As the global prevalence of diabetes continues to rise—driven by aging populations, urbanization, and lifestyle changes—the incidence of diabetic macular edema (DME) is increasing in parallel. The chronic and progressive nature of DME often necessitates long-term treatment and monitoring, contributing to significant economic and logistical challenges for patients, caregivers, and health care providers.

Anti-VEGF therapy has revolutionized the management of DME and is widely regarded as the first-line treatment. Large clinical trials have demonstrated significant improvements in both visual acuity and retinal anatomy with regular anti-VEGF injections. However, real-world outcomes often fall short of those seen in controlled trials, largely due to treatment burden and adherence issues. Moreover, a substantial proportion of eyes with DME exhibit incomplete, delayed, or suboptimal responses to anti-VEGF therapy, with persistent fluid or limited visual gain despite repeated injections. This variability in response underscores the complex, multifactorial pathophysiology of DME, in which inflammation plays a key role alongside VEGF-mediated vascular permeability.¹

Intravitreal corticosteroids have therefore emerged as an essential complementary therapeutic option. By targeting a broad spectrum of inflammatory pathways, steroids can address mechanisms not fully suppressed by anti-VEGF agents alone. Their longer duration of action also offers the advantage of reduced injection frequency, which may improve patient adherence and quality of life. This article provides a comprehensive, practice-oriented review of steroid strategies, including patient selection, dosing approaches, safety considerations, and integration with anti-VEGF therapy.

Rationale for Steroids in DME

The pathogenesis of DME is complex and involves an interplay between VEGF-driven vascular permeability and chronic, low-grade inflammation. Persistent hyperglycemia leads to biochemical changes, including activation of the polyol pathway, accumulation of advanced glycation end products, and oxidative stress, all of which contribute to endothelial dysfunction. This ultimately results in breakdown of the blood-retinal barrier, allowing fluid and plasma constituents to leak into the macula and cause retinal thickening. In parallel, inflammatory mediators—such as interleukins, tumor necrosis factor-alpha, monocyte chemoattractant protein and prostaglandins—further amplify vascular leakage and promote structural damage to retinal tissues.²

In addition to vascular leakage, inflammation also contributes to leukostasis, microglial activation, and neuronal dysfunction, highlighting that DME is not purely a vascular disorder but a neurovascular inflammatory disease. These processes may explain why some patients exhibit persistent edema despite adequate VEGF suppression.

Corticosteroids target multiple components of this pathogenic cascade. They inhibit phospholipase A2, thereby reducing arachidonic acid and prostaglandin synthesis, stabilize endothelial tight junctions, and suppress the expression of inflammatory cytokines and adhesion molecules.³ Steroids also downregulate VEGF expression indirectly and reduce leukocyte adhesion, further contributing to restoration of the blood-retinal barrier. In contrast to anti-VEGF agents, which primarily address vascular permeability mediated by VEGF, corticosteroids exert a broader and more comprehensive anti-inflammatory effect. This makes them particularly valuable in chronic, refractory, or inflammation-driven DME.

Advances in retinal imaging have provided further insights into disease mechanisms and therapeutic response. Optical coherence tomography (OCT) biomarkers, such as hyperreflective foci, subretinal fluid, and disorganization of retinal inner layers (DRIL), are increasingly recognized as indicators of inflammatory activity.⁴ Eyes demonstrating these features may show a more robust anatomic response to steroid therapy.

Emerging evidence also suggests that chronic DME may involve alterations in retinal pigment epithelium function and Müller cell activity, both of which are influenced by inflammatory pathways. By modulating these processes, corticosteroids may help restore retinal homeostasis beyond simple fluid reduction. Together, these considerations support a strong pathophysiologic rationale for incorporating steroids into individualized treatment strategies for DME.

Patient Selection

Selecting the right patient is critical to optimizing outcomes while minimizing adverse effects when considering corticosteroid therapy for DME. A tailored approach that accounts for ocular characteristics, prior treatment response, and patient-specific factors is essential. In general, ideal candidates include the following:

• Pseudophakic eyes: In these patients, steroids are particularly advantageous because the risk of visually significant cataract progression is less of a concern.⁵
• Inadequate response to anti-VEGF therapy: Eyes with persistent intraretinal or subretinal fluid after 3 to 6 consecutive anti-VEGF injections may have a stronger inflammatory component and are often good candidates for steroid therapy.⁶
• Poor adherence or high treatment burden: Patients who struggle with frequent visits may benefit from the longer duration of action associated with steroid implants.
• Vitrectomized eyes: In this setting, faster drug clearance can reduce anti-VEGF durability, whereas steroid implants may provide more consistent therapeutic levels.⁷
• Inflammatory phenotype DME: OCT biomarkers—such as hyperreflective foci, subretinal fluid, or soft exudates—may indicate greater responsiveness to steroid therapy.

