Placental transfer characteristics and functional impact of SGLT2 inhibitors in human experimental models

Understanding the mechanisms of drug transfer across the human placenta is critical for evaluating foetal exposure and developmental safety. Sodium-glucose co-transporter 2 inhibitors (SGLT2i), a novel class of antidiabetics, remain poorly characterized with respect to their placental transfer and potential effect on placental function. Here, we address this knowledge gap. We investigated placental transfer mechanisms of dapagliflozin (DAPA), empagliflozin (EMPA), ertugliflozin (ERTU) and canagliflozin (CANA) using term placentas and complementary in vitro assays. All SGLT2i crossed the barrier within four hours of perfusion at clinically relevant concentrations. DAPA, the smallest compound, showed the fastest transfer, whereas EMPA, the largest, was the slowest. The more lipophilic compounds, CANA and ERTU, accumulated strongly in placental tissue. Transport of all SGLT2i - especially EMPA and ERTU - increased with the addition of an ATP-synthesis inhibitor, indicating the influence of active efflux transporters. Additionally, transport was significantly enhanced under low-bovine serum albumin conditions, implicating protein binding as a key rate-limiting factor. During Transwell® permeability assays, all SGLT2i crossed the BeWo b30 cell layer that mimics early gestational cytotrophoblasts. BeWo cells exposed to SGLT2i showed no impairment in forskolin-induced differentiation, viability, or secretion of pregnancy-related hormones, but revealed increased glycolytic activity. Our findings indicate that at clinically relevant concentrations, SGLT2i cross the placenta by passive diffusion, modulated by efflux transporters and protein binding, and might alter placental glycolytic activity without impairing viability, differentiation, or hormone secretion. Their use during pregnancy should remain contraindicated, but if attempted, monitoring unbound drug concentrations is advised.