Luseogliflozin Hydrate

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.

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).

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.

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.

Impaired glucose‐dependent insulinotropic polypeptide (GIP)‐induced insulin secretion is a characteristic feature of type 2 diabetes, whereas glucagon‐like peptide‐1 (GLP‐1) responsiveness is relatively preserved. Our previous study proposed that chronic β‐cell depolarization alters G protein signaling and contributes to this differential incretin responsiveness, but whether glucose lowering by sodium–glucose cotransporter 2 inhibition restores incretin responsiveness remains unclear. We investigated the effects of chronic luseogliflozin treatment on incretin responsiveness in two diabetic mouse models, KK‐Ay mice with preserved residual β‐cell function and streptozotocin/high‐fat diet‐induced diabetic mice with severe β‐cell impairment. Luseogliflozin improved glycemic control in both models without marked changes in body weight or plasma insulin levels. In KK‐Ay mice, luseogliflozin restored the glucose‐lowering effect of GIP during GIP‐preload glucose tolerance test. In contrast, this effect was not observed in streptozotocin/high‐fat diet‐induced diabetic mice, suggesting that preserved residual β‐cell function is required for recovery of GIP responsiveness. Ex vivo analyses using isolated islets further showed that chronic luseogliflozin treatment altered incretin‐stimulated insulin secretion, including attenuation of enhanced GLP‐1 responsiveness under diabetic conditions. These findings suggest that luseogliflozin may partially normalize aberrant β‐cell incretin signaling and restore GIP responsiveness when sufficient β‐cell function remains.