Oral therapies for diabetic retinopathy: Addressing an unmet need or a distant prospect?

This narrative review examines the role of systemic (oral) therapies in diabetic retinopathy, summarizing their biological rationale, clinical evidence, and practical considerations. We framed mechanistic pathways across the retinal neurovascular unit, distinguishing direct effects on the endothelium, pericytes, Müller glia, retinal pigment epithelium, neurons, and immune cells from indirect downstream actions. We appraised the following key therapeutic oral classes: (a) peroxisome proliferator-activated receptor alpha agonists (fenofibrate), which consistently demonstrate prevention-of-worsening signals; (b) protein kinase C beta inhibitors (ruboxistaurin), showing mixed efficacy but reduced vision-threatening outcomes in specific subsets; (c) redox transcription modulators (APX3330/Ref-1), exhibiting binocular prevention-of-worsening signals; (d) vascular adhesion protein-1/ amine oxidase copper-3 inhibitors, with variable phase-2 results; and (e) rho kinase inhibitors (OPL-0401), which have shown neutral primary endpoints to date. We highlighted that upstream, pleiotropic agents may require longer treatment durations and progression-focused endpoints, whereas therapies targeting permeability/leukostasis targets may yield earlier but subtle signals. We discussed trial-design considerations, including binocular outcomes, prevention-focused endpoints, and patient selection, along with integration into clinical practice-addressing safety, comorbidities, and adherence advantages of oral delivery. Finally, we outlined current gaps-such as limited phase-3 data beyond fenofibrate, endpoint heterogeneity, and the need for robust prevention trials-and proposed a concise research agenda. As a narrative synthesis, this review emphasizes clinical interpretation rather than quantitative meta-analytic estimation.