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

Abstract

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.

Introduction

Global burden and pathophysiology of diabetic retinopathy (DR)

DR constitutes a significant public health challenge. It represents the most common microvascular complication of diabetes mellitus and remains a leading cause of preventable vision impairment and blindness among working-age adults worldwide. ¹ Its prevalence is intrinsically linked to the escalating diabetes epidemic; currently, nearly one-third of individuals with diabetes exhibit DR, translating to almost 100 million people worldwide. ¹ Epidemiological projections suggest this burden will continue to rise substantially in the coming decades. ²

The underlying pathophysiology of DR is complex and is initiated and primarily driven by chronic hyperglycemia. ³ Elevated blood glucose levels trigger a cascade of metabolic derangements within the retinal microvasculature, leading to end-organ damage. ³ Key mechanisms include the activation of alternative glucose metabolism pathways such as the polyol pathway (resulting in sorbitol accumulation and osmotic stress); increased formation of advanced glycation end-products (AGEs), which alter protein structure and function and promote inflammation; and activation of the protein kinase C (PKC) pathway, which enhances vascular endothelial growth factor (VEGF) expression and contributes to vascular dysfunction. ³ Oxidative stress and chronic low-grade inflammation are also critical drivers, contributing to capillary occlusion, hypoxia, and further VEGF upregulation. ¹ This intricate interplay results in the characteristic microvascular pathology of DR, which includes the following: (a) weakening of the capillary walls leading to microaneurysms; (b) increased vascular permeability causing leakage and edema (particularly diabetic macular edema (DME)); (c) capillary occlusion leading to retinal ischemia; and (d) the proliferation of abnormal new blood vessels (neovascularization) in response to ischemia. ³ Recent insights further highlight the involvement of the entire neurovascular unit, including neuronal, glial, and immune cells—underscoring a more complex picture than purely vascular damage. ²

Clinically, DR progresses through distinct stages. Nonproliferative DR (NPDR) represents the earlier phase, characterized by retinal microvascular changes such as microaneurysms, dot-and-blot hemorrhages, hard exudates, cotton wool spots, venous beading, and intraretinal microvascular abnormalities (IRMA). ⁴ NPDR is further classified into mild, moderate, and severe stages based on the presence and extent of these findings, often using the Early Treatment of Diabetic Retinopathy Study (ETDRS) classification. ⁴ Severe NPDR is typically defined by the “4-2-1 rule” as follows: (a) hemorrhages/microaneurysms in four quadrants; (b) venous beading in two or more quadrants; or (c) IRMA in one or more quadrants. ⁴ Progression beyond NPDR leads to proliferative DR (PDR), which is a more advanced stage characterized by abnormal neovascularization in the retina or optic disc. ⁴ These vessels are prone to vitreous hemorrhage or scar tissue formation that can lead to tractional retinal detachment, both potentially causing severe vision loss. ⁴ Although DME, characterized by retinal thickening due to fluid leakage in the macula, can occur at any stage of DR, its prevalence increases with disease severity, and it remains the leading cause of vision loss in many patients. ¹

Early detection through regular dilated eye examinations is crucial, as DR often lacks symptoms in its initial stages. ¹ However, achieving adequate screening compliance remains challenging, particularly in resource-limited settings or among populations facing socioeconomic barriers, leading to delayed diagnoses and presentation at more advanced stages of disease. ⁵

Unmet need with current standards of care

The management of vision-threatening DR (VTDR)—comprising primarily DME and PDR—has been revolutionized by the advent of intravitreal anti-VEGF therapies and refined laser photocoagulation techniques. ¹ Anti-VEGF agents, including aflibercept, ranibizumab, and bevacizumab (off-label use), directly target VEGF, thereby reducing vascular permeability and inhibiting neovascularization. ⁴ Laser photocoagulation—administered as pan-retinal photocoagulation (PRP) for PDR or focal/grid laser for DME—aims to ablate ischemic retina or seal leaking microaneurysms, respectively.^4,5 Vitrectomy surgery is recommended for advanced complications such as persistent vitreous hemorrhage or tractional retinal detachment. ⁵

Despite the proven efficacy of these treatments in significantly lowering the risk of vision loss compared with historical outcomes, ⁶ substantial limitations and unmet needs persist. ¹ A primary concern is the considerable treatment burden associated with anti-VEGF therapy. ¹ Treatment typically involves frequent intravitreal injections, often initiated monthly and continuing for extended periods—sometimes lifelong—warranting numerous clinic visits.^1,2 This regimen imposes significant logistical and emotional strain on patients and their caregivers, encompassing substantial time commitments for travel, clinic waiting times, treatment itself, and recovery as well as potential financial costs and anxiety or discomfort associated with repeated intravitreal injections. ⁷

This high treatment burden directly contributes to suboptimal patient compliance and treatment adherence in real-world clinical practice. ¹ Studies have consistently demonstrated that patients in routine care receive fewer injections and monitoring visits than those in rigorously controlled clinical trials. ⁸ This undertreatment is a major factor contributing to the discrepancy between the robust visual acuity gains achieved in landmark trials (e.g. Protocol T) and the modest outcomes observed in real-world settings.^7,9 Socioeconomic factors, such as insurance status and ethnicity, can further exacerbate these disparities in treatment intensity and outcomes.^7,8 Collectively, these practical challenges in treatment delivery significantly limit the translation of optimal trial efficacy into routine patient care, underscoring the need for more sustainable and less burdensome therapeutic strategies.

Furthermore, efficacy gaps remain. A notable proportion of patients exhibit only partial or suboptimal responses to anti-VEGF therapy, with estimates indicating that only approximately 29%–42% of DME patients achieve significant (≥15 letters) visual acuity gains after 2 years. ⁵ The existence of nonresponders and the potential for tachyphylaxis or resistance over time underscore that VEGF is not the sole pathogenic driver. ¹ Current therapies primarily aim to manage complications rather than fully reversing the underlying retinal damage or addressing all pathogenic pathways, including ischemia and neurodegeneration. ¹

The invasiveness of intravitreal injections carries inherent risks, albeit low, including endophthalmitis, retinal tears or detachment, cataract progression, and transient increases in intraocular pressure. ¹ Laser photocoagulation, while less frequent, is a destructive procedure associated with irreversible side effects such as peripheral visual field loss, impaired night vision (nyctalopia), and occasional worsening of macular edema. ¹ Additionally, the high cost of anti-VEGF biologics imposes a significant economic barrier for healthcare systems and patients. ¹

A critical limitation stemming from these factors is that current treatments are largely reactive, typically initiated only upon the development of vision-threatening complications such as PDR or center-involved DME (CI-DME). ⁵ Although anti-VEGF therapy has shown promise in reducing progression from severe NPDR, ¹⁰ the associated treatment burden renders its widespread application in earlier, often asymptomatic, NPDR stages impractical.^6,11 This creates a substantial therapeutic gap during which the disease progression may remain unchecked, highlighting the need for effective, less burdensome interventions that can be implemented earlier in the disease course.

