In 2002, three large comparative database studies were published examining DM prevalence and risk among several atypical agents and conventional antipsychotics. One analyzed health plan claims databases comprising 2.5 million individuals to report on the odds of developing DM during 12 months of exposure in psychotic patients (diagnosed by ICD-CM-9 codes) taking risperidone(Drug information on risperidone), olanzapine(Drug information on olanzapine), clozapine(Drug information on clozapine), and high-potency and low-potency typical antipsychotics, compared to untreated patients (Gianfrancesco et al., 2002). Only risperidone did not demonstrate significantly increased odds for DM compared to untreated patients (odds ratio [OR]=0.88), while olanzapine (OR=3.10), clozapine (OR=7.44), high-potency typicals (OR=2.13) and low-potency typicals (OR=3.46) had significantly greater risk.
The relationship of treatment with typical or atypical antipsychotics to the diagnosis of DM identified in patients diagnosed with schizophrenia (using ICD-9 codes) was examined in the national U.S. Department of Veterans Affairs databases (Sernyak et al., 2002). Of 38,632 patients studied, 22,648 received atypical antipsychotics, of which 94% received the same atypical during the four-month observation period of the study, with only 8.9% also receiving a prescription for a typical antipsychotic. Overall, patients on atypical antipsychotics were 9% more likely to have DM than those who received conventional antipsychotics (p=0.002). The odds ratio for developing DM was significantly increased for patients of all ages taking clozapine, olanzapine and quetiapine(Drug information on quetiapine), but not risperidone, relative to conventional agents. It is worth noting, however, that among those under age 40, exposure to any of the atypicals increased odds of developing DM compared to those on typicals.
A nested case-control study of 19,637 patients with schizophrenia without diabetes prior to the study period was performed using the General Practice Research Database in the United Kingdom (Koro et al., 2002). Patients taking olanzapine had significantly increased risk of developing DM compared to non-users of antipsychotics and those taking conventional antipsychotics; those on conventional antipsychotics had increased risk compared to non-users; and those on risperidone had a non-significant increased risk of developing DM compared to non-users of antipsychotics and those taking conventional antipsychotics.
Conflicting results have been reported in prospective studies related to glucose dysregulation and atypical antipsychotics, depending upon the population studied. A placebo-controlled study evaluating the effect of olanzapine (10 mg/day) and risperidone (4 mg/day) to placebo on insulin response in normal subjects after 15 days to 17 days found an approximate 25% increase in insulin response to a prolonged hyperglycemic clamp in the olanzapine and risperidone groups (Sowell et al., 2002). There was also an approximate 18% decrease in the insulin sensitivity index in both treatment groups. These changes correlated significantly (r=0.5576, p=0.019) with change in body mass index (BMI). In contrast, another study of oral glucose tolerance testing in age- and BMI-matched patients with schizophrenia receiving clozapine, olanzapine, risperidone and conventional antipsychotics and untreated healthy control subjects found that patients taking either clozapine or olanzapine had significant glucose elevations compared to patients taking conventional antipsychotics and healthy control subjects (Newcomer et al., 2002). Risperidone-treated patients in this study had elevations in fasting and postload glucose levels only in comparison with healthy control subjects and no differences in glucose levels compared to patients receiving conventional antipsychotics.
Despite some limitations on case series analysis and certain large sample retrospective studies, the published data do provide a sense of the relative effects of atypical antipsychotics on glucose regulation and other metabolic changes in psychotic patients. Given the difficulty in studying medication-naive patients with schizophrenia, the extent of glucose dysregulation and other metabolic changes attributable to schizophrenia itself may never be accurately known. However, numerous studies have suggested that pharmacological treatment may be associated with an increased risk of glucose dysregulation and other metabolic abnormalities that are not entirely explained by the diagnosis of schizophrenia itself.
Clinicians are thus confronted with two major practice issues. First, whether there are any significant differences among different antipsychotics that might be associated with these metabolic effects, particularly glucose dysregulation. Second, if the use of atypical agents does have a relationship with glucose intolerance, what potential risk factors are relevant to the establishment of monitoring protocols.