The incidence of diabetes and diabetes-related illnesses is growing worldwide, leading to diabetes moving into the realm of global epidemic.1 It is estimated more than 37 million people in the United States have diabetes.2 There are several vision-threatening manifestations that can accompany the disease.
In 2021, it was estimated that 9.6 million people in the United States had diabetic retinopathy (DR), with 1.84 million people having vision-threatening diabetic retinopathy.3
The number one non-modifiable risk factor correlated with the development of DR is duration of disease. The number one modifiable risk factor is blood sugar control. Once retinopathy is present, the length of disease is the biggest risk factor.4
Ocular manifestations of diabetes
Diabetic retinopathy occurs when the blood vessels in the retina become damaged.
Non-proliferative diabetic retinopathy
Non-proliferative diabetic retinopathy can be categorized by the presence of:5
- Microaneurysms: Located in the inner nuclear layer of the retina
- Dot and blot hemorrhages: Located in the inner nuclear and outer plexiform layer of the retina
- Vascular changes: Including beading, looping, and sausage-like segmentation of the veins
- Hard exudates: Located between the inner plexiform and inner nuclear layer of the retina
- Cotton wool spots (soft exudates): Located in the nerve fiber layer of the retina
- Intraretinal microvascular abnormalities: Capillaries that function as collateral channels adjacent to areas of capillary closure
Non-proliferative diabetic retinopathy is further categorized as:5,6
- Mild: This is evident by at least one microaneurysm. Only hemorrhages and/or microaneurysms are present and are less severe than depicted in ETDRS standard photograph 2A.
- Moderate: This is characterized by hemorrhages and/or microaneurysms greater than that depicted in ETDRS standard photograph 2A in one to three retinal quadrants or cotton wool spots, venous beading, and intraretinal microvascular abnormalities (IRMAs) may be present to a mild degree.
- Severe: This is categorized based on the extent and severity of hemorrhages/microaneurysms or any of the following:
- Hemorrhages/and or microaneurysms > ETDRS standard photograph 2A in four retinal quadrants
- Venous beading in two or more retinal quadrants
- IRMAs in at least one quadrant
- Very severe: Two or more criteria for severe non-proliferative are met with the absence of neovascularization.
- Eyes with very severe non-proliferative diabetic retinopathy have a greater than 75% risk of developing proliferative diabetic retinopathy in 1 year.
Clinical tip: The “4-2-1” rule is critical in determining the risk of progressing to proliferative diabetic retinopathy. Eyes with severe non-proliferative diabetic retinopathy have a greater than 50% risk of developing proliferative diabetic retinopathy in 1 year.
Figures 1 and 2: Fundus images of a 70-year-old male with mild non-proliferative diabetic retinopathy without macular edema in the right and left eye, respectively.
Figure 1: Courtesy of Jill Gottehrer, OD, FAAO.
Figure 2: Courtesy of Jill Gottehrer, OD, FAAO.
Proliferative diabetic retinopathy
Retinal ischemia prompts pathologic neovascularization stimulated by angiogenic factors such as vascular endothelial growth factor (VEGF).7 This results in proliferative diabetic retinopathy.
Characteristics of proliferative diabetic retinopathy include new vessels (neovascularization) on or within one disc diameter of the optic disc (NVD), new vessels elsewhere in the retina—not on or within one disc diameter of the optic disc (NVE), preretinal hemorrhage, and vitreous hemorrhage.
Proliferative diabetic retinopathy is categorized by the presence of NVD or NVE.5,6 High-risk proliferative diabetic retinopathy is characterized by three out of the four risk factors for severe visual loss from diabetic retinopathy:5,6
This includes the presence of:5,6
- Pre-retinal or vitreous hemorrhage
- New vessels
- New vessels on or near the disc
- Moderate or severe new vessels > standard photograph 10A or NVE > ½ disc area, hemorrhage, and a retinal detachment
Figures 3 and 4: 51-year-old male with proliferative diabetic retinopathy with macular edema in the right and left eye, respectively.
Figure 3: Courtesy of Jill Gottehrer, OD, FAAO.
Figure 4: Courtesy of Jill Gottehrer, OD, FAAO.
