AAPs, also called "novel" antipsychotics, include Clozaril® (clozapine, Novartis), Risperdal® (risperidone, Janssen), Seroquel® (quetiapine, AstraZeneca), Geodon® (ziprasidone, Pfizer), and Abilify® (aripiprazole, Bristol Myers Squibb and Otsuka American Pharmaceutical). These prescription medications are used in the treatment of schizophrenia.

Lilly's statement (March 1, 2004) includes the following:

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including Zyprexa. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia related adverse events in patients treated with atypical antipsychotics are not available.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

The mechanism involved in the development of hyperglycemia in patients with schizophrenia are unclear. Studies indicate that the hyperglycemia is not dose dependent, is frequently reversible on cessation of treatment with AAPs, and reappears on reintroduction of these therapies.

Two reports have been published summarizing data about AAPs and hyperglycemia, using data collected in the FDA's MedWatch program. In the first report ², 384 cases of clozapine-associated diabetes were identified. Of these, new-onset diabetes was diagnosed definitively in 242 patients, and 54 patients had exacerbation of preexisting disease. There were 80 cases of metabolic acidosis or ketosis. Twenty-five patients died during hyperglycemic episodes. Forty-six patients had improved glycemic control after discontinuation or dose reduction of the drug. The authors state that a causal relationship between clozapine and diabetes was suggested by the number of reports, the temporal relation to clozapine initiation, the relatively young age of the affected patients, and the prompt reversibility on withdrawal of the drug in some patients. The severity of reported cases ranged from mild glucose intolerance to diabetic ketoacidosis or hyperosmolar coma. In the second report ³, 289 cases of olanzapine-associated diabetes were identified. Of these, new-onset diabetes was diagnosed definitively in 225 patients, and 57 patients had exacerbation of preexisting disease. A causal relationship between olanzapine and diabetes was suggested.

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