Diabetic retinopathy (DR) is a progressive disorder affecting the small blood vessels of the retina caused by the prolonged impact of diabetes mellitus.1 If left untreated, it can result in serious retinal damage and eventual blindness. DR is both preventable and treatable, with successful prevention and treatment depending heavily on early detection.2
A global analysis of 288 studies involving 3.98 million participants from 98 countries identified the leading causes of vision impairment and blindness in 2015, along with projections for 2020.3 In 2015, 216.6 million people (uncertainty interval [UI]: 98.5–359.1 million) experienced moderate or severe vision impairment, primarily due to uncorrected refractive error (116.3 million, UI 49.4–202.1 million), cataract (52.6 million, UI 18.2–109.6 million), age-related macular degeneration (AMD) (8.4 million, UI 0.9–29.5 million), glaucoma (4.0 million, UI 0.6–13.3 million), and diabetic retinopathy (2.6 million, UI 0.2–9.9 million). Blindness affected 36.0 million individuals (UI 12.9–65.4 million), with cataracts (12.6 million, UI 3.4–28.7 million), uncorrected refractive error (7.4 million, UI 2.4–14.8 million), and glaucoma (2.9 million, UI 0.4–9.9 million) as the primary causes.
By 2020, the number of people with moderate or severe vision impairment was projected to rise to 237.1 million (UI 101.5–399.0 million), with uncorrected refractive error affecting 127.7 million (UI 51.0–225.3 million) and cataract affecting 57.1 million (UI 17.9–124.1 million). Similarly, blindness was projected to increase to 38.5 million (UI 13.2–70.9 million), with cataracts affecting 13.4 million (UI 3.3–31.6 million) and uncorrected refractive error affecting 8.0 million (UI 2.5–16.3 million). In 2015, cataract and uncorrected refractive error together accounted for 55% of blindness and 77% of vision impairment in adults aged 50 years and older. High-income regions showed a distinct pattern, with a lower prevalence of cataract-related blindness (<22%) and vision impairment (14.1–15.9%), but a higher prevalence of AMD (>14% of blindness).
Gender disparities were notable, with women having higher odds of vision impairment from diabetic retinopathy (odds ratio [OR] 2.52, UI 1.48–3.73) and cataract (OR 1.21, UI 1.17–1.25), while men were more affected by glaucoma (OR 0.71, UI 0.57–0.86) and corneal opacity (OR 0.54, UI 0.43–0.66). No significant gender differences were observed for AMD-related vision impairment (OR 0.91, UI 0.70–1.14).
Chronic hyperglycemia can lead to microvascular damage, inflammation, and neurodegeneration throughout the body, including the retinal vasculature.4 This damage leads to increased vascular permeability, capillary occlusion, and neovascularization, potentially leading to vision-threatening complications like diabetic macular edema.
Vascular Endothelial Growth Factor (VEGF) is a key mitogen for endothelial cells and is upregulated by hypoxia both in vivo and in vitro. High-affinity, membrane-bound VEGF receptors, which are auto phosphorylating tyrosine kinases, are present on vascular endothelial cells and retinal pigment epithelial cells, with their expression also increased under hypoxic conditions.5 Elevated VEGF expression has been observed in retinal tissues during vasoproliferative retinopathies and in animal models of ocular neovascularization.
Clinically, VEGF levels are significantly higher in the vitreous of patients with active proliferative diabetic retinopathy (PDR) compared to diabetic eyes without retinopathy, those with background retinopathy, or quiescent PDR post-laser photocoagulation. This highlights VEGF's critical role in the pathophysiology of retinal neovascularization and its potential as a therapeutic target.
Management options for diabetic retinopathy include following a healthy diet and lifestyle, medical management of diabetes and associated conditions, timely ophthalmic evaluation, and treatment under the care of an ophthalmologist.6 Treatment focuses on managing microvascular issues using intravitreal anti-VEGF agents, laser photocoagulation, and surgical interventions as well as managing inflammation with intravitreal corticosteroids.
Disease Progression
DR progresses through four stages:2
- Mild non-proliferative diabetic retinopathy (NPDR) – This early stage is marked by the presence of microaneurysms, which are small areas of balloon-like swelling in the retina's blood vessels.
- Moderate NPDR – As the disease progresses, there are more extensive changes, including intraretinal hemorrhages, venous beading, and intraretinal microvascular abnormalities.
- Severe NPDR – This stage is characterized by a significant increase in the number of hemorrhages and microaneurysms along with more pronounced venous beading and intraretinal microvascular abnormalities.
- Proliferative diabetic retinopathy (PDR) – This advanced stage involves neovascularization where new, fragile blood vessels grow on the retina and the posterior surface of the vitreous. These vessels can bleed into the vitreous, leading to vitreous hemorrhage, traction retinal detachment, and potentially severe vision loss or blindness.
Diabetic macular edema (DME) can occur at any stage of diabetic retinopathy and involves retinal thickening and hard exudates near the macula, leading to central vision impairment.