Rationale for oral therapies

In light of these limitations, systemic orally administered therapies represent an attractive potential alternative or adjunct for the management of DR. ⁷ The primary appeal lies in their potential to substantially reduce treatment burden by replacing or decreasing the frequency of invasive procedures. ¹² The convenience of oral administration could enhance patient compliance and support long-term adherence. ¹² Furthermore, systemic delivery can inherently treat both eyes simultaneously, which is advantageous considering the typically bilateral nature of DR.^1,4 Oral agents also enable earlier therapeutic intervention, particularly during the NPDR stages, potentially preventing progression to VTDR. ¹² Additionally, oral drugs could target distinct or complementary pathophysiological pathways beyond VEGF, thereby addressing the multifaceted nature of DR more comprehensively. ¹² The recognition that DR pathophysiology reflects a complex interplay among inflammation, oxidative stress, metabolic dysfunction, and neurodegeneration, alongside VEGF-mediated angiogenesis and permeability, ¹ provides a strong rationale for exploring systemic therapies targeting these diverse mechanisms.

Current standard of care and its limitations

Anti-VEGF therapy: efficacy and mechanisms

VEGF plays a central, well-established role in the pathogenesis of DR and DME. Retinal ischemia and hypoxia trigger VEGF upregulation, which in turn increases vascular permeability, leading to DME, and promotes abnormal neovascularization, which is characteristic of PDR. ³ Intravitreal injection of anti-VEGF agents, such as the monoclonal antibodies ranibizumab and bevacizumab (off-label use) or the fusion protein aflibercept, directly neutralizes VEGF within the eye. ²

Numerous large, randomized controlled trials (RCTs) have established intravitreal anti-VEGF therapy as the standard of care for DME. ¹ Landmark studies such as RISE and RIDE (ranibizumab), ¹³ VIVID and VISTA (aflibercept), ¹⁴ and DRCR Retina Network's Protocol T (comparing aflibercept, bevacizumab, and ranibizumab) ⁹ demonstrated significant improvements in best-corrected visual acuity (BCVA) and reductions in central retinal thickness compared with sham or laser treatment. For instance, Protocol T reported mean BCVA gains of approximately +11 to +13 letters at 1 year across the three agents. Anti-VEGF therapy has also demonstrated efficacy in managing PDR, with multiple studies demonstrating regression of neovascularization and noninferiority—or even superiority in certain aspects such as DME prevention or lower rates of vitrectomy—compared with PRP.^6,15 Furthermore, studies such as PANORAMA and Protocol W have shown that anti-VEGF treatment can reduce the risk of progression from severe NPDR to PDR or DME. ¹⁰

Laser photocoagulation: role and limitations

Before the anti-VEGF era, laser photocoagulation served as the cornerstone of treatment for VTDR. PRP involves applying numerous laser burns to the peripheral retina to reduce oxygen demand and downregulate VEGF production, thereby causing regression of neovascularization in PDR. ³ The Diabetic Retinopathy Study (DRS) definitively demonstrated that PRP reduced the risk of severe vision loss from PDR by over 50%. ¹⁶ Focal or grid laser photocoagulation targets specific leaking microaneurysms or areas of diffuse leakage in the macula to reduce DME, as demonstrated by the ETDRS. ¹⁷

However, laser therapy is inherently destructive. PRP causes irreversible peripheral retinal damage, leading to well-documented side effects such as peripheral visual field constriction, impaired night vision, and color vision disturbances. ¹ Focal/grid laser treatment can result in paracentral scotomas or inadvertent foveal burns and in some cases, exacerbate DME or induce choroidal neovascularization. ¹⁵ Although newer laser delivery systems—such as pattern-scanning lasers and subthreshold micropulse lasers—aim to reduce collateral damage and treatment time, ¹⁸ the fundamental limitation of retinal tissue destruction remains.

Therapeutic limitations and rationale for alternative strategies

The evolution of DR treatment from laser photocoagulation to anti-VEGF injections represents a significant advancement, particularly in improving central visual acuity outcomes for DME. ¹⁵ However, this advancement comes at the cost of a dramatically increased treatment burden. ⁷ Laser therapy often involves a limited number of sessions, while anti-VEGF therapy requires a potentially indefinite regimen of frequent intravitreal injections. ¹ This shift underscores a critical unmet need arising from the success of anti-VEGF itself—the challenge of managing the logistical, financial, and psychosocial burden associated with this intensive therapy.

The observation that real-world anti-VEGF injection frequency and the resulting visual acuity gains are often lower than those reported in clinical trials strongly suggests that clinicians and patients are actively seeking ways to mitigate this burden. ⁷ The adoption of alternative dosing strategies such as “treat-and-extend” (gradually increasing the interval between injections based on disease activity) or “pro re nata” (PRN, or as-needed treatment based on specific criteria) represents attempts toward individualized treatment and reduced visit frequency. ⁷ Although these strategies aim to balance efficacy and practicality, studies indicate a positive correlation between the number of injections and visual acuity gains, implying that reduced treatment intensity may lead to suboptimal long-term outcomes. ⁷ This implicit trade-off between maximizing efficacy and minimizing burden further fuels the need for less-demanding therapeutic options.

In summary, while anti-VEGF and laser therapies are effective tools, their limitations—including the intensive treatment burden and compliance challenges of injections, variable responses and efficacy ceilings, invasiveness and potential adverse effects of both modalities, and the predominantly reactive nature of treatment initiation—create a compelling case for exploring alternative strategies, such as oral medications, that could potentially offer a less burdensome, noninvasive, and perhaps earlier approach to managing DR.

