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 (HbA 1c) 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 HbA 1c from baseline at week 24, analyzed using the full analysis set. Secondary efficacy endpoints included the change in HbA 1c from baseline at week 52 and HbA 1c 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 HbA 1c 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 HbA 1c<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 HbA 1c 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 HbA 1c<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.
(8.0+极速模式)