AbstractAimsTo 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.Materials and MethodsWe 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).ResultsA 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.ConclusionWeight loss with cotadutide is primarily driven by reduced EI, with relatively small compensatory changes in EE.