[Efficacy and safety of olorigliflozin monotherapy in patients with type 2 diabetes mellitus with poor glycemic control on diet and exercise interventions].

Abstract / Summary

Objective: To evaluate the efficacy and safety of olorigliflozin monotherapy in Chinese patients with type 2 diabetes mellitus (T2DM) inadequately controlled with diet and exercise. Methods: The study was a multicenter, randomized, double-blind and placebo-controlled phase Ⅲ clinical trial. A total of 396 T2DM patients with inadequate glycemic control despite diet and exercise were enrolled across 73 research centers nationwide between July 2021 and June 2022. Using a block randomization method stratified by baseline glycated hemoglobin A1c (HbA1c) results (≤8.5% and >8.5%) and prior diabetes treatment status, the patients were randomly allocated in a 1∶1∶1 ratio via an interactive response system to the olorigliflozin 20 mg group, 50 mg group, and placebo group. After 24 weeks, the patients in the placebo group were re-randomized in a 1∶1 ratio to the placebo-to-olorigliflozin 20 mg or placebo-to-olorigliflozin 50 mg for an additional 28 weeks using the same randomization method, while the patients in the olorigliflozin groups continued the original treatment. The primary efficacy endpoint was the change in HbA1c from baseline at week 24, with statistical analysis performed based on the full analysis set (FAS). Secondary efficacy endpoints included: change in HbA1c from baseline at weeks 52; HbA1c target achievement rates. The secondary endpoints included the change of from baseline at 52 weeks of treatment, and the HbA1c compliance rates at 24 weeks and 52 weeks of treatment were analyzed by FAS and FAS-completers(FASc), respectively. Safety set (SS) was used to evaluate the safety of subjects during the whole study period. A mixed-effects model for repeated measures was adopted to assess quantitative efficacy indicators, and descriptive statistics was used for safety evaluation. Results: In FAS, there were 130, 129 and 131 patients in the ololegliflozin 20 mg, 50 mg and placebo groups, respectively; In SS, the corresponding number of patients was 130, 133 and 132, respectively; In FASc, the patient numbers were 123 and 119 in the ololegliflozin 20 mg and 50 mg groups, and 59 and 57 in the placebo-to-ololegliflozin 20 mg and placebo-to-ololegliflozin 50 mg groups, respectively. At week 24, the least squares mean differences (95%CI) in placebo-adjusted changes in HbA1c from baseline between groups for the olorigliflozin 20 mg group and 50 mg group were -0.94% (-1.14% to -0.74%; P<0.001) and -1.01% (-1.21% to -0.81%; P<0.001), respectively. The proportions of patients with HbA1c<7% in the placebo group, olorigliflozin 20 mg group and 50 mg group were 20.6% (27/131), 55.4% (72/130) and 56.6% (73/129), respectively; the proportions of patients with HbA1c≤6.5% were 7.6% (10/131), 31.5% (41/130) and 31.8% (41/129), respectively. At week 52, HbA1c continued to show decreasing trends. The mean changes from baseline in HbA1c were -1.33%±0.77%, -1.38%±0.81%, -1.30%±0.69% and -0.90%±0.83%, in the olorigliflozin 20 mg group, olorigliflozin 50 mg group, placebo-to-olorigliflozin 20 mg group, and placebo-to-olorigliflozin 50 mg group, respectively; The proportions of patients with HbA1c<7% were 59.3% (73/123), 61.3% (73/119), 49.2% (29/59) and 42.1% (24/57) in the four groups, respectively, and the proportions of patients with HbA1c≤6.5% were 36.6% (45/123), 42.0% (50/119), 33.9% (20/59) and 26.3% (15/57), respectively. Throughout the study period, olorigliflozin demonstrated good safety profile without any episodes of severe hypoglycemia or ketoacidosis. Conclusion: For Chinese patients with T2DM inadequately controlled by diet and exercise, monotherapy with olorigliflozin (20 mg and 50 mg) can effectively control blood glucose, and demonstrate good safety. 目的： 探讨奥洛格列净单药在运动和饮食控制不佳的中国2型糖尿病（T2DM）患者中治疗的有效性和安全性。 方法： 该研究为多中心、随机、双盲、安慰剂对照的Ⅲ期临床研究。自2021年7月至2022年6月纳入来自全国73家研究中心的396例饮食和运动血糖控制不佳的T2DM患者，以基线糖化血红蛋白（HbA1c）结果（≤8.5%和>8.5%）和既往糖尿病治疗情况为分层因素，采用区组随机方法，使用交互式网络应答系统按照1∶1∶1比例将患者分配至奥洛格列净20 mg组、50 mg组与安慰剂组。治疗24周后，将安慰剂组患者以1∶1比例按照上述随机方法二次分配至安慰剂转奥洛格列净20 mg组或安慰剂转奥洛格列净50 mg组治疗28周，奥洛格列净组维持原治疗方案。主要疗效终点为治疗24周时HbA1c较基线的变化，采用全分析集（FAS）进行统计分析。次要疗效终点包括：治疗52周时HbA1c较基线的变化，治疗24周及52周时HbA1c达标率，分别采用FAS及延伸治疗分析集（FASc）进行分析。采用安全集（SS）对受试者在整个研究期间的安全性进行评估。采用重复测量的混合效应模型评估定量疗效指标；安全性评价则采用描述性统计分析。 结果： FAS中，奥洛格列净20 mg、50 mg组和安慰剂组分别为130、129、131例；SS中，奥洛格列净20 mg、50 mg组和安慰剂组分别为130、133、132例；FASc中，奥洛格列净20 mg、奥洛格列净50 mg组、安慰剂转奥洛格列净20 mg、安慰剂转奥洛格列净50 mg组分别为123、119、59、57例。第24周时，奥洛格列净20 mg组、50 mg组经安慰剂校正的HbA1c较基线变化的组间差异的最小二乘均值（95%CI）分别为-0.94%（-1.14%~-0.74%；P<0.001）和-1.01%（-1.21%~-0.81%；P<0.001）。安慰剂组、奥洛格列净20 mg组和50 mg组HbA1c<7%的患者比例分别为20.6%（27/131）、55.4%（72/130）与56.6%（73/129）；HbA1c≤6.5%的患者比例分别为7.6%（10/131）、31.5%（41/130）与31.8%（41/129）。第52周时，HbA1c保持持续降低趋势，奥洛格列净20 mg、奥洛格列净50 mg组、安慰剂转奥洛格列净20 mg、安慰剂转奥洛格列净50 mg组HbA1c较基线变化均值分别为-1.33%±0.77%、-1.38%±0.81%、-1.30%±0.69%与-0.90%±0.83%；HbA1c<7%的患者比例分别为59.3%（73/123）、61.3%（73/119）、49.2%（29/59）与42.1%（24/57）；HbA1c≤6.5%的患者比例分别为36.6%（45/123）、42.0%（50/119）、33.9%（20/59）与26.3%（15/57）。整个研究治疗期间，奥洛格列净组安全性良好，无严重低血糖或酮症酸中毒事件。 结论： 对于饮食和运动控制不佳的中国T2DM患者，奥洛格列净单药治疗（20 mg和50 mg）能有效控制血糖，且安全性良好。.

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