Diabetic retinopathy

CLINICAL PROTOCOL FOR DIAGNOSIS AND TREATMENT

Clinically Significant Macular Edema

CNSME Clinically Non-Significant Macular Edema

Clinical forms of maculopathy: • ischemic; • edematous (DME)

By type of DME: • focal (caused by local isolated breakdown of the inner blood-retinal barrier (group of microaneurysms) with impaired autoregulation); • diffuse (caused by capillary hyperpermeability combined with disruption of the outer blood-retinal barrier). In diffuse macular edema, retinal thickening reaches an area of 2 or more disc diameters and extends to the center of the macula; • cystoid - result of fluid accumulation in the outer plexiform and inner nuclear layers of the retina in the center near the fovea with formation of fluid-filled cystic formations. • cystoid with vitreоretinal tractions.

By clinical significance of DME [6,7]: • clinically non-significant; • clinically significant (in the presence of one or more of the following criteria:

• retinal thickening and/or hard exudates involving the center of the macula; retinal thickening and/or hard exudates located closer than 500 μm from the center of the macula but not extending to it; • retinal thickening measuring one disc diameter (1500 m) or more, any part of which is located within one disc diameter from the center of the macula.

DME is distinguished with or without center involvement. Macular edema with center involvement is defined as retinal thickening (retinal edema) affecting the central zone with a diameter of 1000 μm.

METHODS, APPROACHES AND DIAGNOSTIC PROCEDURES Diagnostic criteria: Complaints: • "blurred" vision, appearance of a veil, floating dark spots, "grid", "floaters" and "flashes" before the eyes, disappearing without a trace after some time) [8,9]; • "spot" before the eye, distortion of objects (metamorphopsia), decreased visual acuity (with DME) [8,9]; • sudden and significant vision loss (with vitreous hemorrhage); • vision loss and appearance of a "curtain" in the visual field (with retinal detachment); • deviation of the eyeball, double vision and/or drooping of the upper eyelid (with neuropathy of cranial nerves III and VI); • in the absence of macular zone involvement, DR may be asymptomatic and patients present no complaints.

History: • duration, type, severity, compensation (uncompensated course of DM is a risk factor for DR progression) of carbohydrate metabolism (by HbA1c level), state of lipid metabolism (by levels of total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides); ongoing DM treatment. • presence and duration of arterial hypertension, coronary heart disease, diabetic nephropathy, diabetic neuropathy, lower extremity angiopathy (including diabetic foot) [8,9]. • duration of vision loss, surgical interventions performed, laser coagulation (duration, frequency), intravitreal injections (number, drug used), other types of treatment [8,9]. • clarification of episode(s) of sharp decrease in glycemia level (for diagnosis of "transient diabetic retinopathy") [5].

Physical examination: • External examination of the eyeball (limitation of eyeball mobility resulting from paralysis of ocular muscles due to diabetic neuropathy). • High level of arterial blood pressure (risk factor for development of retinal hemorrhages and vitreous hemorrhage).

• Risk factors for development and progression of DR include pregnancy, post-abortion state, pubertal age and preclimacteric age (in women) [11].

Laboratory investigations Basic laboratory investigations: [12-16]. • Determination of glycated hemoglobin (reflects the state of compensation of the main process (DM) over the previous 3 months): elevated level of glycated hemoglobin (up to 7% - compensation, from 7% to 11% subcompensation, above 11% - decompensation of metabolic processes). • Complete blood count: increased erythrocyte sedimentation rate. • Biochemical blood analysis: elevated blood sugar level, elevated total cholesterol/low-density lipoprotein cholesterol, triglycerides, decreased high-density lipoprotein cholesterol content in blood - risk factors for occurrence and progression of DR. • General urinalysis (presence of protein indicates nephropathy, which is a risk factor for DR development).

Additional laboratory investigations: • coagulogram (hemostasis system study); • blood urea level study (elevated urea level indicates nephropathy, which is a risk factor for DR development); • blood creatinine level study (elevated creatinine level indicates nephropathy, which is a risk factor for DR development); • blood total bilirubin level study (elevated bilirubin level is a risk factor for development and progression of DR).

Instrumental investigations. Basic instrumental investigations: • visometry [8]. With macular edema, retinal or preretinal hemorrhage in the macular zone, as well as with diabetic neuropathy - decreased central visual acuity. With development of vitreous hemorrhage, visual acuity sharply and significantly decreases. Visual acuity is not a determining indicator in the diagnosis of diabetic retinopathy. In the absence of macular zone involvement, visual acuity may remain high even with PDR. • refractometry: change in refraction toward hypermetropia compared to previous data - sign of retinal edema. Transient change in refraction is possible, more often in young people with labile course of DM. Transient refractive disturbances are possible with use of hypoglycemic drugs (sulfonamides), as well as with decrease in glycemia level associated with initiation of insulin therapy. When glycemia level decreases, refraction weakens, and when it increases - strengthens. Appearance or

An increase in myopic refraction may also be due to cataract development [8].

• Tonometry: possible elevation of IOP (with neovascularization of the anterior chamber angle) or reduction (with tractional retinal detachment) [8].
• Biomicroscopy of the anterior segment of the eye: presence of dystrophy (in NPDR and PPDR) or neovascularization (PDR) of the iris; assessment of optical media transparency; lens, vitreous hemorrhages (of varying degrees); corneal epitheliopathy due to impaired innervation [8,15].
• Ophthalmoscopy and/or biomicroscopy of the retina using an aspheric lens [8,17-20].
• Optical coherence tomography (OCT): performed to determine retinal thickness in the central zone, type of retinal architecture in DME, presence of vitreomacular traction syndrome or macular hole. In the presence of diabetic macular edema, the following morphological changes may be observed: retinal thickening, cystic changes, subfoveal neuroepithelial detachment, vitreoretinal tractions, epiretinal fibrosis, macular holes. Allows identification of biomarkers indicating chronicity of DME (presence of pronounced DRIL; disruption of the ellipsoid zone and damage to the external limiting membrane) based on which functional outcomes of anti-VEGF therapy can be predicted [20,21].
• Optical coherence tomography angiography (OCT-A): allows detection of microaneurysms not identified on ophthalmoscopy, IRMA, early retinal neovascularization, areas of nonperfusion (ischemia), and assessment of ischemic area in the macular zone in patients with reduced vision that cannot be explained by optical media opacity and ophthalmoscopic fundus appearance. Marked reduction in deep capillary plexus density is a biomarker of DME chronicity, allowing prediction of functional outcomes of anti-VEGF therapy [22-24].

Additional instrumental investigations:

• Fundus photography (two-field) (refers to screening methods for DR diagnosis, effective with transparent optical media of the eye, performed when technically feasible), including using a non-mydriatic digital fundus camera [25-27]. Fundus photography may be performed by technical personnel with subsequent evaluation of obtained images by an ophthalmologist specializing in vascular pathology of the visual organ [1].
• Cycloscopy - examination of the retinal periphery to identify presence and severity of ischemic zones, neovascularization, vitreoretinal tractions; in recurrent vitreous hemorrhages to clarify the source of hemorrhages [8].
• Amsler test (screening) - distortion of lines, blurring of the pattern (macular zone involvement) [8].

• Perimetry: changes in central visual field (central absolute or relative scotoma); paracentral scotomas; constriction of visual field boundaries [8].
• Ultrasound examination (US) in the presence of significant opacities in the vitreous body and lens (hemophthalmos, presence of fibrous strands, tractional retinal detachment) [8].
• Gonioscopy to detect presence of neovascularization of the anterior chamber angle (with rubeosis iridis, PDR); and/or in patients with impaired regulation of ophthalmotonus to determine the cause of IOP elevation [8,16-17].
• Heidelberg retinal laser tomography (HRT) – allows determination of decreased area and volume of the neuroretinal rim, increased excavation area (in secondary optic nerve atrophy after diabetic optic neuropathy) or signs of glaucomatous optic neuropathy based on refined quantitative assessment of the optic disc [28,29].
• Fluorescein angiography of the fundus (FA): allows assessment of the degree of hemodynamic disturbance in choroidal and retinal vessels, identification of zones of increased vascular permeability (disruption of the inner blood-retinal barrier), detection of ischemic maculopathy and/or ischemic zones in other retinal areas [29-32].
• Electrophysiological studies (EPS) to determine functional state of the optic nerve and retina. Changes in visual evoked potentials are characterized by decreased amplitude of the N75-P100 complex as DR progresses and prolonged latency. Electrophysiological parameters of the retina: decreased amplitude and increased latency of rhythmic and general ERG [33-35].

Table 2 - Fundus changes at various stages of diabetic retinopathy DR Stage Ophthalmoscopy Data Nonproliferative stage

Microaneurysms (local protrusions of capillary walls), hard exudates (yellowish foci with distinct borders), intraretinal dot hemorrhages and retinal blot hemorrhages, possible development of any form of diabetic maculopathy.

Preproliferative stage

In addition to changes characteristic of NPDR: cotton-wool spots (soft exudates), vascular tortuosity, venous loops, beaded vessels), intraretinal microvascular abnormalities (IRMA). Any form of diabetic maculopathy may be present. Diagnostic criteria for PPDR: multiple retinal blot hemorrhages in four quadrants, venous abnormalities (deformities) in two quadrants, multiple IRMA in at least one quadrant of the fundus ("4-2-1" rule).

