2 randomized clinical trial. JAMA Ophthalmol. 2018;136(1):29-38.
- Campochiaro PA, Nguyen QD, Hafiz G, et al. Aqueous levels of fluocinolone acetonide after administration of fluocinolone acetonide inserts or fluocinolone acetonide implants. Ophthalmology. 2013;120(3):583-587.
- Campochiaro PA, Brown DM, Pearson A, et al. Sustained delivery fluocinolone acetonide vitreous inserts provide benefit for at least 3 years in patients with diabetic macular edema. Ophthalmology. 2012;119(10):2125-2132.
- Parrish RK, 2nd, Campochiaro PA, Pearson PA, Green K, Traverso CE, Group FS. Characterization of intraocular pressure increases and management strategies following treatment with fluocinolone acetonide intravitreal implants in the FAME trials. Ophthalmic Surg Lasers Imaging Retina. 2016;47(5):426-435.
- Eaton A. Real-world outcomes in the US following the use of the fluocinolone acetonide (FAc) 0.19 mg (ILUVIEN) implant in patients with diabetic macular edema: the results from the USER study. Paper presented at: EURETINA September 20-23, 2018; Vienna, Austria.
- Riemann C. USER study real world outcomes: reduction in retinal thickness variability with the fluocinolone acetonide implant for diabetic macular edema. Paper presented at: Retina Society; September 14, 2018; San Francisco, CA.