Current and Emerging Pharmacologic Therapies for Diabetic Retinopathy

ABSTRACT

Diabetic retinopathy, a prevalent microvascular complication of diabetes mellitus, is a leading cause of blindness among adults in developed countries. Risk factors include prolonged duration of diabetes, elevated glycosylated hemoglobin levels, hypertension, and dyslipidemia, with rapid glucose reduction also increasing risk for developing diabetic retinopathy. The American Academy of Ophthalmology classifies diabetic retinopathy into non‐proliferative diabetic retinopathy and proliferative diabetic retinopathy, distinguished by the absence or presence of neovascularization, respectively. Complications such as diabetic macular edema, retinal detachment, and irreversible vision loss further underscore the need for effective therapies. Current treatments include laser photocoagulation, vitrectomy, and anti‐vascular endothelial growth factor agents. This narrative review evaluates established pharmacotherapy and explores emerging therapies targeting novel pathways such as inflammation, oxidative stress, and vascular stability. Investigational agents, including integrin inhibitors, gene therapies, and small‐molecule antagonists, alongside innovative delivery systems such as topical formulations and sustained‐release implants, offer the potential to enhance treatment efficacy, patient adherence, and overall outcomes in diabetic retinopathy. By examining these advancements, including innovative delivery systems, this review aims to inform practitioners about the evolving landscape of pharmacotherapy for diabetic retinopathy.

Diabetic retinopathy (DR) is a common microvascular complication of diabetes mellitus and the leading cause of blindness in adults aged 20 to 74 years in developed countries [1]. In 2021, an estimated 9.6 million Americans or 26.4% of those with diabetes had DR, emphasizing its substantial public‐health burden [2]. Globally, DR affects approximately 103.12 million individuals (22.27% prevalence) living with diabetes, as of 2020. Projections estimate a rise to 160.50 million by 2045—a 56% increase—disproportionately burdening regions such as Africa and the Middle East/North Africa due to the rising diabetes incidence and screening gaps. This escalating public health issue amplifies the need for accessible pharmacotherapies beyond current standards [3].

The American Academy of Ophthalmology (AAO) classifies DR into two main stages: non‐proliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR) [4]. NPDR is defined by the absence of neovascularization and can be further classified into three categories, based on symptoms [4]. Mild NPDR is characterized by microaneurysms, which are small balloon‐like swellings in retinal blood vessels that may leak fluid [4]. Moderate NPDR includes microaneurysms, small hemorrhages, or cotton‐wool spots that reduce blood flow [4]. Severe NPDR is defined by intraretinal hemorrhaging across all four quadrants of the eye, venous beading in two quadrants, or intraretinal microvascular anomalies in one quadrant [4]. PDR is characterized by neovascularization of the disc (NVD) or elsewhere (NVE), or vitreous hemorrhage with new vessels prior to leakage [2]. Diabetic macular edema (DME) can occur at any stage and is the primary cause of vision loss in DR. DME is classified as center‐involved (CI‐DME) or non‐center‐involved (NCI‐DME), and can be present in all stages of DR with complications including retinal detachment and irreversible blindness [5]. The pathophysiology of DR is driven by chronic hyperglycemia, which disrupts glucose transport and induces retinal inflammation via the breakdown of the blood‐retinal barrier [6]. This activates biochemical pathways including protein kinase C (PKC), advanced glycation end products (AGEs), and hexosamine biosynthetic pathway (HBP), increasing reactive oxygen species (ROS) and driving oxidative stress, inflammation, and neovascularization. Specific ROS‐related mechanisms trigger mitochondrial dysfunction and lipid peroxidation, amplifying early neurodegeneration. Inflammation is mediated by upregulated cytokines, alongside adhesion molecules. Vascular instability arises from angiopoietin/Tie2 (Ang‐2) dysregulation. Hyperglycemia elevates Ang‐2, competitively inhibiting phosphorylation and destabilizing the blood‐retinal barrier, fostering leakage and neovascularization. Evidence suggests retinal neurodegeneration, including neuronal apoptosis and glial activation, precedes microvascular changes, particularly in those living with diabetes [6]. The duration of hyperglycemia or diabetes remains the strongest predictor of DR. In type 1 diabetes (T1D), retinopathy develops in approximately 25% of people by 5 years, 60% by 10 years, and 80% by 15 years of disease onset [5, 7]. In people with type 2 diabetes (T2D), prevalence of DR within 5 years of diagnosis is approximately 40% in those on insulin therapy versus 24% in non‐insulin users, with rates rising over time [5, 7]. Additional risk factors include elevated glycosylated hemoglobin (A1C), proteinuria, hypertension, dyslipidemia, male sex, and pregnancy [1, 5]. Paradoxically, rapid initiation of intensive glycemic control can also increase the risk for retinopathy [1]. Some randomized trials suggest glucagon‐like peptide‐1 (GLP‐1) receptor agonists are associated with mild DR worsening, potentially due to rapid glycemic improvements [1, 8]. However, a meta‐analysis of cardiovascular outcome trials found no consistent association between GLP‐1 receptor agonists use and DR progression [1, 9]. Further studies specifically designed to evaluate DR risk with GLP‐1 receptor agonists are needed. The American Diabetes Association (ADA) provides recommendations for evidence‐based screening guidelines for DR. Adults with T1D should undergo an initial dilated and comprehensive eye examination within 5 years of diagnosis [1]. People with T2D should have an initial dilated and comprehensive eye examination at the time of diagnosis. Annual examinations are standard, with more frequent monitoring if DR progresses or threatens vision. Those of child‐bearing potential with pre‐existing T1D or T2D should be counseled on the potential risk for development or progression of DR with pregnancy. Eye examinations are recommended prior to pregnancy, in the first trimester, and potentially every trimester based on DR severity. Those with gestational diabetes are not at increased DR risk and do not require eye examinations during pregnancy [1]. Other preventative strategies emphasize optimizing glycemic, blood pressure, and lipid control. Barriers to regular DR screening and treatment adherence include socioeconomic disparities, lack of awareness, limited access to eye care, frequent injection burdens, logistical challenges, high costs, and suboptimal quality of life impacting daily functioning [10]. Although anti‐VEGF agents, laser photocoagulation, and vitrectomy form the therapeutic backbone of DR therapy, each therapy has limitations. Anti‐VEGF therapies stabilize vision yet demand frequent intravitreal injections. Laser photocoagulation reduces severe vision loss in high‐risk PDR but incurs recurrence rates within 2 years, risks of retinal scarring, and peripheral field vision loss. Vitrectomy, reserved for vitreous hemorrhage, achieves a high rate of success but involves surgical complications, such as endophthalmitis risk and extended recovery [5]. Multimodal approaches, integrating patient education, coordinated care, and risk factor management, are critical for improving early detection, adherence, and patient‐centered outcomes.