Proliferative stage

In addition to changes characteristic of severe NPDR – neovascularization on the optic disc and/or in other areas of the retina, retinal and preretinal hemorrhages, vitreous hemorrhage, fibrous tissue, retinal detachment.

Any form of diabetic maculopathy is possible. Neovascularization of the anterior chamber angle, leading to the development of secondary neovascular glaucoma.

The risk of PDR progression and significant vision loss is assessed by the area and localization of neovascularization and the presence of intraocular hemorrhages (DRS study). Risk factors for significant visual acuity loss include:

• preretinal or vitreous hemorrhages; - neovascularization of the optic disc exceeding one-third of its area; - retinal neovascularization in any zone exceeding half the area of the optic disc.

Transient diabetic retinopathy develops against the background of rapid reduction in HbA1c levels, characterized by a large number of "soft" exudates, retinal hemorrhages, IRMA, DME and/or ischemic maculopathy. Less commonly, diabetic papillitis develops: transient optic disc edema, "soft" exudates and retinal hemorrhages in the superficial layers of the retina at the optic disc margin [15].

Table 3 - Changes in the fundus in various forms of diabetic maculopathy.

Form of DM Ophthalmoscopy findings Ischemic maculopathy (caused by severe impairment of blood flow in the vessels of the perifoveal zone)

Minor changes in the fundus in the macular zone (isolated hard exudates, microaneurysms, microhemorrhages) with low visual acuity.

DME without traction Deformation or absence of foveal reflex, retinal thickening in the macular zone, deposition of hard exudates.

DME with traction Pathological macular reflexes and deformation of retinal structures. Presence of retinal edema.

Indications for consultation with narrow specialists: • endocrinologist consultation to determine the degree of compensation of the underlying disease and the possibility of intravitreal injections, surgical or laser treatment; • therapist consultation – to assess the patient's general condition and the possibility of intravitreal injections, surgical or laser treatment; • cardiologist consultation (as indicated, in the presence of cardiovascular complications) – high blood pressure is one of the main risk factors for the development of retinal and optic nerve vascular occlusions; • neurologist consultation (in the presence of diabetic neuropathy), • pediatrician and/or surgeon consultation (in diabetic foot syndrome); • otolaryngologist/dentist consultation to identify and sanitize chronic foci of infection; • nephrologist consultation (in case of impaired kidney function); • neurosurgeon, rheumatologist, infectious disease specialist, vascular surgeon, hematologist consultation – as indicated.

Surgical treatment at the outpatient level: Retinal laser coagulation [36-39]. (LE-B) is performed to eliminate zones of ischemia, microaneurysms and newly formed vessels, to form chorioretinal adhesions that reduce the risk of tractional retinal detachment. RLC can be performed both as monotherapy and in combination with intravitreal anti-VEGF injections or intravitreal corticosteroid injections. Indications for laser coagulation: • clinically significant DME (not more than 350 μm). For DME exceeding 350 μm, RLC is performed in combination with intravitreal administration of angiogenesis inhibitors or intravitreal corticosteroid injections, aimed at improving or stabilizing visual function. Deferred RLC performed after 5 loading injections of angiogenesis inhibitors is more effective than that performed in alternation with intravitreal anti-VEGF injections. • severe NPDR with extensive areas of retinal ischemia (without ischemic maculopathy) with a tendency toward further progression, when regular patient monitoring is not possible, to suppress VEGF expression and prevent the development of neovascularization (panretinal laser coagulation for relative indications);

• presence of neovascular vessels on the optic disc or in any zone of the retina; • PDR with neovascularization of the iris and/or anterior chamber angle (PRP with coagulation of the extreme peripheral retinal areas).

Laser coagulation methods:

• focal laser coagulation – coagulation of "soft" exudates to prevent production of VEGF factor in these zones and appearance of neovascular vessels.
• grid-pattern laser coagulation - (preferably using subthreshold laser coagulation) for focal macular edema not exceeding 350 microns in the absence of possibility for IVVIA or IVVGK, or inability to maintain the intravitreal injection regimen.
• panretinal laser coagulation is performed starting from the lower sections of the mid-periphery, with subsequent application of laser coagulates to the entire surface of the mid-periphery of the fundus from the temporal vascular arcades. The timing of panretinal laser coagulation depends on the stage of DR and presence of DME.

PRP: deferred or immediate. Deferred LCS is performed 24 or more weeks after initiation of angiogenesis inhibitor treatment. According to the international multicenter DRS study, indication for immediate panretinal laser coagulation is proliferative DR combined with "high-risk factors for vision loss," which are defined as:

• prepapillary neovascular vessels whose size exceeds or equals 1/4-1/3 of the optic disc area,
• and/or prepapillary neovascular vessels of any size combined with intravitreal or preretinal hemorrhage,
• and/or preretinal neovascular vessels whose size exceeds 1/2 of the disc area combined with intravitreal or preretinal hemorrhage.

With HbA1c >10% and presence of PDR, PRP is performed without waiting for significant improvement in glycemic control. In PPDR with pronounced peripheral ischemia, PRP is performed with mandatory coagulation of the extreme peripheral retinal areas to exclude the risk of neovascular glaucoma development. In PDR with neovascularization of the iris and/or anterior chamber angle, stage 1 PRP is performed no earlier than 2 weeks after IVVIA with subsequent adherence to IA administration timing and mandatory coagulation of the extreme peripheral retinal areas.

Contraindications to laser coagulation:

• ischemic maculopathy;
• pronounced neovascularization (grade III-IV);
• pronounced glial proliferation (grade III-IV) passing through the posterior pole of the eye;

• vitreoretinal traction of grade 4 or higher.

Intravitreal administration of angiogenesis inhibitors [40-55] (EL-A) in outpatient settings is performed in ambulatory eye microsurgery centers (both as monotherapy and in combination with laser coagulation) and is aimed at blocking VEGF factor to reduce/eliminate macular edema and/or neovascularization of the retina, optic nerve, iris.

Indications for IVVIA:

• diabetic macular edema (more than 350 microns) involving the center of the macula (according to OCT data) at any stage of diabetic retinopathy;
• PDR with iris rubeosis without secondary glaucoma;
• PDR with iris rubeosis with secondary glaucoma;
• PDR with/without DME - IVVIA in combination with PRPC to suppress neovascularization;
• aflibercept 8 mg is prescribed in the absence of positive dynamics (no stabilization or increase in VA of at least 5 letters and/or no reduction in central retinal thickness by 20% from baseline according to OCT data) after 5 loading injections of aflibercept 2 mg;
• DME treatment with aflibercept 8mg is initiated when the patient is unable to maintain the schedule of visits to the medical facility (remote residence, absence of physical ability to independently visit the clinic, patient's comorbid condition) required for treatment with aflibercept 2mg or another anti-neovascular agent.

Contraindications to IVVIA:

• hypersensitivity to drug components;
• ocular or periocular infection;
• active severe intraocular inflammation;
• pregnancy or breastfeeding period;
• vitreomacular traction syndrome and/or macular hole;
• first 3 months after acute cerebral or coronary circulation disorder;
• high risk of cardiovascular disorders.

Indication for the next injection of angiogenesis inhibitor is deterioration of visual acuity by 5 or more letters on the ETDRS visual acuity scale (1 line on the Snellen chart) and/or increase in retinal thickness in the central zone by more than 100 μm according to OCT data. Treatment with angiogenesis inhibitor aflibercept (2mg) begins with 5 loading injections and continues in "treat-and-extend" mode: in the absence of signs of disease reactivation (stabilization of VA and/or anatomical parameters according to OCT data), the interval between injections is gradually increased by 2 weeks (up to an 8-week interval). In case of

deterioration of visual acuity and anatomical parameters, the intervals between injections should be shortened (while monitoring examinations may be more frequent than injections). In each clinical case, the final decision to increase the time interval between injections is made by the physician based on the clinical picture and disease course.

Administration of aflibercept 8 mg after 3 loading injections is continued in a 12-16 week regimen (at least 5 injections per year). If criteria for discontinuation of therapy are met, the patient should remain under ophthalmologist observation (frequency of observation corresponds to the severity of DR) [40-51] (LE-A).

Treatment with ranibizumab begins with 3 or more monthly loading injections. Then intravitreal administration of the drug continues monthly until maximum stable visual acuity and/or stabilization of the clinical picture (absence of increased neovascularization and/or progression of hemorrhagic component) and/or stabilization of anatomical parameters of the retina (according to OCT data) is achieved. The frequency of monitoring and treatment is determined by the physician depending on the disease course. If the "treat-and-extend" regimen is chosen, the interval between injections should be increased by 2 weeks, but not more than 1 month [52-55] (LE-A).

In each clinical case, the final decision on indications for treatment with angiogenesis inhibitors and choice of injection regimen is made by the physician based on assessment of the clinical picture features and disease course.

