Association of increased hepatic insulin clearance and change in serum triglycerides or β‐hydroxybutyrate concentration via the sodium/glucose‐cotransporter 2 inhibitor tofogliflozin

AIMS: Obesity and hepatic fat accumulation diminish hepatic insulin clearance, which can cause hyperinsulinaemia. Sodium/glucose‐cotransporter 2 inhibitors (SGLT2‐is) improve insulin resistance and hyperinsulinaemia by weight loss via increased urinary glucose excretion in type 2 diabetes. However, there are few reports of the influence of SGLT2‐is on hepatic insulin clearance. We examined the impact of an SGLT2‐i on hepatic insulin clearance and explored the clinical influence associated with changes in hepatic insulin clearance via an SGLT2‐i and the mechanism of the effects of SGLT2‐i. MATERIALS AND METHODS: Data were analysed from 419 patients with type 2 diabetes controlled by diet and exercise. Patients received a placebo or the SGLT2‐i tofogliflozin (TOFO) (placebo: n = 56; TOFO: n = 363) orally once daily for ≥24 weeks. Hepatic insulin clearance was calculated from the ratio of areas under the curve (AUC) of C‐peptide and insulin levels derived from oral meal tolerance test data (C‐peptide AUC(0‐120 min)/insulin AUC(0‐120 min): HIC(CIR)). The correlation of HIC(CIR) via the SGLT2‐i with other clinical variables was analysed using multivariate analysis. RESULTS: HIC(CIR) was significantly increased via TOFO at week 24. Furthermore, with TOFO insulin and triglyceride (TG) levels were significantly reduced (P < 0.001) and β‐hydroxybutyrate (BHB) was significantly elevated (P < 0.001). Changes in HIC(CIR) were significantly correlated with changes in TG and BHB via TOFO. CONCLUSIONS: Increased HIC(CIR) was significantly associated with reduced TG via TOFO and contributed to the greater increase in BHB compared with placebo in addition to the correction of hyperinsulinaemia.