1. Methods and Purpose

This narrative review was developed through a systematic literature search of PubMed, Embase, and Cochrane Library databases from January 2010 to July 2025. Keywords included “diabetic retinopathy,” “pharmacotherapy,” “anti‐VEGF,” “corticosteroids,” “emerging therapies,” “gene therapy,” and “drug delivery systems.” Additional sources included ADA and AAO guidelines, ClinicalTrials.gov for pipeline agents (filtered for Phase 2 and 3 trials), and recent reviews on DR management. Articles were included if they were peer‐reviewed, English‐language, and focused on pharmacologic interventions for DR in adults. Exclusions comprised non‐human studies, case reports, and non‐ophthalmic complications. Reference lists of included articles were selectively included based on relevance. The purpose of this review was to examine and summarize findings of current pharmacotherapeutic options and potential advancements in the pipeline for people with DR, with a focus on recently approved agents, those nearing market, and their implications for pharmacy practice.

1.1. Current Standard Pharmacologic Therapies

Standard therapies for DR prioritize early intervention to preserve vision, with anti‐VEGF agents recommended as first‐line for CI‐DME and high‐risk PDR due to superior efficacy in reduction of neovascularization and edema. Frequency of injections and costs are limitations to anti‐VEGF therapy that may influence adherence. Corticosteroids are second‐line for DME refractory to anti‐VEGF or in cases of recent cardiovascular events, prioritizing patients with pseudophakia to minimize cataract risk. Laser photocoagulation serves as adjunct for severe NPDR and PDR to ablate ischemic areas, while vitrectomy addresses vitreous hemorrhage or retinal detachment. However, there are limitations to photocoagulation and vitrectomy, such as recurrence, peripheral vision loss, and pain. Vitrectomy also involves infection and cataract progression, following surgery [11].

2. Anti‐VEGF Agents

Anti‐VEGF agents inhibit VEGF, a protein that promotes abnormal blood vessel growth in DR [1]. These medications are administered via intravitreal injection, delivering the drug directly into the vitreous humor to halt or slow DR progression by reducing neovascularization. Anti‐VEGF agents are used alone or in combination with other treatments, such as pan‐retinal photocoagulation (PRP), depending on disease severity and clinical goals. PRP is indicated to reduce the risk of vision loss in individuals with high‐risk PDR or severe NPDR, with anti‐VEGF agents as a reasonable alternative. For CI‐DME with impaired visual acuity, anti‐VEGF agents are first‐line treatment options [1].

