Treatment of clozapine associated obesity and diabetes with exenatide in people with schizophrenia

Funding

Hospital,Princess Alexandra Hospital Research Support Scheme

Scientific enquiries

A/Prof Dan Siskind

Brief Summary

Schizophrenia has a lifetime risk of 7.2 per 1000 persons with 25-50% of people with schizophrenia failing to respond to typical and atypical antipsychotics. For these people clozapine is the gold standard treatment, however, clozapine greatly increases the risk of weight gain and type 2 diabetes (T2DM) which contribute to cardiovascular disease and premature mortality. Current interventions against antipsychotic-associated metabolic dysregulation are limited and insufficient. The mechanism of a .... Schizophrenia has a lifetime risk of 7.2 per 1000 persons with 25-50% of people with schizophrenia failing to respond to typical and atypical antipsychotics. For these people clozapine is the gold standard treatment, however, clozapine greatly increases the risk of weight gain and type 2 diabetes (T2DM) which contribute to cardiovascular disease and premature mortality. Current interventions against antipsychotic-associated metabolic dysregulation are limited and insufficient. The mechanism of action for metabolic abnormalities associated with clz is not completely understood; however, recent pre-clinical models have shown that clozapine causes acute deficits in glucose metabolism. This occurred via suppression of glucagon-like-peptide-1 (GLP-1) levels and these defects could be overcome by treatment with a GLP-1 agonist. Exenatide, a GLP-1 agonist, is available in a once weekly injectable formulation which is practical for this population with poor adherence. Therefore, in consideration of the promising preclinical data, the use of exenatide, which is already known to improve glycaemic control and reduce body weight in subjects with and without T2DM, may represent an effective therapeutic intervention for clozapine-associated obesity and T2DM. Therefore, the present study is a 24-week investigator-initiated, parallel group, randomised, open-label pilot study designed to evaluate the acceptability of exenatide weekly and determine the preliminary clinical efficacy and tolerability of exenatide for weight loss and glycaemic control in clozapine-associated obesity and T2DM. This study also has exploratory objectives to examine the feasibility of recruitment, retention, assessment methods and implementation of this intervention for subsequent larger scale, multicenter studies.
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Key Inclusion Criteria

Provision of informed consent prior to any study specific procedures Clinical diagnosis of Schizophrenia or Schizoaffective Disorder On oral clozapine for at least 18 weeks Stable body weight (defined as less than 5kg change in weight over the past 3 months before inclusion) For Arm A a) Diagnosis of Type II Diabetes Mellitus b) Current and stable therapeutic doses of oral glucose lowering agents for 3 months prior to recruitment c) BMI greater than or equal to 30kg/m2 and less than 45kg/m2 For .... Provision of informed consent prior to any study specific procedures Clinical diagnosis of Schizophrenia or Schizoaffective Disorder On oral clozapine for at least 18 weeks Stable body weight (defined as less than 5kg change in weight over the past 3 months before inclusion) For Arm A a) Diagnosis of Type II Diabetes Mellitus b) Current and stable therapeutic doses of oral glucose lowering agents for 3 months prior to recruitment c) BMI greater than or equal to 30kg/m2 and less than 45kg/m2 For Arm B a) BMI greater than or equal to 30kg/m2 and less than 45kg/m2
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Key Exclusion Criteria

Pregnancy or lactation Severe gastrointestinal disease Severe renal impairment Allergy/hypersensitivity to investigational product Obesity due to other endocrinologic disorder (e.g Cushing Syndrome) Treatment with corticosteroids or other hormone therapy (except oestrogens or thyroxine) for greater than 10 days Current use of any weight-lowering therapy or previous surgical treatment of obesity Uncontrolled hypertension History of thyroid adenoma or carcinoma Untreated or uncontrolled hypo/hyper .... Pregnancy or lactation Severe gastrointestinal disease Severe renal impairment Allergy/hypersensitivity to investigational product Obesity due to other endocrinologic disorder (e.g Cushing Syndrome) Treatment with corticosteroids or other hormone therapy (except oestrogens or thyroxine) for greater than 10 days Current use of any weight-lowering therapy or previous surgical treatment of obesity Uncontrolled hypertension History of thyroid adenoma or carcinoma Untreated or uncontrolled hypo/hyperthyroidism Acute or chronic pancreatitis or high risk of pancreatitis Concurrent use of insulin For Arm 2: Diagnosis of Diabetes Mellitus Type I or Type II
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