Effect of Combination Therapy with Liraglutide plus Canagliflozin on HGP and HbA1c vs. Each Therapy Alone in T2DM

Abstract

Background: We previously have shown that SGLT2 inhibitors cause an increase in HGP accompanied with an increase in plasma glucagon concentration. We hypothesized that the increase in plasma glucagon concentration is, at least in part, responsible for the increase in HGP. The aim of the present study was to examine whether inhibition of glucagon secretion by liraglutide can prevent the increase in HGP. Research Design and Methods: 51 T2DM patients (age=51±1 yr; 40% female; BMI=34.6±0.7; diabetes duration=6.8±0.8 yr; FPG=175±7; HbA1c=8.3±0.1%) were randomized to receive for 16 weeks: (i) canagliflozin 300 mg; (ii) liraglutide 1.8 mg; or (iii) canagliflozin 300 mg plus liraglutide 1.8 mg. HGP (measured with 3-3H-glucose infusion) and plasma glucagon concentration were measured before and after 16 weeks of treatment. Results: Canagliflozin monotherapy caused a significant reduction in HbA1c (-1.1±0.2%, p<0.01) accompanied with an increase in plasma glucagon concentration (by 28%, p<0.05) and HGP (by 15%, p<0.05) which lasted for 16 weeks. Conversely, liraglutide monotherapy caused a 1.6±0.5% (p<0.01) reduction in HbA1c accompanied by a small (6%) reduction in HGP (P=NS) without significant change in fasting plasma glucagon concentration. The combination of canagliflozin plus liraglutide caused a greater reduction in HbA1c (1.9±0.5%, p<0.vs. canagliflozin and p=NS vs. liraglutide) and attenuated the increase in fasting plasma glucagon and basal HGP at 16 weeks. Conclusion: These results: (1) support a possible role for increased plasma glucagon levels in the long term maintenance of increase in HGP caused by SGLT2i, and (2) suggest that factors other than/in addition to glucagon contribute to the initiation of the increase in HGP. Disclosure M. Abdul-Ghani: None. A.M. Ali: None. R.A. Martinez: None. J.M. Adams: None. E. Cersosimo: Research Support; Self; AstraZeneca, VeroScience, LLC.. Speaker's Bureau; Self; AstraZeneca, Sanofi, Janssen Pharmaceuticals, Inc., Eli Lilly and Company. C.L. Triplitt: Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Eli Lilly and Company. Consultant; Self; Sanofi, Novo Nordisk Inc. R.A. DeFronzo: Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc.. Advisory Panel; Self; AstraZeneca, Novo Nordisk Inc., Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc.. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Takeda Pharmaceuticals U.S.A., Inc..