The AAO provides guidance for the use of anti‐VEGF agents in their Diabetic Retinopathy Preferred Practice Pattern [5, 11]. Table 1 summarizes each anti‐VEGF agent and its related indication, available formulation, significant adverse events, and cost based on average wholesale price. Anti‐VEGF therapy is recommended as first‐line for CI‐DME with impaired vision and high‐risk PDR, often combined with laser photocoagulation [3, 11].

TABLE 1.

Anti‐VEGF agents ^a for diabetic retinopathy [1, 5, 11].

Specific agent	Indication(s)	Formulations	Adverse effects (significant or > 10%)	AWP b
Aflibercept	DR with or without DME; DME; nAMD	Intravitreal injection	Ophthalmic: cataract, conjunctival hemorrhage, eye pain	$1998–$2275.50 per dose
Ranibizumab	DR with or without DME; DME; nAMD	Intravitreal injection, port delivery system	Arterial thromboembolism, anemia, antibody development, headache, arthralgia, ophthalmic, bronchitis	$979.20–$2340 for injection; $9600 for implant
Bevacizumab	Not FDA‐approved for ocular use; used off‐label	Intravitreal injections are compounded from IV formulation	Rate of serious adverse events similar to aflibercept and ranibizumab [12]	$184.02–$239.08 for IV vials
Brolucizumab	DME and nAMD	Intravitreal injection	Antibody development	$2451.05 per dose

Abbreviations: AWP, average wholesale price; DME, diabetic macular edema; DR, diabetic retinopathy; IOP, intraocular pressure; IV, intravenous; nAMD, neovascular age‐related macular degeneration.

^a Intravitreal anti‐VEGF therapy is usually recommended for center‐involving diabetic macular edema (CI‐DME) across moderate non‐proliferative diabetic retinopathy (NPDR) to high‐risk proliferative diabetic retinopathy (PDR) stages; sometimes for severe NPDR or any PDR stage without macular edema or with non‐center‐involving DME (NCI‐DME); rarely for moderate NPDR with NCI‐DME; and not indicated for normal/minimal or mild NPDR without CI‐DME.

^b Average wholesale price is provided as a reference price only; this information should be used for benchmarking purposes only.

A meta‐analysis evaluated high‐quality randomized controlled trials investigating anti‐VEGF agents for NPDR without CI‐DME [13]. The analysis found that aflibercept was the only agent studied in this population. Outcomes included changes in best corrected visual acuity, improvement in Diabetic Retinopathy Severity Scores (DRSS), progression to vision‐threatening complications, changes in central subfield thickness, ocular adverse events, and quality of life. Aflibercept significantly reduced DRSS scores and vision‐threatening complications compared to sham over 2 years, with no significant visual acuity improvement [13]. Safety profiles showed ocular adverse events were monitored without notable differences from sham treatment, whereas adherence and treatment burden were not addressed.

The Protocol W trial assessed aflibercept 2.0 mg in moderate to severe NPDR without CI‐DME [14]. Aflibercept was administered at baseline, months 1, 2, and 4, then every 4 months through 2 years, with treatment deferred if retinopathy improved to mild NPDR or better. The primary outcome was the development of vision‐threatening complications with secondary outcome being a change in best corrected visual acuity. Aflibercept reduced the 2‐year probability of progression to PDR or CI‐DME compared to sham but did not improve visual outcomes [14]. Due to the treatment burden and lack of visual benefit, anti‐VEGF therapy is not widely adopted for moderate to severe NPDR without CI‐DME [1]. In addition, adherence was notably poor in a retrospective cohort study of anti‐VEGF monotherapy for PDR. Over 40% of participants were lost to follow‐up within 1 year. Adherence challenges with frequent 6‐month gaps were associated with worse visual outcomes and increased complications, such as vitrectomy and retinal detachment [15].

Currently, two anti‐VEGF agents are approved by the United States Food and Drug Administration (FDA) for DR. Ranibizumab received approval in 2015 for DR with DME and in 2017 for DR with or without DME. The RISE and RIDE trials enrolled adults with DME causing vision loss and central subfield thickness ≥ 275 μm to evaluate ranibizumab [12]. Participants who received monthly intravitreal ranibizumab (0.3 or 0.5 mg) were compared to a sham injection. The primary outcome was the proportion of participants gaining ≥ 15 letters in best corrected visual acuity at 24 months. Secondary outcomes included the change in DRSS and safety events. The trials demonstrated that ranibizumab significantly improved visual acuity (34%–46% of treated patients gained ≥ 15 letters at 24 months vs. 12%–18% in the sham group) and DRSS scores. Ocular and systemic adverse effects were infrequent and consistent with previous studies [12].

