Combination Therapy With Canagliflozin Plus Liraglutide Exerts Additive Effect on Weight Loss, but Not on HbA1c, in Patients With Type 2 Diabetes

Abstract

OBJECTIVE To examine the effect of combination therapy with canagliflozin plus liraglutide on HbA1c, endogenous glucose production (EGP), and body weight versus each therapy alone. RESEARCH DESIGN AND METHODS Forty-five patients with poorly controlled (HbA1c 7–11%) type 2 diabetes mellitus (T2DM) on metformin with or without sulfonylurea received a 9-h measurement of EGP with [3-3H]glucose infusion, after which they were randomized to receive 1) liraglutide 1.2 mg/day (LIRA), 2) canagliflozin 100 mg/day (CANA), or 3) liraglutide 1.2 mg plus canagliflozin 100 mg (CANA/LIRA) for 16 weeks. At 16 weeks, the EGP measurement was repeated. RESULTS The mean decrease from baseline to 16 weeks in HbA1c was −1.67 ± 0.29% (P = 0.0001), −0.89 ± 0.24% (P = 0.002), and −1.44 ± 0.39% (P = 0.004) in patients receiving CANA/LIRA, CANA, and LIRA, respectively. The decrease in body weight was −6.0 ± 0.8 kg (P < 0.0001), −3.5 ± 0.5 kg (P < 0.0001), and −1.9 ± 0.8 kg (P = 0.03), respectively. CANA monotherapy caused a 9% increase in basal rate of EGP (P < 0.05), which was accompanied by a 50% increase (P < 0.05) in plasma glucagon-to-insulin ratio. LIRA monotherapy reduced plasma glucagon concentration and inhibited EGP. In CANA/LIRA-treated patients, EGP increased by 15% (P < 0.05), even though the plasma insulin response was maintained at baseline and the CANA-induced rise in plasma glucagon concentration was blocked. CONCLUSIONS These results demonstrate that liraglutide failed to block the increase in EGP caused by canagliflozin despite blocking the rise in plasma glucagon and preventing the decrease in plasma insulin concentration caused by canagliflozin. The failure of liraglutide to prevent the increase in EGP caused by canagliflozin explains the lack of additive effect of these two agents on HbA1c.