SGLT2 Inhibitors Are Associated With Suppression of the Sema3A/NRP1/Plexin-A1 Signaling Axis in Postmenopausal Women With Type 2 Diabetes: Evidence From Propensity Score-Matched Analysis.

Propensity score-matched comparison of 23 SGLT2 inhibitor users and 23 non-users revealed that SGLT2 inhibitor use was associated with significantly lower Neuropilin-1 (NRP1) levels (74.25 vs. 87.61 ng/mL; p = 0.015) and a higher Sema3A/NRP1 ratio (0.14 vs. 0.12; p = 0.006), indicating functional impairment of the Sema3A/NRP1/Plexin-A1 bone signaling axis with compensatory Sema3A upregulation. Classical bone turnover markers (P1NP, CTX, coupling index) and DXA-derived BMD did not significantly differ between groups. These findings suggest that SGLT2 inhibitors may perturb the Sema3A/NRP1/Plexin-A1 axis before detectable changes in conventional markers, offering a novel mechanistic perspective to explain the inconsistency between existing meta-analyses on SGLT2 inhibitor bone safety.