Treatment of clozapine‐associated obesity and diabetes with exenatide in adults with schizophrenia: A randomized controlled trial ( CODEX )

Clozapine causes obesity and type 2 diabetes (T2DM). Glucagon‐like peptide‐1 (GLP‐1) receptor agonists (e.g. exenatide) can counter clozapine‐associated GLP‐1 dysregulation in animals, and may be beneficial in people on clozapine. This randomized, controlled, open‐label, pilot trial evaluated weekly exenatide for weight loss among clozapine‐treated obese adults with schizophrenia, with or without T2DM. A total of 28 outpatients were randomized to once‐weekly extended‐release subcutaneous exenatide or usual care for 24 weeks. The primary outcome was proportion of participants with >5% weight loss. All 28 participants completed the study; 3/14 in the exenatide group and 2/14 in the usual care group had T2DM. Six people on exenatide achieved >5% weight loss vs one receiving usual care ( P  = .029). Compared with usual care, participants on exenatide had greater mean weight loss (−5.29 vs −1.12 kg; P  = .015) and body mass index reduction (−1.78 vs −0.39 kg/m 2 ; P  = .019), and reduced fasting glucose (−0.34 vs 0.39 mmol/L; P  = .036) and glycated haemoglobin levels (−0.21% vs 0.03%; P  = .004). There were no significant differences in other metabolic syndrome components. Exenatide may be a promising therapeutic agent for glycaemic control and weight loss in clozapine‐treated people with obesity, and could assist in reducing clozapine‐associated cardio‐metabolic morbidity and mortality.