Aflibercept was approved in 2019 for DR with or without DME based on the PANORAMA trial, which studied adults with moderately severe to severe NPDR without CI‐DME [16]. The interventions were aflibercept every 8 weeks or 16 weeks (with as needed doses), compared to sham injections. A higher‐dose formulation of aflibercept (8 mg) was available, which allowed extended dosing intervals of 12 to 16 weeks [16]. The primary outcome was the proportion of eyes with a ≥ 2‐step improvement in DRSS level at weeks 24, 52, and 100. Key secondary outcomes included the incidence of vision‐threatening complications and CI‐DME. Aflibercept significantly increased the proportion of eyes achieving a ≥ 2‐step improvement and reduced vision‐threatening complications and CI‐DME but did not improve visual acuity over 2 years [16, 17]. The reduced injection burden may improve patient satisfaction and adherence in exploratory quality of life assessments. A meta‐analysis on recurrent of retinopathy of prematurity following anti‐VEGF therapy did not directly address adherence, compliance, or lost to follow‐up for ranibizumab or aflibercept [18]. Indirectly, variability in follow‐up durations (ranging from 6 months to 5 years) is noted as a limitation that may underreport late recurrences, potentially implying challenges in long‐term monitoring but without quantifiable adherence metrics [18].

Bevacizumab is commonly used off‐label in this setting due to its lower cost. There are no clinical trials directly comparing ranibizumab, aflibercept, and bevacizumab for the treatment of DR without DME. For CI‐DME, research has demonstrated that these three agents improve visual acuity, but aflibercept provides greater visual acuity improvement in eyes with baseline vision of 20/50 or worse [19]. No significant differences in serious adverse events, hospitalizations, or major cardiovascular events were observed among ranibizumab, aflibercept, and bevacizumab [19]. The ADA and AAO recommend aflibercept and ranibizumab as first‐line anti‐VEGF agents for DR (with or without DME) [1, 5].

Despite their efficacy, anti‐VEGF agents are limited by the burden of frequent intravitreal injections and variability in patient response. Adherence to follow‐up is important, as lapses in treatment can lead to worse visual acuity and anatomic outcomes [1]. To address the treatment burden, a Port Delivery System (PDS) has been investigated as a surgically implanted, refillable device. It is FDA‐approved for neovascular age‐related macular degeneration (nAMD) and has been studied for DR. The PAVILION trial, published in March 2025, evaluated the PDS with ranibizumab in adults with moderately severe to severe NPDR without CI‐DME [20]. Participants receiving PDS refilled every 36 weeks were compared to those under standard of care monitoring without anti‐VEGF therapy. At 52 weeks, 81% of PDS‐treated participants achieved at least a 2‐step improvement in DRSS, compared to 9% in the control group. A transient best corrected visual acuity loss of 7.4 letters occurred 4 weeks post‐implantation but resolved within 8 weeks [20]. The PDS with ranibizumab reduced the risk of CI‐DME, PDR, and anterior segment neovascularization compared to standard of care monitoring [20]. Although the PDS with ranibizumab option offers a promising alternative for reducing treatment frequency while maintaining efficacy in preventing disease progression, long‐term safety and efficacy data are still needed to fully characterize the risk–benefit profile of PDS in DR. The ongoing PAGODA trial evaluates PDS re‐implantation with ranibizumab versus intravitreal ranibizumab injections [21]. Long‐term safety and efficacy data are still needed.

3. Corticosteroids

Inflammation plays a significant role in the pathogenesis of DR; therefore, corticosteroids are utilized for their potent anti‐inflammatory and anti‐angiogenic properties. However, due to their side effect profiles, intraocular corticosteroids serve as second‐line options for DME unresponsive to anti‐VEGFs, leveraging anti‐inflammatory effects [5]. Long‐term use is associated with increased risks of cataract formation and elevated intraocular pressure (IOP), which necessitate careful patient selection and monitoring [22]. Corticosteroids are typically considered in cases of inadequate response to an anti‐VEGF agent, contraindication to anti‐VEGF agents (including a recent major cardiovascular event), and inability to adhere to frequent injection schedule required for anti‐VEGF treatments. They can also be considered for patients with pseudophakic eyes, as pseudophakia reduces the risk of steroid‐induced cataracts [1, 5]. Available intraocular corticosteroids include a biodegradable dexamethasone intravitreal implant, a non‐biodegradable fluocinolone acetonide (FAc) implant, and intravitreal triamcinolone acetonide. Table 2 summarizes each corticosteroid for DR and its related indication, available formulation, significant adverse events, and cost based on average wholesale price.

