In the February 2004 issue of Diabetes Care, the American Diabetes Association (ADA) published a summary of their conclusions drawn from the Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes (1). Although the ADA ranked the diabetes risk for second-generation antipsychotics (SGAs), the U.S. Food and Drug Administration’s Division of Neuropharmacological Drug Products (DNDP) does not believe that the evidence currently available allows such a ranking.

The ADA concluded that aripiprazole and ziprasidone have no effect on the risk of diabetes. The ADA notes that because these two drugs have not been included in epidemiological studies, this conclusion is solely based on data from clinical trials that did not reveal the risk of treatment-emergent hyperglycemia and diabetes. We must point out that the clinical trial data have not provided strong evidence of a diabetes risk for any of the SGAs. It is not clear whether this is due to the timing of glucose measurements (random in most cases), the low absolute frequency for diabetes events, the short duration of many of the trials, or other factors. Therefore, the DNDP does not consider the absence of a signal in clinical trial data to rule out the risk of diabetes with SGAs.

Based on a review of epidemiological studies, the ADA concluded that there is an increased risk of diabetes with olanzapine and clozapine and discrepant results with quetiapine and risperidone. The ADA correctly identifies many of the limitations of these epidemiological studies, including “their retrospective nature, heterogeneity of methodology, selection or ascertainment bias, and absence of appropriate or well-characterized control subjects, … relatively short periods of study, … failure to control for a possible treatment sequence bias in ‘switchover’ studies, and … not always using clinically equivalent dosages of the medications.” The DNDP believes that although these studies support an increased risk of treatment-emergent hyperglycemia or diabetes, compared with patients treated with older antipsychotic drugs, the limitations of these studies preclude firm conclusions about the relative risk for diabetes among the studied SGAs.

The ADA asserts that “weight gain and changes in body composition may account for many of the purported metabolic complications associated with SGA therapy, e.g., … diabetes… ” The ADA correctly points out that SGAs have different weight gain liabilities. Although weight gain may be a factor in explaining the increased diabetes risk for SGAs, DNDP is not aware of evidence proving that the treatment-emergent diabetes risk for these drugs is wholly or in part due to treatment-emergent weight gain. Although weight gain is widely recognized as a risk factor for diabetes in the general population, the clinical trial and epidemiological evidence has not shown a direct link between these treatment-emergent side effects. A substantial proportion (∼25%) of adverse event reports submitted to the U.S. Food and Drug Administration do not mention weight gain as part of the presentation of SGA-associated hyperglycemia or diabetes.

Although the DNDP agrees with the ADA’s recommendation to monitor patients treated with SGAs for evidence of diabetes, we do not believe that the available evidence allows the ranking of diabetes risk for these drugs at this time. We agree with the ADA that additional studies are needed to clarify many of the issues surrounding the diabetes-SGA risk relationship. In the meantime, DNDP recommends that clinicians remain vigilant in monitoring all patients treated with SGAs to assure their safe use.

American Diabetes Association: Consensus development conference on antipsychotic drugs and obesity and diabetes (Consensus Statement).
Diabetes Care