After cardiovascular disease and oncological pathology, diabetes mellitus (DM) is the third-most dangerous nosology globally.
The most significant visual organ complications in diabetes mellitus are lesions of the retina and blood vessels, such as diabetic retinopathy (DR) and diabetic macular oedema (DMO), leading to vision loss and disability in working-age patients.
The study of DR began in 1856, when an Austrian ophthalmologist, Eduard Jaeger, used an ophthalmoscope to sketch the fundus of a patient with diabetes for the first time.
The most significant causes of DR and DMO development and progression are the duration of diabetes, high glycaemia levels, high blood pressure, and impaired lipid metabolism. Other risk factors included patient age, type of diabetes, blood clotting system, nephropathy and low physical activity.
Chronic hyperglycaemia, which results in a number of pathophysiological links of biochemical and haemodynamic genesis, is the initiating factor in the development of DR.
In essence, the development of DMO is associated with fluid accumulation in the intercellular space of the neuroepithelium owing to a breach of the internal hemato-retinal barrier and the discrepancy between the output of the liquid and the ability of pigment epithelial cells to reabsorb it.
The results showed that during 10 years of observation, 20% of patients with type 1 diabetes and 25% of patients with type 2 diabetes developed DMO.
In general, patients with T2DM have a higher risk of macular oedema than patients with T1DM. It is also important to note that the incidence of DMO increases with increasing severity of DR, reaching 70% in the proliferative stage of this complication.
DM – diabetes mellitus; DR – diabetic retinopathy; DMO – diabetic macular oedema; VEGF – vascular endothelial growth factor
Bibliography:
1. Bikbov M.M., Fayzrahmanov R.R Macular edema as a manifestation of diabetic retinopathy. Diabetes mellitus. 2017;20(4):263–269. https://doi.org/10.14341/DM8328
2. Demidova T., Kozhevnikov A. A. Diabetic retinopathy: history, current management approaches, promising views on prevention and treatment. Diabetes mellitus. 2020;23(1):95–105.
3. Zaynullina S.A., Fayzrakhmanov R.R., Yarmukhametova A.L. Diabetic macular oedema, clinic, diagnosis (literature review). East-West. 2012. p.275.
4. Astakhov Yu.S., Zaitseva O.V., Okhotsimskaya T.D. et al. Federal Clinical Guidelines. Diagnosis and treatment of diabetic retinopathy and diabetic macular edema – 2013.
5. Daruich A, et al., Mechanisms of macular edema: Beyond the surface. Prog Retin Eye Res. 2018 Mar;63:20–68.
6. Shin E.S. et al., Diabetes and retinal vascular dysfunction. J Ophthalmic Vis Res. 2014 Jul–Sep;9(3):362–73.
7. The Diabetic Retinopathy Clinical Research Network: Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med 372(13):1193–1203, 2015.
8. White NH, Sun W, Cleary PA. Effect of prior intensive in type 1 diabetes on 10-year progression retinopathy in the DCCT/EDIC: comparison of adults and adolescents. Diabetes. 2010; 59: 1244–1253.
9. Klein R, Klein BE, Moss SE et al. The Wisconsin epidemiologic study of diabetic retinopathy. IV. Diabetic macular edema. Ophthalmology. 1984; 91: 1464–1474.
10. Bresnick G.H. Diabetic macular edema // Ophthalmology. – 1986. – Vol. 73, No. 7. – P. 989–997.
Diabetes-related retinal diseases are projected to become epidemic in the coming decades. Already, the incidence of diabetes mellitus and, subsequently, the incidence of retinal diseases have increased sharply.
There are 93 million people worldwide with diabetic retinopathy (DR) and 21 million with diabetic macular oedema (DMO), but the expected increase in the incidence of diabetes will increase the prevalence of DMO to 29 million cases by 2045.
According to the WESDR epidemiological study, with a duration of type 1 diabetes mellitus (DM) of more than 20 years, the incidence of DR reaches almost 100%, with complete loss of vision in every 30th patient.
In cases of type 2 diabetes (DM2), about 2/3 of patients have DR about 20 years after the onset of the disease, with a fifth of patients presenting in the proliferative stage.
