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

Abstract

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 ; 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.

The Lancet Psychiatry Commission: a blueprint for protecting physical health in people with mental illness

“…Although schizophrenia is typically associated with the greatest degree of cardiovascular risk (partly due to the side-effects of antipsychotic medications), there is now compelling evidence that obesity, metabolic syndrome, diabetes and cardiometabolic disease are similarly elevated in other mental disorders, including CMDs. [26][27][28][29][66][67][68][69][70][71][72][73] Given the higher prevalence of these mental disorders across the population, developing transdiagnostically-applicable strategies for improving cardiometabolic health outcomes in these populations (along with SMIs) could considerably reduce the premature mortality and lifelong burden of poor physical health which affects people with mental illness across the globe. Within this, the impact and prevalence of other NCDs and infectious diseases, in both high income and LMIC setting, cannot be neglected.…”

“…Part 1 identified cardiometabolic diseases as a category of physical comorbidities that are particularly pervasive and impactful on well-being, morbidity and mortality, across many mental disorders. [26][27][28][29][55][56][57][66][67][68][69][70][71][72][73]82 Along with side-effects of psychotropic medications (covered in Part 3), reasons for the increased cardiometabolic morbidity and mortality in people with mental illness can be divided into patient-related and provider/system-level factors. 25 Clear modifiable patient-related factors known to heavily influence cardiometabolic diseases are 'lifestyle risk factors' such as smoking, poor diet, and inactivity 35,[83][84][85] ; adverse health behaviours which also influence many other aspects of physical health.…”

“…25 Clear modifiable patient-related factors known to heavily influence cardiometabolic diseases are 'lifestyle risk factors' such as smoking, poor diet, and inactivity 35,[83][84][85] ; adverse health behaviours which also influence many other aspects of physical health. [26][27][28][29][66][67][68][69][70][71][72][73] However, the extent to which lifestyle-related risk factors across various mental disorders differs from the general population across is not fully established. This may result in an imprecision in current lifestyle interventions for people with mental illness, or even an over-focus on one specific behavioral modification at the expense of neglecting other important risk factors (e.g.…”

One‐year follow‐up on liraglutide treatment for prediabetes and overweight/obesity in clozapine‐ or olanzapine‐treated patients

“…Two other randomized clinical trials also evaluated a GLP-1RA, exenatide 2 mg s.c. onceweekly, in patients with schizophrenia or schizo-affective disorder treated either with clozapine (40,41) or a mixture of antipsychotics (41)(42)(43). One study showed a significant weight reduction of 5.3 kg in the treatment group vs. 1.1 kg in the placebo group (P = 0.02) (40), while the other one did not show any difference (2.2 kg in the treatment group vs. 2.2 kg in the placebo group, P = 0.98) (42,43). However, to what degree the statistically significant and clinically meaningful improvements observed during active liraglutide treatment are sustained after liraglutide is stopped is unknown.…”

“…Patients treated with antipsychotic medications are known to have a reduced life-expectancy mainly due to cardiovascular disease (16), and therefore GLP-1RAs could offer an attractive new treatment option. While liraglutide is administered as a once-daily injection, which may limit the compliance and widespread use in clinical practise, several once-weekly GLP-1RAs are already on the market, which might be more suitable for psychiatric patients instead of daily injections (40,59).…”