Rationale for oral therapies

Rationale revisited: Systemic modulation of diverse pathways

The rationale for exploring oral therapies extends beyond simply overcoming the burden of injections. As the pathophysiology of DR involves a complex interplay of multiple interconnected pathways—including inflammation, oxidative stress, advanced glycation, PKC activation, neurodegeneration, and altered hemodynamics, alongside VEGF-driven processes¹—systemic agents offer the potential to simultaneously target these diverse mechanisms. Unlike intravitreal anti-VEGF therapy, which primarily addresses one key downstream mediator, oral drugs under investigation seek to modulate various upstream or parallel pathways implicated in retinal damage. These include activating protective receptors such as peroxisome proliferator–activated receptor alpha (PPARα), inhibiting pro-inflammatory enzymes like PKC beta (PKCβ) or vascular adhesion protein-1 (VAP-1)/amine oxidase copper (AOC3), blocking signaling hubs like Ref-1 or rho kinase (ROCK), providing antioxidant support, or modulating integrin interactions. ³ This multifaceted therapeutic potential holds promise for a more comprehensive approach to disease modification—particularly in the earlier stages preceding irreversible damage.

Review of key oral drug candidates and clinical trial evidence

Several oral agents have been investigated or are currently under investigation for DR, targeting various pathways.

PPARα agonists (fenofibrate)

Fenofibrate, a PPARα agonist primarily used to manage dyslipidemia, has emerged as one of the most studied oral agents for DR. ⁵

Its beneficial effects extend beyond lipid modification, potentially involving anti-inflammatory, antioxidant, antiangiogenic, and direct protective effects on the blood–retinal barrier (BRB) and retinal cells. ¹⁹

Two large-scale RCTs provided the initial evidence. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, comprising over 9700 patients with type 2 diabetes, found that fenofibrate (200 mg/day) significantly reduced the need for first laser treatment for DME or PDR by 31% over 5 years compared with placebo. ²⁰ A FIELD sub-study also demonstrated a 37% reduction in the odds of two-step DR progression. ²¹ The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye Study, involving over 2800 participants, demonstrated that fenofibrate (160 mg/day) added to simvastatin significantly reduced the risk of DR progression by 40% over 4 years, based on a composite outcome of ≥3-step progression, PDR requiring photocoagulation, or vitrectomy, compared with simvastatin plus placebo. ²² Notably, this benefit was independent of the baseline lipid levels or glycemic control. However, in the ACCORD Follow-On (ACCORDION) Eye Study, the beneficial effect of fenofibrate on retinopathy progression did not persist following drug cessation, unlike the sustained benefit observed from prior intensive glycemic control. ²³ Fenofibrate was generally well-tolerated across trials. ²⁴ Based on this evidence, Australia approved the use of fenofibrate for slowing DR progression in patients with type 2 diabetes in 2013. ²⁴ More recently, the LENS trial in Scotland demonstrated that fenofibrate (145 mg/day) reduced the relative risk of progression to referable DR by 27% in patients with type 1 diabetes or type 2 diabetes and existing early DR. ²⁰ The ongoing DRCR Retina Network's Protocol AF is evaluating fenofibrate (160 mg/day) versus placebo for preventing DR worsening over 4–6 years in patients with mild-to-moderate NPDR in the US. ²⁵ The study aims to provide definitive evidence for its use in earlier stages and assess models for co-management.

PKC inhibitors (ruboxistaurin; PKCβ inhibitor)

Ruboxistaurin mesylate (RBX) is an oral selective inhibitor of PKCβ, an isoform centrally involved in hyperglycemia-induced vascular dysfunction. ³ Two large, similarly designed phase 3 trials—PKC-DRS and PKC-DRS2—evaluated RBX (32 mg/day) over 3 years in patients with moderately severe to very severe NPDR. ²⁶ Although RBX did not meet the primary endpoint of preventing progression to PDR in the initial PKC-DRS study, a pooled analysis of both trials (n = 813 patients) demonstrated significant improvements in vision-related outcomes. ²⁶ RBX treatment resulted in a 41% relative risk reduction in sustained moderate visual loss (SMVL; ≥15-letter loss sustained for ≥6 months) compared with placebo (6.1% vs. 10.2%; P = 0.011). ²⁶ Furthermore, a significantly higher number of RBX-treated eyes gained ≥15 letters (4.7% vs. 2.4%; P = 0.021) and a significantly fewer number of eyes lost ≥15 letters (7.4% vs. 11.4%, P = 0.012). RBX also significantly reduced the need for initial focal/grid laser photocoagulation among eyes without prior laser treatment (26.7% vs. 35.6%, P = 0.008), suggesting that its primary effect may have been mediated through DME reduction. ²⁶ RBX demonstrated a favorable safety profile with no major concerns identified in the combined analysis. ²⁶ Despite these positive findings on visual outcomes and DME, the development of ruboxistaurin for DR appears to have stalled, and the drug has not received regulatory approval. An earlier PKC inhibitor, PKC412, demonstrated some anatomical benefit in DME in a phase 2 trial but was limited by dose-dependent gastrointestinal (GI) and hepatic toxicity. ²⁷

Ref-1 inhibitors (APX3330)

APX3330 is a first-in-class, orally administered small molecule inhibitor of reduction-oxidation effector factor-1 (Ref-1/APE1). ²⁸ Ref-1 regulates key transcription factors like HIF-1α and NF-κB, which play central roles in angiogenesis and inflammation. By inhibiting Ref-1, APX3330 aims to exert broad anti-angiogenic and anti-inflammatory effects. ²⁸ The ZETA-1 phase 2 b trial randomized 103 patients with moderately severe NPDR, severe NPDR, or mild PDR to receive APX3330 (600 mg daily) or placebo for 24 weeks. ²⁹ The trial did not meet its primary endpoint: the percentage of patients achieving a ≥2-step improvement in the DR Severity Scale (DRSS) score in the study eye at week 24 (8% in both groups). However, APX3330 achieved statistical significance (P = 0.04) on a key pre-specified secondary endpoint: prevention of clinically meaningful disease progression, defined as a binocular ≥3-step worsening of DRSS. No patients (0%) in the APX3330 group experienced this degree of worsening compared to 16% of patients in the placebo group. Additionally, a trend (P = 0.07) toward fewer APX3330-treated patients experiencing a ≥5-letter loss in visual acuity (6% vs. 19%) was observed. The drug demonstrated a favorable safety and tolerability profile, consistent with prior studies for other indications, with no major organ toxicities reported. Ocuphire Pharma has announced plans for an End-of-phase 2 meeting with the Food and Drug Administration (FDA) to discuss advancing APX3330 into phase 3 trials using the binocular prevention-of-worsening endpoint. ³⁰

VAP-1/AOC3 inhibitors (ASP8232, BI 1467335)

VAP-1, also known as AOC3, is an enzyme expressed in the endothelial cells that mediates leukocyte adhesion and contributes to inflammation and oxidative stress.^31,32 Two oral inhibitors targeting this pathway have undergone phase 2 evaluation for diabetic eye disease.

