Development of Diabetes in Patients Taking Risperidone & Olanzap
Development of Diabetes in Patients Taking Risperidone & Olanzap
Objectives: A growing body of literature suggests that certain atypical antipsychotics, especially olanzapine and clozapine, may induce glucoregulatory dysfunction. We assessed the differences in risk of developing diabetes mellitus during treatment with olanzapine and risperidone by using patients treated with haloperidol and fluphenazine as control subjects in whom we would not expect to see an increased risk.
Methods: We conducted a retrospective analysis of the Veteran's Integrated Service Network 10 Veterans Affairs (VA) database. Data for patients receiving olanzapine, risperidone, haloperidol, or fluphenazine from January 1, 1997-December 31, 2000, were included. Diabetes was defined as any health system encounter associated with the International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis for diabetes (250.xx) or prescription for a hypoglycemic agent. Data of patients with markers for diabetes within 1 year before their index date, female patients, racial groups other than Caucasian or African-American, and patients receiving clozapine were not analyzed. We performed a Cox regression, with antipsychotic therapy as a time-dependent covariate. Other covariates considered for inclusion in the final model were number of days supply of antipsychotic drug, age, race, psychiatric diagnoses, substance abuse, lithium, valproic acid, and other typical or atypical antipsychotic agents.
Results: Data for 5837 patients were analyzed. Overall rate of developing diabetes in the study population was 6.3% (368 of 5837 patients). Olanzapine therapy was associated with a significantly higher risk of development of diabetes compared with risperidone (hazard ratio [HR] 1.37, 95% confidence interval 1.06-1.76, p=0.016) while controlling for race, age, diagnosis, substance abuse, lithium, valproic acid, and other atypical antipsychotic agents. No differences in the rate of developing diabetes were detected between fluphenazine and risperidone (HR 1.11, p=0.69), or haloperidol and risperidone (HR 0.89, p=0.41).
Conclusions: Olanzapine was associated with a 37% (HR 1.37) increased risk of development of diabetes compared with risperidone in a VA population, even after adjusting for other factors associated with the development of diabetes and temporal exposure to study drug. Because of limitations associated with database research, prospective studies should be conducted to corroborate these findings.
Hyperglycemia and diabetes mellitus are major public health problems. Type 2 diabetes mellitus is 2 times more prevalent in individuals with schizophrenia compared with the general population and is associated with both acute and chronic complications related to macrovascular and microvascular disease. Evidence is mounting to indicate that this increased risk of diabetes is amplified by treatment with certain atypical antipsychotics. Although to our knowledge no long-term prospective longitudinal study has been conducted, data suggest that clozapine, olanzapine, and quetiapine are more likely to be associated with diabetes than is risperidone. Ziprasidone became commercially available in 2001. In a recent head-to-head study of ziprasidone and olanzapine, olanzapine significantly increased fasting insulin and insulin resistance from baseline compared with nonsignificant increases for ziprasidone. Currently, no cases of diabetes requiring emergency treatment have been reported with ziprasidone. However, a case of hyperglycemia was reported. To our knowledge, no reports have been published on aripiprazole, the newest addition to the antipsychotic drug class, and an association with diabetes. Data suggesting an association between older typical antipsychotics and diabetes are limited, although the low-potency agents (e.g., chlorpromazine) may have a greater risk compared with that of high-potency agents (e.g., haloperidol).
Potential mechanisms for antipsychotic-induced diabetes are numerous. Weight gain is an important risk factor for the development of type 2 diabetes mellitus. Ninety percent of patients with diabetes have type 2 diabetes, and up to 90% of type 2 diabetics are overweight. Antipsychotic drugs induce weight gain to varying degrees. An increase in weight may explain some or all of the treatment-related changes in glucose metabolism; however, case reports and controlled studies suggest that this may also be a direct adverse effect of dibenzo-diazepine-derived compounds, clozapine and olanzapine, on glucose tolerance independent of the contribution of weight gain. Antipsychotics may cause insulin resistance. When pancreatic
cells cannot produce adequate insulin to compensate for insulin resistance, hyperglycemia results. Blockade of serotonin (5-HT) receptors 5-HT 1A on pancreatic
cells also has been postulated as a mechanism for hyperglycemia, and the 5-HT2 receptors may be involved in glucose metabolism as well. However, the precise role that these receptors may play in regulating glucose metabolism remains unknown.
Several large comparative database studies that evaluated the prevalence and risk of diabetes among various atypical and typical antipsychotic agents have been published. However, these studies were limited by a short study duration and analyses that failed to consider therapeutic switching among antipsychotic agents. We assessed the differences in risk of developing diabetes between patients who were prescribed risperidone and those who received olanzapine; patients treated with haloperidol and fluphenazine were the control subjects.
