Assessment of anti psychotic-related risk of diabetes mellitus in a Medicaid psychosis population: Sensitivity to study design

Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, United States
American Journal of Health-System Pharmacy (Impact Factor: 1.88). 03/2006; 63(5):431-41. DOI: 10.2146/ajhp050144
Source: PubMed


The effect of study design on findings regarding diabetes risk associated with antipsychotics was studied.
This study was a retrospective analysis of data from more than 100,000 Medicaid patients. Diabetes odds ratios (ORs) for patients treated with clozapine, olanzapine, quetiapine, risperidone, ziprasidone, or conventional antipsychotics versus untreated patients were estimated with and without the following design enhancements: screening for preexisting diabetes, selecting for antipsychotic monotherapy, and identifying diabetes with prescription claims only. Logistic regression controlled for patient sex, race and ethnicity, type of psychosis, length of observation and treatment, antipsychotic dosage, pre-existing excess weight or dyslipidemia, and use of other drugs with potential diabetogenic effects.
Under the weakest study design (none of the above enhancements), all antipsychotics were associated with significantly higher odds of diabetes relative to no treatment (p < 0.05). Estimated ORs were as follows: clozapine, 1.468; olanzapine, 1.108; quetiapine, 1.270; ziprasidone, 1.226; risperidone, 1.232; and conventional antipsychotics, 1.159. Under the strongest design (all of the above enhancements), ORs relative to no treatment were significant for clozapine (1.484) and olanzapine (1.149) and nonsignificant for quetiapine (0.998), risperidone (1.124), ziprasidone (0.717), and conventional antipsychotics (1.025). The data also strongly suggest selection bias by clinicians (i.e., selecting antipsychotics based on preexisting diabetes or risk factors for diabetes), disfavoring risperidone and favoring olanzapine. Although the evidence is weaker, quetiapine may also have been affected by unfavorable selection bias.
In large database studies, estimated risks of diabetes among patients treated with antipsychotics appeared to be influenced by study design. When a more rigorous design was used, only clozapine and olanzapine were associated with diabetes risk significantly greater than that in untreated patients.