The VIDI study evaluated ASP8232 (40 mg daily) as monotherapy or combined with intravitreal ranibizumab versus ranibizumab alone in 96 patients with CI-DME over 12 weeks. ³¹ Despite achieving near-complete inhibition of plasma VAP-1 activity, ASP8232 monotherapy demonstrated no benefit in the primary endpoint—mean percent change in excess central subfield thickness, CST) or BCVA. Furthermore, adding ASP8232 to ranibizumab provided no additional benefit over ranibizumab monotherapy, suggesting that VAP-1 inhibition alone is ineffective in cases of established CI-DME, where VEGF likely plays a dominant pathogenic role.

The ROBIN study evaluated BI 1467335 (10 mg daily) versus placebo for 12 weeks in 79 patients with NPDR without CI-DME. ³² The primary endpoint was safety (ocular adverse events (AEs) over 24 weeks).

Although BI 1467335 was generally well-tolerated—with similar treatment-related AE rates as placebo but higher overall ocular AEs—it failed to demonstrate a clear efficacy signal. Only two patients (5.7%) in the treatment group achieved a ≥2-step DRSS improvement at week 12 versus none in the placebo group; high inter-individual variability in the DRSS levels was observed over time. Given the gradual nature of DRSS progression, long-term studies are warranted to adequately demonstrate the efficacy of AOC-3 inhibitors.

VX01, another AOC-3 inhibitor under development by Vantage Biosciences, is being evaluated in the ongoing phase 2 RCT DR-201, a 12-month RCT in patients with NPDR without CI-DME. ³³ The study enrolled individuals with DRSS scores of 43–53, corresponding to moderate-to-severe NPDR—stages where progression to PDR is more likely within a year. The ongoing trial aims to recruit approximately 100 participants, randomized to receive active IP (150 mg twice a day) or placebo.

ROCK inhibitors (OPL-0401)

ROCK inhibitors target the ROCK signaling pathway, which is involved in regulating vascular tone, permeability, and inflammation. ³⁴ OPL-0401, an oral, nonselective ROCK1/2 inhibitor, has demonstrated favorable retinal drug bioavailability in preclinical studies. The phase 2 SPECTRA trial randomized 114 patients with moderately severe to severe NPDR or mild PDR to receive OPL-0401 or placebo for 24 weeks. ³⁴ Valo Health announced that the trial did not meet its primary endpoint (proportion of patients with ≥2-step DRSS score improvement) or the key secondary endpoint (proportion with ≥3-step binocular DRSS change). However, the company noted that post-hoc analyses provided potential evidence for disease progression prevention at certain doses, requiring confirmation in future studies, and that the drug demonstrated a favorable safety profile, being well-tolerated.

VEGF/platelet-derived growth factor (PDGF) inhibitors (X-82/tyrogenex)

X-82 is an oral tyrosine kinase inhibitor (TKI) designed to dually inhibit both VEGF and PDGF receptors—key mediators of angiogenesis and potential fibrosis. ³⁵ Although TKIs have primarily been explored via intravitreal routes for retinal diseases, X-82 represents a novel oral approach. A phase 1 open-label, dose-escalation trial (NCT01674569) primarily evaluated X-82 in 35 patients with wet age-related macular degeneration (AMD) over 24 weeks. ³⁶ The results revealed an overall trend toward improved visual acuity (+4.3 letters) and decreased foveal thickness (−48 µm). Notably, 15 of the 25 patients who completed the 24-week study required no rescue anti-VEGF injections and experienced a mean VA gain of +5.3 letters. X-82 was generally well-tolerated; however, 6 of the 35 patients withdrew due to AEs, most commonly GI issues (diarrhea and nausea) and elevated liver transaminases, which reversed upon drug cessation. A phase 2 trial (APEX) on wet AMD was subsequently initiated. ³⁵ Information regarding specific trials or results for X-82 in DR is limited in the provided materials.

Other potential oral approaches

Several other systemic approaches have been considered or studied, often with limited or preliminary evidence for DR, as follows:

Antioxidants. Given the role of oxidative stress, ¹ various antioxidant supplements (vitamins C, E, A; polyphenols such as flavonoids; carotenoids such as lutein/zeaxanthin; alpha-lipoic acid; and omega-3 fat acids) have been investigated. ³⁷ A systematic review suggested a low level of evidence (IIB recommendation) supporting their use as complementary therapy in early or mild NPDR without DME. However, robust, large-scale clinical trial data confirming efficacy are generally lacking.

Glibenclamide (low-dose). This sulfonylurea, typically used for glycemic control, demonstrated potential benefits in a type 2 diabetic rat model (Goto-Kakizaki) when administered chronically at a nonhypoglycemic oral dose. ³⁸ It improved retinal function (ERG implicit times) and structure (reduced thickening, ischemia, and improved capillary coverage), possibly via effects on SUR1 channels. However, clinical validation in humans is warranted.

Integrin antagonists. Although agents such as risuteganib and THR-687 targeting integrin pathways have demonstrated promise in early clinical studies for DME and AMD via intravitreal injection, their development as oral therapies for DR is less evident from the available data. ³⁹

Systemic antidiabetic drugs. An umbrella review of systematic reviews concluded that common oral antidiabetic classes (GLP-1 RA, SGLT-2i, DPP-4i, metformin, sulfonylureas, TZDs, acarbose, and meglitinides) were generally not associated with a statistically significant increased risk of DR compared with placebo or other agents in RCTs, suggesting safety from a retinopathy perspective. ⁴⁰ However, rapid glycemic improvement, sometimes seen with initiation of intensive therapy including GLP-1 RAs, can be associated with early worsening of existing retinopathy, warranting careful monitoring. ⁴¹ Insulin use was associated with higher DR risk in observational studies, likely due to confounding by indication (used in more severe/longstanding diabetes). ⁴⁰

Traditional Chinese patent medicines (OCPMs). A network meta-analysis of predominantly lower-quality RCTs suggested potential benefits for certain OCPMs (e.g. Compound Danshen Dripping Pill and Compound Xueshuantong Capsule)—which are often administered in combination with calcium dobesilate—in improving clinical efficacy rates, visual acuity, or fundus signs in NPDR. ⁴² However, due to methodological limitations of the primary studies, these findings require confirmation through rigorously designed trials.