DMO is clinically identified in fundus biomicroscopy as a thickening of the retina or the presence of solid exudates within an area equal to one diameter of the optic disc centred in the fovea.
Solid exudates result from diffusion through the walls of microaneurysms and the dilated segments of the plasma capillaries and their deposition in the retina.
There are focal, diffuse, mixed, and ischemic forms of DMO.
Separately, “clinically significant macular oedema (CSMO)” can be highlighted, which is used as a standard for determining the indications for starting laser treatment. The concept of CSMO includes the following changes:
- Thickening of the retina in a 500 μm area in the centre of the macula;
- Presence of hard exudates in the 500-μm zone at the centre of the macula in combination with thickening of the retina (excluding residual solid exudates after resolution of macular oedema);
- Retinal thickening of at least 1 diameter of the optic disc when it is separated from the center of the macula within 1 disc diameter.
Clinical classification of DMO is also applied which takes into account only the degree of involvement of the centre of the macula in the pathological process.
A standard ophthalmologic examination includes: visometry, biomicroscopy, tonometry and ophthalmoscopy with a high- dioptriality aspheric lens or a Goldmann contact lens. Additional tests are done to identify the full range of anatomic changes in the retina that are characteristic of DMO.
- Optical coherence tomography (OCT) visualises cystic areas and deposits of solid exudates, and enables assessment of oedema extent, the relationships of the retinal layers, the integrity of the external hematoretinal barrier, and indirect assessment of the degree of ischemia. OCT can be used to screen, classify, monitor and evaluate the effectiveness of DMO treatment.
- OCT angiography (OCTA) provides new opportunities for rapid and non-invasive assessment of macular vessels. OCTA visualises the vessels in both the superficial and deep plexus, identifies microaneurysms, and evaluates the degree of ischemia.
- Fluorescein angiography (FAG) enables assessment of the retinal blood vessels, detecting changes such as microaneurysms, intraretinal microvascular abnormalities and neovascularisation, and also shows the degree of transudation through pathologically altered vessels.
- Ocular ultrasound can detect a disorder of vitreoretinal interactions and is recommended for all patients with diabetic retinal lesions and lack of transparency of optical media.
Bibliography:
1. Leasher JL, et al. Global Estimates on the Number of People Blind or Visually Impaired by Diabetic Retinopathy: A Meta-Analysis from 1990 to 2010. Diabetes Care. 2016; 39:1643-9.
2. Yau JWY, Rogers SL, Kawasaki R, et al. Global Prevalence and Major Risk Factors of Diabetic Retinopathy. Diabetes Care. 2012; 35: 556-564.
3. Astakhov Y.S., Zaitseva O.V., Okhotsimskaya T.D. et al. Federal clinical guidelines. Diagnosis and treatment of diabetic retinopathy and diabetic macular oedema – 2013.
4. Dedov I.I., Shestakova M.V., Vikulova O.K. Epidemiology of diabetes in the Russian Federation: report on the data of the federal register of diabetes. – 2017. – Vol. 20. – No. 1. – P. 13−41.
5. Bresnick G.H. Diabetic macular edema // Ophthalmology. - 1986. - Vol. 73, № 7. - P. 989-997.
6. Early. Treatment Diabetic Retinopathy Study Research Group, report number 2. Treatment techniques and clinical guidelines for photocoagulation of diabetic macular edema// Ophthalmology. - 1987. - Vol. 94, № 7. - P. 761-774.
7. International Council of Ophthalmology, Guidelines for Diabetic Eye Care, 2017.
8. Eye health and diabetes. Guidance for Healthcare Professionals. IDF and the Fred Hollows Foundation. – Brussels, Belgium. – 2017. – 40 pages.
9. Ophthalmology: National Guidelines/Ed. S.E. Avetisov, E.A. Yegorov, L.K. Moshetova, V.V.Neroev, Kh.P. Takhchidi. – 2nd Edition – Moscow: GEOTAR-Media, 2018. – 904p. – (“National Guidelines” series).
