Safety assessment of the SGLT2 inhibitors empagliflozin, dapagliflozin and canagliflozin during pregnancy: An ex vivo human placenta perfusion and in vitro study

Although uncontrolled hyperglycaemia during pregnancy can cause complications for both the mother and her offspring, pharmacological treatment options for gestational and type 2 diabetes in pregnancy are still limited. Empagliflozin (EMPA), dapagliflozin (DAPA) and canagliflozin (CANA) are three sodium glucose co-transporter 2 (SGLT2) inhibitors, a newer group of oral antidiabetics that are well established in the treatment of type 2 diabetes mellitus in non-pregnant patients. To date, no data regarding their placental transfer and safety in pregnant women are available. We performed ex vivo human placental perfusions (n = 4, term placentas, creatinine and antipyrine as connectivity controls) to evaluate the transplacental transfer of EMPA, DAPA and CANA across the placental barrier and assessed their influence on the secretion of two placental peptide hormones, leptin and β-human chorionic gonadotropin (β-hCG). We discovered that all three SGLT2 inhibitors cross the placental barrier and attained maximal foetal to maternal concentration ratios of 0.38 ± 0.09 (EMPA), 0.67 ± 0.05 (DAPA) and 0.62 ± 0.05 (CANA) within the tested 360 min. A moderate but statistically significant decrease in placental leptin - but not β-hCG - secretion was observed during perfusions with SGLT2 inhibitors, which was confirmed in experiments performed with human placental BeWo cells. SGLT2 inhibitors are able to cross the human placental barrier and seem to interfere with placental leptin production. These observations should be considered in the ongoing discussion on the optimal treatment for gestational diabetes and type 2 diabetes mellitus in pregnancy.