Diabetic retinopathy (DR) is a retinal microvascular disorder caused by metabolic abnormalities due to hyperglycemia, which induce various cytokines and chemokines. This leads to diverse fundus lesions and is considered one of the three major complications along with diabetic neuropathy and diabetic nephropathy. In recent years, it has been redefined as a “neurovascular disease” rather than just a microvascular disease 2).
It is the second leading cause of acquired visual impairment, with approximately 3,000 people becoming blind annually due to DR.
Diabetic macular edema (DME) is the most common type of diabetic maculopathy. Diabetic maculopathy includes three types: macular edema, ischemic maculopathy, and retinal pigment epitheliopathy, but macular edema is the most frequent and clinically significant cause of vision loss. DME can occur at any stage of DR. The pathophysiology of DME is complex, involving multiple factors such as increased vascular permeability, blood flow impairment due to vascular occlusion, decreased colloid osmotic pressure, and traction from the posterior hyaloid membrane.
Major epidemiological data in Japan are shown below1).
Globally, 34.6% of diabetic patients (approximately 93 million) have DR2). In 2020 estimates, DR affected 131.2 million people, vision-threatening DR (VTDR) 28.54 million, and clinically significant macular edema (CSME) 18.83 million, with projections of 160.5 million by 20452). In type 1 diabetes, approximately 90% develop DR after 20 years of disease11).
In large Japanese cohorts, DR develops at a rate of 3.8–4.0% per year, and approximately 30% of patients already have DR at the time of type 2 diabetes diagnosis1). Globally, 34.6% of diabetic patients (approximately 93 million) have DR2), and about 90% of type 1 diabetes patients develop DR after 20 years11).
Early DR often progresses without symptoms. By the time symptoms appear, moderate or more severe lesions are usually already present.
In the early stage, there are almost no subjective symptoms, and the disease progresses asymptomatically. When symptoms such as decreased visual acuity, floaters, or metamorphopsia appear, moderate to severe lesions are often already present. Therefore, once diagnosed with diabetes, regular fundus examinations are necessary even without symptoms.
The main fundus findings by disease stage are shown below.
Simple Retinopathy
Microaneurysms: The earliest finding of DR. They appear as punctate hyperfluorescent spots on fluorescein angiography.
Retinal hemorrhages: Dot and blot hemorrhages. They occur when red blood cells leak from capillaries.
Hard exudates: Plasma components leak due to increased vascular permeability, and lipids are deposited.
Preproliferative Retinopathy
Soft exudates (cotton-wool spots): Localized infarcts due to impaired axonal transport in the optic nerve fibers. They reflect retinal ischemia.
Beaded venous dilation and loop formation: Appears adjacent to areas of vascular occlusion.
IRMA (Intraretinal Microvascular Abnormalities): Shunt formation around non-perfused areas. A key differentiating feature from neovascularization is the lack of prominent leakage on fluorescein angiography.
Proliferative Retinopathy
Neovascularization: Appears on the retina and optic disc due to excessive VEGF production from widespread capillary occlusion. Shows profuse fluorescein leakage on angiography.
Fibrovascular proliferative membrane: Forms as fibroblast-like cells proliferate around new vessels.
Tractional retinal detachment: Occurs when vitreous traction is added to the adhesion between the proliferative membrane and the retina. Involvement of the macula leads to poor visual prognosis.
Severe NPDR is defined by the “4-2-1 rule” 2): meeting any one or more of the following criteria.
The New Fukuda Classification 1) broadly divides into benign (Group A) and malignant (Group B).
| Classification | Stage | Findings |
|---|---|---|
| A1 | Mild nonproliferative | Microaneurysms, dot hemorrhages |
| A2 | Moderate nonproliferative | Blot hemorrhages, hard exudates, few soft exudates |
| B1 | Preproliferative | Soft exudates, venous beading, IRMA, NPA on fluorescein angiography |
| B2 | Early proliferative | Neovascularization not directly connected to the optic disc |
| B3 | Moderate proliferative | Neovascularization directly connected to the optic disc |
| B4 | Advanced proliferative | Vitreous hemorrhage / preretinal hemorrhage |
| B5 | Advanced proliferative | Fibrovascular proliferative tissue |
| A3 to A5 | Inactive proliferative | Old neovascularization / VH / proliferative tissue |
When the condition remains quiescent for 6 months or more after treatment, it is called inactive proliferative retinopathy. Complications are noted as M (macular lesion), D (tractional RD), G (NVG), N (ischemic optic neuropathy), P (photocoagulation), and V (vitrectomy).
OCT tomographic images of macular edema are evaluated based on a combination of three basic types: retinal swelling, cystoid macular edema, and serous retinal detachment.