Comparative summary of key oral DR drug candidates

The landscape of oral therapies investigated for DR is diverse, targeting different mechanisms and demonstrating varied results. A comparative summary highlights the following key features.

Mechanisms across the retinal neurovascular unit (cell types and timing)

DR involves dysfunction across the retinal neurovascular unit—endothelial cells, pericytes, Müller glia, retinal pigment epithelium (RPE), neurons, and immune cells. Early NPDR shows endothelial activation, leukostasis, and pericyte stress; later stages involve ischemia-driven signaling and neurodegeneration. Framing oral agents by direct (target-expressing cell) versus indirect (downstream) effects helps align expectations and endpoints.^1,2

PPARα agonists (fenofibrate)

Direct transcriptional effects in endothelium/RPE support barrier integrity and lipid/oxidative control; indirect anti-inflammatory benefits extend to pericytes/neurons. Clinically, benefits manifest as slower DR progression and reduced need for laser treatment, rather than rapid regression in the DRSS scores.^19–21

PKCβ inhibitors (ruboxistaurin)

Direct endothelial pericyte effects reduce vascular permeability, while indirect benefits to Müller cells and neurons occur through edema control. Clinical trials demonstrated improvements in SMVL and visual acuity and reduced need for laser treatment, despite not meeting the primary progression endpoint.^26,27

Ref-1 inhibitors (APX3330)

Direct modulation of redox transcription pathways in the RPE and endothelium dampens angiogenic/inflammatory signaling pathways, with indirect stabilization of downstream pathways. These agents are more likely to prevent disease progression than induce short-term regression (e.g. ZETA-1 binocular ≥3-step prevention signal).^29,30

VAP-1/AOC3 inhibitors (ASP8232, BI 1467335)

These agents exert a direct effect on endothelial leukocyte adhesion/oxidative deamination, with indirect microvascular preservation. Early antileukostasis effects are expected; however, phase 2 results have been variable.^31,32

ROCK inhibitors (OPL-0401)

These agents directly modulate the endothelial cytoskeleton and vasoreactivity, indirectly reducing permeability and inflammation to support neuronal and glial homeostasis. Early-to-intermediate signals on leakage/perfusion-linked outcomes are anticipated; however, SPECTRA was negative for both primary and secondary DRSS endpoints. ³⁶

Implications for trials

Upstream transcriptional/metabolic modulators (e.g. PPARα and Ref-1) typically need longer duration and progression-focused endpoints (e.g. prevention of DRSS worsening, and VTDR events), whereas permeability/leukostasis targets (PKCβ, ROCK, and VAP-1) may show earlier but subtle effects.^27,31,36

Analyzing the evidence: key contrasts and potential paradigm shifts

A notable pattern emerges when comparing the clinical trial results. Older, repurposed drugs targeting broader metabolic or signaling pathways (Fenofibrate via PPARα, Ruboxistaurin via PKCβ) demonstrated positive effects on clinically relevant outcomes such as DR progression, need for laser therapy, or sustained vision loss in large phase 3 studies, regardless of meeting the originally intended primary endpoints related to PDR prevention. ²⁶ In contrast, several newer oral agents designed to inhibit more specific targets implicated in DR pathophysiology (VAP-1/AOC3, Ref-1, ROCK) have yielded largely variable results concerning their primary efficacy endpoints in recent phase 2 trials.^29,30 This deviation could suggest several possibilities: the specific newer targets, while biologically relevant, may not be the dominant drivers amenable to systemic modulation in the disease stages studied; the pleiotropic effects of the older drugs might more effectively address the multifactorial nature of DR; or challenges related to achieving adequate ocular bioavailability with the newer agents might have limited their efficacy. Furthermore, limitations in the trial design, inadequate dosage-finding studies, and the duration of the clinical trials may have contributed to failures in meeting the primary end points.

Furthermore, the experience with APX3330 in the ZETA-1 trial highlights a potential strategic shift in evaluating oral therapies. Although the trial failed to meet the primary endpoint of achieving ≥2-step DRSS improvement, it demonstrated a statistically significant secondary outcome: preventing ≥3-step binocular DRSS worsening.^29,30 Pursuing regulatory approval based on preventing progression rather than inducing regression represents a pragmatic adjustment. This approach recognizes the difficulty for systemic agents to replicate the potent, localized effects of intravitreal anti-VEGF in reversing established damage while leveraging the potential advantages of oral therapy—convenience and suitability for long-term use—to address the unmet need for preventing disease advancement in earlier, asymptomatic stages. Interestingly, DR-201 VX01, an AOC3 inhibitor, is currently being evaluated in a 12-month phase 2 RCT (with an additional 3-month follow-up) against placebo. ³³ The study was designed to address limitations such as long-term DRSS assessment and evaluate 3 step DRSS score progression assessment in patients with moderate-to-severe NPDR (non CI-DME) with DRSS scores of 43 to 53 (Table 1).

Table 1.

Comparative summary of key oral drug candidates investigated for diabetic retinopathy.