TABLE 2.

Corticosteroids for diabetic retinopathy [1, 5, 11].

Corticosteroid	Indication(s)	Formulations	Adverse effects (Significant or > 10%)	AWP a
Dexamethasone	CI‐DME	Intravitreal implant	Hypertension, cataract, conjunctival hemorrhage, elevated IOP	$1647 per dose
Fluocinolone	CI‐DME	Intravitreal implant	Cataract, conjunctival hemorrhage, decreased visual acuity, eye pain, elevated IOP	$10,957–$22,830 per implant
Triamcinolone	Not FDA‐approved for DME, used off‐label	Intravitreal injection (suspension)	Eye pain, elevated IOP, progression of cataract	$1132–$1980 per single use vial or dose

Abbreviations: AWP, average wholesale price; CI‐DME, center‐involved diabetic macular edema; IOP, intraocular pressure.

^a Average wholesale price is provided as a reference price only; this information should be used for benchmarking purposes only.

The dexamethasone implant is FDA‐approved for DME based on a pivotal trial involving adults with DME, best corrected visual acuity of 20/50 to 20/200 and central retinal thickness ≥ 300 μm [23]. The trial compared intravitreal dexamethasone implants at doses of 0.35 or 0.7 mg administered with re‐treatment no more than every 6 months to sham procedure. The primary efficacy outcome was the proportion of patients achieving a ≥ 15‐letter improvement in best corrected visual acuity from baseline, with secondary end points including change in central retinal thickness and safety outcomes. The dexamethasone group demonstrated statistically significant improvements in visual acuity and greater reductions in central retinal thickness compared to the sham group. However, safety outcomes included cataract‐related adverse events and elevated IOP, consistent with known corticosteroid risks [23].

The BEVORDEX trial enrolled adults with CI‐DME to compare intravitreal dexamethasone implant (administered every 16 weeks) to intravitreal bevacizumab (administered every 4 weeks as needed) [24]. The primary outcome was the proportion of eyes gaining ≥ 10 letters in best corrected visual acuity at 12 months. Dexamethasone achieved comparable visual outcomes to bevacizumab with superior anatomic improvements and fewer injections. However, a higher incidence of vision loss was observed in the dexamethasone group, primarily due to cataract development. This trial concludes excellent adherence based on the 1‐year primary outcome visit; however the study did not assess quality of life or patient‐reported outcomes [24].

The FAc intravitreal implant is FDA‐approved for treatment of DME in patients previously treated with corticosteroids without a clinically significant rise in IOP. The FAME trial compared intravitreal FAc implant with sustained intraocular delivery as compared to sham control and demonstrated delayed progression to PDR with improvement in DRSS [25]. Retention rates were high in this trial, indicating no notable treatment burden‐related dropouts [25]. In addition, the Phase 4 PALADIN study followed participants for 36 months post‐implantation of FAc to confirm efficacy and safety end points [26]. The results confirmed visual benefits at 36 months, such as gain in visual acuity and reduction in central subfield thickness. Safety was favorable with stable mean IOP, as approximately 11% experienced elevations. Despite these positive results, the study emphasized the need for ongoing monitoring for IOP elevations and cataract development [25]. Both trials were limited to 36 months of follow‐up, excluding long‐term outcomes and lacked assessment on quality of life or cost‐effectiveness [25, 26].

Although not FDA‐approved for DME, intravitreal triamcinolone acetonide is used off‐label. A randomized trial included adults with DME and compared intravitreal triamcinolone prior to macular laser photocoagulation to laser photocoagulation alone. The combination therapy improved visual acuity but was associated with a higher incidence of cataract surgery and elevated IOP [22]. Another study enrolled adults with DME, randomized to intravitreal ranibizumab plus immediate laser (within 3–10 days of first injection), intravitreal ranibizumab plus delayed laser photocoagulation (≥ 24 weeks after first injection), intravitreal triamcinolone plus immediate laser photocoagulation, and laser photocoagulation alone [27]. Both ranibizumab groups achieved greater improvements in visual acuity compared with laser photocoagulation alone, while combination therapy was not superior to laser photocoagulation alone, except in pseudophakic eyes. Elevated IOP and cataract surgery were more frequent in the triamcinolone group [27].