Intravitreal administration of glucocorticoids [63-66] (LE-A) implant (0.7 mg dexamethasone) for intravitreal administration is performed on an outpatient basis in centers of outpatient eye microsurgery. use of the drug after registration in RK

Indications: Indications for intravitreal administration of glucocorticoids as an implant at disease onset: • presence of inflammatory biomarkers according to OCT data (large number of hyperreflective foci, hard exudate, large intraretinal cysts, neuroepithelial detachment); • history of stroke/myocardial infarction and other cardiovascular and cerebrovascular diseases, as well as very high risk of serious vascular complications; • inability to comply with frequent visit schedule and/or attend medical facility during the first 6 months after intravitreal drug administration; • absence of risks of increased intraocular pressure; • pseudophakia or in case of planned phacoemulsification cataract surgery; • pregnancy; • after vitrectomy.

Indications for intravitreal administration of glucocorticoids as an implant as second-line therapy: • with minimal response or lack of response to anti-VEGF therapy (3–6 injections). The criterion for refractoriness to ongoing therapy is the absence of gain in best corrected visual acuity of +5 letters or more and/or reduction in central retinal thickness <20% from baseline.

Contraindications: • hypersensitivity to drug components; • ocular or periocular infection; • active severe intraocular inflammation; • vitreomacular traction syndrome and/or macular hole; • first 3 months after acute cerebral or coronary circulation disorder; • advanced stage glaucoma with IOP decompensation not controlled by medical therapy; • aphakia with posterior capsule rupture; • presence of anterior chamber IOL, iris-clip IOL, posterior chamber IOL with transscleral fixation with simultaneous presence of posterior capsule rupture. Use of dexamethasone as an implant requires long-term regular IOP monitoring. Repeated implant administration is possible after 6 months in case of decreased visual acuity, recurrent development of macular edema, or progression of existing DME (increase in CRT according to OCT data). The number of IVGC as an implant is determined by the physician individually in each case (however, there is no data on efficacy and safety of using more than 7 injections of dexamethasone implant).

Drug therapy. Includes drugs for pharmacological support of surgical treatment (anti-inflammatory, antibacterial, carbonic anhydrase inhibitors, antiseptics), as well as local hypotensive therapy drugs. Patients with diabetic retinopathy may be prescribed antioxidants, antihypoxants, antiplatelet agents, hemostatics, and angioprotectors depending on the clinical picture.

List of essential medicines (with 100% probability of use in adults and children): Drug group

ORGANIZATIONAL ASPECTS OF THE PROTOCOL 7.1 List of protocol developers with qualification data: 1) Stepanova Irina Stanislavovna – Doctor of Medical Sciences, LLP "Kazakh Research Institute of Eye Diseases," senior lecturer of the postgraduate education department. 2) Kanafyanova Elmira Gazizovna – Doctor of Medical Sciences, LLP "Kazakh Research Institute of Eye Diseases," chief physician. 3) Umbetiar Almas Bekimovich – Candidate of Medical Sciences, LLP "Kazakh Research Institute of Eye Diseases," head of laser department. 4) Al-Astal Mukhammed Salikhovich – Candidate of Medical Sciences, LLP "Kazakh Research Institute of Eye Diseases," ophthalmologist of department 2. 5) Esimova Asel Askerbekovna – Candidate of Medical Sciences, LLP "Kazakh Research Institute of Eye Diseases," senior lecturer of the postgraduate education department. 6) Otarova Zhanar – branch of LLP "Kazakh Research Institute of Eye Diseases" in Astana city, ophthalmologist of laser department. 7) Shubaeva Aigul Temirovna – ophthalmologist of the highest category, State Enterprise on REM "Almaty Multidisciplinary Clinical Hospital." 8) Abilzhamanova Aliya Amangeldinovna – clinical pharmacologist LLP "Kazakh Research Institute of Eye Diseases."

Approved by the Joint Commission on Quality of Medical Services of the Ministry of Health

of the Republic of Kazakhstan dated April 10, 2025

Protocol No. 229

DIABETIC RETINOPATHY

Introductory Part 1.1 ICD-10 Code(s):

ICD-10

Code Name

H 36.0 E10.3 E11.3 E13.3

Diabetic retinopathy Insulin-dependent diabetes mellitus with ophthalmic complications Non-insulin-dependent diabetes mellitus with ophthalmic complications Other specified diabetes mellitus with ophthalmic complications

Date of protocol development/revision: 2018 (revised 2023)

Abbreviations used in the protocol:

IOP

Intraocular pressure

AMD

Age-related macular degeneration

DR

ONH

Optic nerve head

DM

Diabetic maculopathy

DME

Diabetic macular edema

DRIL

Disorganization of retinal inner layers ETDRS Early Treatment of Diabetic Retinopathy Study

IVGC Intravitreal administration of glucocorticoids

IVAI Intravitreal administration of angiogenesis inhibitors

IOL

Intraocular lens

IRMA

Intraretinal microvascular abnormalities

CSME

Clinically significant macular edema

LPC

Laser photocoagulation of the retina

NPDR

Non-proliferative diabetic retinopathy

HRT

Heidelberg retinal laser tomography HbA1c Glycated hemoglobin

NE OCT OCT-A TC PDR PRP Pre-PDR RPE DM RCT US FA LDL-C HDL-C VEGF

CRT

Neuroepithelium Optical coherence tomography Optical coherence tomography angiography Total cholesterol Proliferative diabetic retinopathy Panretinal photocoagulation Pre-proliferative diabetic retinopathy Retinal pigment epithelium Diabetes mellitus Randomized clinical trials Ultrasound examination Fluorescein angiography Low-density lipoprotein cholesterol High-density lipoprotein cholesterol Vascular endothelial growth factor Central retinal thickness

Protocol users: – pediatric and adult ophthalmologists, ophthalmic surgeons.

Patient category: adults and children.

Evidence level scale: A High-quality meta-analysis, systematic review of RCTs or large RCT with very low probability (++) of systematic error, the results of which can be generalized to the relevant population. B High-quality (++) systematic review of cohort or case-control studies or high-quality (++) cohort or case-control study with very low risk of systematic error or RCT with low (+) risk of systematic error, the results of which can be generalized to the relevant population. C Cohort or case-control study or controlled study without randomization with low risk of systematic error (+), the results of which can be generalized to the relevant population or RCT with very low or low risk of systematic error (++ or +), the results of which cannot be directly generalized to the relevant population. D Case series description or uncontrolled study or expert opinion.

Classification of diabetic retinopathy: Classification proposed by E. Kohner and M. Porta (1991) and approved by WHO [4]. By stages: • non-proliferative; • pre-proliferative; • proliferative.

Transient diabetic retinopathy occupies a special place, which represents the manifestation or progression of DR occurring within 6-12 months after rapid reduction of glycated hemoglobin levels by more than 2%, the cause of which may be intensified insulin therapy, transfer of type 2 DM patients to insulin therapy, insulin pumps, pancreas transplantation, pregnancy, bariatric surgery [5].

By degree of gliosis: 1 – areas of gliosis in the posterior pole of the eye or in the middle part of the vascular arcades, not involving the ONH; 2 – gliosis only in the ONH area; 3 – gliosis in the ONH area and vascular arcades; 4 – circular bands of gliosis involving the ONH, vascular arcades and temporal interarcade zones of the retina.

By degree of vitreoretinal tractions: 1 – part of the inner surface of the retina subjected to glial proliferation or neovascularization advances toward the central parts of the vitreous body; 2 – vitreoretinal adhesions extend along one of the vascular arcades (more often temporal) and are limited to one segmental zone; 3 – vitreoretinal adhesions occupy more than one segmental zone of the retina (more often in the zones of the superior and inferior vascular arcades);

4 – significant shrinkage of the vitreous body leads to pulling of the sensory part of the retina from the pigment epithelium; 5 – the entire central part of the retina is moderately detached; 6 – moderately detached retina in the center and cone-shaped posterior vitreous detachment; 7 – pronounced retinal detachment with traction and high posterior vitreous detachment; 8 – retina is pushed forward to the retrolental space (high posterior vitreous detachment).

Table 1 - Classification of diabetic maculopathy by severity: Severity level Biomicroscopic signs No DM No retinal thickening or hard exudates in the posterior pole of the eye

Early DM Retinal thickening or hard exudates in the posterior pole of the eye at a distance from the center of the macula

Moderate DM Retinal thickening or hard exudates near the center of the macula but not involving the center

Severe DM Retinal thickening or hard exudates involving the center of the macula

Diagnostic algorithm: Appendix 1.

Differential diagnosis and justification for additional examination methods:

Table 4 - Differential diagnosis of diabetic retinopathy Diagnosis Justification for differential diagnosis Examinations Exclusion criteria for diagnosis History Gradual decrease in vision Age-related macular degeneration (AMD) Decreased central vision, central scotoma in the visual field Ophthalmoscopy

Dystrophic changes in the choriocapillary layer, RPE and Bruch's membrane (exudative-hemorrhagic detachment of RPE and/or NE, subretinal neovascular membrane, retinal drusen (hard and soft), defects and atrophies of RPE).

Optical coherence tomography Presence of drusen, atrophy and hypertrophy of retinal pigment epithelium, pigment epithelium detachment, neuroepithelium detachment, choroidal neovascularization (of any type) of subretinal fibrosis.

Questioning

Vision loss suddenly, more often – in the morning hours, against the background of headache and/or increased blood pressure. May be preceded by transient impairment of visual acuity and visual field.

