Endogenous Glucose Production and Hormonal Changes in Response to Canagliflozin and Liraglutide Combination Therapy

The decrement in plasma glucose concentration with SGLT2 inhibitors (SGLT2i) is blunted by a rise in endogenous glucose production (EGP). We investigated the ability of incretin treatment to offset the EGP increase. Subjects with type 2 diabetes (n = 36) were randomized to 1) canagliflozin (CANA), 2) liraglutide (LIRA), or 3) CANA plus LIRA (CANA/LIRA). EGP was measured with [3-H-3]glucose with or without drugs for 360 min. In the pretreatment studies, EGP was comparable and decreased (2.2 +/- 0.1 to 1.7 +/- 0.2 mg/kg . min) during a 300-to 360-min period (P < 0.01). The decrement in EGP was attenuated with CANA (2.1 +/- 0.1 to 1.9 +/- 0.1 mg/kg . min) and CANA/LIRA (2.2 6 0.1 to 2.0 +/- 0.1 mg/kg . min), whereas with LIRA it was the same (2.4 +/- 0.2 to 1.8 +/- 0.2 mg/kg . min) (all P < 0.05 vs. baseline). After CANA, the fasting plasma insulin concentration decreased (18 +/- 2 to 12 +/- 2 mu U/mL, P < 0.05), while it remained unchanged in LIRA (18 +/- 2 vs. 16 +/- 2 mu U/mL) and CANA/LIRA (17 +/- 1 vs. 15 +/- 2 mu U/mL). Mean plasma glucagon did not change during the pretreatment studies from 0 to 360 min, while it increased with CANA (69 +/- 3 to 78 +/- 2 pg/mL, P < 0.05), decreased with LIRA (93 +/- 6 to 806 +/- pg/mL, P < 0.05), and did not change in CANA/LIRA. LIRA prevented the insulin decline and blocked the glucagon rise observed with CANA but did not inhibit the increase in EGP. Factors other than insulin and glucagon contribute to the stimulation of EGP after CANA-induced glucosuria.