3.1. Recent Developments in Pharmacotherapy

Faricimab is a novel bispecific monoclonal antibody that inhibits both angiopoietin‐2 (Ang‐2) and VEGF. The angiopoietin‐tyrosine kinase with immunoglobulin‐like domain‐2 (Tie‐2) signaling pathway regulates vascular homeostasis and controls vessel permeability [28]. Angiopoietin‐1 (Ang‐1) activates Tie‐2 to promote vascular stability, whereas Ang‐2 levels are upregulated in conditions like hyperglycemia and competitively binds to Tie‐2, inhibiting Ang‐1 signaling. This disruption leads to vascular destabilization, breakdown of the blood‐retinal barrier, and inflammation. By inhibiting both Ang‐2 and VEGF, faricimab enhances vascular stability and reduces retinal inflammation [28].

Faricimab is FDA‐approved for DME and nAMD based on results from the Phase 2 BOULEVARD trial [28]. In this specific trial, treatment‐naïve participants were randomized to intravitreal injections of faricimab 6, 1.5, or 0.3 mg dosed monthly for 20 weeks. Previously‐treated participated were randomized to either 6‐mg faricimab or 0.3‐mg ranibizumab dosed monthly for 20 weeks. Interventions were observed up to 36 weeks to evaluate durability. Faricimab achieved greater visual acuity gains than ranibizumab in treatment‐naive participants. It also demonstrated extended durability, allowing longer intervals (monthly) between injections for both treatment‐naive and previously‐treated participants. Safety was comparable across groups, though common adverse events of faricimab included mild ocular events, such as conjunctival hemorrhage, elevated IOP, and eye pain, with a safety profile comparable to ranibizumab. The trial did not assess quality of life or adherence metrics [28]. Due to the modest sample size with limited statistical power for secondary end points from the BOULEVARD trial, faricimab is also under investigation for NPDR in the ongoing Phase 3 MAGIC trial, expected to conclude in 2026 [29]. The MAGIC trial will evaluate efficacy for a treat‐and‐extend dosing regimen as one group receives faricimab every 4 weeks through week 48, then every 16 weeks through week 96, and the second group receives it every 4 weeks from week 48 to 92 [29].

In the phase 3 YOSEMITE and RHINE trials, adults with CI‐DME were randomized to faricimab (using a treat‐and‐extend regimen, up to 16 weeks), faricimab (fixed dosing every 8 weeks after loading doses), or aflibercept (every 8 weeks after loading doses) [30]. The primary outcome was the change in best corrected visual acuity over 2 years. In both trials, noninferior visual acuity gains from year 1 were sustained through year 2. Superior anatomic efficacy was observed with faricimab, based on greater reduction in central subfield thickness. In addition, higher proportions achieved resolution and absence of intraretinal fluid with faricimab. Most patients on faricimab achieved extended dosing intervals of up to every 16 weeks, with fewer injections required and a comparable safety profile, which could enhance adherence. Direct adherence metrics or quality of life data from patient‐reported outcomes were not emphasized in the trials. A key limitation is the focus on noninferiority against aflibercept without a sham or no treatment arm for comparison [30].

3.2. Adjunctive Therapy

Fenofibrate, a peroxisome proliferator‐activated receptor (PPAR) alpha agonist, is commonly used for hypertriglyceridemia or mixed dyslipidemia [31]. Elevated serum cholesterol and triglyceride levels are associated with the development and progression of DR, prompting research into fenofibrate's role in slowing the progression of DR. Its benefits are not primarily due to lipid‐lowering effects but rather through modulation of inflammation and reduction of vascular leakage. PPAR‐alpha activation downregulates pro‐inflammatory cytokines and VEGF expression, contributing to these effects [31].

The FIELD study evaluated fenofibrate 200 mg daily versus placebo in adults aged 50 to 75 years with T2D, with or without pre‐existing DR [32]. The primary outcome of the study was the need for first laser treatment for DR and progression of retinopathy. Fenofibrate significantly reduced the need for laser treatment and slowed retinopathy progression in those with pre‐existing DR, independent of baseline lipid levels. The most notable adverse events from the FIELD study were increased rates of pulmonary embolism and deep vein thrombosis with fenofibrate, compared to placebo. Other adverse events included decreased hemoglobin, hematocrit, and white blood cell counts, as well as rare hypersensitivity reactions [32].

