Erythropoiesis-Stimulating Agents and the Risk of Vision-Threatening Diabetic Retinopathy

ABSTRACT

Purpose

Animal studies have suggested that Erythropoiesis-Stimulating Agents (ESAs) may increase vascular endothelial growth factor (VEGF)-related retinopathies, but this effect is unclear in humans. This study evaluates the risk of vision-threatening diabetic retinopathy (VTDR), defined as either diabetic macular edema (DME) or proliferative diabetic retinopathy (PDR), in patients exposed to an ESA.

Methods

Two analyses were performed. First, a retrospective matched-cohort study was designed using a de-identified commercial and Medicare Advantage medical claims database. The ESA cohort of non-proliferative diabetic retinopathy patients who were new users of an ESA from 2000 to 2022 was matched to controls up to a 3:1 ratio. Exclusion criteria included less than 2 years in the plan, history of VTDR or history of other retinopathy. Multivariable Cox proportional hazards regression with inverse proportional treatment weighting (IPTW) was used to assess the hazard of developing VTDR, DME, and PDR. The second analysis was a self-controlled case series (SCCS) evaluating the incidence rate ratios (IRR) of VTDR during 30-day periods before and after initiating an ESA.

Results

After inclusion of 1502 ESA-exposed patients compared with 2656 controls, IPTW-adjusted hazard ratios found the ESA cohort had an increased hazard of progressing to VTDR (HR = 3.0 95%CI:2.3–3.8;p < .001) and DME (HR = 3.4,95%CI:2.6–4.4,p < .001), but not PDR (HR = 1.0,95%CI:0.5–2.3,p = .95). Similar results were found within the SCCS which demonstrated higher IRRs for VTDR (IRRs = 1.09–1.18;p < .001) and DME (IRRs = 1.16–1.18;p < .001), but not increased IRRs in PDR (IRR = 0.92–0.97,p = .02–0.39).

Conclusion

ESAs are associated with higher risks for VTDR and DME, but not PDR. Those studying ESAs as adjunctive therapy for DR should be cautious of possible unintended effects.

Keywords:

• Erythropoiesis-Stimulating Agents
• Vision threatening diabetic retinopathy
• Diabetic macular edema
• proliferative diabetic retinopathy

Disclosure statement

BVB has been a paid consultant for EyePoint Pharmaceuticals.

Financial Support

National Institutes of Health K23 Award (1K23EY025729–01) and University of Pennsylvania Core Grant for Vision Research (2P30EYEY001583). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Additional funding was provided by Research to Prevent Blindness and the Paul and Evanina Mackall Foundation. Funding from each of the above sources was received in the form of block research grants to the Scheie Eye Institute. The sponsor or funding organization had no role in the design or conduct of this research.

Portions of this work have been presented at the 2022 Macula Society meeting. This submission has not been published anywhere previously, and it is not simultaneously being considered for any other publication.

Supplemental data

Supplemental data for this article can be accessed online at https://doi.org/10.1080/09286586.2023.2235001.

Additional information

Funding

The work was supported by the National Institutes of Health [1K23EY025729 - 01]; University of Pennsylvania Core Grant for Vision Research is a National Institute of Health Grant as p- grant [2P30EYEY001583]; Paul MacKall and Evanina Bell MacKall Trust Research to Prevent Blindness .