Comparative Effectiveness of Glucagon-Like Peptide-1 Receptor Agonists, Sodium-Glucose Cotransporter 2 Inhibitors, Dipeptidyl Peptidase-4 Inhibitors, and Sulfonylureas for Sight-Threatening Diabetic Retinopathy

Abstract

Objective: To investigate whether the choice of glucose-lowering agent for type 2 diabetes (T2D) impacts a patient's risk of developing sight-threatening diabetic retinopathy complications.

Design: Retrospective observational database study emulating an idealized target trial.

Subjects: Adult (≥21 years) enrollees in United States commercial, Medicare Advantage, and Medicare fee-for-service plans from January 1, 2014, to December 31, 2021, with T2D and moderate cardiovascular disease (CVD) risk who had no baseline history of advanced diabetic retinal complications, initiating treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RA), sodium-glucose cotransporter 2 inhibitors (SGLT2i), dipeptidyl peptidase-4 inhibitors (DPP-4i), and sulfonylureas.

Methods: We used inverse propensity scoring weights in time-to-event Cox proportional hazards models.

Main outcome measures: Treatment for either diabetic macular edema or proliferative diabetic retinopathy.

Results: The final study population included 371 698 patients, of whom 42 265 initiated GLP-1 RA, 53 476 initiated SGLT2i, 78 444 initiated DPP-4i, and 197 513 initiated sulfonylurea agents. The probability of treatment for sight-threatening retinopathy within 2 and 5 years was 0.3% and 0.7% for patients initiating SGLT2i (median follow-up 830 [interquartile range (IQR), 343-1401] days), 0.4% and 1.0% for GLP-1 RA (669 [IQR, 256-1167] days), 0.4% and 0.9% for DPP-4i (1263 [IQR, 688-1938] days), and 0.5% and 1.2% for sulfonylurea (1223 [IQR, 662-1879] days). Sodium-glucose cotransporter 2 inhibitors use was associated with a lower risk of treatment for sight-threatening retinopathy compared with all other medication classes, including GLP-1 RA (hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.55-0.97), DPP-4i (HR, 0.79; 95% CI, 0.64-0.97), and sulfonylurea (HR, 0.61; 95% CI, 0.50-0.74). Glucagon-like peptide-1 receptor agonists use was associated with a similar risk of sight-threatening retinopathy as DPP-4i (HR, 1.07; 95% CI, 0.85-1.35) and sulfonylurea (HR, 0.83; 95% CI, 0.67-1.03).

Conclusions: Sodium-glucose cotransporter 2 inhibitors use was associated with a lower risk of sight-threatening diabetic retinopathy among adults with T2D and moderate CVD risk compared with other glucose-lowering therapies. Glucagon-like peptide-1 receptor agonists do not confer increased retinal risk, relative to DPP-4i and sulfonylurea medications.

Financial disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Keywords: Diabetic macular edema; Diabetic retinopathy; GLP-1 RA; Proliferative diabetic retinopathy; SGLT2i.

Figure 1.

Cumulative incidence of treatment for sight-threatening retinopathy (diabetic macular edema and/or proliferative diabetic retinopathy). DPP-4i = dipeptidyl peptidase-4 inhibitors; GLP-1 RA = glucagon-like peptide-1 receptor agonists; SGLT2i = sodium-glucose cotransporter 2 inhibitors.

Figure 2.

Association between glucose-lowering treatment and sight-threatening retinopathy outcomes by duration of treatment: intention-to-treat analysis. DME = diabetic macular edema; DPP-4i = dipeptidyl peptidase-4 inhibitors; GLP-1 RA = glucagon-like peptide-1 receptor agonists; PDR = proliferative diabetic retinopathy; SGLT2i = sodium-glucose cotransporter 2 inhibitors; SU = sulfonylurea.