10. International Council of Ophthalmology. Guidelines for Diabetic Eye Care. 2017. – 40 p.
11. American Academy of Ophthalmology Preferred Practice Patterns Committee. Preferred Practice PatternR Guidelines. Comprehensive Adult Medical Eye Evaluation. San Francisco, CA: AAO (2005). Available at: http://www.aao.org/ppp.
12. Schields М.В. Glaucoma in diabetic patients / Ocular problems in diabetes mellitus //Blackwell Scientific Publ. – Boston. – 1992. – P. 307-319.
Currently, anti-VEGF drugs are first-line therapy for diabetic macular edema (DME) involving the center of the macula.
Prevention plays an important role in DME - screening and identification of risk factors (hyperglycemia, arterial hypertension, dyslipidemia), as this slows the progression of diabetic retinopathy (DR) and diabetic macular edema (DME).
In the presence of clinically significant DME, intravitreal injections of angiogenesis inhibitors or glucocorticosteroids (GCS) in the form of an implant for intravitreal administration are recommended , possibly in combination with laser retinal coagulation (LRC).
Currently, anti-VEGF drugs are the first-line therapy for DME involving the center of the macula.
Laser retinal photocoagulation has been a mainstay of treatment for DME since the early 1980s. The largest ophthalmological study to confirm the efficacy of LRC as a treatment for diabetic maculopathy was the ETDRS study.
Focal laser coagulation of the retina can be used for DME without central involvement. FLC is not applied to lesions within 300-500 µm of the center of the macula. Laser coagulation prevents further vision loss but does not improve vision.
Intravitreal administration of GCS in the form of an implant is recommended in patients with DME resistant to angiogenesis inhibitors and laser treatment, especially in cases of pseudophakia.
When intravitreal administration of angiogenesis inhibitors or GCS in the form of an implant should take into account the potential risk of complications, such as infectious and non-infectious endophthalmitis, iatrogenic cataract, hemophthalmos, retinal detachment, increased intraocular pressure, and others.
In the presence of DME of traction genesis, as well as in proliferative DR complicated by organized hemophthalmos, traction (or traction-rhegmatogenous) retinal detachment with the capture of the macular area, surgical treatment is recommended - vitrectomy.
There is evidence of the effectiveness of vitrectomy with removal of the internal limiting membrane (ILM), which contributes to significant regression of retinal edema in the macula, stabilization, and in some cases, improvement of visual functions.
Vitrectomy with removal of the ILM affects only one of the links in the pathogenesis of DME, therefore, it is advisable to use it in combination with other types of DME treatment.
Despite the proven efficacy of existing anti-VEGF agents, frequent clinic visits and cyclic injections create a heavy treatment burden that worsens the results of the method in real clinical practice and is considered today as a key problem of antiangiogenic therapy. In addition, the patient and the healthcare system face other challenges in treatment:
- the need for regular monitoring
- relatively short duration of the therapeutic effect of existing drugs;
- the possibility of developing tachyphylaxis or resistance against the background of multiple repeated IVVI;
- limited availability of treatment due to high treatment costs
- possible complications and cases of poor tolerability of therapy.
For this reason, the search for new treatment methods continues, the main goal of which is to increase the duration of the therapeutic effect while maintaining a balance between efficacy and safety.
Bibliography:
1. Dedov I.I., Shestakova M.V., Vikulova O.K. Epidemiology of diabetes mellitus in the Russian Federation: report on the federal register of diabetes // Diabetes mellitus. - 2017. - Vol. 20. - No. 1. - P. 13−41.
2. Zainullina S.A., Faizrakhmanov R.R., Yarmukhametova A.L. Diabetic macular edema, clinical picture, diagnosis (literature review). East-West. 2012. p.275.
3. Astakhov Yu.S., Zaitseva O.V., Okhotsimskaya T.D. et al. Federal clinical guidelines. Diagnosis and treatment of diabetic retinopathy and diabetic macular edema – 2013.
4. Leasher JL, et al. Global Estimates on the Number of People Blind or Visually Impaired by Diabetic Retinopathy: A Meta-Analysis from 1990 to 2010. Diabetes Care. 2016; 39:1643-9.
