This two-arm randomized pilot trial was conducted to evaluate the efficiency of adding a single dose of SCTA to IVB, as a popular anti-VEGF agent especially in developing countries, in managing CI-DME in treatment-naive eyes. The findings showed significant clinical and statistical improvements in BCVA and retinal anatomical outcomes in the eyes injected with this novel combination compared to in those receiving IVB.
Today, anti-VEGF agents are commonly used as the first-line therapy for macular edema caused by retinal diseases such as age-related macular degeneration, retinal vein occlusion, certain retinal tumors and diabetic retinopathy. 17–20 Despite their global applications and undeniable benefits, these agents have been reported to cause numerous adverse ocular and systemic events and different responses in patients. 17,18,21 Bressler et al. found six monthly injections of ranibizumab to insignificantly resolve macular edema in approximately 40% of the eyes. They reported chronic DME in 55.8% and 40.1% of the patients, respectively, despite continuing the injections based a specific two- and three-year follow-up protocol. Furthermore, they found macular edema to be more likely to persist in the eyes managed with IVB injections (72.9% after twelve weeks, 65.6% after 24 weeks and 68.2% after 2 years). 22 Similarly, the present findings suggested CST did not fall below the gender-specific normal thresholds in 75% of the participants managed with three consecutive monthly IVB injections.
Reviewing the pathophysiology of DME can clarify the high unresponsiveness rates observed. Das et al. explained the pathophysiology of diabetic retinopathy by reporting four major biochemical mechanisms induced by hyperglycemia. 1 These pathways upregulate many mediators, including VEGFs and inflammatory cytokines such as tumor necrosis factor, interleukin 6, interleukin 8, intercellular adhesion molecule-1 and matrix metalloproteinases, and ultimately cause blood-retinal barrier breakdown. 1,2 Kim et al. predicted the response rates to IVB and intravitreal triamcinolone acetonide (IVTA) injections by reporting that these mechanisms can cause different OCT patterns. They observed the best responses to IVB in cases with the sponge-like patterns of diffuse retinal thickening mainly caused by increased vascular permeability. More effective responses to intravitreal steroids were also reported in cystoid patterns mainly caused by Müller cell death and its liquefaction. 21 Given that anti-VEGF agents cannot entirely inhibit the underlying mechanisms of DME, other medical modalities with anti-inflammatory mechanisms are required for obtaining better results.
Compared to IVB alone, IVB in combination with fusadil hydrochloride as a Rho/Rho kinase inhibitor was found by Ahmadieh et al. to cause better and prolonged visual outcomes and no significant adverse effects on patients with CI-DME. 16
The properties of corticosteroids have been well addressed in literature. 5–7, 23 The one- and two-year results of BEVORDEX trial showed approximately equal improvements in BCVA and better anatomical outcomes in patients receiving intravitreal dexamethasone implant compared to in those injected with IVB. 6,7 Maturi et al. found adding intravitreal dexamethasone to monthly ranibizumab injections ineffective in improving visual outcomes in patients with persistent DME. 8 Significant complications reported after administering corticosteroids included elevated IOP and cataract. 10,23 Intravitreal corticosteroids and implants were therefore considered a second-line therapy for DME.
SCS lies between the choroid and sclera in healthy eyes. Exploring the safety and pharmacodynamics of SCTA injections in rabbit models, Chen et al. reported a significantly-higher drug concentration in the posterior retina than in the anterior segment. They also found that the resolution of both anterior and posterior segment inflammations was also significantly higher in suprachoroidal drug delivery compared to in posterior sub-tenon injection of TA. 9 According to Habot-Wilner et al. injecting pharmacological agents into SCS precipitates the distribution to the posterior segment. They also reported the TA concentration to be twelve times higher in the posterior segment and only 5% in aqueous humor, ciliary body and lens compared to IVTA injections. 10 Given its negligible concentration in anterior segment structures, SCTA injection appears to significantly decrease the risk of elevated IOP and cataract compared to intravitreal drug delivery. 9 Major adverse events such as elevated intraocular pressure and clinically-significant cataract were not observed in any of the present study participants.
According to the Tanzanite clinical trial, SCTA plus intravitreal aflibercept (IVA) was well tolerated compared to IVA alone in patients with retinal vein occlusion. The number of injections also significantly decreased and BCVA and retinal thickness significantly improved in the combination arm. 14 Yeh et al. investigated the effects of two doses of SCTA injections with a three-month interval on macular edema caused by noninfectious uveitis. They reported significant improvements in BCVA and resolution of edema. They also found the injection not to cause remarkable adverse ocular events. 12 Wykoff et al. administered either a single or multiple SCTA injections combined with a single IVA injection in patients with naive or persistent DME, and found the CST resolution to exceed 50% in almost 90% of the patients after six months. 13 In line with these studies, we obtained significant improvements in anatomical and functional outcomes through adding SCTA injections.
The present study limitations mainly comprised its small sample and relatively short-term follow-ups. Given the COVID-19 pandemic in Iran, the eight-week follow-up was not completed in the majority of the participants, resulting in unreliable data. To the best of the authors’ knowledge, this study pioneered the investigation of the synergistic effects of SCTA and IVB in patients with diabetes. The strengths of the present research encompassed its randomization, the patients and evaluators masking to avoid possible bias, adherence to the study protocol and not depriving the patients from a confirmed treatment (ant-VEGFs). It is recommended that large clinical trials with longer-term follow-ups be performed to investigate the synergistic and sole effects of SCTA injections and report its potential adverse effects in patients with DME.