Clinically significant macular edema (CSME) is defined by the ETDRS as meeting any of the following criteria 2):
A central retinal thickness of 300 μm or more on SD-OCT is used as the threshold for DME involving the fovea (by device: Spectralis 320/305 μm, Cirrus 305/290 μm, Stratus 250/250 μm, male/female) 1). The international severity classification of DME has three stages: mild (thickening or hard exudates away from the fovea), moderate (near the fovea but not involving it), and severe (involving the fovea). DME increases with progression of NPDR, complicating 1.7–6.3% of mild NPDR and 20.3–63.2% of moderate NPDR 1).
The main risk factors associated with the progression of DR are shown below.
| Risk Factor | Main Evidence |
|---|---|
| Duration of diabetes | The greatest risk factor. About 30% of patients with type 2 DM already have DR at diagnosis 1) |
| Glycemic control | HbA1c <7.0% prevents microvascular complications (Kumamoto Study). A 1% reduction in HbA1c reduces the risk of microvascular complications by 37% (UKPDS) 1) |
| Hypertension | WESDR: A 10 mmHg increase in systolic blood pressure increases the risk of early DR by 10% and proliferative DR/DME by 15%. UKPDS: A 10 mmHg reduction decreases DR progression by 35% and vision loss by 47% 1) |
| Dyslipidemia | Fenofibrate (FIELD Study): 31% reduction in introduction of photocoagulation, 30% reduction in proliferative DR, 31% reduction in DME. ACCORD Eye Study: 40% reduction in odds of DR progression1) |
| Renal dysfunction | Proteinuria and decreased GFR correlate with DR prevalence. Nephropathy → 29% increased risk of PDR progression1) |
| Pregnancy | No pre-existing DR → onset of DR during pregnancy 8–33%. Pre-existing NPDR → worsening during pregnancy 10–67%1) |
| Severe hypoglycemia | DR incidence increases approximately 4-fold (JDCS)1) |
Multiple large-scale trials have shown that strict glycemic control is effective in preventing and slowing the progression of DR1).
On the other hand, when blood glucose is rapidly improved in patients with long-term poor glycemic control, transient worsening of diabetic retinopathy (DR), known as “early worsening,” may occur. Since visual acuity decline persists in about 50% of cases, gradual improvement in blood glucose is desirable, and collaboration with an internist is important 1).
Additionally, retinal cells once exposed to hyperglycemia undergo epigenetic changes, leading to “metabolic memory,” where lesions persist or progress even after normalization of blood glucose 11). Downregulation of SOD2 and hypermethylation of mitochondrial DNA have been reported as mechanisms.
Targeting HbA1c below 7.0% prevents microvascular complications (Kumamoto Study) 1). A 1% reduction in HbA1c reduces the risk of microvascular complications by 37% (UKPDS) 1). Since cells once exposed to hyperglycemia retain “metabolic memory,” long-term follow-up is necessary even after blood glucose normalization 11).
| Examination Method | Main Use | Remarks |
|---|---|---|
| Dilated fundus examination (indirect ophthalmoscopy/contact lens) | Gold standard for staging classification | Without dilation, only about 50% are accurately classified2) |
| Slit-lamp examination | Assessment of corneal damage, iris rubeosis, cataract, and anterior chamber inflammation | Detailed observation of the macula using a contact lens |
| Color fundus photography | Objective documentation and longitudinal comparison | ETDRS 7-field photography. Peripheral areas can also be recorded with ultra-widefield SLO3) |
| Fluorescein angiography (FA) | Identification of non-perfusion areas, neovascularization, and leakage points. Differentiation between focal and diffuse DME | FA overall adverse reaction rate 1.1–11.2%, severe 0.005–0.48%, death 0.0005–0.002%1) |
| Optical coherence tomography (OCT) | Quantitative assessment and follow-up of macular edema | SD-OCT depth resolution 5 μm. Central retinal thickness ≥300 μm indicates foveal DME1) |
| OCTA | Assessment of capillary dropout, non-perfusion area (NPA), and neovascularization without contrast agent | Non-invasive. Also enables quantification of FAZ3) |
| Ultrasound | Evaluation of retinal and vitreous relationships when media opacities are present | Assessment of extent of tractional retinal detachment and location of proliferative membranes |
| Electroretinography (ERG) | Objective assessment of retinal function | Prolonged OP latency appears early in DR. Negative ERG suggests poor postoperative visual acuity1) |
| Stage (Modified Davis Classification) | Recommended Interval |
|---|---|
| Diabetes (no retinopathy) | Once a year |
| Simple diabetic retinopathy (mild to moderate NPDR) | Once every 6 months |
| Preproliferative diabetic retinopathy (severe NPDR) | Once every 2 months |
| Proliferative diabetic retinopathy | Once a month |
(AAO PPP recommends every 3–4 months for severe NPDR, slightly different from the values in GL Table 3) 1)2)
The main differential diagnoses include hypertensive retinopathy, retinal arteriovenous occlusion, Eales disease, Coats disease, blood disorders (anemia, leukemia, Hodgkin disease), interferon retinopathy, radiation retinopathy, Purtscher disease, Takayasu disease, and uveitis (Behçet disease, sarcoidosis, SLE).