5. Ciulla TA, Amador AG, Zinman B. Diabetic retinopathy and diabetic macular edema: pathophysiology, screening, and novel therapies. Diabetes Care.2003;26(9); 2653-2664.
6. White NH, Sun W, Cleary PA. Effect of prior intensive in type 1 diabetes on 10-year progressionretinopathy in the DCCT/EDIC: comparison of adults and adolescents. Diabetes. 2010; 59: 1244-1253.
7. Klein R, Klein BE, Moss SE et al. The Wisconsin epidemiologic study of diabetic retinopathy. IV. Diabetic macular edema. Ophthalmology. 1984; 91: 1464-1474.
8. Funatsu H., Noma H., Mimura T. et al. Association of vitreous inflammatory factors with diabetic macular edema. Ophthalmology. 2009;116(1): 73-79.
9. Early. Treatment Diabetic Retinopathy Study Research Group, report number 2. Treatment techniques and clinical guidelines for photocoagulation of diabetic macular edema // Ophthalmology. - 1987. - Vol. 94, No. 7. - P. 761-774.
10. Cohen SR, Gardner TW. Diabetic Retinopathy and Diabetic Macular Edema. Developments in ophthalmology. 2016; 55:137-146.
11. Shields M.V. Glaucoma in diabetic patients / Ocular problems in diabetes mellitus //Blackwell Scientific Publ. – Boston. – 1992. – P. 307-319.
12. International Council of Ophthalmology. Guidelines for Diabetic Eye Care. 2017. – 40 p.
13. American Academy of Ophthalmology Preferred Practice Patterns Committee. Preferred Practice PatternR Guidelines. Comprehensive Adult Medical Eye Evaluation. San Francisco, CA: AAO (2005). Available at: http://www.aao.org/ppp.
14. Diabetic Retinopathy PPP 2019, Diabetic retinopathy and diabetic macular oedema pathways and management: UK Consensus Working Group 2020, EURORETINA 2017
15. Wang W, Lo AC. Diabetic retinopathy: pathophysiology and treatments. Int J Mol Sci. 2018;19(6). pii:E1816.
16. The Diabetic Retinopathy Clinical Research Network: Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med372(13):1193-1203, 2015.
17. Instructions for medical use of the medicinal product Lucentis®, LSR-004567/08, amended on 15.06.20
18. Instructions for medical use of the medicinal product Eylea®, LP 003544-170419, amended on 05/28/20
19. State Register of Medicines, [Electronic resource] 07/16/2021 URL: https://grls.rosminzdrav.ru/Default.aspx
20. Aderman CF, Garg SJ, Intravitreal anti-VEGF injection treatment algorythms for DME, [Electronic resource] 07/16/2021 URL: https://retinatoday.com/pdfs/0717RT_Cover_Garg.pdf
21. AAO, Treat-and-Extend Strategy, Is There a Consensus? [Electronic resource] 07/16/2021 URL: https://www.aao.org/eyenet/article/treat-extend-strategy-is-there-consensus
22. ETDRS, Ophthalmology, 1991 May;98(5 Suppl):741-56. doi: 10.1016/s0161-6420(13)38009-9
23. International Council of Ophthalmology, Guidelines for Diabetic Eye Care, 2017.
24. Ophthalmology: national guide / ed. S.E. Avetisov, E.A. Egorov, L.K. Moshetova, V.V. Neroev, Kh.P. Takhchidi. – 2nd ed. – M.: GEOTAR-Media, 2018. – 904 p. – (Series “National Guidelines”).
25. Saharinen P et al, Nat Rev Drud Discov 2017; 16(9):635-661
26. Panos GD, Lakshmanan A, Dadoukis P, Ripa M, Motta L, Amoaku WM. Faricimab: Transforming the Future of Macular Diseases Treatment - A Comprehensive Review of Clinical Studies. Drug Des Devel Ther. 2023 Sep 18;17:2861-2873.
27. Heier JS, et al. Lancet. 2022;399(10326):729-40.
28. Wykoff CC, et al. Lancet. 2022;399(10326):741-755.
29. Regula JT et al. EMBO Mol Med 2016;8:1265–88.
30. Regula JT et al. EMBO Mol Med. 2019;11(5):e10666.