Diabetic macular edema
When diabetes leads to swelling in the macula, the result is diabetic macular edema (DME). This can be further categorized as clinically significant or non-clinically significant diabetic edema. Non-clinically significant edema can be defined as retinal thickening or hard exudates at least one disc diameter to the center of the macula. Visual acuity may or may not be affected in these patients.8
The Early Treatment Diabetic Retinopathy Study (ETDRS) defines clinically significant macular edema as follows:9
- Retinal thickening at or within 500μm of the center of the fovea
- Hard exudates at or within 500μm of the center of the fovea with associated adjacent retinal thickening
- Retinal thickening of at least one disc area within one disc diameter of the center of the fovea
Macular edema is also categorized as focal or diffuse. Focal refers to localized areas of leakage within the macula, typically caused by microaneurysms. Diffuse refers to widespread leakage of fluid across the entire macular region, resulting from a breakdown in the blood-retinal barrier.8,10
Figure 5: OCT imaging of a 73-year-old patient with cystoid macular edema in the left eye.
Figure 5: Courtesy of Jill Gottehrer, OD, FAAO.
Additional complications of DR
Neovascular glaucoma may occur due to severe diabetic eye diseases, amongst other ocular conditions. This is caused by new blood vessels occluding the drainage angle, leading to elevated intraocular pressure. Patients with neovascular glaucoma often have a poor visual prognosis.
In addition, cataracts, defined as the natural clouding of the crystalline lens, occur due to aging. In diabetics, this may occur earlier due to high glucose levels, causing deposits and buildup in the lens.
Further, diabetic third nerve palsies are the most common etiologic subset of third nerve palsy in adults.11 A fourth or sixth cranial nerve palsy is a less common complication that may occur in diabetics with poor blood sugar control.12
This is due to hyperglycemia-induced damage to nerve cells and neuronal ischemic damage.11 Diabetic nerve palsies often self-resolve within 3 to 6 months; blood sugar control and/or blood pressure control can help with the recovery process.
Diagnosis of diabetic eye diseases
The use of imaging is especially helpful in diagnosing eye disease, including optical coherence tomography (OCT), optical coherence tomography angiography (OCT-A), and fluorescein angiography (FA).
OCT
OCT can aid in the diagnosis of diabetic macular edema and monitor the degree of subretinal fluid to decide further therapy. Disorganization of retinal layers (DRIL) may also be seen on OCT. DRIL is the inability to clearly discriminate between the ganglion cell inner plexiform layer, inner nuclear layer, and outer plexiform layer.
Disorganization of more than 50% or 500μm of the central 1mm retinal zone is associated with worse visual prognosis of visual acuity in eyes with active center involving, non-center involving, or resolved macular edema.13
Müller cells are primarily located in the inner nuclear layer, providing structural support and homeostasis. DRIL tends to affect the Müller cells more than other retinal components, such as microganglia, which is why DRIL is associated with a worse visual prognosis.14,15
OCT-A
OCT-A is a non-invasive imaging technique that can help distinguish the various vascular networks of the retina and choroid without the administration of fluorescein dye.16 OCT-A does this by presenting adjacent structural OCT B-scans, which obtain cross-sectional images. Together, the images provide detailed flow imaging of the deep retinal vascular plexus and choriocapillaris.17
OCT-A can indicate areas of capillary non-perfusion, presence of collaterals of neovascularization, abnormalities of the fovea avascular zone, and the added advantage of analyzing each of the three retinal capillary plexi, which can show pathophysiological changes in diabetic retinopathy.18 In addition, OCT-A can detect microaneurysms before they are appreciated clinically or on fundus photography.19,20
Fluorescein angiography
Fluorescein angiography is considered to be the gold standard for evaluating the retina in diabetes.21 This technique will show capillary non-perfusion, enlargement or irregularity of the fovea avascular zone, and neovascularization.
Current treatments for diabetic eye diseases
There are several treatment options for diabetic eye disease, including:
- Oral medications
- Topical medications
- Injections
- Anti-VEGF
- Steroid
- Genetic therapy
- Surgical interventions
Oral
Fenofibrate
Fenofibrate is an oral cholesterol medication that has been found to reduce diabetic retinopathy progression. Fenofibrate led to a lower risk of progression of maculopathy and retinopathy when studied in patients with mild to moderate non-proliferative diabetic retinopathy.22
The FIELD study showed that patients treated with fenofibrate had a statistically significant relative risk reduction in the need for laser for diabetic macular edema and proliferative diabetic retinopathy.
