Incretin-Based Therapies and Diabetic Retinopathy: Real-World Evidence in Older U.S. Adults

Abstract

Objective: Recent large trials yield conflicting results on the association between incretin-based therapies (IBTs) and diabetic retinopathy (DR). We examined whether IBTs increase DR risk compared with other antihyperglycemics.

Research design and methods: We implemented an active comparator, new-user cohort design using a nationwide 20% random sample of fee-for-service U.S. Medicare beneficiaries aged 65 years or older with Parts A, B, and D coverage between 2007 and 2015. We identified the following cohorts without prior treatment for retinopathy: dipeptidyl peptidase 4 inhibitors (DPP4i) versus sulfonylureas (SU), DPP4i versus thiazolidinediones (TZD), glucagon-like peptide-1 receptor agonists (GLP1RA) versus long-acting insulin (LAI), and GLP1RA versus TZD. Primary outcome was advanced diabetic retinopathy requiring treatment (ADRRT), defined as a procedure code for retinopathy treatment. Incident diabetic retinopathy (IDR), identified by a diagnosis code, was a secondary outcome. We estimated propensity scores to balance confounders and adjusted hazard ratios (95% CI) using weighted Cox proportional hazards models.

Results: We identified 213,652 eligible patients. During a median duration of 0.58 to 0.87 years across comparisons, with a rate from 6.0 to 12.8 per 1,000 person-years, IBTs were not associated with increased ADRRT or IDR risk. The adjusted hazard ratios (95% CI) for ADRRT were 0.91 (0.79-1.04) by comparing DPP4i to SU (n = 39,292 and 87,073); 0.91 (0.75-1.11), DPP4i to TZD (n = 51,410 and 22,231); 0.50 (0.39-0.65), GLP1RA to LAI (n = 9,561 and 82,849); and 0.75 (0.53-1.06), GLP1RA to TZD (n = 10,355 and 27,345).

Conclusions: Our population-based cohort study of older U.S. adults with diabetes suggests that IBTs used for approximately 1 year do not increase the DR risk.

Figure 1

SMR-weighted Kaplan-Meier plots of ADRRT. A: DPP4i vs. SU cohort. HR 0.91 (95% CI 0.79–1.04). B: DPP4i vs. TZD cohort. HR 0.91 (95% CI 0.75–1.11). C: GLP1RA vs. LAI cohort. HR 0.50 (95% CI 0.39–0.65). D: GLP1RA vs. TZD cohort. HR 0.75 (95% CI 0.53–1.06). SMR weights create a pseudo-population of the untreated (comparators: SU, TZD, or LAI), which has the same covariate distribution as the treated (IBT). Every patient receiving IBT has a weight of 1, whereas every patient in the comparator group is weighted by PS/(1 − PS). The risks on the y-axis were obtained by a SMR-weighted Cox model (weighting comparator drug initiators by the PS odds [PS/(1 − PS)]). HR treats comparators as reference, and adjusted HR <1 indicates a lower risk for IBT.