[Efficacy and safety of combining olorigliflozin with metformin in patients with type 2 diabetes mellitus inadequately controlled on metformin monotherapy].

Abstract / Summary

Objective: To evaluate the efficacy and safety of combining olorigliflozin with metformin in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin monotherapy. Methods: This study was a multicenter, randomized, double-blind, parallel, placebo-controlled phase Ⅲ clinical trial. A total of 390 T2DM patients with inadequately controlled blood glucose and receiving oral metformin were prospectively enrolled from 62 research centers nationwide between February 2021 and June 2023. Using a block randomization method stratified by baseline glycated hemoglobin A1c (HbA1c) results (≤8.5% and>8.5%), patients were randomly allocated in a 1∶1∶1 ratio via an interactive response system to the placebo group, olorigliflozin 20 mg group, and olorigliflozin 50 mg group. All patients were treated with metformin in combination for 24 consecutive weeks. After 24 weeks of treatment, patients in the placebo group were randomly reassigned in a 1∶1 ratio using the aforementioned randomization method to either the placebo-to-olorigliflozin 20 mg group or the placebo-to-olorigliflozin 50 mg group, entering a 28-week extended treatment period. Patients in the olorigliflozin 20 mg and 50 mg groups maintained their original treatment regimens. The primary efficacy endpoint was the change in HbA1c from baseline at week 24, analyzed using the full analysis set. Secondary efficacy endpoints included the change in HbA1c from baseline at week 52 and HbA1c target achievement rates at weeks 24 and 52, analyzed using the full analysis set and the extended treatment analysis set, respectively. Safety was evaluated for volunteers throughout the study period using the safety set. Quantitative efficacy indicators were analyzed using a mixed-effects model for repeated measures, while the differences in the achievement rates across treatment groups were compared employing a logistic regression model. Safety outcomes were summarized with descriptive statistics. Results: A total of 384 patients were included in the full analysis set, including 242 males and 142 females, with the age of (54.9±10.1) years. The placebo group, olorigliflozin 20 mg group, and olorigliflozin 50 mg group comprised 129, 125, and 130 patients, respectively. After 24 weeks of treatment, the least squares mean (LSM) changes (95%CI) in HbA1c from baseline in the three groups were -0.43%(-0.58% to -0.28%), -0.98%(-1.12% to -0.83%), and -1.04%(-1.18% to -0.90%), respectively. The proportions of patients with HbA1c<7.0% were 16.3%(21/129), 28.0%(35/125), and 40.8%(53/130), respectively. Logistic regression analysis showed that, compared with the placebo group, the OR values (95%CI) were 2.04(1.07-3.87) and 3.85(2.08-7.14) in the otigliflozin 20 mg group and 50 mg group, respectively. A total of 348 patients were included in the extended treatment analysis set, with 117, 121, 55, and 55 patients in the olorigliflozin 20 mg group, olorigliflozin 50 mg group, placebo-to-olorigliflozin 20 mg group, and placebo-to-olorigliflozin 50 mg group, respectively. At week 