Diabetic retinopathy (DR) remains one of the leading causes of preventable vision loss worldwide, affecting nearly one-third of individuals with diabetes and imposing a growing burden as the prevalence of diabetes continues to rise.1 For decades, the therapeutic landscape was defined by 2 pillars, laser photocoagulation and intravitreal anti-VEGF injections. Each represented a transformative advance in its time, yet gaps remain in durability, access, and overall disease management.
Technological advancements have changed the way retinal conditions are diagnosed and managed. Pharmacologic innovation, multimodal imaging, and emerging artificial intelligence technologies are converging to provide deeper insight into DR. Together, these approaches are reshaping earlier detection, monitoring of disease progression, and treatment across the DR spectrum, from subclinical retinal neurodegeneration to advanced proliferative disease. This review examines key advances and their implications for clinical practice.
Figure 1. Diabetic retinopathy demonstrating microvascular pathology. Emerging therapies and extended-duration treatments are reshaping management strategies and improving disease control.
Pharmacologic Agents
The anti-VEGF armamentarium for DR has expanded considerably over the past 2 decades, with new agents receiving US Food and Drug Administration (FDA) approval in recent years and numerous therapies in development.
Faricimab (Vabysmo; Genentech), the first bispecific antibody approved for retinal disease, introduced a novel approach by targeting both VEGF-A and angiopoietin-2 (Ang-2). Inhibition of Ang-2 addresses vascular destabilization and inflammation that may not be fully controlled by anti-VEGF monotherapy.2 Faricimab is FDA approved for neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME); however, it is not currently approved for DR, as clinical trials are ongoing.3 The YOSEMITE and RHINE trials in DME also demonstrated meaningful improvements in diabetic retinopathy severity score (DRSS), along with extended dosing intervals of up to every 16 weeks in a subset of patients.4
Among aflibercept formulations, both aflibercept 2 mg (Eylea; Regeneron) and aflibercept 8 mg (Eylea HD) have FDA approval for DR.5 The recommended dosing for Eylea HD is 8 mg every 4 weeks for 3 months, followed by 8 mg every 8 to 12 weeks; patients who do not respond adequately at 8-week intervals may be treated every 4 weeks.6 This approach allows for fewer injections while maintaining visual and anatomic outcomes comparable to the 2 mg formulation.
Ranibizumab (Lucentis; Genentech) is also FDA approved for DR. Susvimo (Genentech), a refillable port delivery system, received FDA approval for DR in May 2025, representing the first continuous-delivery treatment for the disease. The implant is filled with 100 mg/mL of ranibizumab and requires refill every 9 months. FDA approval was based on the phase 3 PAVILION study, in which 80% of patients treated with Susvimo achieved at least a 2-step DRSS improvement at week 52, compared with 9% in the clinical observation control arm.7
The biosimilar landscape has also expanded, with 2 ranibizumab biosimilars and 6 aflibercept biosimilars now FDA approved.8 Their availability is beginning to reshape cost and access dynamics, particularly for patients requiring long-term treatment who face affordability barriers with branded agents. Adoption of biosimilars among retina specialists has been gradual, as access, cost considerations, and patent litigation remain factors. For high-volume retina practices, however, biosimilars offer a clinically equivalent, cost-conscious alternative that may improve treatment adherence over time.
Pipeline Agents
The pipeline for DR is rapidly expanding, with 2 therapeutic classes showing potential to redefine treatment durability.
The mechanism of tyrosine kinase inhibitors (TKIs) is based on intracellular blockade of VEGF receptors, in contrast to anti-VEGF biologics, which typically bind a single extracellular ligand or receptor. Because TKIs are small molecules, they can diffuse into cells and inhibit phosphorylation across multiple VEGF receptor isoforms (VEGFR-1, VEGFR-2, and VEGFR-3). This approach may offer broader pathway inhibition, including effects on other receptor tyrosine kinases, such as platelet-derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR), which have also been implicated in vascular permeability and inflammation.
Vorolanib, for example, has also been shown to inhibit JAK1, thereby suppressing interleukin-6, a proinflammatory cytokine upregulated in many patients with DME, offering broader pathway inhibition beyond anti-VEGF monotherapy.9,10
EyePoint Pharmaceuticals is investigating Duravyu (EYP-1901), a bioerodible intravitreal insert designed to deliver sustained vorolanib for at least 6 months.9 The phase 2 VERONA trial in DME met its primary endpoint, demonstrating extended time to first supplemental treatment vs aflibercept, with a reduction in treatment burden. Phase 3 trials in DME (COMO and CAPRI) are currently underway.
Ocular Therapeutix is investigating Axpaxli (OTX-TKI), an intravitreal implant expressing the TKI axitinib, for DR. In the phase 1/2 HELIOS trial, 100% of treated patients maintained or improved their DRSS score, compared with 25% progression in the control arm. Phase 3 trials (HELIOS-2 and HELIOS-3) in diabetic retinopathy have been initiated.
