Rate of New-Onset Diabetes Among Patients Treated With Atypical or Conventional Antipsychotic Medications for Schizophrenia

Daniel A. Ollendorf, MPH; Amie T. Joyce, MPH; Malcolm Rucker, MS

In This Article

Abstract and Introduction

Context: Understanding the association between use of antipsychotics and onset of diabetes.

Objective: To compare the rates of new-onset diabetes mellitus (DM) between patients treated for schizophrenia with atypical or conventional antipsychotics.

Design: Retrospective analysis of medical and pharmacy claims data.

Setting: 61 US health plans.

Patients: Patients with schizophrenia who were treated with atypical or conventional antipsychotics between September 1996 and June 2001 and were enrolled for 12 or more months before and 3 or more months after therapy initiation.

Main Outcome Measures: New-onset DM was defined based on 2 or more claims with a diabetes diagnosis or initiation of antidiabetic therapy during follow-up. Rates of DM were compared between patients receiving atypical and conventional antipsychotics, and among 4 subgroups of patients receiving atypical antipsychotics (olanzapine, clozapine, risperidone, quetiapine). Statistical analyses employed logistic regression and Cox proportional hazards models.

Results: Patients treated with atypical antipsychotics (N = 1826) were younger, had a lower rate of diagnosed hypertension, and longer duration of therapy than those receiving conventional antipsychotics (N = 617). The crude incidence of DM did not differ (2.46% vs 2.76% for atypical antipsychotics and conventional antipsychotics, P = .525). In Cox proportional hazards models, patients treated with atypical antipsychotics had a statistically significant, moderately increased risk of DM relative to conventional antipsychotics (hazard ratio [HR] = 1.17, 95% confidence interval [CI] = 1.06, 1.30); no significant differences in risk were observed when atypical antipsychotic cohorts were compared. In logistic regression models, no significant differences in DM risk were observed.

Conclusions: Patients with schizophrenia treated with atypical antipsychotics had a moderately increased risk of DM relative to those treated with conventional antipsychotics, as measured by Cox proportional hazards models; such risk was not significantly different among patients treated with individual atypical medications.

Schizophrenia is a disabling condition characterized by profound disruption in cognition and emotion, affecting language, thought, perception, affect, and sense of self. The array of symptoms, while substantially varied among patients, frequently includes psychotic manifestations such as hallucinations and delusions.[1] Prior research has documented that in addition to psychiatric difficulties, patients with schizophrenia are also at greater risk than the general population of concurrent medical conditions such as vision and dental problems, high blood pressure, diabetes, and sexually transmitted diseases.[2,3]

Beginning in 1990, a new generation of antipsychotic medication was introduced. These "atypical" antipsychotic medications, in comparison with first-generation (or "conventional") antipsychotics, have been associated with improved efficacy in treating both positive and negative symptoms of schizophrenia, and have exhibited a superior safety profile in regard to adverse events such as extrapyramidal symptoms.[4,5] In the past decade, atypical antipsychotics such as risperidone, olanzapine, and quetiapine have become first-line treatment options for patients with schizophrenia.

Although atypical antipsychotics have greatly improved the treatment of schizophrenia, weight gain, increased serum prolactin levels, and QTc prolongation have been reported during treatment with some atypical antipsychotics.[6,7,8,9] More recently, the results of several case reviews and database studies have examined a potential association between atypical antipsychotic use and increased insulin resistance or risk of developing overt DM.[9,10,11,12,13,14,15,16,17,18,19,20,21,22,23] These studies have varied greatly, however, in their study populations, methods, results, magnitude of identified risk, and implication of specific atypical medications over others. For example, using logistic regression techniques, Gianfrancesco and colleagues[20] found DM risk for risperidone users to be similar to that among untreated subjects, while excess risk was observed among olanzapine, clozapine, and selected conventional drugs. In contrast, findings from survival-based research on 2 databases by Sowell and colleagues[19] indicated that risperidone and olanzapine had similar effects on DM risk; in fact, a significantly greater risk was attributed to risperidone in one of these analyses.

While all of these methodologic factors may contribute to discrepant findings, choice of methodology is an actionable variable that may have a significant effect on study conclusions. Although fixed follow-up techniques are widely accepted, the introduction of accrued person-time (ie, allowing all candidate populations to contribute observation times of varying duration) provides an alternative that may better reflect the nature of usual psychiatric practice for patients with schizophrenia in the United States. Specifically, antipsychotic therapy is often sporadic, and patients may be lost to follow-up for a variety of reasons (eg, changes in healthcare coverage, death, confinement, or imprisonment).

The present study examined the rate of new-onset DM in a large, geographically diverse, commercially insured population treated with atypical or conventional antipsychotics. We present findings using both fixed follow-up and accrued person-time techniques to examine the effects of choice of methodology on these results.


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