Ophthalmology. Retina · 2026
Systemic Anemia and the Risk of Diabetic Macular Edema and Anti-VEGF Injections.
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Muayad Jawad, Butt Fahad R, Loya Asad, Chauhan Muhammad Z, Hussain Zain S, Lee Andrew G, Sallam Ahmed B, Dahr Sami S
Аннотация
PURPOSE: To investigate a severity gradient between anemia and the 1-year risk of developing diabetic macular edema (DME) and the need for anti-VEGF injections in patients with type 2 diabetes mellitus (T2DM).
DESIGN: Multicenter retrospective cohort study.
PARTICIPANTS: Patients with newly recorded T2DM and no prior diabetic eye disease in the TriNetX US Collaborative Network, with a documented ambulatory encounter in the 12 months preceding the index T2DM diagnosis, were included. Exclusions included hemolytic and aplastic anemias, bone marrow failure syndromes, and retinal vascular occlusions.
METHODS: Patients were stratified by hemoglobin level into combined and sex-specific cohorts. A sensitivity analysis evaluated patients with a hemoglobin level of <12.0 g/dL receiving iron supplementation within 6 months of index versus matched controls. Independent 1:1 propensity score matching was performed for all subanalyses. Prespecified negative control outcomes (chalazion and ingrown toenail) and E-value analyses were performed to assess unmeasured confounding.
MAIN OUTCOME MEASURES: One-year risk of developing DME and 1-year risk of receiving anti-VEGF injections.
RESULTS: In the combined cohort (N = 127 260), the risk of DME increased stepwise across anemia severity compared with controls with normal hemoglobin: mild (hazard ratio [HR], 1.47; 95% confidence interval [CI], 1.36-1.59), moderate-low (HR, 1.66; 95% CI, 1.50-1.84), moderate-high (HR, 1.99; 95% CI, 1.75-2.28), and severe (HR, 2.32; 95% CI, 1.84-2.91). The risk of anti-VEGF injection increased through moderate-high anemia (HR, 1.86) and plateaued in severe anemia (HR, 1.78). Sex-stratified analyses confirmed this gradient across both subgroups. In the sensitivity analysis (N = 19 214), initiating iron supplementation reduced 1-year DME risk (HR, 0.86; 95% CI, 0.75-0.99). Negative control outcomes demonstrated null associations across all severity strata; E-values for the primary outcome ranged from 2.30 to 4.07, supporting robustness to unmeasured confounding.
CONCLUSIONS: Declining hemoglobin levels are associated with a graded increase in DME risk and anti-VEGF treatment burden across both sexes. The reduced risk observed with iron supplementation suggests that anemia may serve as a modifiable systemic factor in DME pathogenesis, warranting prospective investigation.
FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
DESIGN: Multicenter retrospective cohort study.
PARTICIPANTS: Patients with newly recorded T2DM and no prior diabetic eye disease in the TriNetX US Collaborative Network, with a documented ambulatory encounter in the 12 months preceding the index T2DM diagnosis, were included. Exclusions included hemolytic and aplastic anemias, bone marrow failure syndromes, and retinal vascular occlusions.
METHODS: Patients were stratified by hemoglobin level into combined and sex-specific cohorts. A sensitivity analysis evaluated patients with a hemoglobin level of <12.0 g/dL receiving iron supplementation within 6 months of index versus matched controls. Independent 1:1 propensity score matching was performed for all subanalyses. Prespecified negative control outcomes (chalazion and ingrown toenail) and E-value analyses were performed to assess unmeasured confounding.
MAIN OUTCOME MEASURES: One-year risk of developing DME and 1-year risk of receiving anti-VEGF injections.
RESULTS: In the combined cohort (N = 127 260), the risk of DME increased stepwise across anemia severity compared with controls with normal hemoglobin: mild (hazard ratio [HR], 1.47; 95% confidence interval [CI], 1.36-1.59), moderate-low (HR, 1.66; 95% CI, 1.50-1.84), moderate-high (HR, 1.99; 95% CI, 1.75-2.28), and severe (HR, 2.32; 95% CI, 1.84-2.91). The risk of anti-VEGF injection increased through moderate-high anemia (HR, 1.86) and plateaued in severe anemia (HR, 1.78). Sex-stratified analyses confirmed this gradient across both subgroups. In the sensitivity analysis (N = 19 214), initiating iron supplementation reduced 1-year DME risk (HR, 0.86; 95% CI, 0.75-0.99). Negative control outcomes demonstrated null associations across all severity strata; E-values for the primary outcome ranged from 2.30 to 4.07, supporting robustness to unmeasured confounding.
CONCLUSIONS: Declining hemoglobin levels are associated with a graded increase in DME risk and anti-VEGF treatment burden across both sexes. The reduced risk observed with iron supplementation suggests that anemia may serve as a modifiable systemic factor in DME pathogenesis, warranting prospective investigation.
FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.