超速效赖脯胰岛素在2型糖尿病治疗中效果与安全性的随机对照研究

Efficacy and safety of ultra rapid lispro in the treatment of type 2 diabetes mellitus:a randomized controlled clinical trial

目的评估和比较超速效赖脯胰岛素(URLi)和赖脯胰岛素(HL)治疗2型糖尿病的效果与安全性。方法国际多中心、双盲、随机对照研究。纳入2019年5月至2021年1月上海交通大学医学院附属第六人民医院等中国34家研究中心的481例使用胰岛素至少90 d且血糖控制不佳的2型糖尿病患者,通过分层区组随机分为URLi组(319例)和HL组(162例)。主要终点指标为治疗26周后糖化血红蛋白(HbA_(1c))相对基线的变化。次要终点指标为治疗26周后HbA_(1c)(<7.0%和≤6.5%)达标率、第26周混合餐耐量试验中餐后1 h血糖(1hPG)及餐后2 h血糖(2hPG)增幅和安全性指标等。计量资料组间比较采用重复测量混合效应模型或协方差分析模型,计数资料组间比较采用logistic回归模型或Fisher精确检验。结果中国数据显示,URLi组和HL组在男性比例[56.1%(179/319)比56.2%(91/162);P=0.990]、年龄[(59.5±8.4)比(59.6±9.3)岁;P=0.839]等基线特征上的差异无统计学意义。HbA_(1c)相对基线变化方面,URLi组与HL组差异无统计学意义(-0.59%±0.05%比-0.66%±0.06%;P=0.312)。URLi组和HL组在HbA_(1c)<7.0%[47.3%(138/292)比45.2%(70/155);P=0.907]和HbA_(1c)≤6.5%[27.7%(81/292)比27.7%(43/155);P=0.816]达标率上的差异无统计学意义。URLi组1hPG增幅和2hPG增幅均低于HL组[(6.20±0.21)比(6.90±0.25)mmol/L,P=0.001;(8.10±0.27)比(9.30±0.31)mmol/L,P<0.001],差异均有统计学意义。安全性方面,URLi组和HL组治疗期间发生不良事件的受试者比例差异无统计学意义[49.8%(159/319)比50.0%(81/162);P=1.000]。URLi组夜间低血糖发生比率低于HL组[(0.53±0.10)比(0.89±0.16)事件/患者年;P=0.040],差异有统计学意义。结论URLi具有良好的血糖控制作用,非劣效于HL,对餐后血糖增幅控制更佳;并且其夜间低血糖风险低于HL。

Objective To evaluate and compare the efficacy and safety of ultra-rapid lispro insulin(URLi)and humalog lispro(HL)in the treatment of type 2 diabetes mellitus.Methods This was an international multicenter,double-blind,randomized controlled study.From May 2019 to January 2021,a total of 481 patients with type 2 diabetes mellitus,who had been using insulin for at least 90 days and had poor glycemic control,were included.These patients were recruited from 34 research centers in China,including Shanghai Jiao Tong University School of Medicine Affiliated Sixth People′s Hospital.They were assigned to either the URLi group(319 patients)or the HL group(162 patients)using stratified blocked randomization.The primary endpoint was the change in hemoglobin A_(1c)(HbA_(1c))relative to baseline after 26 weeks of treatment.Secondary endpoints included the proportion of patients who achieved HbA_(1c)<7.0%and≤6.5%after 26 weeks of treatment,1-h postprandial glucose(1hPG)or 2-h postprandial glucose(2hPG)excursions during a mixed meal tolerance test at week 26,as well as safety parameters.Continuous variables were compared using mixed model repeated measures or analysis of covariance,and categorical variables were compared using logistic regression or Fisher′s exact test.Results Data based on the Chinese subgroup showed that there were no statistically significant differences between the URLi and HL groups in terms of male percentage[56.1%(179/319)vs.56.2%(91/162);P=0.990],age[(59.5±8.4)vs.(59.6±9.3)years;P=0.839]and other baseline characteristics.Regarding the change in HbA_(1c) relative to baseline,the URLi group was non-inferior to the HL group(-0.59%±0.05%vs.-0.66%±0.06%;P=0.312).There were no statistically significant differences between the URLi and HL groups in proportion of patients who achieved HbA_(1c)<7.0%[47.3%(138/292)vs.45.2%(70/155);P=0.907]and≤6.5%[27.7%(81/292)vs.27.7%(43/155);P=0.816].The excursions in 1hPG[(6.20±0.21)vs.(6.90±0.25)mmol/L;P=0.001]and 2hPG[(8.10±0.27)vs.(9.30±0.31)mmol/L;P<0.001]were lower in the URLi group than the HL group,with statistically significant differences.In terms of safety,there were no statistically significant differences in the percentage of subjects who reported treatment-emergent adverse events between the URLi and HL groups[49.8%(159/319)vs.50.0%(81/162);P=1.000].The event rate of nocturnal hypoglycemia was lower in the URLi group than the HL group,with statistically significant differences[(0.53±0.10)vs.(0.89±0.16)events per patient-year;P=0.040].Conclusions With good glycemic control,URLi showed non-inferiority for HbA_(1c) improvement versus HL and was superior to HL for postprandial glucose excursion control.Meanwhile the rate and incidence of nocturnal hypoglycemia were lower in the URLi group than the HL group.