Patients requiring caution include (1) known steroid responders with a history of significant IOP elevation; (2) those with preexisting glaucoma or ocular hypertension, particularly eyes with optic nerve cupping greater than 0.8; and (3) younger phakic patients, due to the higher lifetime risk of cataract progression.

Steroid Therapies and Dosing Strategies

Triamcinolone acetonide (Triesence; Harrow) is a cost- effective, short-acting corticosteroid frequently used as a diagnostic or bridging therapy. Its relatively rapid onset of action and affordability make it especially useful in real-world and resource-limited settings. 

The dexamethasone intravitreal implant 0.7 mg (Ozdurex; AbbVie) is a biodegradable implant that provides sustained drug delivery for approximately 3 to 4 months. The MEAD trial demonstrated significant improvements in both visual acuity and central retinal thickness compared with sham treatment.⁵ Its predictable duration, ease of administration, and favorable efficacy-safety balance make it one of the most widely used steroid options in routine clinical practice.

The fluocinolone acetonide implant 0.19 mg (Iluvien; ANI Pharmaceuticals) is a nonbiodegradable implant designed for long-term therapy, delivering continuous low-dose corticosteroid for up to 36 months.⁸ The FAME trials demonstrated sustained visual gains in patients with chronic DME, particularly those insufficiently responsive to other treatments.⁹ Careful patient selection is essential due to its prolonged duration of action.

Choice of agent depends on disease chronicity, prior treatment response, lens status, glaucoma risk, and patient tolerance to steroids. Triamcinolone is typically administered at a dose of 2 to 4 mg, with a duration of effect of approximately 8 to 12 weeks. The dexamethasone implant is generally repeated every 3 to 4 months, although earlier retreatment (around 10 to 12 weeks) may be required in some patients depending on recurrence patterns. The fluocinolone implant is given as a single injection with a duration of 3 years and provides long-term therapy, significantly reducing treatment burden in chronic DME. Individualization of treatment intervals based on OCT findings and clinical response remains essential. Treatment intervals should be individualized based on OCT findings, visual acuity trends, and recurrence timing. A proactive approach—treating before significant recurrence—may improve long-term outcomes and reduce fluctuations in vision.

Patients should undergo a comprehensive baseline evaluation, including best-corrected visual acuity (BCVA), OCT, and IOP measurement. A follow-up visit at 4 to 6 weeks postinjection is particularly important, because this corresponds to both peak therapeutic effect and the early window for steroid-induced intraocular pressure (IOP) elevation. Thereafter, follow-up every 2 to 3 months is generally appropriate, although intervals may be individualized based on response and risk profile.

Monitoring and Safety Considerations

Careful and structured monitoring is essential to ensure both efficacy and safety when using intravitreal corticosteroids in DME. Given the potential for adverse effects such as IOP elevation and cataract progression, a proactive surveillance strategy is critical.

IOP elevation remains the most significant and common adverse effect associated with intravitreal steroid therapy, and it occurs in approximately 20% to 30% of patients receiving steroid implants in real-world trials.^5,8-9 Although most cases are mild to moderate, a small subset may develop significant or sustained pressure elevation requiring intervention. Topical IOP-lowering medications are considered the first-line treatment and are effective in most cases. In patients who do not respond adequately to medications, laser trabeculoplasty may be considered as an alternative option. Although less commonly required, surgical interventions such as trabeculectomy or the use of glaucoma drainage devices may become necessary in refractory cases where other treatments have failed.

Cataract formation is a well-recognized and predictable consequence of repeated or sustained corticosteroid exposure. It occurs in a substantial proportion of phakic patients receiving intravitreal corticosteroids, with risk varying by agent. Clinical studies report cataract development in approximately 60% to 70% of eyes treated with dexamethasone implants and up to 80% to 85% with fluocinolone acetonide implants, with many patients ultimately requiring cataract surgery.^5,8-9 The risk increases with cumulative dose and duration of therapy.

Careful pretreatment counseling regarding the risk of cataract formation is essential. Regular monitoring of lens clarity should be performed during follow-up visits. When visually significant cataract develops, timely cataract surgery should be planned in coordination with adequate control of macular edema. Postoperatively, continuation or resumption of DME therapy is often required to maintain visual improvement. With appropriate planning and monitoring, visual outcomes following cataract surgery are generally favorable, and cataract progression should be considered a manageable aspect of long-term steroid therapy rather than a contraindication.

Switching Strategy

Patients who demonstrate an inadequate response after 3 to 6 consecutive anti-VEGF injections—typically defined by persistent intraretinal or subretinal fluid or limited visual improvement—should be considered for a switch to steroid therapy rather than continuation of ineffective treatment.¹⁰ Early switching in nonresponders may help prevent chronic structural damage and improve long-term visual outcomes.

