Abstract：
To evaluate the tolerability, safety and pharmacodynamics of different dose-escalation schemes of the oral small-molecule glucagon-like peptide-1 receptor (GLP-1R) agonist danuglipron.
This Phase 2a, double-blind, placebo-controlled, parallel-group study randomly assigned adults with type 2 diabetes (T2D) treated with metformin to placebo or danuglipron (low [5-mg] or high [10-mg] starting dose, with 1- or 2-week dose-escalation steps, to target doses of 80, 120 or 200 mg twice daily [BID]) and adults with obesity without diabetes to placebo or danuglipron 200 mg BID.
Participants with T2D (n = 123, mean glycated haemoglobin [HbA1c] 8.19%) or obesity without diabetes (n = 28, mean body mass index 37.3 kg/m2 ) were randomly assigned and treated. Discontinuation from study medication occurred in 27.3% to 72.7% of participants across danuglipron groups versus 16.7% to 18.8% for placebo, most often due to adverse events. Nausea (20.0%-47.6% of participants across danuglipron groups vs. 12.5% for placebo) and vomiting (18.2%-40.9% danuglipron vs. 12.5% placebo, respectively) were most commonly reported in participants with T2D. Gastrointestinal adverse events were generally related to danuglipron target dose and were not substantially affected by starting dose. In participants with T2D, least squares mean changes from baseline in HbA1c (-1.04% to -1.57% across danuglipron groups vs. -0.32% for placebo), fasting plasma glucose (-23.34 mg/dL to -53.94 mg/dL danuglipron vs. -13.09 mg/dL placebo) and body weight (-1.93 to -5.38 kg danuglipron vs. -0.42 kg placebo) at Week 12 were generally statistically significant for danuglipron compared with placebo (P < 0.05).
Danuglipron resulted in statistically significant reductions in HbA1c, FPG and body weight over 12 weeks, in the setting of higher discontinuation rates and incidence of gastrointestinal adverse events with higher target doses.
gov identifier: NCT04617275.
This Phase 2a, double-blind, placebo-controlled, parallel-group study randomly assigned adults with type 2 diabetes (T2D) treated with metformin to placebo or danuglipron (low [5-mg] or high [10-mg] starting dose, with 1- or 2-week dose-escalation steps, to target doses of 80, 120 or 200 mg twice daily [BID]) and adults with obesity without diabetes to placebo or danuglipron 200 mg BID.
Participants with T2D (n = 123, mean glycated haemoglobin [HbA1c] 8.19%) or obesity without diabetes (n = 28, mean body mass index 37.3 kg/m2 ) were randomly assigned and treated. Discontinuation from study medication occurred in 27.3% to 72.7% of participants across danuglipron groups versus 16.7% to 18.8% for placebo, most often due to adverse events. Nausea (20.0%-47.6% of participants across danuglipron groups vs. 12.5% for placebo) and vomiting (18.2%-40.9% danuglipron vs. 12.5% placebo, respectively) were most commonly reported in participants with T2D. Gastrointestinal adverse events were generally related to danuglipron target dose and were not substantially affected by starting dose. In participants with T2D, least squares mean changes from baseline in HbA1c (-1.04% to -1.57% across danuglipron groups vs. -0.32% for placebo), fasting plasma glucose (-23.34 mg/dL to -53.94 mg/dL danuglipron vs. -13.09 mg/dL placebo) and body weight (-1.93 to -5.38 kg danuglipron vs. -0.42 kg placebo) at Week 12 were generally statistically significant for danuglipron compared with placebo (P < 0.05).
Danuglipron resulted in statistically significant reductions in HbA1c, FPG and body weight over 12 weeks, in the setting of higher discontinuation rates and incidence of gastrointestinal adverse events with higher target doses.
gov identifier: NCT04617275.
摘要：
目的：为了评估耐受性，口服小分子胰高血糖素样肽-1受体（GLP-1R）激动剂danuglipron的不同剂量递增方案的安全性和药效学。
方法：这个阶段2a，双盲,安慰剂对照,平行组研究将接受二甲双胍治疗的2型糖尿病（T2D）成人随机分配给安慰剂或danuglipron（低[5-mg]或高[10-mg]起始剂量，1或2周剂量递增步骤，目标剂量为每天两次80、120或200mg[BID]），而肥胖无糖尿病的成年人则服用安慰剂或danuglipron200mgBID。
结果：患有T2D（n=123，平均糖化血红蛋白[HbA1c]8.19%）或无糖尿病肥胖（n=28，平均体重指数37.3kg/m2）的参与者被随机分配和治疗。在danuglipron组中，有27.3％至72.7％的参与者停止了研究药物治疗，而安慰剂组的参与者为16.7％至18.8％。通常是由于不良事件。恶心（danuglipron组参与者的20.0％-47.6％与安慰剂为12.5％）和呕吐（18.2％-40.9％danuglipronvs.12.5%安慰剂，分别）最常见于T2D参与者。胃肠道不良事件通常与danuglipron目标剂量有关，并且基本不受起始剂量的影响。在T2D的参与者中，HbA1c相对于基线的最小二乘均值变化（danuglipron组的-1.04%至-1.57%与-安慰剂为0.32%)，空腹血糖（-23.34mg/dL至-53.94mg/dLdanuglipronvs.-13.09mg/dL安慰剂）和体重（-1.93至-5.38kgdanuglipronvs.-0.42kg安慰剂）在第12周与安慰剂相比，danuglipron通常具有统计学意义（P<0.05）。
结论：Danuglipron导致HbA1c有统计学意义的降低，FPG和体重超过12周，在目标剂量较高的情况下，停药率和胃肠道不良事件发生率较高。
结果：gov标识符：NCT04617275。
方法：这个阶段2a，双盲,安慰剂对照,平行组研究将接受二甲双胍治疗的2型糖尿病（T2D）成人随机分配给安慰剂或danuglipron（低[5-mg]或高[10-mg]起始剂量，1或2周剂量递增步骤，目标剂量为每天两次80、120或200mg[BID]），而肥胖无糖尿病的成年人则服用安慰剂或danuglipron200mgBID。
结果：患有T2D（n=123，平均糖化血红蛋白[HbA1c]8.19%）或无糖尿病肥胖（n=28，平均体重指数37.3kg/m2）的参与者被随机分配和治疗。在danuglipron组中，有27.3％至72.7％的参与者停止了研究药物治疗，而安慰剂组的参与者为16.7％至18.8％。通常是由于不良事件。恶心（danuglipron组参与者的20.0％-47.6％与安慰剂为12.5％）和呕吐（18.2％-40.9％danuglipronvs.12.5%安慰剂，分别）最常见于T2D参与者。胃肠道不良事件通常与danuglipron目标剂量有关，并且基本不受起始剂量的影响。在T2D的参与者中，HbA1c相对于基线的最小二乘均值变化（danuglipron组的-1.04%至-1.57%与-安慰剂为0.32%)，空腹血糖（-23.34mg/dL至-53.94mg/dLdanuglipronvs.-13.09mg/dL安慰剂）和体重（-1.93至-5.38kgdanuglipronvs.-0.42kg安慰剂）在第12周与安慰剂相比，danuglipron通常具有统计学意义（P<0.05）。
结论：Danuglipron导致HbA1c有统计学意义的降低，FPG和体重超过12周，在目标剂量较高的情况下，停药率和胃肠道不良事件发生率较高。
结果：gov标识符：NCT04617275。
