Insulin secretion in patients receiving clozapine, olanzapine, quetiapine and risperidone

BackgroundSecond-generation antipsychotics (SGAs) increase the risk of type 2 diabetes. The mechanism is thought to center on drug-induced weight gain, which starts the dysmetabolic cascade of insulin resistance, increased insulin production and pancreatic beta-cell failure. An independent effect of SGAs on insulin secretion has been suggested in animal models, but has not been demonstrated in clinical samples.ObjectiveTo determine the post-challenge insulin secretion in patients treated with SGAs.MethodWe identified 520 non-diabetic individuals treated with clozapine (N = 73), olanzapine (N = 190), quetiapine (N = 91) or risperidone (N = 166) in a consecutive, single-site cohort of 783 adult psychiatric inpatients who underwent a comprehensive metabolic assessment. Insulin secretion was measured as the area under the curve (AUCinsulin) generated by levels recorded at baseline, 30, 60 and 120 min after the intake of 75 g of glucose. The independent predictors of insulin secretion were determined with regression analysis in the entire sample and separately in patients with normal glucose tolerance (NGT) and prediabetes.ResultsThe post-challenge AUCinsulin was independently predicted by AUCglucose, waist circumference, triglyceride levels and younger age (p < 0.0001); non-smoking status (p = 0.0012); and treatment with clozapine (p = 0.021). The model explained 33.5% of the variance in insulin secretion (p < 0.0001). The clozapine effect was present in the NGT group, but not in prediabetics.ConclusionsClozapine, but not olanzapine, quetiapine and risperidone, is an independent predictor of post-challenge insulin secretion in non-diabetics, particularly in those with normal glucose tolerance. The findings suggest that the diabetogenic risk of clozapine may persist even after weight reduction.