Retinal vein thrombosis Decreased vision, changes in visual field Ophthalmoscopy Hemorrhages have the form of smears, petechiae, strokes or flame-shaped, Veins are engorged, pathologically tortuous, have a darker color. The area of altered retina resembles in shape a triangle, the apex of which is directed to the site of occlusion and coincides with the zone of arteriovenous crossing.

INN

Method of administration

LE

Instillations of eye drops into the conjunctival sac: adults 1 drop of 10 mg/ml M-anticholinergic Tropicamide* solution 2 times with 5-minute C interval or adults and children over 8 years 1-2 drops of 5 mg/ml solution.

• use of the drug in children under 8 years of age is possible after obtaining

informed consent from parents.

List of additional medications used in adults (less than 100% probability of use):

Drug group

Intravitreally aflibercept 2mg solution Angiogenesis inhibitor Aflibercept 2 mg for injections (0.05 ml) administered once a month (5 loading injections), then the interval A between injections may be increased in treat- and-extend regimen.

Intravitreally aflibercept 8mg solution Angiogenesis inhibitor Aflibercept 8 mg for injections (0.05 ml) administered once a month (3 loading injections), subsequent A injections - after 12 and 16 weeks (at least 5 injections per year).

Angiogenesis inhibitor Ranibizumab Intravitreally ranibizumab is administered at 0.5 mg (0.05 ml) solution for injections once a month (3 loading injections), In case of choosing the "treat- A and-extend" regimen, the interval between injections should be increased by 2 weeks, but not more than 1 month.

Selective beta-adrenoblockers Betaxolol instillations of eye drops into the conjunctival sac 2 drops 2 times a day (for B DR accompanied by increased IOP) Non-selective beta-adrenoblockers Timolol instillations of eye drops into the conjunctival sac 2 drops 2 times a day (for B DR accompanied by increased IOP) Carbonic anhydrase inhibitors Dorzolamide instillations of eye drops into the conjunctival sac 2 drops 2 times a day (for B DR accompanied by increased IOP) Carbonic anhydrase inhibitors Brinzolamide instillations of eye drops into the conjunctival sac 2 drops 2 times a day (for B DR accompanied by increased IOP) Nonsteroidal anti-inflammatory drug for topical use in ophthalmology Bromfenac Instillations of eye drops into the conjunctival sac 1 drop 2 times a day for 14 days (for prevention of development of inflammatory C process after surgical/laser treatment and reduction of macular edema) Antimicrobial drug of the fluoroquinolone group for topical Ofloxacin use in ophthalmology Instillations of eye drops into the conjunctival sac 2 drops 5 times a day for 14 days (for prevention C of postoperative inflammation) Antimicrobial Instillations of eye drops drug of the into the conjunctival sac fluoroquinolone group for topical Moxifloxacin 2 drops 5 times a day for 14 days (for prevention C use in of postoperative ophthalmology inflammation) instillations of eye drops Antimicrobial drug of the fluoroquinolone group for topical Levofloxacin use in ophthalmology

into the conjunctival sac 2 drops 5 times a day duration of use depending on severity of condition (for prevention of postoperative

C inflammation) 1/2-1 tablet per day for no more than 3 consecutive days, repeated administration is possible Carbonic anhydrase Acetazolamide inhibitors after 7 days (duration of administration is determined by the physician B individually) (for DR accompanied by increased IOP and DME).

Duration of administration – at the discretion of the physician) Antioxidant, retinoprotector Ascorbic acid Solution for injections 200 mg (2ml) intramuscularly once a day, 5-10 injections C Glucocorticoids instillations of eye drops for topical and systemic Dexamethasone into the conjunctival sac 2 drops 6 times a day after B use in surgery and then according to ophthalmology tapering regimen Glucocorticoids for topical and systemic Dexamethasone Solution for injections parabulbarly 2 mg/ml (0.5 B use in ml) - 4 mg/ml (1 ml) ophthalmology Glucocorticoid (intravitreal implant 700 mcg) for Dexamethasone* implant (0.7 mg dexamethasone) for A topical intravitreal administration use in ophthalmology Anticoagulant Sulodexide Solution for injections intravenously or intramuscularly 650 LSU once a day for 15-20 days, then B

LSU (1 tablet) 2 times a

day – 30-40 days.

At the dose recommended

by therapist/endocrinologist

Lipid-lowering drug Fenofibrate (adults in tablet form micronized* 200-400 mg/day in 3 doses) Duration of use at B discretion of endocrinologist

and/or therapist

• use of the drug after registration in RK

Timing of ophthalmological examinations for patients with diabetes mellitus [7,10, 60].

Timing of ophthalmological examinations for children with diabetes mellitus:

• children with DM, until reaching puberty - once every 2 years;
• children with DM, during puberty with compensated DM and absence of DR signs - once a year;
• children with DM, during puberty with uncompensated course of DM or presence of DR signs - at least 2 times a year;
• frequency of subsequent examinations is determined by the ophthalmologist in accordance with the stage of DR, but not less than once a year.

Timing of ophthalmological examinations for adults with diabetes mellitus:

• a patient with type 2 DM should be examined immediately or as soon as possible after diagnosis of "diabetes mellitus";
• if DR is not detected during the initial examination of a patient with type 2 DM, further examinations are conducted at least once a year;
• for type 1 DM, examination should be conducted no later than 5 years from disease onset;
• patients with high glycemia levels (HbA1c more than 9%) and proteinuria should be examined at least once every 6 months even in the absence of pathological changes in the fundus during initial examination;
• in the presence of DR, the frequency of examinations is determined depending on the disease stage, presence of DME and treatment method, but examinations should be conducted: for NPDR (without DME) at least twice a year; for pre-PDR or PDR (without DME) at least three times a year; for NPDR, pre-PDR, PDR with presence of DME - depending on the treatment being administered, but at least once every 2 months with mandatory OCT monitoring;
• ophthalmological examination of patients with DM is mandatory before starting intensive insulin therapy or when switching to insulin therapy. In case of rapid decrease in blood sugar level, exceptionally strict ophthalmological monitoring is necessary;
• in case of unexpected decrease in visual acuity or appearance of any complaints from the visual organ in patients with DM, examination is conducted immediately, regardless of the timing of the next scheduled visit to the ophthalmologist;
• examination of women suffering from DM who wish to have a child is conducted before conception (during pregnancy planning period) and every 3 months after its confirmation.

For the purpose of preventing the occurrence and development of DR (in adults), Sulodexide is administered at 650 LU intravenously or intramuscularly once a day for 15-20 days, then 250 LU (1 tablet) 2 times a day for 30-40 days [56-59] and the lipid-lowering drug fenofibrate at a dose and duration determined by the endocrinologist and/or therapist for all stages of DR [60-63].

Treatment effectiveness indicators:

Stabilization of the diabetic process in the fundus.

* Against the background of antihypertensive therapy

≥ 70 and < 80

Treatment tactics at the inpatient level Appendix 2.

Medication treatment: at the inpatient level includes drugs for pharmacological support of laser and surgical treatment (anti-inflammatory, antibacterial, carbonic anhydrase inhibitors, antiseptics), as well as local hypotensive therapy drugs.

List of essential medicines (with 100% probability of use in adults and children): Drug group

Instillation of eye drops into conjunctival sac: M-anticholinergic Tropicamide* adults 1 drop of 10 mg/ml solution 2 times with 5-minute interval or C adults and children over 8 years 1-2 drops of 5 mg/ml solution.

• use of the drug in children under 8 years of age is possible after obtaining informed consent from parents

List of additional medicines used in adults (less than 100% probability of use): Drug group

Intravitreal aflibercept 2mg solution for injection (0.05 Angiogenesis inhibitor ml) administered once a month (5 Aflibercept 2 mg loading injections), then the

interval between injections A may be increased in treat-and-extend regimen.

Intravitreal aflibercept 8mg solution for injection (0.05 Angiogenesis inhibitor Aflibercept 8 mg ml) administered once a month (3 loading injections), A subsequent injections - after 12 and 16 weeks (at least 5 injections per year).

Intravitreal ranibizumab administered at 0.5 mg (0.05 ml) solution for injection once a month (3 Angiogenesis inhibitor Ranibizumab loading injections). If the "treat-and-extend" regimen is chosen, A the interval between injections should be increased by 2 weeks, but not more than 1 month.

