Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK.
Diabetes Obes Metab. 2024 Jul;26(7):2634-2644. doi: 10.1111/dom.15579. Epub 2024 Apr 1.
To establish which components of energy balance mediate the clinically significant weight loss demonstrated with use of cotadutide, a glucagon-like peptide-1 (GLP-1)/glucagon receptor dual agonist, in early-phase studies.
We conducted a phase 2a, single-centre, randomized, placebo-controlled trial in overweight and obese adults with type 2 diabetes. Following a 16-day single-blind placebo run-in, participants were randomized 2:1 to double-blind 42-day subcutaneous treatment with cotadutide (100-300 μg daily) or placebo. The primary outcome was percentage weight change. Secondary outcomes included change in energy intake (EI) and energy expenditure (EE).
A total of 12 participants (63%) in the cotadutide group and seven (78%) in the placebo group completed the study. The mean (90% confidence interval [CI]) weight change was -4.0% (-4.9%, -3.1%) and -1.4% (-2.7%, -0.1%) for the cotadutide and placebo groups, respectively (p = 0.011). EI was lower with cotadutide versus placebo (-41.3% [-66.7, -15.9]; p = 0.011). Difference in EE (per kJ/kg lean body mass) for cotadutide versus placebo was 1.0% (90% CI -8.4, 10.4; p = 0.784), assessed by doubly labelled water, and -6.5% (90% CI -9.3, -3.7; p < 0.001), assessed by indirect calorimetry.
Weight loss with cotadutide is primarily driven by reduced EI, with relatively small compensatory changes in EE.
确定在早期研究中使用胰高血糖素样肽-1 (GLP-1)/胰高血糖素受体双重激动剂 cotadutide 可显著减轻体重的原因。
我们进行了一项 2a 期、单中心、随机、安慰剂对照试验，纳入超重和肥胖的 2 型糖尿病成人患者。在为期 16 天的单盲安慰剂导入期后，参与者按照 2:1 的比例随机分配至双盲 42 天的皮下 cotadutide（每天 100-300μg）或安慰剂治疗。主要结局为体重变化的百分比。次要结局包括能量摄入 (EI) 和能量消耗 (EE) 的变化。
cotadutide 组共有 12 名（63%）参与者和安慰剂组 7 名（78%）参与者完成了研究。cotadutide 组和安慰剂组的平均（90%置信区间 [CI]）体重变化分别为-4.0%（-4.9%，-3.1%）和-1.4%（-2.7%，-0.1%）（p=0.011）。与安慰剂相比，cotadutide 组的 EI 更低（-41.3%[-66.7, -15.9]；p=0.011）。cotadutide 与安慰剂相比，通过双标记水评估的 EE（每千克瘦体重每千焦）差值为 1.0%（90% CI -8.4, 10.4；p=0.784），通过间接测热法评估的 EE 差值为-6.5%（90% CI -9.3, -3.7；p<0.001）。
cotadutide 引起的体重减轻主要是由于 EI 减少，EE 代偿性变化较小。