Special Clinical Scenarios

Corticosteroid therapy may be particularly advantageous in select clinical scenarios in which treatment burden, systemic considerations, or ocular comorbidities influence therapeutic decision-making. Careful patient selection and monitoring remain essential to balance efficacy with safety.

• Bilateral DME: In patients with bilateral disease, steroids may reduce treatment burden by decreasing injection frequency in both eyes; however, careful bilateral IOP monitoring is essential.
• Systemic cardiovascular risk: In patients with recent cardiovascular or cerebrovascular events, steroids may be preferred due to the theoretical systemic risks associated with anti-VEGF agents.
• Pregnancy: During pregnancy, corticosteroids are generally favored because of their minimal systemic exposure compared with anti-VEGF therapies.
• Renal compromise: In patients with significant renal impairment, corticosteroids may be preferred due to minimal systemic absorption, whereas anti-VEGF agents carry a theoretical risk of worsening proteinuria and hypertension.

Future Directions

Ongoing innovations in drug delivery and patient stratification are expected to further refine the role of steroids in DME. Suprachoroidal delivery of triamcinolone allows targeted drug deposition in the posterior segment, potentially reducing anterior segment exposure and lowering the risk of IOP elevation and cataract. Early clinical trials have demonstrated promising efficacy and safety profiles.¹¹ Next-generation implants and delivery systems aim to provide more consistent drug release while minimizing complications and treatment burden. Advances in imaging, including OCT-based biomarkers and artificial intelligence–driven analysis, may enable clinicians to identify patients most likely to benefit from steroid therapy, facilitating a more personalized treatment approach.

Conclusion

Corticosteroids remain a cornerstone in the management of DME, particularly in patients who do not respond adequately to anti-VEGF therapy or who demonstrate a significant inflammatory component to their disease. As our understanding of DME has evolved from a purely VEGF-driven condition to a complex, multifactorial disorder, the role of steroids has become increasingly well-defined and clinically relevant.

With thoughtful patient selection, individualized dosing strategies, and careful monitoring of IOP and cataract progression, corticosteroids can provide meaningful and durable improvements in both retinal anatomy and visual function. Their longer duration of action offers an important advantage in reducing treatment burden, which can translate into improved adherence and real-world outcomes. In addition, the ability of steroids to target multiple inflammatory pathways makes them particularly valuable in chronic, refractory, or difficult-to-treat cases.

Looking ahead, advances in imaging, biomarker identification, and drug delivery systems are likely to further refine the use of corticosteroids in DME. Personalized treatment algorithms that incorporate disease phenotype, treatment response, and patient-specific factors will continue to evolve. As such, corticosteroids are poised to remain an essential component of comprehensive, individualized DME care, playing a key role in improving long-term visual outcomes and quality of life for patients. RP

Ashish Sharma, MD, is a Senior Retina Consultant and Director of Clinical Research at Lotus Eye Hospital and Institute, Coimbatore, India. He reports consultancy relationships with Ajanta, Allergan, Bayer, Intas, Lupin, Novartis, Oculis, Sun Pharma, and Zudus Lifesciences, and speaker fees from Abdi İbrahim İlaç San. Ve Tic, MS Pharma, Nitto Meditech, Samil Pharma, and Sandoz.

Baruch D. Kuppermann, MD, PhD, is the Steinert Endowed Professor, Chair of the Department of Ophthalmology and Visual Sciences, and Director of the Gavin Herbert Eye Institute at the University of California, Irvine. He reports clinical research support from AbbVie, Adverum, Apellis, Clearside, EyePoint, Genentech, Ionis, jCyte, Ray Therapeutics, Regeneron Pharmaceuticals, RegenXBio and consultancy roles with Aadvantgarde, AbbVie, Adverum, Alkeus, Amgen, Apellis, Astellas, Aviceda Therapeutics, Boehringer Ingelheim, Clearside, EyeBio, Eyedaptic, EyePoint, 4DMT, Genentech, Glaukos Corporation, InflammX Therapeutics, jCyte, Lucina Biotherapeutics, Merck, Mobius, Molecular Partners, Neurotech, Novartis Pharmaceuticals, Ocugen, Ocular Therapeutix, Oculis, ONL Therapeutics, Outlook Therapeutics, Priviterra, Ray Therapeutics, Regeneron Pharmaceuticals, ReVana Therapeutics, Ripple Therapeutics, Roche Pharmaceuticals, Sanofi, Santen, Stealth Therapeutics, Theravance Biopharma, Visgenx. He reports an unrestricted grant from Research to Prevent Blindness to the Gavin Herbert Eye Institute. Reach him at bdkupper@uci.edu.

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