Glucocorticoid (intravitreal implant 700 mcg) for Dexamethasone* local implant (0.7 mg dexamethasone) for intravitreal administration A use in ophthalmology Glucocorticoids for local use in ophthalmology Dexamethasone

instillation into conjunctival sac 2 drops 6 times daily eye drops (after surgery and then according to tapering schedule)

B Glucocorticoids for local use in ophthalmology Dexamethasone 2 mg/ml (0.5 ml) - 4 mg/ml (1 ml) solution for injection parabulbarly (after surgery) B Beta- instillation of eye drops into adrenoblockers Betaxolol conjunctival sac 2 B selective drops 2 times daily (for DR, accompanied by increased IOP) beta-adrenoblockers Timolol non-selective instillation of eye drops into conjunctival sac 2 drops 2 times daily (for DR, B accompanied by increased IOP) instillation of eye drops into Carbonic anhydrase inhibitors Dorzolamide conjunctival sac 2 drops 2 times daily (for DR, accompanied by increased B IOP) instillation of eye drops into Carbonic anhydrase inhibitors Brinzolamide conjunctival sac 2 drops 2 times daily (for DR, accompanied by increased B IOP) Non-steroidal anti-inflammatory drug for local use in ophthalmology Bromfenac

Instillation of eye drops into conjunctival sac 1 drop 2 times daily for 14 days (for prevention of postoperative inflammation)

C Antimicrobial drug Instillation of eye drops into fluoroquinolone conjunctival sac 2 group Ofloxacin drops 5 times daily for 14 days (for C for topical use in ophthalmology

prevention of postoperative inflammation)

Antimicrobial drug from the fluoroquinolone group for topical use in ophthalmology Moxifloxacin eye drops Instillation of eye drops into the conjunctival sac 2 drops 5 times a day for 14 days (for C

Antimicrobial drug from the fluoroquinolone group for topical use in ophthalmology Levofloxacin instillation of eye drops into the conjunctival sac 2 drops 5 times a day duration of use depending on severity of C

condition (for prevention of postoperative inflammation)

Carbonic anhydrase inhibitors Acetazolamide

1/2-1 tablet per day (for DR accompanied by increased IOP, Duration of administration – at the discretion of the physician)

B Antioxidant, retinoprotector Ascorbic acid 200 mg (2ml) solution for injection intramuscularly once a day, 5-10 injections C

Further management: • instillation of anti-inflammatory and antibacterial drugs for 1 month after surgical treatment and 7 days – after LC and/or IVVIA; • monitoring of intraocular pressure at least once a week after vitreoretinal surgery, intravitreal administration of angiogenesis inhibitors or corticosteroids;

• topical hypotensive drugs (with high IOP level); • OCT monitoring (monthly after IVVIA or IVVGC); • after vitreoretinal surgery – examination at least once a month.

INDICATORS OF EFFECTIVENESS AND DIAGNOSIS AND TREATMENT: • elimination of vitreoretinal tractions; • reduction of macular edema; • improvement of transparency of optical media of the eye; • stabilization of the diabetic process on the fundus.

SAFETY

Indication of absence of conflict of interest: absent.

Reviewers: Utelbayeva Zauresh Tursunovna – Doctor of Medical Sciences, Professor of the Department of Eye Diseases, NAO "Kazakh National Medical University named after S.D. Asfendiyarov".

Indication of conditions for protocol revision: revision no less than once every 5 years and no more than once every 3 years in the presence of new diagnostic and treatment methods with level of evidence.

List of references used:

Yau JW, Rogers SL, Kawasaki R, Lamoureux EL, et al. Meta-Analysis

for Eye Disease (META-EYE) Study Group. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care. 2012;35(3):556-

https://doi.org/10.2337/dc11-1909

Van de Kreeke JA, Darma S, Chan Pin Yin JMPL, Tan HS, Abramoff MD, Twisk

JWR, Verbraak FD. The spatial relation of diabetic retinal neurodegeneration with diabetic retinopathy. PLoS One. 2020;15(4):e0231552.

Retinal Neurodegeneration in Diabetes: an Emerging Concept in Diabetic

Retinopathy. Curr Diab Rep. 2021 Dec 13;21(12):65. doi: 10.1007/s11892-021-01428- x.

Porta M., Kohner E. M. Screening for diabetic retinopathy in Europe / Diabetic

Medicine. – 1991. – V. 8. – P. 197-198.

Wen Lim S, van Wijngaarden P, Harper CA, et al. Early worsening of diabetic

retinopathy due to intensive glycaemic control. Clin Exp Ophthalmol. 2019;47(2):265-

https://doi.org/10.1111/ceo.13393

International Council of Ophthalmology | Standards of the International Council on

diabetic retinopathy Copyright © ICO January 2014

Schmidt-Erfurth U. et al. Guidelines for the Management of Diabetic Macular Edema

by the European Society of Retina Specialists (EURETINA) / Ophthalmologica. – 2017

• Vol. 237 № 4 – P. 185-222.

ICO Guidelines for Diabetic Eye Care Standards of the International Council of

Ophthalmology (International Council of Ophthalmology) on diabetic retinopathy. Translation from English – Doctor Vurdaft Anton Esibovich, FCOphth(ECSA), FICO. antonvurdaft@gmail.com June 2016.

Mike Trott , Robin Driscoll , Shahina Pardhan Associations between diabetic

retinopathy and modifiable risk factors: An umbrella review of meta-analyses Diabet Med. 2022 Jun;39(6):e14796. doi: 10.1111/dme.14796. Epub 2022 Feb 5.

Jensen ET, Rigdon J, Rezaei KA, Saaddine J, Prevalence, Progression, and

Modifiable Risk Factors for Diabetic Retinopathy in Youth and Young Adults With Youth-Onset Type 1 and Type 2 Diabetes: The SEARCH for Diabetes in Youth Study.

Diabetes Care. 2023 Apr 12:dc222503. doi: 10.2337/dc22-2503.

McElvy SS, Miodovnik M, Rosenn B, et al. A focused preconceptional and early

pregnancy program in women with type 1 diabetes reduces perinatal mortality and malformation rates to general population levels. J Matern Fetal Med. 2000;9(1):14-20.

American Diabetes Association. Standards of medical care in diabetes - 2021.

Diabetes Care, 2021, Sep;44(9):2182. doi: 10.2337/dc21-ad09. Epub 2021 Jun 16.

Rubino F, Nathan DM, Eckel RH et al. Metabolic surgery in the treatment algorithm

for type 2 diabetes: a joint statement by international diabetes organizations. Diabetes Care 2016;39:861-877.

Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). DiabetesCare 2018 Dec; 41(12): 2669-2701. 15. American Academy of Ophthalmology Preferred Practice Patterns Committee. Diabetic Retinopathy Preferred Practice Pattern®. AAO (2019); ISSN 0161-6420/19. 16. Bain SC, Klufas MA, Ho A, Matthews DR. Worsening of diabetic retinopathy with rapid improvement in systemic glucose control: A review. Diabetes Obes Metab. 2019;21(3):454-466. 17. Lee M. Jampol, M.D., Adam R. Glassman, M.S., and Jennifer Sun, M.D., M.P.H. Evaluation and Care of Patients with Diabetic Retinopathy List of authors. N Engl J Med 2020; 382:1629-1637 DOI: 10.1056/NEJMra1909637. 18. Mohamed Ashraf , Kristen M Hock , Jerry D Cavallerano , Frank L Wang , Paolo S Silva Comparison of Widefield Laser Ophthalmoscopy and ETDRS Retinal Area for Diabetic Retinopathy. Ophthalmol Sci. 2022 Jun 28;2(4):100190. doi: 10.1016/j.xops.2022.100190. eCollection 2022 Dec. 19. Fernando Korn Malerbi,, Paulo Henrique Morales, Michel Eid Farah et al.Comparison between binocular indirect ophthalmoscopy and digital retinography for diabetic retinopathy screening: the multicenter Brazilian Type 1 Diabetes Study/ On behalf of The Brazilian Type 1 Diabetes Study Group Diabetology & Metabolic Syndrome volume7, Article number: 116 (2015) Cite this article. 20. Rodolfo Mastropasqua , Rossella D'Aloisio , Luca Di Antonio , Emanuele Erroi , Enrico Borrelli , Federica Evangelista , Giada D'Onofrio , Marta Di Nicola , Giuseppe Di Martino , Lisa Toto Widefield optical coherence tomography angiography in diabetic retinopathy. Acta Diabetol. 2019 Dec;56(12):1293-1303. doi: 10.1007/s00592-019-01410-w. Epub 2019 Aug 29. 21. Kim K, Kim ES, Yu SY. Optical coherence tomography angiography analysis of foveal microvascular changes and inner retinal layer thinning in patients with diabetes. The British Journal of Ophthalmology. 2018;102(9):1226-1231. 22. Kai Yuan Tey et al. Optical coherence tomography angiography in diabetic retinopathy: a review of current applications / Eye and Vision. – 2019. – Vol. 6. – P.3747. 23. Johannesen S.K. et al. Optical coherence tomography angiography and microvascular changes in diabetic retinopathy: a systematic review / Acta Ophthalmol. – 2019. – Vol. 97. № 1. – P. 7-14. 24. Wong BS, Sharanjeet-Kaur S, Ngah NF, Sawri RR. The Correlation between Hemoglobin A1c (HbA1c) and Hyperreflective Dots (HRD) in Diabetic Patients. International Journal of Environmental Research and Public Health. 2020;17(9):3154. 25. Nakayama LF, Ribeiro LZ, Malerbi FK and Regatieri CVS (2022) Ophthalmology and Artificial Intelligence: Present or Future? A Diabetic Retinopathy Screening Perspective of the Pursuit for Fairness. Ophthalmol. 2:898181. doi: 10.3389/fopht.2022.89818. 26. Artificial intelligence for diabetic retinopathy screening: a review / A. Grzybowski, P. Brona, G. Lim, P. Ruamviboonsuk, G. S. Tan, M. Abramoff, D. S. Ting // Eye. 2020. Vol. 34, iss. 3. P. 451-460. https://doi.org/10.1038/s41433-019-0728-0