Drug	Target/Mechanism	Key trial(s)	Phase	Population	Key inclusion notes	N	Dose	Primary endpoint (trial specific)	Duration	Key efficacy result	Key safety results
Fenofibrate	PPARα agonist	FIELD; ACCORD Eye; LENS; DRCR Protocol AF (ongoing)	Phase 3; (Protocol AF ongoing)	T2D (FIELD/ACCORD); T1/T2D with early NPDR (LENS); Mild–Moderate NPDR (Protocol AF)	Established DR at baseline in major trials; early NPDR in LENS; mild–moderate NPDR in Protocol AF	∼9700 (FIELD); >2800 (ACCORD Eye); per LENS; (Protocol AF ongoing)	200 mg/day (FIELD); 160 mg/day (ACCORD Eye & Protocol AF); 145 mg/day (LENS)	Laser need; DR progression/composite worsening; Prevention of DR worsening (Protocol AF)	5 years (FIELD); 4 years (ACCORD Eye); per LENS; 4–6 years (Protocol AF)	Reduced laser need (FIELD); ∼40% lower DR progression (ACCORD Eye); 27% lower risk of progression to referable DR (LENS)	Generally well-tolerated across trials
Ruboxistaurin (RBX)	PKCβ inhibitor	PKC-DRS; PKC-DRS2 (combined analysis)	Phase 3	Moderately severe to very severe NPDR	Eyes without prior focal/grid laser showed greater effect on laser need	n = 813 (combined analysis)	32 mg/day	Prevention of progression to PDR/DR progression	3 years	Primary progression endpoint negative; 41% relative risk reduction in SMVL; ↑≥15-letter gains; ↓need for focal/grid laser	Favorable overall safety profile
APX3330	Ref-1/APE1 redox signaling inhibitor	ZETA-1	Phase 2 b	Mod–severe NPDR or mild PDR	Moderately severe to severe NPDR and mild PDR included	n = 103	600 mg/day	≥2-step DRSS improvement (study eye) at 24 weeks	24 weeks	Primary negative; significant prevention of binocular ≥3-step DRSS worsening	Favorable safety/tolerability; no major organ toxicities reported
ASP8232	VAP-1 (AOC3) inhibitor	VIDI	Phase 2a	CI-DME	Monotherapy and add-on arms vs. ranibizumab in CI-DME	n = 96	40 mg/day	Mean % change in excess CST (monotherapy vs. ranibizumab)	12 weeks	No benefit vs. control; no added benefit with ranibizumab	Safe / well-tolerated
BI 1467335	AOC3 (VAP-1) inhibitor	ROBIN	Phase 2a	NPDR without CI-DME	NPDR, no CI-DME	n = 79	10 mg/day	Safety (ocular AEs over 24 weeks); exploratory ≥2-step DRSS improvement	12 weeks treatment; 24-week safety follow-up	Inconclusive efficacy; small % achieved ≥2-step DRSS improvement	Generally tolerated; higher ocular AEs vs. placebo; similar treatment-related AE rates
OPL-0401	ROCK1/2 inhibitor	SPECTRA	Phase 2	Mod–severe NPDR or mild PDR	Moderately severe to severe NPDR / mild PDR	n = 114	NR (not reported in manuscript)	≥2-step DRSS improvement	24 weeks	Primary and secondary endpoints negative	Favorable safety profile overall
X-82	Oral VEGF/PDGF receptor TKI	Phase 1 (AMD); APEX (AMD)	Phase 1–2 (AMD)	Neovascular AMD (context, not DR)	Included as systemic retinal TKI example from pipeline	—	Varied (AMD studies)	Safety; VA/OCT (AMD context)	Varied (AMD studies)	Signal in AMD phase 1; not studied in DR	GI issues, elevated LFTs in some (AMD phase 1)
VX01 (DR-201)	AOC3 inhibitor	DR-201 (ongoing)	Phase 2 (ongoing)	NPDR (non–CI-DME), DRSS 43–53	Moderate–severe NPDR; prevention-of-worsening focus	Planned n = 100	150 mg twice daily	DRSS 3-step progression over 12 months	12 months of treatment + 3 months of follow-up	Ongoing	Ongoing

Abbreviations: AE: adverse event; AMD: age-related macular degeneration; AU: Australia; CI-DME: center-involved diabetic macular edema; CST: central subfield thickness; DR: diabetic retinopathy; DRSS: diabetic retinopathy severity scale; LFT: liver function test; Mod-Sev: moderately severe to severe; NPDR: non-proliferative diabetic retinopathy; OCT: optical coherence tomography; Ph: phase; PDR: proliferative diabetic retinopathy; PPARα: peroxisome proliferator–activated receptor alpha; PKCβ: protein kinase C beta; ROCK: rho kinase; SMVL: sustained moderate visual loss; T1/T2D: type 1/type 2 diabetes; TKI: tyrosine kinase inhibitor; VA: visual acuity; VAP-1/AOC3: vascular adhesion protein-1/amine oxidase copper-containing 3; VEGF: vascular endothelial growth factor; PDGF: platelet-derived growth factor; GI: gastrointestinal.

Pills in the DR picture

Addressing unmet needs

Following the completion of current studies demonstrating safety and efficacy, oral therapies could significantly reshape the management landscape for DR by directly addressing key limitations of current standards of care.

Reducing treatment burden. The most evident potential benefit is alleviating the substantial burden associated with frequent intravitreal injections and clinic visits. ⁷ A daily pill could drastically simplify treatment logistics for patients, caregivers, and healthcare systems.

Improving compliance. The convenience and noninvasive nature of oral administration are expected to lead to better long-term adherence compared with injections or laser procedures, potentially translating into more consistent disease control and improved outcomes. ¹

Noninvasive option. An oral route eliminates the procedural discomfort, anxiety, and rare but serious risks associated with intraocular injections, making treatment more acceptable for many patients, particularly those with needle phobia or logistical challenges in accessing specialized care. ¹⁵

Earlier intervention. Oral agents are promising for early intervention, specifically during the NPDR stages. ³⁷ Current practice often involves monitoring NPDR until the development of vision-threatening complications. A safe oral therapy that slows or prevents progression could fill this crucial gap, potentially reducing the number of patients developing PDR or DME. The positive data for fenofibrate and ruboxistaurin in reducing progression or vision loss in NPDR cohorts, along with the secondary prevention endpoint met by APX3330, support this potential role.^29,30

Bilateral treatment. As DR is a systemic disease affecting both eyes, often asymmetrically, the systemic nature of oral therapy offers the inherent advantage of treating both eyes simultaneously with a single intervention.^3,4

Potential clinical niches

Based on the available evidence and theoretical advantages, several potential clinical niches for oral DR therapies can be envisioned.

Primary prevention. Although currently lacking strong evidence, the ultimate goal might be to identify individuals at high risk of diabetes before the onset of retinopathy and use safe oral agents to prevent its development altogether.

