Amin Neeta B, Frederich Robert, Tsamandouras Nikolaos, Haggag Amina Z, Schuster Tilman, Zmuda Witold, Palmer Alexandra, Vasas Szilard, Buckley Gina, Smith Timothy R, DuBrava Sarah J, Zhu Qi, Johnson Margot
Internal Medicine, Pfizer Research & Development, Cambridge, Massachusetts, USA.
Clinical Development and Operations, Pfizer Research & Development, Groton, Connecticut, USA.
Diabetes Obes Metab. 2025 Jan;27(1):215-227. doi: 10.1111/dom.16005. Epub 2024 Oct 16.
The aim was to investigate the effects of lotiglipron, a once-daily, oral small-molecule glucagon-like peptide-1 (GLP-1) receptor agonist, in participants with type 2 diabetes (T2D) or obesity.
A phase 2, randomized, double-blind, placebo-controlled, dose-ranging study investigated the efficacy and safety of lotiglipron. The study was terminated early for safety reasons after routine data and monitoring review. The planned analyses for the end points were modified prior to unblinding the study.
In total, 901 participants were treated with at least one dose of the study drug (T2D cohort: n = 512, obesity cohort: n = 389). Although the majority of participants who were randomly assigned to higher doses did not reach their target maintenance dose, statistically significant changes in HbA1c and body weight were observed. In the T2D cohort, reductions in HbA1c were observed across all lotiglipron doses at week 16 (p < 0.0001), with least squares mean decreases up to -1.44% (90% confidence interval [CI]: -1.63, -1.26) (lotiglipron 80 mg), versus placebo, -0.07% (90% CI: -0.25, 0.11). In the obesity cohort, decreases in body weight were observed across all lotiglipron doses at week 20 (p < 0.01), up to -7.47% (90% CI: -8.50, -6.43) (lotiglipron 200 mg, five-step titration), versus placebo, -1.84% (90% CI: -2.85, -0.83). Across cohorts, the most frequently reported treatment-emergent adverse events were gastrointestinal related (most mild to moderate severity), with nausea being the most common (ranging from 4% [placebo] to 28.8% [80 mg] in the T2D cohort and 12.5% [placebo] to 60.6% [200 mg, four-step titration] in the obesity cohort). Transaminase elevations were observed in a subset of participants (6.6% and 6.0% of participants on lotiglipron in the T2D and obesity cohorts, respectively, compared with 1.6% on placebo in the obesity cohort).
The efficacy (HbA1c and/or body weight) of a range of lotiglipron doses was demonstrated in T2D and obesity cohorts. The safety profile was largely consistent with what has been previously known about the mechanism of action. Our results are unique in reporting elevations in liver transaminases in a subset of participants treated with lotiglipron, with attempts to identify the at-risk population unsuccessful and therefore clinical development of lotiglipron terminated.
GOV: NCT05579977.
旨在研究洛替普隆（一种每日一次的口服小分子胰高血糖素样肽-1（GLP-1）受体激动剂）对2型糖尿病（T2D）患者或肥胖患者的影响。
一项2期、随机、双盲、安慰剂对照、剂量范围研究对洛替普隆的疗效和安全性进行了调查。在常规数据和监测审查后，该研究因安全原因提前终止。在揭盲研究之前，对终点的计划分析进行了修改。
共有901名参与者接受了至少一剂研究药物治疗（T2D队列：n = 512，肥胖队列：n = 389）。尽管大多数随机分配到较高剂量的参与者未达到其目标维持剂量，但观察到糖化血红蛋白（HbA1c）和体重有统计学意义的变化。在T2D队列中，第16周时所有洛替普隆剂量组的HbA1c均有所降低（p < 0.0001），最小二乘均值下降高达-1.44%（90%置信区间[CI]：-1.63，-1.26）（洛替普隆80 mg），而安慰剂组为-0.07%（90% CI：-0.25，0.11）。在肥胖队列中，第20周时所有洛替普隆剂量组的体重均有所下降（p < 0.01），下降幅度高达-7.47%（90% CI：-8.50，-6.43）（洛替普隆200 mg，五步滴定法），而安慰剂组为-1.84%（90% CI：-2.85，-0.83）。在所有队列中，最常报告的治疗中出现的不良事件与胃肠道有关（大多为轻度至中度严重程度），恶心最为常见（在T2D队列中从4%[安慰剂]到28.8%[80 mg]，在肥胖队列中从12.5%[安慰剂]到60.6%[200 mg，四步滴定法]）。在一部分参与者中观察到转氨酶升高（T2D队列和肥胖队列中接受洛替普隆治疗的参与者分别为6.6%和6.0%，而肥胖队列中接受安慰剂治疗的参与者为1.6%）。
在T2D和肥胖队列中证明了一系列洛替普隆剂量的疗效（HbA1c和/或体重）。安全性概况在很大程度上与先前已知的作用机制一致。我们的结果独特之处在于报告了一部分接受洛替普隆治疗的参与者出现肝转氨酶升高，试图识别高危人群未成功，因此洛替普隆的临床开发终止。
美国国立医学图书馆（NLM）：NCT05579977。