Development and validation of a deep learning algorithm for detection of diabetic retinopathy in retinal fundus photographs / V. Gulshan, L. Peng, M. Coram, M. C. Stumpe, D. Wu, A. Narayanaswamy, D. R. Webster // Jama. 2016. Vol. 316, iss. 22. P. 2402-2410. https://doi.org/10.1001/jama.2016.17216 28. Kreuz A.C. Macular and Multifocal PERG and FD-OCT in Preperimetric and Hemifield Loss Glaucoma / A.C. Kreuz A, C.G.de Moraes, M.Hatanaka et al. / J. Glaucoma. – 2018. - Vol. 27(2). – P. 121-132. 29. Mohamed Ashraf , Walaa Wagdy 2 Mohamed A Tawfik , Islam Shereen Hamdy Ahmed , Ahmed Souka Potential impact of fluorescein angiography as a primary imaging modality in the management of diabetic retinopathy. Indian J Ophthalmol. 2022 Oct;70(10):3579-3583. 30. Schmidt-Erfurth U. et al. Guidelines for the Management of Diabetic Macular Edema by the European Society of Retina Specialists (EURETINA) / Ophthalmologica. – 2017. – Vol. 237. № 4. – P. 185-222. 31. Cennamo G., Romano M.R., Nicoletti G., Velotti N., de Crecchio G. Ramsay R.C., Goetz F.C., Sutherland D.E., Mauer S.M., Robison L.L., Cantrill H.L.Optical coherence tomography angiography versus fluorescein angiography in the diagnosis of ischaemic diabetic maculopathy. Acta Ophthalmol. 2017;95(1):36–42. DOI:10.1111/aos.13159 32. Russell JF, Shi Y, Hinkle JW, Scott NL, Fan KC, Lyu C, Gregori G, Rosenfeld PJ. Longitudinal Wide-Field Swept-Source OCT Angiography of Neovascularization in Proliferative Diabetic Retinopathy after Panretinal Photocoagulation. Ophthalmology Retina. 2019;3(4):350-361. https://doi.org/10.1016/j.oret.2018.11.008 33. Fan W., Nittala M.G., Fleming A., Robertson G., Uji A., Wykoff C.C., Brown D.M.,van Hemert J., Ip M., Wang K., Falavarjani K.G., Singer M., Sagong M., Sadda S.R. Relationship Between Retinal Fractal Dimension and Nonperfusion in Diabetic Retinopathy on Ultrawide-Field Fluorescein Angiography. Am J Ophthalmol. 2020;209:99–106. DOI: 10.1016/j.ajo.2019.08.015. 34. Angela Corduneanu , Veronica Chişca , Natalia Ciobanu , Stanislav Groppa Evaluation of visual pathways using visual evoked potential in patients with diabetic retinopathy/ Rom J Ophthalmol. 2019 Oct-Dec;63(4):367-371. 35. Harrison, W.W. Multifocal electroretinograms predict onset of diabetic retinopathy in adult patients with diabetes / W.W. Harrison, M.A. Jr. Bearse, J.S. Ng, N.P. Jewell, S. Barez, D. Burger, M.E. Schneck, A.J. Adams // Invest.Ophthalmol. Vis. Sci. – 2011. – No. 52. – P. 772-777. 36. Yoshihiro Yonekawa , Yasha S Modi , Leo A Kim , Dimitra Skondra , Judy E Kim , Charles C Wykoff . American Society of Retina Specialists Clinical Practice Guidelines on the Management of Nonproliferative and Proliferative Diabetic Retinopathy without Diabetic Macular Edema. J Vitreoretin Dis. 2020 Mar 1;4(2):125135. doi: 10.1177/2474126419893829. Epub 2020 Jan 6. 37. American Diabetes Association. 6. Glycemic Targets: Standards of Medical Carein Diabetes-2019. Diabetes Care. 2019;42(Supplement1): S61–S70.doi:10.2337/dc19S006. 38. Royle P, Mistry H, Auguste P, Shyangdan D, Freeman K, Lois N, Waugh N.Health Panretinal photocoagulation and other forms of laser treatment and drug therapies for

non-proliferative diabetic retinopathy: systematic review and economic evaluation. Technol Assess. 2015 Jul;19(51):v-xxviii, 1-247. doi: 10.3310/hta19510. 39. Lu AQ, Todorich B.J. Combination Antivascular Endothelial Growth Factor and Modified Panretinal Photocoagulation in Management of Proliferative Diabetic Retinopathy. Vitreoretin Dis. 2020 Jul 3;4(5):401-410. doi: 10.1177/2474126420930501. eCollection 2020 Sep-Oct.PMID: 37008297 Free PMC a 40. Yoshihiro Yonekawa , Yasha S Modi , Leo A Kim , Dimitra Skondra , Judy E Kim , Charles C Wykoff . American Society of Retina Specialists Clinical Practice Guidelines on the Management of Nonproliferative and Proliferative Diabetic Retinopathy without Diabetic Macular EdemaJ Vitreoretin Dis. 2020 Mar 1;4(2):125135. doi: 10.1177/2474126419893829. Epub 2020 Jan 41. Villegas VM, Schwartz SG. Current and Future Pharmacologic Therapies for Diabetic Retinopathy. Curr Pharm Des. 2018;24(41):4903-4910. doi: 10.2174/1381612825666190130140717. 42. American Academy of Ophthalmology Retina/Vitreous Panel. Preferred Practice Pattern® Guidelines. Diabetic Retinopathy. San Francisco, CA: American Academy of Ophthalmology; 2017. Available at: www.aao.org/ppp. 43. Do D.V. et al. One-year outcomes of the DA Vinci Study of VEGF Trap-Eye in eyes with diabetic macular edema / Ophthalmology. – 2012. – Vol. 119. – P. 1658-1665. 44. Do D.V. et al. The DA VINCI Study: phase 2 primary results of VEGF Trap-Eye in patients with diabetic macular edema / Ophthalmology. – 2011. – Vol. 118. – P. 18191826. 45. Brown D.M. et al. Intravitreal aflibercept for diabetic macular edema. 100 week results from the VISTA and VIVID studies / Ophthalmology. – 2015. – Vol. 122. – P. 1-9. 46. Schmidt-Erfurth U. et al. Guidelines for the Management of Diabetic Macular Edema by the European Society of Retina Specialists (EURETINA) / Ophthalmologica. – 2017. – Vol. 237. № 4. – P. 185-222. 47. Garweg, J.G., Štefanickova, J., Hoyng, C. et al. Dosing Regimens of Intravitreal Aflibercept for Diabetic Macular Edema Beyond the First Year: VIOLET, a Prospective Randomized Trial. Adv Ther (2022). https://doi.org/10.1007/s12325-022-02119-z 48. David M Brown, David S Boyer , Diana V Do , Charles C Wykoff , Taiji Sakamoto , Peter Win , Sunir Joshi , Hani Salehi-Had , András Seres , Alyson J Berliner , Sergio Leal , Robert Vitti , Karen W Chu , Kimberly Reed , Rohini Rao , Yenchieh Cheng , Wei Sun , Delia Voronca , Rafia Bhore , Ursula SchmidtOtt , Thomas Schmelter , Andrea Schulze , Xin Zhang , Boaz Hirshberg , George D Yancopoulos , Sobha Sivaprasad. Intravitreal aflibercept 8 mg in diabetic macular oedema (PHOTON): 48-week results from a randomised, double-masked, noninferiority, phase 2/3 trial. Lancet. 2024 Mar 23;403(10432):1153-1163. doi: 10.1016/S0140-6736(23)02577-1. Epub 2024 Mar 7. 49. https://www.cadth.ca/aflibercept-8mg007ml-0. 50. Okada M et al. Nonadherence or Nonpersistence to Intravitreal Injection Therapy for Neovascular Age-Related Macular Degeneration.Ophthalmol. 2020. DOI.org/10.1016/j.ophtha.2020.07.060.

