目的:本研究的目的是评估皮下胰高血糖素受体/胰高血糖素样肽-1受体双重激动剂survodutide(BI456906)对HbA1c水平和体重降低的剂量反应效应。
方法:第二阶段,多中心,随机化,双盲,平行组,安慰剂对照研究,在临床研究中心进行,评估了18-75岁2型糖尿病患者的survodutide,在二甲双胍治疗背景下,HbA1c水平为53-86mmol/mol(7.0-10.0%),BMI为25-50kg/m2。通过交互式反应技术将参与者随机分配为接受survodutide(每周一次最多0.3、0.9、1.8或2.7mg[qw;剂量组(DG)1-4,分别]或每周两次1.2或1.8mg[DG5和6]),安慰剂或斯马鲁肽(最多1.0mgqw)。参与者和所有参与试验进行/分析的人都是盲目的;semaglutide臂是开放标签的。主要终点是治疗16周后HbA1c相对于基线的绝对变化。关键次要终点是治疗16周后体重相对于基线的相对变化。
结果:共有413名参与者被随机分组(DG1,n=50;DG2,n=50;DG3,n=52;DG4,n=50;DG5,n=51;DG6,n=50;司马鲁肽,n=50;安慰剂,n=60)。完整的分析集包括411名接受治疗的参与者(DG6,n=49;安慰剂,n=59)。调整后的平均值(95%CI)HbA1c从基线降低(平均±SD64.7±9.2mmol/mol[8.07±0.84%]治疗16周后:DG1(n=41),-9.92mmol/mol(-12.27,-7.56;-0.91%[-1.12,-0.69]);DG2(n=46),-15.95mmol/mol(-18.27,-13.63;-1.46%[-1.67,-1.25]);DG3(n=36),-18.72mmol/mol(-21.15,-16.29;-1.71%[-1.94,-1.49]);DG4(n=33),-17.01mmol/mol(-19.59,-14.43;-1.56%[-1.79,-1.32]);DG5(n=44),-17.84mmol/mol(-20.18,-15.51;-1.63%[-1.85,-1.42]);DG6(n=36),-18.38mmol/mol(-20.90,-15.87;-1.68%[-1.91,-1.45])。低剂量舒托肽(DG2:-15.95mmol/mol[-1.46%];n=46)和司马鲁肽(-16.07mmol/mol[-1.47%];n=45)的平均HbA1c降低相似。平均(95%CI)体重剂量依赖性下降高达-8.7%(-10.1,-7.3;DG6,n=37);survodutide≥1.8mgqw比semaglutide产生更大的体重减轻(-5.3%[-6.6,-4.1];n=45)。77.8%的survodutide治疗的参与者(主要是胃肠道)报告了不良事件(AE)。52.5%接受安慰剂,52.0%接受司马鲁肽。
结论:Survodutide降低了2型糖尿病患者治疗16周后的HbA1c水平和体重。剂量相关的胃肠道AE可以用较慢的剂量递增来减轻。
背景:ClinicalTrials.govNCT04153929和EudraCT2019-002390-60。
背景:勃林格栅英格海姆制药有限公司英格尔海姆,德国。
OBJECTIVE: The aim of this
study was to assess the dose-response effects of the subcutaneous glucagon receptor/glucagon-like peptide-1 receptor dual agonist survodutide (BI 456906) on HbA1c levels and bodyweight reduction.
METHODS: This Phase II, multicentre, randomised, double-blind, parallel-group, placebo-controlled
study, conducted in clinical research centres, assessed survodutide in participants aged 18-75 years with type 2 diabetes, an HbA1c level of 53-86 mmol/mol (7.0-10.0%) and a BMI of 25-50 kg/m2 on a background of metformin therapy. Participants were randomised via interactive response technology to receive survodutide (up to 0.3, 0.9, 1.8 or 2.7 mg once weekly [qw; dose group (DG) 1-4, respectively] or 1.2 or 1.8 mg twice weekly [DG 5 and 6, respectively]), placebo or semaglutide (up to 1.0 mg qw). Participants and all those involved in the
trial conduct/analysis were blinded; the semaglutide arm was open-label. The primary endpoint was absolute change from baseline in HbA1c after 16 weeks\' treatment. The key secondary endpoint was relative change from baseline in bodyweight after 16 weeks\' treatment.
RESULTS: A total of 413 participants were randomised (DG1, n=50; DG2, n=50; DG3, n=52; DG4, n=50; DG5, n=51; DG6, n=50; semaglutide, n=50; placebo, n=60). The full analysis set comprised 411 treated participants (DG6, n=49; placebo, n=59). Adjusted mean (95% CI) HbA1c decreased from baseline (mean ± SD 64.7±9.2 mmol/mol [8.07±0.84%] after 16 weeks\' treatment: DG1 (n=41), -9.92 mmol/mol (-12.27, -7.56; -0.91% [-1.12, -0.69]); DG2 (n=46), -15.95 mmol/mol (-18.27, -13.63; -1.46% [-1.67, -1.25]); DG3 (n=36), -18.72 mmol/mol (-21.15, -16.29; -1.71% [-1.94, -1.49]); DG4 (n=33), -17.01 mmol/mol (-19.59, -14.43; -1.56% [-1.79, -1.32]); DG5 (n=44), -17.84 mmol/mol (-20.18, -15.51; -1.63% [-1.85, -1.42]); DG6 (n=36), -18.38 mmol/mol (-20.90, -15.87; -1.68% [-1.91, -1.45]). The mean reduction in HbA1c was similar with low-dose survodutide (DG2: -15.95 mmol/mol [-1.46%]; n=46) and semaglutide (-16.07 mmol/mol [-1.47%]; n=45). Mean (95% CI) bodyweight decreased dose-dependently up to -8.7% (-10.1, -7.3; DG6, n=37); survodutide ≥1.8 mg qw produced greater bodyweight reductions than semaglutide (-5.3% [-6.6, -4.1]; n=45). Adverse events (AEs) were reported for 77.8% of survodutide-treated participants (mainly gastrointestinal), 52.5% receiving placebo and 52.0% receiving semaglutide.
CONCLUSIONS: Survodutide reduced HbA1c levels and bodyweight after 16 weeks\' treatment in participants with type 2 diabetes. Dose-related gastrointestinal AEs could be mitigated with slower dose escalations.
BACKGROUND: ClinicalTrials.gov NCT04153929 and EudraCT 2019-002390-60.
BACKGROUND: Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.