Objectives: A growing body of literature suggests that certain atypical antipsychotics, especially olanzapine and clozapine, may induce glucoregulatory dysfunction. We assessed the differences in risk of developing diabetes mellitus during treatment with olanzapine and risperidone by using patients treated with haloperidol and fluphenazine as control subjects in whom we would not expect to see an increased risk.
Methods: We conducted a retrospective analysis of the Veteran's Integrated Service Network 10 Veterans Affairs (VA) database. Data for patients receiving olanzapine, risperidone, haloperidol, or fluphenazine from January 1, 1997-December 31, 2000, were included. Diabetes was defined as any health system encounter associated with the International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis for diabetes (250.xx) or prescription for a hypoglycemic agent. Data of patients with markers for diabetes within 1 year before their index date, female patients, racial groups other than Caucasian or African-American, and patients receiving clozapine were not analyzed. We performed a Cox regression, with antipsychotic therapy as a time-dependent covariate. Other covariates considered for inclusion in the final model were number of days supply of antipsychotic drug, age, race, psychiatric diagnoses, substance abuse, lithium, valproic acid, and other typical or atypical antipsychotic agents.
Results: Data for 5837 patients were analyzed. Overall rate of developing diabetes in the study population was 6.3% (368 of 5837 patients). Olanzapine therapy was associated with a significantly higher risk of development of diabetes compared with risperidone (hazard ratio [HR] 1.37, 95% confidence interval 1.06-1.76, p=0.016) while controlling for race, age, diagnosis, substance abuse, lithium, valproic acid, and other atypical antipsychotic agents. No differences in the rate of developing diabetes were detected between fluphenazine and risperidone (HR 1.11, p=0.69), or haloperidol and risperidone (HR 0.89, p=0.41).
Conclusions: Olanzapine was associated with a 37% (HR 1.37) increased risk of development of diabetes compared with risperidone in a VA population, even after adjusting for other factors associated with the development of diabetes and temporal exposure to study drug. Because of limitations associated with database research, prospective studies should be conducted to corroborate these findings.
Hyperglycemia and diabetes mellitus are major public health problems. Type 2 diabetes mellitus is 2 times more prevalent in individuals with schizophrenia compared with the general population and is associated with both acute and chronic complications related to macrovascular and microvascular disease. Evidence is mounting to indicate that this increased risk of diabetes is amplified by treatment with certain atypical antipsychotics. Although to our knowledge no long-term prospective longitudinal study has been conducted, data suggest that clozapine, olanzapine, and quetiapine are more likely to be associated with diabetes than is risperidone. Ziprasidone became commercially available in 2001. In a recent head-to-head study of ziprasidone and olanzapine, olanzapine significantly increased fasting insulin and insulin resistance from baseline compared with nonsignificant increases for ziprasidone. Currently, no cases of diabetes requiring emergency treatment have been reported with ziprasidone. However, a case of hyperglycemia was reported. To our knowledge, no reports have been published on aripiprazole, the newest addition to the antipsychotic drug class, and an association with diabetes. Data suggesting an association between older typical antipsychotics and diabetes are limited, although the low-potency agents (e.g., chlorpromazine) may have a greater risk compared with that of high-potency agents (e.g., haloperidol).
Potential mechanisms for antipsychotic-induced diabetes are numerous. Weight gain is an important risk factor for the development of type 2 diabetes mellitus. Ninety percent of patients with diabetes have type 2 diabetes, and up to 90% of type 2 diabetics are overweight. Antipsychotic drugs induce weight gain to varying degrees. An increase in weight may explain some or all of the treatment-related changes in glucose metabolism; however, case reports and controlled studies suggest that this may also be a direct adverse effect of dibenzo-diazepine-derived compounds, clozapine and olanzapine, on glucose tolerance independent of the contribution of weight gain. Antipsychotics may cause insulin resistance. When pancreatic
cells cannot produce adequate insulin to compensate for insulin resistance, hyperglycemia results. Blockade of serotonin (5-HT) receptors 5-HT 1A on pancreatic
cells also has been postulated as a mechanism for hyperglycemia, and the 5-HT2 receptors may be involved in glucose metabolism as well. However, the precise role that these receptors may play in regulating glucose metabolism remains unknown.
Several large comparative database studies that evaluated the prevalence and risk of diabetes among various atypical and typical antipsychotic agents have been published. However, these studies were limited by a short study duration and analyses that failed to consider therapeutic switching among antipsychotic agents. We assessed the differences in risk of developing diabetes between patients who were prescribed risperidone and those who received olanzapine; patients treated with haloperidol and fluphenazine were the control subjects.