Patients were either assigned to 200mg/day of fenofibrate or a placebo. The control group required laser treatment more often compared to the treatment group. The mechanism of action includes anti-inflammatory, anti-oxidative, and neuroprotective effects.23
MS-553
MS-553 (Shenzhen MingSight Relin Pharmaceuticals) is a selective protein kinase C-β (PKC-β) inhibitor currently studied for the treatment of chronic lymphocytic leukemia and small lymphocytic leukemia and autoimmune diseases.24
In diabetic retinopathy, PKC-β leads to oxidation-reduction reactions, causing increased permeability and angiogenesis.25 MS-553 is currently in phase 1 trial. The applicability of this drug to DR is not well established.26
APX330
APX3330 (Ocuphire Pharma) is a reduction-oxidation effector factor (Ref-1) inhibitor in phase 2 trial shown to reduce VEGF and inflammatory cytokines that lead to neovascularization.27 The completed phase 2 ZETA-1 trial evaluated the safety and efficacy of APX3330 in 103 participants with moderate to severe non-proliferative diabetic retinopathy and proliferative diabetic retinopathy.28
Participants either received 600mg/day of APX3330 or a placebo. The primary endpoint was the percentage of participants with a two-step or greater improvement in the Diabetic Retinopathy Severity Scale by week 24.
While this primary endpoint was not met, a statistically significant number of subjects had binocular 3-step or greater worsening on the diabetic retinopathy severity scale when taking the placebo compared to APX3330. APX3330 also showed a favorable safety profile and will be heading into a phase 3 trial.29
Topical
OCS-01
OCS-01 (Oculis) contains 15mg/mL of dexamethasone. The DIAMOND study assessed OCS-01 topical eye drops in participants with diabetic macular edema versus a vehicle. Treatment was administered 6 times daily for 6 weeks then 3 times daily for another 6 weeks.
At 6 weeks, a mean gain of 7 or more letters was achieved and maintained throughout the study. A 60μm reduction in central retinal thickness was achieved at 2 weeks and maintained during the duration of the study. Stage 2 of this study began in December 2023 with 400 patients followed over 52 weeks.30
To read the most recent update on OCS-01, check out the Glance story: Phase 3 enrollment concludes for Oculis' DME eye drop program!
Injections: Anti-VEGF, steroids, gene therapies
Anti-VEGF
Anti-VEGF therapy, such as ranibizumab, bevacizumab, and aflibercept, is often used to treat macular edema and neovascularization to stop fluid leakage and block the growth of abnormal vessels in the eye.
Aflibercept 8mg
Aflibercept 8mg (Eylea HD, Regeneron Pharmaceuticals and Bayer) is a higher dose formulation of Eylea, allowing for a longer time between injections. In the CANDELA study, it illustrated its therapeutic benefit over 2mg of aflibercept by a larger proportion of eyes remaining fluid-free and improved visual acuity.31
Eylea HD was approved by the FDA in August 2023 for the treatment of diabetic macular edema.
Sozinibercept
Sozinibercept (OPT-302, Opthea) is an intravitreal anti-VEGF injection that blocks VEGF-C and VEGF-D. Sozinibercept is intended to work synergistically with other anti-VEGF agents.
In the phase 2 trial, 52.8% of patients with diabetic macular edema treated with Sozinibercept combined with aflibercept achieved a visual gain of ≥ 5 ETDRS letters at 12 weeks compared to baseline.32
Phase 3 trials are currently underway to determine if combination therapy is superior to ranibizumab and aflibercept at improving visual acuity 12 months from baseline.
MK-300
MK-3000 (Restoret, Eyebio/Merck) is a tetravalent, tri-specific Wnt antibody that reduces vascular leakage in retinal diseases by agonizing the Wnt pathway with the goal of restoring and maintaining the blood-retinal barrier. The phase 2b/3 BRUNELLO trial began in the fall of 2024.