For type 2 diabetes, about 30% already have DR at diagnosis, so an eye exam at diagnosis is recommended 1). For type 1 diabetes, the exam should be within 5 years after diagnosis 1). If pregnancy is complicated, an exam should be done as early as possible in the first trimester, and follow-up every 3 months during pregnancy is necessary 1).
Management of systemic risk factors is fundamental for prevention and suppression of DR progression, and should be continued throughout all stages.
Anti-VEGF Therapy
First-line: Standard treatment for DME involving the fovea 1).
Ranibizumab (Lucentis): 0.5 mg/0.05 mL intravitreal injection. Administered monthly until vision stabilizes.
Aflibercept 2 mg (Eylea): 2 mg/0.05 mL. 5 monthly loading doses, then every 2 months.
Faricimab (Vabysmo): 6 mg/0.05 mL. Anti-VEGF + anti-Ang-2 bispecific antibody. In YOSEMITE/RHINE trials, 50–70% maintained 12–16 week intervals 9).
Brolucizumab (Beovu): 6 mg/0.05 mL. Molecular weight 26 kDa. In KESTREL/KITE trials, >50% maintained q12w 5).
Re-treatment regimens: Three approaches: PRN (as needed), fixed dosing, and TAE (treat and extend) 1).
Steroid Therapy
Triamcinolone acetonide (MacuAid): 4 mg/0.1 mL intravitreal injection. Used for anti-VEGF resistant cases or as sub-Tenon injection1).
Dexamethasone implant (Ozurdex): Sustained-release. Considered for pseudophakic eyes or poor responders to anti-VEGF therapy5)2).
Precautions: Risk of cataract progression (in phakic eyes) and increased intraocular pressure.
Laser Photocoagulation (DME)
Indication: Option for DME not involving the fovea1).
Focal coagulation: Directly irradiates leaking microaneurysms.
Grid coagulation: Irradiates areas of diffuse leakage or non-perfusion.
Modified ETDRS method: Avoids irradiation within 500 μm of the foveal center, performed with low power and wide spacing1).
Caution: Risk of atrophic creep (scar expansion) and subretinal fibrosis1).
| Drug Name (Brand Name) | Dose | Characteristics |
|---|---|---|
| Ranibizumab (Lucentis) | 0.5mg/0.05mL | Fab fragment. Administered once a month. Continue until vision stabilizes. |
| Aflibercept 2mg (Eylea) | 2mg/0.05mL | VEGF-A/B and PlGF binding fusion protein. After 5 loading doses, every 2 months. |
| Aflibercept 8mg (Eylea 8mg) | 8mg/0.07mL | High dose. Up to 16-week intervals 2) |
| Brolucizumab (Beovu) | 6mg/0.05mL | Molecular weight 26kDa. Over 50% on q12w. Caution for intraocular inflammation risk 5)7) |
| Faricimab (Vabysmo) | 6mg/0.05mL | Anti-VEGF + anti-Ang-2. Up to q16w 9) |
For DME involving the fovea with good visual acuity (20/25 or better), deferring treatment until vision drops to 20/30 or worse is an option 2).
For DME involving the fovea, anti-VEGF therapy is the first-line treatment 1). Ranibizumab, aflibercept, faricimab, and brolucizumab are all effective, with faricimab (up to q16w) and brolucizumab (≥50% at q12w) attracting attention for their potential to extend dosing intervals 5)9). If anti-VEGF is insufficient, consider steroid therapy with triamcinolone or dexamethasone implant 2).
The basic pathologies of DR are broadly classified into three categories: increased vascular permeability, vascular occlusion, and angiogenesis. The stages of simple retinopathy, preproliferative retinopathy, and proliferative retinopathy roughly correspond to these basic pathologies.