NPDR management. This appears to be the most promising and logical niche. Oral therapies could be administered to patients with established mild, moderate, or severe NPDR to slow or halt progression to PDR or CI-DME, thereby delaying or potentially avoiding the need for injections or laser.^29,30 The convenience and bilateral effects are well-suited for managing this often asymptomatic, chronic stage where the burden of injections is a major deterrent to early intervention. ³⁷

Adjunctive therapy. Oral agents can be used in combination with intravitreal anti-VEGF or laser therapy in patients with PDR or DME. ¹² The goal could be to reduce the required frequency of injections (thereby lessening burden), enhance treatment response in partial responders by targeting complementary pathways, or provide a broader mechanistic effect. However, the negative results of the VIDI combination arm (ASP8232 + ranibizumab) moderate the expectations for this approach, at least for VAP-1 inhibition. ³¹

Post-SoC maintenance. Following initial stabilization of PDR or DME with intensive injections or laser, oral therapy could potentially be used as a maintenance strategy to sustain remission and prevent recurrence or progression over the long term.

The available evidence suggests that the most viable role for oral therapies, given the current state of development and the efficacy profiles observed, lies in managing NPDR to prevent progression. Treating established, advanced complications such as PDR and DME likely requires the potent, localized effect of intravitreal anti-VEGF agents and PRP.

The suitability of oral agents for long-term, preventative use in NPDR aligns well with their potential advantages of convenience, noninvasiveness, and bilateral action, addressing a clear unmet need where the burden of current interventions is prohibitive.

Successful integration of oral therapies, particularly for NPDR management, would likely necessitate a significant shift in the current DR treatment paradigm. It would encourage a move from reactive treatment of complications toward proactive, preventative management initiated earlier in the disease course. This shift would also likely require enhanced collaboration between ophthalmologists and primary care physicians or endocrinologists, who typically manage systemic medications and monitor for potential systemic effects. Establishing clear protocols for prescribing, monitoring, and co-management, as explored conceptually in DRCR Protocol AF, would be crucial for the safe and effective implementation of oral DR therapies in routine clinical practice. ²⁵

From trial to clinic

Clinical decision-making and integration

As oral therapies for DR progress through clinical trials, their future integration into routine practice will likely focus on early-stage intervention and complementary use with current treatments. Oral agents have the greatest potential in the areas outlined below.

Preventive treatment of NPDR. This will help in targeting patients at mild–to-moderate stages, before the onset of vision-threatening complications, when the burden of intravitreal injections is unjustifiable.

Adjunctive therapy. In combination with intravitreal anti-VEGF agents or laser photocoagulation to reduce injection frequency, this therapy can enhance the response in partial responders or provide systemic benefit.

Successful integration warrants the development of clear clinical algorithms, including when to initiate oral treatment, how to monitor efficacy, and when to escalate to intravitreal therapies in case of disease progression.

Patient selection and subgroups likely to benefit

Optimal patient selection will be critical for maximizing benefit and minimizing unnecessary exposure. Likely target subgroups include the following:

Patients with moderate-to-severe NPDR at high risk of progression to PDR or DME, especially those with the following conditions:

Poor access to frequent ophthalmic follow-up;

Difficulty tolerating or complying with intravitreal therapy;

Bilateral disease requiring systemic coverage;

Patients with partial or suboptimal response to anti-VEGF therapy, where complementary mechanisms (e.g. anti-inflammatory and anti-oxidative) may enhance outcomes;

Patients with high-risk systemic profiles (e.g. uncontrolled diabetes and hypertension) where systemic modulation could provide dual ophthalmic and systemic benefits.

Biomarker-guided stratification (once available) may further refine selection.

Challenges for adoption in routine practice

Several practical hurdles must be addressed before widespread clinical adoption:

Regulatory approval and reimbursement. Payers require clear evidence of clinical benefit, cost-effectiveness, and appropriate indications.

Safety concerns. Oral therapies need an excellent long-term safety profile, as patients are often asymptomatic and at early disease stages.

Collaboration with other specialties. Coordination between ophthalmologists, diabetologists, and primary care physicians is critical for prescribing, monitoring, and adjusting systemic therapies.

Patient adherence. Although oral administration is theoretically more convenient, ensuring adherence in a population already burdened by polypharmacy remains a challenge.

Why progress is hard?

Despite the strong rationale and potential benefits, the development of effective and safe oral therapies for DR faces significant challenges inherent to systemic drug delivery targeting a localized ocular condition.

Systemic side effects and toxicity

Oral administration distributes the drug throughout the body, increasing the risk of off-target effects and systemic AEs compared to localized intravitreal delivery. ¹² Clinical trials have highlighted the following risks: (a) PKC412 development was hampered by dose-limiting gastrointestinal and liver toxicity; ²⁷ (b) X-82 showed signals for GI issues and elevated liver enzymes in some patients in its phase 1 AMD trial; and (c) even the generally well-tolerated APX3330 caused mild AEs such as pruritus and rash in some individuals. ²⁹ Systemic drugs can also interact with other medications the patient is taking, which is particularly concerning in the diabetic population, who often have multiple comorbidities. ⁴³ Ensuring an excellent long-term safety profile is paramount, especially if these drugs are intended for chronic use in patients with NPDR who may otherwise be asymptomatic and have good vision. ²⁹ The tolerance for systemic side effects is likely lower for an eye condition compared with that for life-threatening diseases such as cancer.

Ocular bioavailability: crossing the BRB

A fundamental challenge is achieving therapeutically relevant drug concentrations in the retina and choroid following oral administration. ¹² The BRB, composed of tight junctions between retinal capillary endothelial cells and the retinal pigment epithelium, strictly controls the passage of molecules from the systemic circulation into the neural retina. ¹ Many drugs, particularly larger molecules or those with unfavorable physicochemical properties (e.g. low lipophilicity), struggle to cross the BRB efficiently. ⁴³ Consequently, achieving adequate intraocular drug levels might require high systemic doses, which in turn increases the risk of systemic toxicity. ¹² Although some compounds such as OPL-0401 showed promising retinal exposure in preclinical models, this did not translate into clinical efficacy, highlighting the complexity of this issue. ⁴⁴ Overcoming the BRB effectively and safely remains a major pharmacological obstacle. This dual challenge—achieving sufficient drug levels in the eye without causing unacceptable systemic side effects—represents the central difficulty in developing successful oral therapies for retinal diseases.