Patients were randomized and received low and high-dose regimens of MK-3000 or ranibizumab every 4 weeks for the first year. In the second year, the frequency of treatments will change to an individualized treatment period algorithm. Primary endpoints for the trial are safety and mean change in BCVA from baseline to week 52.33
Susvimo
Susvimo (Roche) is a refillable ocular implant that provides a continuous, customized delivery of ranibizumab over time. This is recommended for those who have had at least two anti-VEGF injections.
In the 2-year Pagoda study, patients gained 9.8 letters of vision at 1 year.34 In the Pavilion study, 80% of patients achieved a two-step greater improvement of the Diabetic Retinopathy Severity Scale from pre-implant baseline at week 100.35
Steroids
Steroid injections (i.e., Ozurdex) may also be used in the treatment of diabetic macular edema when anti-VEGF therapy is ineffective. OXU-001 (Oxular) is a suprachoroidal injection of dexamethasone microspheres.
OXEYE, a 52-week phase 2 study assessed the adverse effects in those with diabetic macular edema comparing OXU-001 and Ozurdex. The results of this study have not yet been released.36
Gene therapies
RGX-314
RGX-314 (Regenxbio) is a transgene encoding for anti-VEGF, packaged in an AAV8 vector for a one-time suprachoroidal injection. In the ALTITUDE trial, assessing patients with mild to severe non-proliferative diabetic retinopathy, nearly 100% of patients had stable or improved retinopathy. It is currently in phase 3 trials.37
4D-150
4D-150 (Molecular Therapeutics) is a gene therapy intravitreally injected that expresses aflibercept and a micro-RNA to target VEGF-C. The phase 2 trial began at the end of 2023 with the primary outcome the number of rescue injections and secondary measures including change in BCVA, central retinal thickness, and adverse events through 104 weeks.38
IBE-814 IVT
IBE-814 IVT (Ripple Therapeutics) is an intravitreal dexamethasone implant. In the phase 2 RIPPLE-1 trial, the 6-month data showed a mean BCVA gain of +8.7 letters (one patient required rescue) in the high-dose cohort and a mean BCVA loss of -1.9 letters (eight required rescue) in the low-dose cohort.39
Surgical interventions
Panretinal photocoagulation (PRP) is used to treat proliferative diabetic retinopathy by reducing the risk of vision loss by destroying the new, abnormal vessels. During PRP, 1,200 to 2,000 laser burns are applied to the peripheral retina to improve oxygenation and anti-VEGF levels.40
In proliferative diabetic retinopathy, a vitrectomy, or removal of the vitreous gel, may be performed for a non-clearing vitreous hemorrhage, tractional retinal detachment, traction-induced macular edema, and neovascularization of the disc.41,42
Those with persistent vitreous hemorrhages are at a higher risk for developing ghost cell glaucoma, where red blood cells break down and form “ghost cells” that block the trabecular meshwork, increasing the intraocular pressure. An early vitrectomy can remove these ghost cells and lower the intraocular pressure.43
Focal laser treatment is used for microaneurysms, intraretinal hemorrhages, and macular edema located 500 to 3000μm from the center of the macula (non-center involving diabetic macular edema).
Grid laser is also used to treat non-center involving diabetic macular edema. Treatment cannot be placed within 500μm of the central macula and within 500μm of the disc margin.44 Grid laser treats more diffuse areas of retinal thickening, meanwhile, focal directly targets leaking microaneurysms.
Systemic factors in diabetic eye disease
Aside from medical therapy, optimal control of blood glucose, blood pressure, and cholesterol, is recommended in the treatment of diabetic retinopathy.45 Lowering of blood glucose, blood pressure, and cholesterol reduces the risk of microvascular end point damage and vision loss.46,47
Conclusion
Despite public health awareness of diabetic eye disease and advances in detection, as eyecare providers, we still face challenges treating patients.
Diabetic eye disease is asymptomatic in the beginning stages, leading patients to either be in denial of their condition or not attend their annual eye exam. Other barriers may include financial, transportation, language, cultural beliefs, and denial/fear.48
Diabetic eye disease can cause permanent vision loss if left untreated. By promoting screenings and utilizing technology available, it can be detected earlier in its course, preventing this dire outcome.
Improving team outcomes by involving primary care providers and endocrinologists in discussions with patients about the importance of eyecare can enhance surveillance and also help prevent vision loss.