Charles C Wykoff, Muneeswar G Nittala, Brenda Zhou, Wenying Fan, Swetha Bindu Velaga, Shaun I R Lampen, Alexander M Rusakevich, Justis P Ehlers, Amy Babiuch, David M Brown, Michael S Ip, SriniVas R Sadda. Intravitreal Aflibercept for Retinal Nonperfusion in Proliferative Diabetic Retinopathy: Outcomes from the Randomized RECOVERY Trial. Ophthalmol Retina. 2019 Dec;3(12):1076-1086 doi 10.1016/j.oret.2019.07.011. Epub 2019 Jul 24. 52. Elman M.J., Ayala A., Bressler N.M. et al.; Diabetic Retinopathy Clinical Research Network. Intravitreal Ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: 5-year randomized trial results. Ophthalmology. 2015; 122 (2): 375-381. 53. Massin P., Bandello F., Garweg J.G. et al. Safety and efficacy of ranibizumab in diabetic macular edema (RESOLVE Study): a 12-month, randomized, controlled, double-masked, multicenter phase II study // Diabetes Care. – 2010. – V. 33, N 11.– P.2399-2405. 54. Mitchell P., Bandello F., Schmidt-Erfurth U. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema // Ophthalmology.- 2011.- V. 118, N. 4.- P. 615-25. 55. Papadopoulos N, Martin J, Ruan Q, et al. Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis. 2012; 15: 171–185. 56. Study (DRESS): «Effect of sulodexide in patients with non-proliferative diabetic retinopathy: diabetic retinopathy sulodexide», Ji Hun Song & Hee Seung Chin & Oh Woong Kwon & Su Jin Lim & Ha Kyoung Kim & for the DRESS Research Group, Revised: 1 July 2014 /Accepted: 8 July 2014 /Published online: 12 August 2014 # The Author(s) 2014. This article is published with open access at Springerlink.com/ 57. Clinical Study "Effect of Sulodexide on Urinary Biomarkers of Kidney Injury in Normoalbuminuric Type 2 Diabetes", Randomized Controlled Trial, Hindawi Publishing Corporation Journal of Diabetes Research Volume 2015, Article ID 172038, 6 pages. 58. «Sulodexide inhibits retinal neovascularization in a mouse model of oxygen-induced retinopathy», Hyoung Jo, Sang Hoon Jung, Jun Kang, Hye Bin Yim & Kui Dong Kang, BMB Reports, Received 8 January 2014, Revised 26 January 2014, Accepted 11 February 2014. 59. Sachiko Y Kataoka, Noemi Lois, Sumihiro Kawano, Yuki Kataoka, Kana Inoue, Norio Watanabe Fenofibrate for diabetic retinopathy Cochrane Database Syst Rev. 2023 Jun 13;6(6):CD013318. doi: 10.1002/14651858.CD013318.pub2. 60. A. C Keech, P Mitchell, P A Summanen, J O'Day, T M E Davis, M S Moffitt, M-R Taskinen, R J Simes, D Tse, E Williamson, A Merrifield, L T Laatikainen, M C d'Emden, D C Crimet, R L O'Connell, P G Colman; FIELD study investigators Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet. 2007 Nov 17;370(9600):1687-97. doi: 10.1016/S0140-6736(07)61607-9. Epub 2007 Nov 7. 61. A.C. Keech, P. Mitchell, P.A. Summanen, J. O'Day, T. M.E. Davis, M.S. Moffitt, M-R. Taskinen, R.J. Simes, D.Tse, E. Williamson, A. Merrifield, L.T. Laatikainen, M.C. d'Emden, D.C. Crimet, R. L. OConnell, P.G. Colman Effect of fenofibrate on the

need for laser treatment for diabetic retinopathy: a randomized controlled trial (FIELD)// Arterial Hypertension.- 2008.- Volume 14, № 3.-P.245-256. 62. Endo N, Kato S, Haruyama K, Shoji M, Kitano S Efficacy of bromfenacsodium ophthalmicsolutioninpreventing cystoidmacular oedema aftercataract surgery in patients with diabetes: 2010-12, Acta Ophthalmol., 88(8):896-900. 63. Callanan DG, Gupta S, Boyer DS et al. Ozurdex PLACID Study Group. Dexamethasone intravitreal implant in combination with laser photocoagulation for the treatment of diffuse diabetic macular edema. Ophthalmology. 2013;120(9):184351. 64. Boyer D.S., Yoon Y., Belfort R., Jr. et al. Ozurdex MEAD Study Group. Threeyear, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology.2014; 121: 1904-1914. 65. Raj K Maturi, Adam R Glassman, Danni Liu, Roy W Beck, Abdhish R Bhavsar, Neil M Bressler, Lee M Jampol, Michele Melia, Omar S Punjabi, Hani Salehi-Had, Jennifer K Sun Effect of Adding Dexamethasone to Continued Ranibizumab Treatment in Patients With Persistent Diabetic Macular Edema: A DRCR Network Phase 2 Randomized Clinical Trial. JAMA Ophthalmol. 2018 Jan 1;136(1):29-38. doi: 10.1001/jamaophthalmol.2017.4914. 66. J. Ramu, Y Yang, G Menon, C Bailey, N Narendran, C Bunce, A T Prevost, P Hykin, S Sivaprasad A randomized clinical trial comparing fixed vs pro-re-nata dosing of Ozurdex in refractory diabetic macular oedema (OZDRY study). Eye (Lond). 2015 Dec;29(12):1603-12. doi: 10.1038/eye.2015.214. Epub 2015 Oct 23. 67. Sakamoto M., Hashimoto R., Yoshida I. et al. Risk factors for requirement of filtration surgery after vitrectomy in patients with proliferative diabetic retinopathy // Clin. Ophthalmol. (Auckland, NZ). – 2018. – Vol. 12. – P. 733. 68. Sato T., Tsuboi K., Nakashima H. et al. Characteristics of cases with postoperative vitreous hemorrhage after 25-gauge vitrectomy for repair of proliferative diabetic retinopathy // Graefe's Arch. Clin. Exp. Ophthalmol. – 2017. – Vol. 255. – № 4. – P. 665-671. 69. Scott M.N., Weng C.Y. The evolution of pars plana vitrectomy to 27-G microincision vitrectomy surgery // Int. Ophthalmol. Clinics. – 2016. – Vol. 56. – № 4. – P. 97-111. 70. Khan M., Kuley A., Riemann C. Long term visual outcomes and safety profile of 27gauge pars plana vitrectomy for posterior segment disease. Ophthalmology. 2018;125(3):423–431. DOI: 10.1016/j.ophtha.2017.09.013

Appendix 1 Diagnostic Algorithm for DR and DME

Patient with DM (standard ophthalmological examination with mandatory fundus examination under mydriasis conditions). Fundus photography is possible (if technical equipment is available and ocular optical media are transparent)

PPDR

PDR

Fundus examination is not possible (opaque ocular optical media) OCT, OCT-A (especially when fundus picture and VA do not correspond)

Ultrasound, EFI

No DME

No DR

Examination at least once a year. Correction of modifiable risk factors for DR development For PDR PLCS or vitreoretinal

surgery

Non-center-involving DME

Dynamic observation. OCT at least once a month

Correction of modifiable risk factors for DR development

Center-involving DME

Vitreoretinal surgery as monotherapy

or in combination with IVAI

Appendix 2 IVAI or IVGC (in management algorithm for patients with DR and DME

or in combination with LC and/or vitreoretinal surgery)

DR complicated by

• vitreoretinal tractions in

combination with vitreous hemorrhage;

• tractional retinal detachment

involving the macular zone, or with threat of its development;

• combined tractional-rhegmatogenous retinal

detachment.

Vitrectomy without/with simultaneous endolaser coagulation, schwartectomy, membrane peeling, endotamponade of vitreous cavity with perfluorocarbons, expanding ophthalmological gases or silicone oils, without/with simultaneous phacoemulsification of cataract with IOL implantation (volume of surgical intervention is determined individually).

Without DME Dynamic observation Diabetic retinopathy

• vitreous hemorrhage

not allowing performance of complete LCS;

-active neovascularization of retina (and/or anterior segment) in combination with vitreous hemorrhage;

-recurrent vitreous hemorrhage.

DME without center involvement Dynamic observation. Correction of modifiable risk factors.

DME with center involvement

Retinal LC VA less than 0.7 VA more than 0.7

IVAI or IVGC

CRT less than 350 microns

Retinal LC (mono- or in combination with IVAI

or IVGC) No traction

CRT more than 350 microns

IVAI or IVGC; (mono- or in combination with LCS) Traction present Vitrectomy Control of BG, BP, blood lipids.

IVAI, IVGC possible (monotherapy or in combination with LCS)

Treatment Tactics at Outpatient Level: The main direction of DR treatment is prevention of the development of processes leading to irreversible blindness. The success of DR treatment depends on stable compensation of DM, normalization of blood pressure and lipid metabolism indicators. Treatment methods: • Surgical (retinal laser coagulation, IVVIA and/or IVVGK); • Medication therapy.

Indications for Hospitalization with Type of Hospitalization Specified: Hospitalization is possible with compensation of the main process (glycated hemoglobin level, blood glucose and blood pressure should be within target indicators).

Table 3 - Target HbA1c Indicators [12] Criteria Age Elderly Age Young Middle Without Dementia Senile Dementia No atherosclerotic cardiovascular diseases and/or risk of severe hypoglycemia < 6.5% <7.0% Presence of atherosclerotic cardiovascular severe diseases <7.0% <7.5% <8% and/or risk of severe hypoglycemia <8.5% With low expected life expectancy (<5 years) treatment goals may be less strict Table 4 - Target Values of Pre/Postprandial Plasma Glucose Level Corresponding to Target HbA1c Levels [12] HbA1c* Fasting/Before Meal Plasma Glucose, mmol/l Plasma Glucose 2 Hours After Meal, mmol/l < 6.5 < 6.5 < 8.0 < 7.0 < 7.0 < 9.0 < 7.5 < 7.5 < 10.0 < 8.0 < 8.0 < 11.0 Table 5 - Target Lipid Metabolism Indicators in DM Patients [12] Risk Groups Target LDL Cholesterol Values, mmol/l With moderate cardiovascular risk < 2.6 With high cardiovascular risk <1.8 With very high cardiovascular risk <1.4, or 50% reduction Table 6 - Target Blood Pressure Indicators in DM Patients [12] Age Systolic BP, mm Hg Diastolic BP mm Hg * 18-65 years ≥ 120 and < 130 > 65 years ≥ 130 and < 140

Indications for Planned Hospitalization. Hospitalization in Round-the-Clock Inpatient Facility: • hemophthalmos persisting for more than 3 months; • PDR with tractional retinal detachment involving the macular area or threatening it; • PDR with rhegmatogenous retinal detachment;

• PDR with vitreoretinal traction or preretinal hemorrhage in patients with active neovascularization; • PDR with tractional deformity of the optic nerve; • PDR with tractional maculopathy; • non-transparent (not allowing full performance of retinal laser coagulation) vitreous hemorrhage in patients who have not previously received panretinal laser coagulation; • non-transparent vitreous hemorrhage combined with tractional retinal deformity (confirmed by ultrasound data) or with anterior segment neovascularization; • anterior hyaloid fibrovascular proliferation.