In a hyperglycemic state, four major metabolic pathways are activated, leading to retinal damage through oxidative stress and inflammation 11).
| Pathway | Main Products/Changes | Major Downstream Damage |
|---|---|---|
| Polyol pathway | Sorbitol accumulation | NADPH depletion → decreased glutathione → amplified oxidative stress |
| AGEs formation | RAGE activation | NF-κB↑ → VEGF↑, pericyte apoptosis |
| PKC activation | PKC-β activation | VEGF/Nox upregulation |
| Hexosamine pathway | UDP-GlcNAc excess | TGF-β/PAI-1 increase |
Both the inner BRB (tight junctions of retinal capillary endothelium) and outer BRB (tight junctions between RPE cells) are disrupted8).
The retina expresses a local RAAS independent of the circulatory system9). The classical pathway (ACE/AngII/AT1R axis) promotes pericyte apoptosis, leukocyte stasis, and BRB breakdown, while the protective pathway (ACE2/Ang-(1-7)/Mas axis) counteracts it. Intraretinal AngII concentration is higher than in circulation, and the DIRECT trial showed that candesartan treatment led to 34% regression of DR9).
Retinal cells once exposed to hyperglycemia maintain epigenetic changes even after normalization of blood glucose (SOD2 suppression, mitochondrial DNA hypermethylation) 11). Mechanisms reported include increased ROS production from mitochondrial electron transport chain Complex I/III, excessive mitochondrial fragmentation due to Drp1/OPA1 imbalance, and impaired antioxidant response via Nrf2/KEAP1 and SIRT1.
DR has been redefined as a “neurovascular disease” 2), and GCIPL thinning can be detected by OCT before vascular lesions appear 13). Macular NFL thins by 0.25 μm per year, and GCIPL by 0.29 μm per year. Müller cell gliosis (increased GFAP) and microglial activation have also been confirmed. Fractalkine (CX3CL1) is produced by retinal ganglion cells and acts on the CX3CR1 receptor to exert anti-inflammatory and neuroprotective effects 10).
In diabetic patients, glucose concentration in the vitreous increases, and glycation of collagen fibers progresses. The degree of glycation correlates with DR progression, and collagen structural changes promote liquefaction, contraction of the vitreous cortex, and posterior vitreous detachment (PVD). If complete PVD without traction occurs, progression to proliferative DR is almost absent. In contrast, incomplete PVD (strong adhesion between vitreous and proliferative tissue) leads to persistent vitreous traction, making tractional retinal detachment and vitreous hemorrhage more likely.
Blood glucose control is most important for preventing and slowing DR progression, with a target HbA1c below 7.0% 1). However, according to the concept of “metabolic memory,” cells once exposed to hyperglycemia retain epigenetic changes, and lesions may persist or progress even after glucose normalization 11). The DCCT/EDIC follow-up study showed that early intensive therapy suppressed DR progression over a long period.
Aflibercept 8 mg was approved for DME indication in 2023, with expected extension of up to 16-week intervals 2). In DRCR Protocol W, prophylactic anti-VEGF for severe NPDR prevented PDR/DME onset, but long-term visual outcomes were equivalent to initial observation 2).
LumineticsCore (formerly IDx-DR) is the first autonomous AI-based retinal diagnostic system approved by the FDA in 2018 that does not require physician interpretation 3). Deep learning models have reported a sensitivity of 96.8% and specificity of 87% 3), and new systems such as EyeArt and AEYE-DS are also being developed 2).
Administration of a soluble fractalkine-expressing AAV vector (rAAV-sFKN) has shown improvement in visual acuity, reduction in fibrin leakage, and normalization of microglia 10). It has neuroprotective and anti-inflammatory mechanisms distinct from anti-VEGF therapy.
The EUROCONDOR phase II-III trial (NCT01726075) evaluated somatostatin and brimonidine eye drops, but overall analysis did not show efficacy; however, in the subgroup with abnormal baseline mfERG, progression of neuronal dysfunction was halted 13). A 36-month double-blind RCT of citicoline plus vitamin B12 eye drops reported suppression of functional, structural, and vascular progression in mild DR 13).
miRNAs are attracting attention as “master regulators” that integratively modulate multiple axes of DR pathology (oxidative stress, inflammation, neurodegeneration, vascular dysfunction) 14). The possibility of SIRT1 stabilization by miR-195 inhibition and VEGF-A translational inhibition by miR-497a-5p has been shown; approximately 350 miRNAs are expressed in the retina, and more than 86 are aberrantly expressed in DR models.
Metformin has pleiotropic effects including antioxidant, anti-inflammatory, anti-angiogenic, and neuroprotective actions via AMPK activation, and observational studies have shown an aHR of 0.29 for STDR (sight-threatening DR) in users 12). However, RCT data for ophthalmic indications are currently insufficient.
The nonsteroidal MR antagonist finerenone has been shown to reduce BRB breakdown, angiogenesis, and inflammation in preclinical models, and the significance of MR as an independent therapeutic target for DR is being investigated 9).
