Kang Yu Mi, Punov Viktoria, Lim Soo, Nauck Michael A
Division of Endocrinology, Diabetes and Hypertension and TIMI Study Group, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Diabetes, Endocrinology, Metabolism Section Medical Department I, Josef-Hospital, Ruhr University Bochum, Bochum, Germany.
Diabetes Obes Metab. 2025 Jul;27(7):3736-3746. doi: 10.1111/dom.16398. Epub 2025 Apr 11.
This study compares the therapeutic efficacy, gastrointestinal (GI) adverse event (AE) rates and the relationship between the therapeutic efficacy and GI AEs in randomized, placebo-controlled clinical trials (RCTs) of GLP-1 RAs and the dual GLP-1/GIP agonist tirzepatide.
A systematic PubMed search identified 38 phase 3 or 4 placebo-controlled RCTs of exenatide (b.i.d. and q.w.), lixisenatide, liraglutide, dulaglutide, albiglutide, semaglutide (s.c. and oral) and tirzepatide with a total of 16 660 individuals with type 2 diabetes (T2D) across 104 study arms. Changes in HbA1c, fasting plasma glucose and body weight and the proportion of GI AEs (nausea, vomiting or diarrhoea) were calculated by agent, preparation and dose. The correlation between odds ratios (ORs) for GI AEs and the magnitude of therapeutic efficacy was assessed in a linear regression analysis.
Baseline characteristics were similar across studies: mean age 57 ± 10 years, diabetes duration 8 ± 6 years, body mass index (BMI) 31.9 ± 5.8 kg/m and HbA1c 8.2% ± 0.9%. HbA1c reductions ranged from -0.63% ± 0.03% (lixisenatide, 20 μg q.d.) to -1.79% ± 0.09% (tirzepatide, 15 mg q.w.; p < 0.0001). Weight reductions ranged from -0.75 ± 0.10 kg to -9.65 ± 0.56 kg. Despite the high variability in therapeutic efficacy, ORs for GI AEs were similar across compounds/preparations.
The magnitude of efficacy for intended therapeutic actions (HbA1c and body weight reduction) varied widely between incretin mimetic glucose-lowering agents. However, larger therapeutic efficacy was not systematically associated with higher GI AE or drug discontinuation rates, indicating better tolerability of the more effective agents/preparations.
本研究在胰高血糖素样肽-1受体激动剂（GLP-1 RAs）和双重GLP-1/胃抑制多肽（GIP）激动剂替尔泊肽的随机、安慰剂对照临床试验（RCT）中，比较其治疗效果、胃肠道（GI）不良事件（AE）发生率以及治疗效果与GI不良事件之间的关系。
通过PubMed系统检索，确定了38项艾塞那肽（每日两次和每周一次）、利司那肽、利拉鲁肽、度拉鲁肽、阿必鲁肽、司美格鲁肽（皮下注射和口服）和替尔泊肽的3期或4期安慰剂对照RCT，涉及104个研究组中的总共16660例2型糖尿病（T2D）患者。按药物、制剂和剂量计算糖化血红蛋白（HbA1c）、空腹血糖和体重的变化以及GI不良事件（恶心、呕吐或腹泻）的比例。在线性回归分析中评估GI不良事件的比值比（OR）与治疗效果大小之间的相关性。
各研究的基线特征相似：平均年龄57±10岁，糖尿病病程8±6年，体重指数（BMI）31.9±5.8kg/m²，HbA1c 8.2%±0.9%。HbA1c降低幅度从-0.63%±0.03%（利司那肽，每日20μg）至-1.79%±0.09%（替尔泊肽，每周15mg；p<0.0001）。体重减轻幅度从-0.75±0.10kg至-9.65±0.5mg。尽管治疗效果存在高度变异性，但各化合物/制剂的GI不良事件OR相似。
肠促胰岛素模拟降糖药物在预期治疗作用（降低HbA1c和体重）方面的疗效大小差异很大。然而，更大的治疗效果与更高的GI不良事件或停药率并无系统性关联，表明更有效药物/制剂的耐受性更好。