Hospitalization in Day Hospital. Indications for hospitalization in day hospital: • DME at any stage of DR (for IVVIA in monotherapy or in combination with retinal laser coagulation); • PPDR combined with DME with high risk of progression to PDR (PLK when IVVIA is not possible); • PDR without maculopathy (PLK). • PDR with iris rubeosis without presence of secondary glaucoma (IVVIA and PLK); • PDR with iris rubeosis with presence of secondary glaucoma (IVVIA and PLK).

Indications for Emergency Hospitalization in Round-the-Clock Inpatient Facility: endophthalmitis after IVVIA or IVVGK.

Surgical Treatment at Day Hospital Level Intravitreal administration of angiogenesis inhibitors [47-55] (EL-A) (possible as monotherapy, in combination with laser coagulation and/or vitreoretinal surgery), aimed at blocking VEGF-factor to reduce/eliminate macular edema and/or neovascularization of the retina, optic nerve, iris.

Indications for IVVIA: • diabetic macular edema (more than 350 microns) involving the center of the macula (according to OCT data) at any stage of diabetic retinopathy; • PDR with iris rubeosis without presence of secondary glaucoma; • PDR with iris rubeosis with presence of secondary glaucoma; • PDR with/without DME - IVVIA in combination with PLKS to suppress neovascularization.

Intravitreal administration of glucocorticoids [63-66] (EL-A). • implant (0.7 mg dexamethasone) for intravitreal administration* (EL-A)

• use of the drug after registration in RK

Indications: Indications for intravitreal administration of glucocorticoids in implant form at disease onset: • presence of inflammation biomarkers according to OCT data (large number of hyperreflective foci, hard exudate, large intraretinal cysts, neuroepithelial detachment); • history of stroke/myocardial infarction and other cardiovascular and cerebrovascular diseases, as well as at very high risk of serious vascular complications; • inability to comply with frequent visit schedule and/or visit medical facility during the first 6 months after intravitreal drug administration; • absence of risks of intraocular pressure elevation; • pseudophakia or in case of planned cataract phacoemulsification surgery; • pregnancy; • after vitrectomy.

Indications for intravitreal administration of glucocorticoids in the form of an implant as second-line therapy: • with minimal response or absence of response to anti-VEGF therapy (3–6 injections). The criterion for refractoriness to ongoing therapy is the absence of an increase in best-corrected visual acuity by +5 letters or more and/or a reduction in central retinal thickness <20% from baseline.

Contraindications: • hypersensitivity to the components of the drug; • ocular or periocular infection; • active severe intraocular inflammation; • vitreomacular traction syndrome and/or macular hole; • first 3 months after acute cerebrovascular or coronary circulatory event; • advanced stage glaucoma with decompensation of IOP not controlled by medical therapy; • aphakia with posterior capsule rupture; • presence of anterior chamber IOL, iris-clip IOL, posterior chamber IOL with transscleral fixation with concurrent posterior capsule rupture.

The use of dexamethasone* in the form of an implant requires long-term regular monitoring of IOP. Repeated administration of the implant is possible after 6 months in case of decreased visual acuity, recurrent development of macular edema, or progression of existing DME (increase in CRT according to OCT data). The number of intravitreal glucocorticoid administrations in the form of an implant is determined by the physician individually in each case.

Retinal laser coagulation [36-39] is performed to eliminate zones of ischemia, microaneurysms and neovascular vessels, to form chorioretinal adhesions that reduce the risk of tractional retinal detachment (LE-B). Retinal laser coagulation can be performed both as monotherapy and in combination with intravitreal anti-VEGF agents or intravitreal glucocorticoids.

Indications for laser coagulation: • clinically significant DME (not more than 350 μm). With DME more than 350 μm, retinal laser coagulation, performed in combination with intravitreal administration of angiogenesis inhibitors or intravitreal glucocorticoids, is aimed at improving or stabilizing visual function. Deferred retinal laser coagulation, performed after 5 loading injections of angiogenesis inhibitors, is more effective than that performed in alternating mode with intravitreal anti-VEGF agents. • severe NPDR with the presence of extensive areas of retinal ischemia (without ischemic maculopathy) with a tendency to further progression, in case of impossibility of regular patient monitoring, with the aim of suppressing VEGF expression and preventing the development of neovascularization (panretinal laser coagulation according to relative indications);

• presence of neovascular vessels on the optic disc or in any zone of the retina; • PDR with neovascularization of the iris and/or anterior chamber angle (panretinal laser coagulation with coagulation of the extreme peripheral parts of the retina).

Methods of laser coagulation: • focal laser coagulation – coagulation of "soft" exudates with the aim of preventing the production of VEGF factor in these zones and the appearance of neovascular vessels. • grid laser coagulation - (preferably using laser coagulation in subthreshold mode) for focal macular edema not more than 350 microns in the absence of the possibility of intravitreal anti-VEGF agents or intravitreal glucocorticoids, or inability to comply with the intravitreal injection regimen. • panretinal laser coagulation is performed starting from the lower parts of the mid-periphery, with subsequent application of laser coagulates to the entire surface of the mid-periphery of the fundus from the temporal vascular arcades.

The timing of panretinal laser coagulation depends on the stage of DR and the presence of DME. Panretinal laser coagulation: deferred or immediate.

Deferred retinal laser coagulation is performed 24 or more weeks after the start of treatment with angiogenesis inhibitors.

The indication for immediate panretinal laser coagulation, according to the international multicenter DRS study, is proliferative DR in combination with "high-risk factors for vision loss," which are defined as:

• prepapillary neovascular vessels, the size of which exceeds or equals 1/4-1/3 of the optic disc area,
• and/or prepapillary neovascular vessels of any size in combination with intravitreal or preretinal hemorrhage,
• and/or preretinal neovascular vessels, the size of which exceeds ½ of the disc area in combination with intravitreal or preretinal hemorrhage.

With HbA1c >10% and the presence of PDR, panretinal laser coagulation is performed without waiting for significant improvement in glycemic control.

In severe NPDR with pronounced peripheral ischemia, panretinal laser coagulation is performed, with mandatory coagulation of the extreme peripheral parts of the retina, to exclude the risk of developing neovascular glaucoma. In PDR with neovascularization of the iris and/or anterior chamber angle, the first stage of panretinal laser coagulation is performed no earlier than 2 weeks after intravitreal anti-VEGF agents, with further adherence to the timing of angiogenesis inhibitor administration and mandatory coagulation of the extreme peripheral parts of the retina.

Contraindications to laser coagulation: • ischemic maculopathy; • pronounced neovascularization (grade III-IV); • pronounced glial proliferation (grade III-IV) passing through the posterior pole of the eye;

• vitreoretinal traction of grade 4 or more.

Surgical treatment (vitrectomy), performed in an inpatient setting with round-the-clock stay, is aimed at restoring the transparency of the optical media of the eye, removing the vitreous body, which is a "depot" of toxic substances, with elimination of traction and the posterior hyaloid membrane as the basis for proliferation (LE-A) [67-70]. Vitrectomy can be combined with simultaneous endolaser coagulation of the retina, membrane dissection, membrane peeling, endotamponade of the vitreous cavity with perfluorocarbons, expanding ophthalmic gases or silicone oils, with simultaneous phacoemulsification of cataract with IOL implantation. Vitrectomy may be preceded by intravitreal anti-VEGF agents (in the absence of vitreomacular tractions or macular hole) or dexamethasone implant (in the absence of uncompensated glaucoma, vitreomacular tractions or macular hole) with the aim of reducing the risk of hemorrhagic complications.

Indications for vitrectomy: • hemophthalmos persisting for more than 3 months; • PDR with tractional retinal detachment involving the macular area or threatening it; • PDR with rhegmatogenous retinal detachment; • PDR with vitreoretinal traction or preretinal hemorrhage in patients with active neovascularization; • PDR with tractional deformity of the optic nerve; • PDR with tractional maculopathy; • non-transparent (not allowing full-volume retinal laser coagulation) vitreous hemorrhage in patients who have not previously received panretinal laser coagulation; • non-transparent vitreous hemorrhage combined with tractional retinal deformity (confirmed by ultrasound data) or with neovascularization of the anterior segment; • anterior hyaloid fibrovascular proliferation; • Vitrectomy may be performed in the compensated stage of the underlying process after consultation (treatment) with an endocrinologist and internist. If necessary, consultation with a nephrologist, cardiologist, podiatrist and/or vascular surgeon (in case of diabetic foot syndrome).