Translational Medicine, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
Novo Nordisk Research Centre Oxford, UK.
Diabetes Obes Metab. 2019 Jun;21(6):1311-1321. doi: 10.1111/dom.13654. Epub 2019 Mar 15.
There is an unmet need for a safer and more effective treatment for obesity. This study assessed the effects of licogliflozin, a dual inhibitor of sodium-glucose co-transporter (SGLT) 1/2, on body weight, metabolic parameters and incretin hormones in patients with type 2 diabetes mellitus (T2DM) and/or obesity.
Patients with obesity (BMI, 35-50 kg/m ) were enrolled into a 12-week study (N = 88; licogliflozin 150 mg q.d.). Patients with T2DM were enrolled into a second, two-part study, comprising a single-dose cross-over study (N = 12; 2.5 - 300 mg) and a 14-day dosing study (N = 30; 15 mg q.d). Primary endpoints included effects on body weight, effects on glucose, safety and tolerability. Secondary endpoints included urinary glucose excretion (UGE ) and pharmacokinetics, while exploratory endpoints assessed the effects on incretin hormones (total GLP-1, PYY , and GIP), insulin and glucagon.
Treatment with licogliflozin 150 mg q.d. for 12 weeks in patients with obesity significantly reduced body weight by 5.7% vs placebo (P < 0.001) and improved metabolic parameters such as significantly reduced postprandial glucose excursion (21%; P < 0.001), reduced insulin levels (80%; P < 0.001) and increased glucagon (59%; P < 0.001). In patients with T2DM, a single dose of licogliflozin 300 mg in the morning prior to an oral glucose tolerance test (OGTT) remarkably reduced glucose excursion by 93% (P < 0.001; incremental AUC ) and suppressed insulin by 90% (P < 0.01; incremental AUC ). Treatment with licogliflozin 15 mg q.d. for 14 days reduced 24-hour average glucose levels by 26% (41 mg/dL; P < 0.001) and increased UGE to 100 g (P < 0.001) in patients with T2DM. In addition, this treatment regimen significantly increased total GLP-1 by 54% (P < 0.001) and PYY by 67% (P < 0.05) post OGTT vs placebo, while significantly reducing GIP levels by 53% (P < 0.001). Treatment with licogliflozin was generally safe and well tolerated. Diarrhea (increased numbers of loose stool) was the most common adverse event in all studies (90% with licogliflozin vs 25% with placebo in the 12-week study), while a lower incidence of flatulence, abdominal pain and abdominal distension (25%-43% with licogliflozin vs 9%-11% with placebo in the 12-week study) were among the other gastrointestinal events reported.
Licogliflozin treatment (1-84 days) leads to significant weight loss and favourable changes in a variety of metabolic parameters and incretin hormones. Dual inhibition of SGLT1/2 with licogliflozin in the gut and kidneys is an attractive strategy for treating obesity and diabetes.
对于肥胖症患者，我们需要一种更安全、更有效的治疗方法。本研究评估了钠-葡萄糖共转运蛋白（SGLT）1/2 双重抑制剂 licogliflozin 对 2 型糖尿病（T2DM）和/或肥胖症患者体重、代谢参数和肠促胰岛素激素的影响。
肥胖症患者（BMI，35-50kg/m2）被纳入为期 12 周的研究（N=88；licogliflozin 150mg q.d.）。T2DM 患者被纳入第二项、两部分研究，包括单次交叉研究（N=12；2.5-300mg）和为期 14 天的给药研究（N=30；15mg q.d.）。主要终点包括对体重的影响、对葡萄糖的影响、安全性和耐受性。次要终点包括尿葡萄糖排泄（UGE）和药代动力学，而探索性终点评估肠促胰岛素激素（总 GLP-1、PYY 和 GIP）、胰岛素和胰高血糖素的影响。
在肥胖症患者中，每天服用 150mg licogliflozin 治疗 12 周，与安慰剂相比，体重显著降低 5.7%（P<0.001），并改善了代谢参数，如餐后血糖明显降低（21%；P<0.001），胰岛素水平降低（80%；P<0.001），胰高血糖素升高（59%；P<0.001）。在 T2DM 患者中，口服葡萄糖耐量试验（OGTT）前早晨给予 licogliflozin 300mg 单次剂量，可显著降低葡萄糖波动 93%（P<0.001；增量 AUC），并抑制胰岛素 90%（P<0.01；增量 AUC）。在 T2DM 患者中，每天服用 15mg licogliflozin 治疗 14 天，可使 24 小时平均血糖水平降低 26%（41mg/dL；P<0.001），并使 UGE 增加至 100g（P<0.001）。此外，与安慰剂相比，这种治疗方案可使 OGTT 后总 GLP-1 增加 54%（P<0.001），PYY 增加 67%（P<0.05），而 GIP 水平降低 53%（P<0.001）。服用 licogliflozin 通常是安全且耐受良好的。腹泻（大便次数增多）是所有研究中最常见的不良事件（服用 licogliflozin 的患者中有 90%，而服用安慰剂的患者中有 25%），而腹胀、腹痛和腹部膨隆的发生率较低（服用 licogliflozin 的患者中有 25%-43%，而服用安慰剂的患者中有 9%-11%）是其他报告的胃肠道事件之一。
Licogliflozin 治疗（1-84 天）可显著减轻体重，并对多种代谢参数和肠促胰岛素激素产生有利变化。SGLT1/2 的双重抑制作用，在肠道和肾脏中使用 licogliflozin，是治疗肥胖症和糖尿病的一种有吸引力的策略。
