Sodium–glucose cotransporter 2 inhibition and injection burden in mild diabetic macular edema: An exploratory post hoc analysis of the COMET trial

AIMS: To investigate the potential of sodium-glucose cotransporter 2 inhibitors (SGLT2i) as a less invasive treatment option for mild diabetic macular edema (DMO) via post hoc subgroup analysis. Previous findings were derived exclusively from observational studies, and no interventional trials based on protocol-defined criteria had been conducted. MATERIALS AND METHODS: Based on the COMET trial data, this post hoc analysis targeted mild DME cases, defined by baseline central retinal thickness (CRT) ≤375 μm and best-corrected visual acuity (BCVA) ≤0.155 (logMAR). Patients were randomized to SGLT2i (luseogliflozin) or sulfonylurea (SU, glimepiride) groups. Mild subgroups were compared with the corresponding non-mild cases. The primary outcome was the 48-week frequency of intravitreal ranibizumab injections (IVRs). RESULTS: In the CRT ≤375 μm subgroup, IVR frequency was significantly lower with SGLT2i vs SU (mean 0.5 ± 1.0 vs 4.3 ± 0.8; P = 0.005, adjusted ancova. Cohen's d of 2.1). The cumulative mean number of IVRs was significantly lower in the SGLT2i group than in the SU group (P = 0.004, hazard ratio 0.29, 95% confidence interval 0.12-0.67). In the BCVA ≤ 0.155 subgroup, whose mean CRT exceeded 400 μm, no significant difference in IVR frequency was observed between the SGLT2i-treated and SU-treated patients. In addition, no intergroup differences were found in patients outside the mild subgroups. CONCLUSIONS: In this exploratory analysis, SGLT2 inhibition was associated with fewer intravitreal injections in patients meeting the CRT-based mild criteria. These findings are hypothesis-generating and warrant confirmation in future prospective studies.