The ACCORD Eye study enrolled adults with T2D at high risk for cardiovascular events, including those with and without pre‐existing DR. Interventions included (i) intensive glycemic control (A1C target < 6%), (ii) intensive blood pressure control (systolic < 120 mmHg), and (iii) combination lipid therapy with fenofibrate (160 mg daily) plus simvastatin [33]. The comparison group had an A1C target of 7%–7.9%, systolic blood pressure < 140 mmHg, and simvastatin plus placebo. The primary outcome was the progression of DR. Both intensive glucose control and fenofibrate plus simvastatin reduced the risk of DR progression. Fenofibrate's DR‐slowing by 25% can enhance long‐term quality of life via lipid control, though myopathy risks (1%–2%) necessitate monitoring for adherence in cohorts with dyslipidemia. In the ACCORD Eye trial, fenofibrate plus simvastatin was associated with elevated serum creatinine and reversible liver enzyme elevations [33]. Real‐world evidence with fenofibrate supports benefits via reduced laser needs, though pharmacists should monitor for myopathy and hepatotoxicity. In the ADA guidelines, fenofibrate is listed as a potential adjunctive therapy for early DR in individuals with dyslipidemia, reducing progression independently of lipids via anti‐inflammatory effects [1]. In clinical practice, fenofibrate can have serious side effects including hepatotoxicity, myopathy, rhabdomyolysis, and increased serum creatinine, which require careful consideration before prescribing.

3.3. Emerging and Investigational Therapies

A diverse list of emerging and investigational therapies for DR and DME is under development, targeting unmet needs through multiple pathways, including inflammation, angiogenesis, and vascular stability. In addition, these options offer non‐injectable administration for early NPDR to reduce anti‐VEGF burden. Most agents are in Phase 2 trials with potential for adjunctive use in refractory cases. Below is an overview of key mechanisms of action and the clinical trial status of notable agents, and Table 3 summarizes the therapeutic classification, specific agent, and latest clinical trials for emerging DR therapies.

TABLE 3.

Emerging therapies summary [34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49].

Medication class	Medication name	Trial phase
Integrin inhibitor	Risuteganib	Phase 2
	THR‐687	Phase 1
	OTT166	Phase 2
Gene therapy	RGX‐314	Phase 2
	4D‐150	Phase 2, with RMAT distinction
VE‐PTP antagonist	Razuprotafib	Phase 2
Cyclic GMP activator	Runcaciguat	Phase 2
Ref‐1 inhibitor	APX3330	Phase 2
Connexin43 hemichannel blocker	Tonabersat	Phase 2

Abbreviations: Ref‐1, reduction–oxidation effector factor‐1; RMAT, Regenerative Medicine Advanced Therapy; VE‐PTP, vascular endothelial‐protein tyrosine phosphatase.

Integrins mediate inflammation, vascular leakage, angiogenesis, and neurodegeneration, all of which are implicated in DR and DME [34]. Risuteganib is an intravitreally administered integrin inhibitor and showed promising results compared to bevacizumab in individuals with DME [34]. However, safety or efficacy data from this Phase 2 trial are not yet published. THR‐687, another intravitreal integrin inhibitor, completed a Phase 1 trial demonstrating no safety concerns and improved visual acuity with a single injection in DME [34, 35]. A topical anti‐integrin agent (OTT166) is in Phase 2 development as a potential non‐invasive treatment option [36, 37]. This study involved adults with NPDR and PDR, where OTT166 eyedrops (administered twice daily or four times daily) were well tolerated with no serious adverse events. In addition, visual acuity remained stable throughout the trial with OTT166 eyedrops [37].

Gene therapy introduces synthetic genetic material to modify disease progression [38]. RGX‐314 delivers coding for a ranibizumab‐like anti‐VEGF monoclonal antibody fragment via a single subretinal or suprachoroidal injection, aiming for sustained intraocular VEGF inhibition after a single administration. Its Phase 2 trial for DR is actively recruiting to evaluate dosing strategies and safety [39]. Similarly, 4D‐150 encodes an aflibercept‐like protein and is administered intravitreally [40]. 4D‐150 has shown promising results with good tolerability in early trials; it is currently in a Phase 2 trial for DME, assessing safety and efficacy in DME [41]. Additionally, 4D‐150 has been given the Regenerative Medicine Advanced Therapy (RMAT) designation by the FDA for treatment of DME to expedite the development and review process. In contrast, ADV‐022, as another gene therapy, was discontinued for DME due to safety concerns, including severe intraocular inflammation and hypotony [40].

The Tie2 receptor, expressed on vascular endothelial cells, promotes vascular stability when activated by Ang‐1, increasing endothelial cell survival and adhesion and stabilizing the vasculature. Vascular endothelial‐protein tyrosine phosphatase (VE‐PTP) inactivates Tie2, contributing to vascular dysfunction [42, 43]. Razuprotafib is a small molecule VE‐PTP antagonist that enhances Tie2 signaling to improve vascular stability. In a Phase 1 trial, twice‐daily subcutaneous razuprotafib improved visual acuity in some patients with DME [42]. The subsequent Phase 2 trial combining razuprotafib with ranibizumab showed greater reductions in central subfield thickness compared to ranibizumab alone [43]. Adverse events were generally mild, primarily injection‐site reactions and increased blood pressure [43]. Razuprotafib remains under evaluation in ongoing clinical trials.