52, all 4 groups showed reductions in HbA1c from baseline (-1.0%±0.8%, -1.2%±0.7%, -1.2%± 1.0%, and -1.0%±0.8%, respectively). The proportions of patients with HbA1c<7.0% were 38.5%(45/117), 46.3%(56/121), 34.5%(19/55), and 32.7%(18/55), respectively. A total of 386 patients were included in the safety set during the 24week core treatment period, with 129, 127, and 130 patients in the placebo, olorigliflozin 20 mg, and olorigliflozin 50 mg groups, respectively. The incidence rates of treatmentemergent adverse events (TEAE) were 70.5%(91/129), 77.2%(98/127), and 75.4%(98/130), respectively. The incidence of TEAE leading to permanent discontinuation of the investigational product was 2.3%(3/129), 0.8% (1/127), and 2.3%(3/130), respectively. No serious adverse events related to the investigational product were reported. All hypoglycemic events occurred in the olorigliflozin treatment groups: the olorigliflozin 20 mg group had 2 cases of probable symptomatic hypoglycemia and 2 cases of hypoglycemic alert values, while all 5 events in the olorigliflozin 50 mg group were hypoglycemic alert values; all resolved completely. In the safety set for the 28week extended treatment period (group assignments and patient numbers identical to those in the extended treatment analysis set), the main types, incidence rates, and severity of TEAE were similar to those reported during the 24week core treatment period. Conclusion: For Chinese patients with T2DM inadequately controlled with metformin monotherapy, combining olorigliflozin can significantly improve glycemic control and has a good safety profile. 目的： 探讨二甲双胍单药治疗血糖控制不佳的2型糖尿病（T2DM）患者联用奥洛格列净的有效性和安全性。 方法： 该研究为多中心、随机、双盲、平行、安慰剂对照的Ⅲ期临床研究。前瞻性纳入了2021年2月至2023年6月全国62家研究中心的390例口服二甲双胍血糖控制不佳的T2DM患者。采用以基线糖化血红蛋白（HbA1c）结果（≤8.5%和>8.5%）为分层因素的分层区组随机方法，按1∶1∶1比例将患者分配至安慰剂组、奥洛格列净20 mg组和奥洛格列净50 mg组，均联用二甲双胍连续治疗24周。24周治疗结束后安慰剂组按1∶1比例将患者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，进入为期28周的延伸治疗期，而奥洛格列净20 mg组及50 mg组的患者维持原治疗方案。主要疗效终点为治疗24周时HbA1c较基线的变化，采用全分析集进行统计分析。次要疗效终点为治疗52周HbA1c较基线的变化、治疗24和52周时HbA1c达标率，分别采用全分析集及延伸治疗期分析集进行分析。采用安全集对患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，采用logistic回归模型比较治疗组间各指标达标率差异。安全性评价则采用描述性统计分析。 结果： 全分析集共384例患者，其中男242例，女142例，年龄（54.9±10.1）岁。安慰剂组、奥洛格列净20 mg组和奥洛格列净50 mg组分别为129、125和130例。治疗24周后以上3组HbA1c相较于基线变化的最小二乘均值（LSM）（95%CI）分别为-0.43%（-0.58%~-0.28%）、-0.98%（-1.12%~-0.83%）和-1.04%（-1.18%~-0.90%）；HbA1c<7.0%的患者比例分别为16.3%（21/129）、28.0%（35/125）和40.8%（53/130），奥洛格列净20 mg组及50 mg组与安慰剂组比较logistic回归模型结果显示，OR值（95%CI）分别为2.04（1.07~3.87）和3.85（2.08~7.14）。延伸治疗期分析集共348例患者，奥洛格列净20 mg组、奥洛格列净50 mg组、安慰剂转奥洛格列净20 mg组和安慰剂转奥洛格列净50 mg组各117、121、55和55例。第52周观察到以上4组HbA1c比基线均下降（分别为-1.0%±0.8%，-1.2%±0.7%，-1.2%±1.0%，-1.0%±0.8%），HbA1c<7.0%的患者比例分别为38.5%（45/117）、46.3%（56/121）、34.5%（19/55）和32.7%（18/55）。24周核心治疗期安全集共386例，安慰剂组、奥洛格列净20 mg组和奥洛格列净50 mg组分别为129、127和130例，3组治疗期间不良事件（TEAE）发生率依次为70.5%（91/129）、77.2%（98/127）和75.4%（98/130），导致试验用药品永久停用的TEAE发生率分别为2.3%（3/129）、0.8%（1/127）和2.3%（3/130）。未发生与试验用药品相关的严重不良事件。所有低血糖事件均发生在奥洛格列净治疗组，其中奥洛格列净20 mg组出现2例可能的症状性低血糖和2例低血糖警惕值，奥洛格列净50 mg组5例均为低血糖警惕值，转归均为痊愈。28周延伸治疗期安全集（分组与例数同延伸治疗期分析集），TEAE主要类型、发生率、严重程度等与24周核心治疗期间报告的情况相似。 结论： 对于二甲双胍单药治疗血糖控制不佳的中国T2DM患者，加用奥洛格列净治疗可显著改善血糖且安全性良好。.

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