Gene Therapy
Gene therapy involves the introduction of genetic material to achieve a therapeutic effect. This material is typically delivered via an adeno-associated viral vector (AAV). Once inside retinal cells, the transgene leverages the cell’s natural protein synthesis machinery to produce a therapeutic protein. Three routes of administration are under investigation: subretinal (surgical), suprachoroidal (in-office), and intravitreal (in-office).
Investigational gene therapies for DR generally use a one-time administration of an AAV encoding anti-VEGF proteins. By enabling continuous intraocular production of these agents, gene therapy has the potential to substantially reduce treatment burden.11,12
The most advanced program in DR is surabgene lomparvovec, or sura-vec (ABBV-RGX-314; Regenxbio/AbbVie), an AAV8 vector encoding an anti-VEGF antibody fragment delivered via a single in-office suprachoroidal injection. Two-year data from the phase 2 ALTITUDE trial demonstrated a favorable safety and efficacy profile, with no drug-related serious adverse events and no intraocular inflammation observed at dose level 3 with short-course topical prophylactic steroids. These findings supported initiation of a pivotal, 2-part, placebo-controlled phase 2b/3 trial, with a primary endpoint of greater than a 2-step improvement in DRSS at 1 year.13
Imaging-Guided Monitoring
Advanced imaging remains central to retina practice. The available imaging toolkit has evolved substantially, with important implications for how DR is staged, monitored, and treated, many of which are still being integrated into routine care.
Optical coherence tomography angiography (OCT-A) has emerged as a major addition to DR evaluation over the past decade. OCT-A is a noninvasive modality that uses motion contrast from blood flow to generate layer-specific angiograms of the superficial and deep capillary plexuses, making it well suited for detecting vascular changes in early and preclinical DR. Quantitative metrics, including vessel density, foveal avascular zone (FAZ) area, and fractal dimension, are increasingly used as objective biomarkers. Enlargement of the FAZ due to progressive capillary nonperfusion is associated with visual decline and is considered an important marker of disease progression.
In treatment monitoring, anti-VEGF therapy administered over 3 to 9 months has been associated with reduced vessel diameter and improvement in FAZ parameters, suggesting potential vascular remodeling.14,15
Ultra-widefield fluorescein angiography (UWF-FA) has challenged the adequacy of the ETDRS 7-field standard. DRCR Retina Network Protocol AA demonstrated that peripheral lesions (primarily microaneurysms) identified on UWF-FA were associated with a 70% increased risk of DR progression, suggesting improved prognostic capability compared with 7-field imaging.16 In proliferative DR, identification of peripheral nonperfusion can inform laser planning and may help explain refractory DME when ischemia extends beyond the posterior pole.
Together, these tools support a shift from protocol-driven management toward individualized, biomarker-guided care. Rather than applying uniform monitoring and treatment intervals, OCT-A metrics and UWF-FA findings can help stratify patients by disease biology and risk of progression.
Integration Into Clinical Practice
Translating these advances into clinical practice requires a structured approach to matching the right tool to the right patient at the appropriate time. For treatment-naïve DR and DME, initiating therapy with newer-generation agents is increasingly supported by their extended dosing intervals and favorable DRSS outcomes. In eyes with high-risk proliferative disease or significant peripheral ischemia identified on widefield imaging, the threshold to initiate or intensify anti-VEGF therapy may be lower. For patients with high treatment burden and a demonstrated response to anti-VEGF therapy, the port delivery system with ranibizumab (Susvimo) offers an FDA-approved alternative that warrants discussion. In parallel, emerging therapies, including TKIs and gene therapy, aim to further improve durability.
Communicating the evolving treatment landscape to patients can be challenging. Patient education is most effective when reinforced over multiple visits. Although it may not be feasible to review all options at the initial encounter, discussions can expand as trust develops. Transitioning from frequent injections to extended-interval or sustained-delivery therapies should be framed carefully; longer intervals reflect improved drug design rather than reduced need for monitoring.
Integration of widefield imaging and OCT-A should be guided by disease stage rather than applied uniformly at every visit, to avoid workflow bottlenecks. Establishing artificial intelligence–assisted referral pathways with primary care and endocrinology practices may facilitate earlier detection and expand access to care for patients with diabetes.
Conclusion
Management of DR continues to evolve around 3 central pillars: efficacy, durability, and access. Novel pharmacologic therapies are extending treatment intervals and targeting disease pathways beyond VEGF alone. Advanced imaging enables biomarker-driven, individualized monitoring that more accurately reflects disease burden. In parallel, artificial intelligence–based screening offers a pathway to identify patients earlier, including those at risk of being lost to follow-up. Collectively, these advances provide an opportunity to reduce vision loss at a population level and to fundamentally change the long-term trajectory of diabetic retinopathy. RP
References
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