RCT of Exenatide for Clozapine-associated Obesity

Background: Clozapine is the most effective antipsychotic for treatment refractory schizophrenia but causes significant metabolic disturbances including obesity and type 2 diabetes. The metabolic adverse reactions may be mediated in part by clozapine-induced dysregulation of glucagon-like-peptide-1 (GLP-1). GLP-1 is an intestinal epithelial-derived peptide, released with ingestion of food, that triggers satiety, reduces glucagon production, promotes insulin production, and slows gut motility. Clozapine has been shown to interfere with GLP-1 function in animal models, leading to metabolic dysregulation including obesity and preference for high-calorie meals. Administration to animals of exogenous GLP-1 agonists such as exenatide have been shown to counter this effect of clozapine. Exenatide subcutaneous weekly injections may assist obese people on clozapine to lose weight.

Methods: This randomized, controlled, open-label, pilot trial aims to evaluate the effect of exenatide on weight loss among clozapine-treated obese adults who have schizophrenia, with or without poorly controlled diabetes. Thirty outpatients will be randomized to once-weekly, extended-release subcutaneous exenatide or treatment as usual for 24 weeks. This trial examines the safety, tolerability, and acceptability of exenatide among obese people with schizophrenia on clozapine, with an evaluation of change in weight, glycaemic control, psychosis severity, and metabolic parameters.

Results: Of the participants who have completed 12 weeks of the 24-week intervention, only 1 of the treatment as usual participants lost any weight (mean weight change +0.28kg, SD 3.40) while all exenatide participants had lost weight (mean weight change −4.55kg, SD 3.49). The exenatide participants have reported reduced appetite and earlier satiety. The most frequently reported adverse event among the exenatide group is transient nausea in the 3 hours postinjection. No other significant adverse events have been reported.

Conclusion: This is the first trial investigating GLP-1 agonists for glycemic control and weight loss in clozapine-treated people with either diabetes or obesity. Early data suggest that the intervention is tolerable and acceptable, with suggestion of weight loss in the intervention group. If found to be effective, GLP-1 agonists could assist in reducing the cardiometabolic-associated morbidity and mortality secondary to clozapine.