Demonstrating robust clinical efficacy

Proving that an oral agent provides a clinically meaningful benefit for DR, especially compared with highly effective local therapies such as anti-VEGF, is challenging. As evidenced by the recent phase 2 trials (VIDI, ROBIN, ZETA-1 primary endpoint, and SPECTRA primary endpoint), translating promising preclinical data or inhibiting a specific pathway does not automatically result in successful clinical outcomes.^29,31,32 Measuring the efficacy in managing NPDR presents the following unique challenges: (a) visual acuity often remains good, making it an insensitive endpoint; and (b) changes in the DRSS score can exhibit significant variability and may not always correlate directly with visual function, as observed in the ROBIN study. ³² Demonstrating a clear advantage over simple observation or standard systemic diabetes care in early disease requires large, long-term trials.

Patient heterogeneity and selection

DR progression is highly variable among individuals and is influenced by factors such as duration of diabetes, glycemic control, blood pressure, genetics, and other comorbidities. ⁴⁵ This heterogeneity makes it challenging to design trials and identify patient subgroups most likely to respond to a specific oral therapy. The lack of reliable biomarkers for predicting disease progression or treatment response further complicates patient selection and trial interpretation. ⁴⁶ Efforts to use computational platforms and real-world data to identify high-risk patients, as mentioned for OPL-0401 development, can address this challenge.^44,47

Regulatory considerations

Navigating the regulatory pathway for oral DR therapies presents specific hurdles. Defining clinically meaningful and acceptable endpoints for NPDR trials is crucial and still evolving. ⁴⁸ Although DRSS improvement (e.g. ≥2-step change) has been used, its limitations (variability and failure in recent trials) are apparent. ²⁹ Alternative endpoints such as prevention of DRSS worsening (e.g. ≥3-step binocular change, as proposed for APX3330) or time to development of PDR or CI-DME (the primary outcome in Protocol AF) may be more appropriate for preventative therapies but require validation and regulatory acceptance.^25,48 Regulatory agencies such as the FDA demand robust evidence of both efficacy and safety from adequate and well-controlled studies, typically requiring two positive pivotal phase 3 trials for common conditions. ⁴⁹ The safety bar for a systemically administered drug intended for potentially long-term use in an ophthalmic condition, often in patients with good vision, is particularly high. ⁴¹ Demonstrating not only statistical significance but also a clinically meaningful benefit–risk profile compared with existing management strategies (including observation for early NPDR) is essential for approval. ⁴⁹

Conclusions

Synthesis of current evidence

The pursuit of oral therapies for DR is driven by a clear and compelling unmet need for overcoming significant limitations, particularly the treatment burden associated with current standards of care such as intravitreal anti-VEGF injections. The theoretical advantages of an oral approach—noninvasiveness, improved compliance, bilateral treatment, and the potential for earlier intervention in NPDR—are substantial.

Historical evidence from large trials of repurposed drugs such as fenofibrate (FIELD and ACCORD Eye) and ruboxistaurin (PKC-DRS/DRS2) provided encouraging signals, demonstrating that oral agents targeting broader metabolic or signaling pathways could indeed reduce DR progression and the need for invasive treatments, particularly in patients with existing NPDR. ²⁶ However, the translation of this promise into new, approved therapies has been slow, and recent phase 2 trials evaluating novel oral agents with more specific molecular targets (VAP-1/AOC3 inhibitors, Ref-1 inhibitors, and ROCK inhibitors) have largely failed to meet their primary efficacy endpoints, although some demonstrated potential secondary benefits in preventing disease worsening.^31,35,36

This underscores the persistent and formidable challenges facing oral drug development for retinal diseases. Demonstrating robust clinical efficacy via the systemic route, achieving adequate drug concentrations across the BRB without causing unacceptable systemic toxicity, and defining appropriate regulatory endpoints for preventative strategies in NPDR remain significant challenges. ¹²

Future directions

Despite recent setbacks, the quest for effective oral DR therapies continues, fueled by the magnitude of the unmet need. Future progress will likely depend on several key areas:

Completion of ongoing trials. Results from large, ongoing phase 2 and 3 trials, such as DRCR Protocol AF evaluating fenofibrate in mild-to-moderate NPDR, are eagerly awaited and could provide definitive evidence to support the use of this agent.^21,25 The potential advancement of APX3330 into phase 3 is also of interest. Additionally, the interesting 12-month DR-201 VX01 study assessing 3-step DRSS score progression, focusing on prevention-of-worsening endpoints, will be critical to monitor.^29,33

Refined trial designs and endpoints. Continued dialogue with regulatory agencies is needed to establish validated and clinically meaningful endpoints for NPDR trials, potentially focusing on preventing progression to VTDR or using composite binocular scales. ⁴⁸ Long-term trials may be necessary to capture these progression events.

Biomarker development. Identifying biomarkers that predict DR progression or response to specific oral therapies could enable better patient selection, improving trial efficiency and targeting treatment to those most likely to benefit. ⁴⁶

Combination therapies. Exploring rational combinations of oral agents targeting different pathways or combining oral agents with less frequent intravitreal injections might offer synergistic benefits; however, robust preclinical rationale and careful trial design are warranted.

Novel delivery strategies. Although this review focused on conventional oral administration, research into novel systemic delivery systems or formulations designed to enhance ocular bioavailability could potentially improve the therapeutic index of future candidates.

Continued pathophysiological research. Deeper understanding of the intricate molecular mechanisms driving DR, particularly in its earlier stages and including neurovascular interactions, may reveal more effective systemic targets. ²

Final thoughts

Oral therapies for DR hold significant potential to transform patient management by offering a noninvasive, less burdensome, and binocular alternative to current treatments, particularly for preventing disease progression in the vast population of patients with NPDR. However, the journey from concept to clinical reality has proven challenging.

The critical balance between achieving adequate ocular drug delivery and maintaining systemic safety remains the central pharmacological challenge. ¹² Overcoming this and demonstrating clear clinical benefit using accepted regulatory endpoints are warranted for the approval and widespread clinical adoption of any oral agent.

Therefore, although the prospect of a “pill for DR” is highly desirable and continues to drive research investment, it remains to be proven in phase 3 registrational trials. Continued rigorous research, innovative trial designs, and a potentially strategic focus on prevention rather than reversal are key to determining if and when oral therapies can truly fulfill their promise in combating this major cause of vision loss. The persistent effort, despite setbacks, reflects the profound need for better, more patient-friendly, safe, cost effective, and binocular options for the long-term management of DR.