Risk Factors
Risk factors for developing and worsening DR include duration of diabetes, hemoglobin A1C, elevated blood pressure, and high cholesterol levels. A 2018 study of 418 individuals with Type1 DM found that compared to those with non-vision-threatening DR and those without DR, those with DR impeding vision had diabetes for longer (38 years vs 32 and 22), had a higher mean A1C (78 mmol/mol vs 65 and 61), greater A1C variability (7.8 coefficient of variation vs 6.9 and 5.9), lower HDL (1.38 mmol/L vs 1.46 and 1.56), and higher total cholesterol (5.1 mmol/L vs 4.9 and 4.9).7 A 2001 study (n=3,250) found that those with PDR had a higher average blood pressure than those without (119/77 vs 117/74 mmHg).1,8
Further for contributing factors, a study analysed factors that predict the development or progression of DR in 544 high-risk patients with type 2 diabetes who underwent annual eye exams over a median follow-up period of 6 years.9 Ambulatory blood pressure (BP) monitoring and aortic stiffness (measured by carotid-femoral pulse wave velocity) were also assessed. Using multivariate Cox survival analysis, the study identified independent predictors for DR progression. During follow-up, 156 patients either developed new DR or experienced worsening of their condition. These patients had longer durations of diabetes, higher ambulatory and clinic BP, greater aortic stiffness, and poorer blood sugar control compared to those whose DR did not progress. After adjusting for factors such as baseline retinopathy, age, and sex, the study found the following as independent predictors of DR progression:
- Longer diabetes duration (p < 0.001)
- Higher baseline ambulatory BP, specifically 24-hour diastolic BP (p = 0.013)
- Higher cumulative HbA1c (p < 0.001)
- Elevated clinic diastolic BP (p < 0.001)
- Higher LDL cholesterol levels during follow-up (p = 0.05)
BP factors were significant predictors only for the development of new DR cases. Among these, cumulative clinic diastolic BP emerged as the strongest BP-related predictor. In conclusion, longer diabetes duration, poor blood sugar and cholesterol control, and higher BP were key predictors of DR progression. Managing these factors may help reduce the risk of worsening DR.
Predictors of Development and Progression of Retinopathy in Patients with Type 2 Diabetes: Importance of Blood Pressure Parameters
Prevention and Screening
Individuals with diabetes can help to prevent complications such as DR by managing their blood sugar through a combination of healthy eating, regular exercise, and prescribed medications.1,10,11
DR can be asymptomatic until vision loss begins, making screening crucial.1,10 The American Diabetes Association (ADA) recommends that people with type 1 diabetes have an initial dilated and comprehensive eye exam within five years of onset of diabetes and that people with type 2 diabetes have an eye exam at the time of diagnosis.1 Patients are then recommended to get subsequent eye exams annually. If there is no evidence of DR from one or more annual eye exams and the patient has glycemic control, then screening every 1-2 years can be considered. If any level of DR is detected, dilated retinal exams should be repeated at least annually. If retinopathy is progressing or threatening the patient’s sight, then they may require more frequent eye exams. For patients of child-bearing age with preexisting diabetes, they should receive and eye exam before pregnancy and during the first trimester and have subsequent monitoring every trimester and for one year postpartum with exact timing determined by the presence or degree of DR, if any.
References
- 12. Retinopathy, Neuropathy, and Foot Care: Standards of Care in Diabetes-2024. Diabetes Care. Jan 1 2024;47(Suppl 1):S231-s243. doi:10.2337/dc24-S012
- Lim JI, Kim SJ, Bailey ST, et al. Ophthalmology. 2025;132(4):P75-P162. doi:10.1016/j.ophtha.2024.12.020
- Flaxman SR, Bourne RRA, Resnikoff S, et al. Global causes of blindness and distance vision impairment 1990–2020: a systematic review and meta-analysis. The Lancet Global Health. 2017;5(12):e1221-e1234. doi:10.1016/S2214-109X(17)30393-5
- Stewart MW. Pathophysiology of Diabetic Retinopathy. In: Browning DJ, ed. Diabetic Retinopathy: Evidence-Based Management. Springer New York; 2010:1-30.
- Boulton M, Foreman D, Williams G, McLeod D. VEGF localisation in diabetic retinopathy. British Journal of Ophthalmology. 1998;82(5):561-568. doi:10.1136/bjo.82.5.561
- Flaxel CJ, Adelman RA, Bailey ST, et al. Diabetic Retinopathy Preferred Practice Pattern®. Ophthalmology. 2020;127(1):P66-P145. doi:10.1016/j.ophtha.2019.09.025
- Schreur V, van Asten F, Ng H, et al. Risk factors for development and progression of diabetic retinopathy in Dutch patients with type 1 diabetes mellitus. Acta Ophthalmol. Aug 2018;96(5):459-464. doi:10.1111/aos.13815
- Porta M, Sjoelie AK, Chaturvedi N, et al. Risk factors for progression to proliferative diabetic retinopathy in the EURODIAB Prospective Complications Study. Diabetologia. Dec 2001;44(12):2203-9. doi:10.1007/s001250100030
- Cardoso CRL, Leite NC, Dib E, Salles GF. Predictors of Development and Progression of Retinopathy in Patients with Type 2 Diabetes: Importance of Blood Pressure Parameters. Sci Rep. Jul 7 2017;7(1):4867. doi:10.1038/s41598-017-05159-6
- Fong DS, Aiello L, Gardner TW, et al. Retinopathy in Diabetes. Diabetes Care. 2004;27(suppl_1):s84-s87. doi:10.2337/diacare.27.2007.S84
- 3. Prevention or Delay of Diabetes and Associated Comorbidities: Standards of Care in Diabetes-2024. Diabetes Care. Jan 1 2024;47(Suppl 1):S43-s51. doi:10.2337/dc24-S003
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