Nitric oxide and cyclic GMP signaling influence DR progression. Runcaciguat, an oral cyclic GMP activator, was investigated in the NEON‐NPDR Phase 2 trial in adults with NPDR. Results have not yet been published regarding measures of DR progression, retinal function, and retinal morphology [44]. Preclinical studies in animal models showed improved retinal morphology, supporting its potential in DR [45].

APX3330 is an oral small molecule that inhibits reduction–oxidation effector factor‐1 (Ref‐1), a regulator of angiogenic and inflammatory pathways [46]. Preclinical studies demonstrated that Ref‐1 inhibition reduces retinal angiogenesis, suggesting therapeutic potential for DR [46]. Clinical trials are ongoing, including the ZETA‐1 trial. This Phase 2 trial assessed the efficacy of APX3330 on improvement in the DRSS with moderately severe to severe NPDR or mild PDR [47]. Results of this trial are not yet available or published.

Tonabersat, an oral investigational agent, inhibits connexin43 hemichannel opening, reduces inflammation, and decreases retinal vascular leakage in animal models [48]. A Phase 2 trial in adults with DR is ongoing, comparing oral tonabersat to placebo, with the primary outcome evaluating effect on central subfield thickness [49]. Specific inclusion criteria are not publicly detailed, and results are still pending.

Interleukin (IL‐6) is a pro‐inflammatory cytokine involved in the pathogenesis of DR, with inflammation contributing to increased vascular permeability and fluid accumulation [50]. The therapeutic role of IL‐6 inhibition remains under investigation with early studies suggesting benefit. The READ‐4 trial, a Phase 2 study, aimed to evaluate intravenous tocilizumab combined with ranibizumab for DME; however, it was withdrawn due to lack of funding [50, 51]. The study would have primarily assessed safety and tolerability, along with changes in best corrected visual acuity and central subfield thickness, as well as safety data, between the treatment groups (ranibizumab monotherapy, tocilizumab monotherapy, and combination therapy). IL‐6 inhibitors remain a promising area for future research.

Vicasinabin is an oral cannabinoid receptor 2 agonist (CB2R) agonist. CB2R is mainly expressed on immune cells, including retinal microglia, and its activation can reduce vascular permeability [52]. A Phase 2 trial in adults with moderately severe to severe NPDR compared daily oral vicasinabin to placebo over 36 weeks, assessing the proportion of participants with a ≥ 2‐step improvement in DRSS from baseline and adverse events. Vicasinabin did not demonstrate efficacy in improving DRSS but showed favorable systemic and ocular safety profiles [52]. No further trials are currently planned, though CB2R agonists remain a potential area of exploration.

4. Conclusion

Anti‐VEGF agents remain the cornerstone of pharmacologic treatment for DR and DME, offering significant improvements in visual outcomes and disease management. However, pitfalls such as frequent injections, high costs, recurrence risks, and variable response underscore the need for alternatives targeting inflammation, neurodegeneration, and vascular stability. Corticosteroids address inflammation but increase risk of cataracts, limiting long‐term use. Emerging therapies like faricimab, high‐dose aflibercept, and the PDS promise extended intervals and better stability, potentially improving adherence and quality of life. Adjunct therapy, such as fenofibrate, can slow the progression of DR in those living with dyslipidemia. Emerging therapies, such as integrin inhibitors, gene therapies, and delivery innovations, promise durable effects and potentially better quality of life. Future directions include precision medicine, early detection, and combination therapy to personalize care. This evolving landscape underscores the need for pharmacists as key players in interdisciplinary care by optimizing medication reconciliation, counseling on adherence/technologies, managing comorbidities (e.g., diabetes, dyslipidemia), and collaborating with specialists to personalize therapy and mitigate barriers. Challenges with equitable access and cost must be addressed through interdisciplinary efforts. Practitioners can optimize adherence via education on injectable or implants, monitor adverse events, and provide interdisciplinary coordination to address access barriers.

Author Contributions

Jennifer N. Clements: conceptualization; writing – original draft; writing – reviewing, editing, and revising. Julia Mesawich: writing – original draft; methodology; writing – reviewing and editing. Cassandra Twisdale: writing – original draft; methodology; writing – reviewing and editing.

Funding

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Clements J. N., Mesawich J., and Twisdale C., “Current and Emerging Pharmacologic Therapies for Diabetic Retinopathy,” Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy 46, no. 3 (2026): e70119, 10.1002/phar.70119.

Data Availability Statement

The authors have nothing to report.