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    • "Atypical antipsychotic agents are first-line therapy for symptoms of schizophrenia and other psychotic disorders. However, numerous studies have documented a higher incidence of diabetes and hyperglycemia among patients treated with atypical antipsychotics (at least partially attributed to effects of weight gain) compared to typical agents (Caro et al., 2002; Koller and Doraiswamy, 2002; Kornegay et al., 2002; Koro et al., 2002; Sernyak et al., 2002; Buse et al., 2003; Gianfrancesco et al., 2003a, 2003b; Lindenmayer et al., 2003; Citrome et al., 2004; Leslie and Rosenheck, 2004; Gianfrancesco et al., 2006; Ramaswamy et al., 2006; DuMouchel et al., 2008; Smith et al., 2008). In addition, case reports and case series have suggested that these drugs may also have acute hyperglycemic effects, occasionally leading to diabetic ketoacidosis (DKA), coma, and death (Muench and Carey, 2001; Roefaro and Mukherjee, 2001; Jin et al., 2002; Koller et al., 2003; Wilson et al., 2003; Koller et al., 2004; Takahashi et al., 2005; Marlowe et al., 2007; Kohen et al., 2008; Makhzoumi et al., 2008). "
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    ABSTRACT: Objective To evaluate the relationship between initiation of atypical antipsychotic agents and the risk of hyperglycemic emergencies. Method We conducted a multicentre retrospective cohort study using administrative health data from 7 Canadian provinces and the UK Clinical Practice Research Datalink. Hospitalizations for hyperglycemic emergencies (hyperglycemia, diabetic ketoacidosis, hyperosmolar hyperglycemic state) were compared between new users of risperidone (reference), and new users of olanzapine, other atypical antipsychotics, and typical antipsychotics. We used propensity scores with inverse probability of treatment weighting and proportional hazard models to estimate the site-specific hazard ratios of hyperglycemic emergencies in the year following drug initiation separately for adults under and over age 66 years. Site-level results were pooled using meta-analytic methods. Results Among 725,489 patients, 55% were aged 66 + years; 5% of younger and 19% of older patients had pre-existing diabetes. Hyperglycemic emergencies were rare (1–2 per 1000 person years), but more frequent in patients with pre-existing diabetes (6–12 per 1000 person years). We did not find a significant difference in risk of hyperglycemic emergencies with initiation of olanzapine versus risperidone; however heterogeneity existed between sites. The risk of an event was significantly lower with other atypical (99% quetiapine) compared to risperidone use in older patients [adjusted hazard ratio, 95% confidence interval (CI): 0.69, 0.53–0.90]. Conclusions Risk for hyperglycemic emergencies is low after initiation of antipsychotics, but patients with pre-existing diabetes may be at greater risk. The risk appeared lower with the use of quetiapine in older patients, but the clinical significance of the findings requires further study.
    Full-text · Article · Apr 2014 · Schizophrenia Research
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    • "Over the past decade, there has been increasing recognition that some of the second-generation antipsychotic medications, termed the atypical antipsychotics (AAPs), are associated with an increased incidence of obesity (1), type 2 diabetes (2,3), and cardiovascular disease (4,5). The implications for public health are tremendous (6) due to the large number of adult patients treated with these agents and the increasing use of off-label prescriptions to children (7) and the elderly (8). "
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    ABSTRACT: Atypical antipsychotic (AAP) medications that have revolutionized the treatment of mental illness have become stigmatized by metabolic side effects, including obesity and diabetes. It remains controversial whether the defects are treatment induced or disease related. Although the mechanisms underlying these metabolic defects are not understood, it is assumed that the initiating pathophysiology is weight gain, secondary to centrally mediated increases in appetite. To determine if the AAPs have detrimental metabolic effects independent of weight gain or psychiatric disease, we administered olanzapine, aripiprazole, or placebo for 9 days to healthy subjects (n = 10, each group) under controlled in-patient conditions while maintaining activity levels. Prior to and after the interventions, we conducted a meal challenge and a euglycemic-hyperinsulinemic clamp to evaluate insulin sensitivity and glucose disposal. We found that olanzapine, an AAP highly associated with weight gain, causes significant elevations in postprandial insulin, glucagon-like peptide 1 (GLP-1), and glucagon coincident with insulin resistance compared with placebo. Aripiprazole, an AAP considered metabolically sparing, induces insulin resistance but has no effect on postprandial hormones. Importantly, the metabolic changes occur in the absence of weight gain, increases in food intake and hunger, or psychiatric disease, suggesting that AAPs exert direct effects on tissues independent of mechanisms regulating eating behavior.
    Full-text · Article · Jul 2013 · Diabetes
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    • "2004; Holt et al. 2005; Newcomer. 2005) and higher levels of glycated hemoglobin (HBA1c) and blood glucose (Lieberman et al. 2005; Gianfrancesco et al. 2006; Nasrallah. 2008). "
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    ABSTRACT: Antipsychotic affinity for the histamine H1 receptor and the muscarinic M3 receptor have been associated with the side effects weight gain, and development of diabetes, respectively. We investigated polymorphisms of the histamine H1 (HRH1) and muscarinic acetylcholine receptor M3 (CHRM3) receptor genes for an association with body mass index (BMI) and glycated hemoglobin (HbA1c). We included 430 Caucasian patients with a non-affective psychotic disorder using antipsychotics for at least 3 months. Primary endpoints of the study were cross-sectionally measured BMI and HbA1c; secondary endpoints were obesity and hyperglycaemia. Two single-nucleotide polymorphisms (SNPs) in the HRH1 gene, rs346074 and rs346070, and one SNP in the CHRM3 gene, rs3738435, were genotyped. Our primary hypothesis in this study was an interaction between genotype on BMI and antipsychotic affinity for the H1 and M3 receptor. A significant association of interaction between haplotype rs346074-rs346070 and BMI (p value 0.025) and obesity (p value 0.005) in patients using high-H1 affinity antipsychotics versus patients using low-H1 affinity antipsychotics was found. There was no association of CHRM3 gene variant rs3738435 with BMI, and we observed no association with HbA1c or hyperglycaemia in any of the variants. This study, for the first time, demonstrates a significant association between HRH1 variants and BMI in patients with a psychotic disorder using antipsychotics. In future, genotyping of HRH1 variants may help predicting weight gain in patients using antipsychotics.
    Full-text · Article · Feb 2011 · Psychopharmacology
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