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.

中文翻译：

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Canagliflozin加Liraglutide的联合疗法对2型糖尿病患者的体重减轻具有加重作用，但对HbA1c无作用。

目的探讨与卡那列净联合利拉鲁肽联合治疗与单独治疗相比对HbA1c，内源性葡萄糖生成（EGP）和体重的影响。研究设计与方法45例接受或不接受磺脲类药物的二甲双胍控制不佳（HbA1c 7-11％）2型糖尿病（T2DM）的患者接受了[3-3H]葡萄糖输注的9小时EGP测量，之后他们被随机分配接受1）利拉鲁肽1.2毫克/天（LIRA），2）卡那列净100毫克/天（CANA）或3）利拉鲁肽1.2毫克加卡那列净100毫克（CANA / LIRA），持续16周。在16周时，重复EGP测量。结果在接受CANA /治疗的患者中，HbA1c从基线到16周的平均下降为-1.67±0.29％（P = 0.0001），-0.89±0.24％（P = 0.002）和-1.44±0.39％（P = 0.004）。 LIRA，CANA和LIRA。体重下降分别为-6.0±0.8 kg（P <0.0001），-3.5±0.5 kg（P <0.0001）和-1.9±0.8 kg（P = 0.03）。CANA单一疗法使EGP基础率增加9％（P <0.05），同时血浆胰高血糖素与胰岛素之比增加50％（P <0.05）。LIRA单一疗法可降低血浆胰高血糖素浓度并抑制EGP。在CANA / LIRA治疗的患者中，即使血浆胰岛素反应维持在基线水平且CANA诱导的血浆胰高血糖素浓度的升高被阻止，EGP也增加了15％（P <0.05）。结论这些结果表明，利拉鲁肽尽管阻断了血浆胰高血糖素的升高并阻止了卡那列净引起的血浆胰岛素浓度的降低，却未能阻止卡那列净引起的EGP升高。