Systemic Anemia and the Risk of Diabetic Macular Edema and Anti-VEGF Injections

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).

Multicenter retrospective cohort study.

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.

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.

One-year risk of developing DME and 1-year risk of receiving anti-VEGF injections.

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.

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.

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.