title: In search of moderators and mediators of hyperglycemia with atypical antipsychotic treatment.
abstract: Signal detection methods were used to identify values of metabolic variables that predict development of prediabetes or diabetes before (moderators) or associated with treatment (mediators), utilizing data from two multi-center clinical trials of patients with schizophrenia, treated for 6 months with olanzapine (OLZ) or ziprasidone (ZIP). At baseline, participants were often overweight/obese (63% with a body mass index >or=25.0kg/m(2)), dyslipidemic [more than one-third had elevated triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) concentrations], and prediabetic (20%). Weight gain was significantly greater in OLZ-treated patients, as was accentuation of dyslipidemia. However, there were no significant correlations between weight gain and lipid changes from baseline to weeks 2, 4, 8 or to last observation. Type 2 diabetes developed in 4% and prediabetes in 18% of the population. Significant baseline predictors of diabetes were a HDL-C concentration <28mg/dL, or being >or=58-years-old if HDL-C concentration was >or=28mg/dL. Baseline plasma glucose concentration >or=92mg/dL was the only significant predictor of developing prediabetes, accounting for 60% of cases. Post-treatment increments in plasma TG concentrations >or=145mg/dL or >or=59mg/dL were significant predictors of diabetes (23%) or prediabetes (27%), respectively. If the increase in TG was <145mg/dL, rapid weight gain >or=6.1kg in 2 weeks predicted development of diabetes (18%). These findings provide a quantitative approach to identify those at greatest treatment-associated risk to develop glucose intolerance, and emphasize the need to address co-morbid medical disorders in these patients.
authors.affiliation: Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. greaven@cvmed.stanford.edu
authors.forename: Gerald M
authors.initials: GM
authors.lastname: Reaven
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Lieberman
authors.forename: Gopalan
authors.initials: G
authors.lastname: Sethuraman
authors.forename: Helena
authors.initials: H
authors.lastname: Kraemer
authors.forename: John M
authors.initials: JM
authors.lastname: Davis
authors.forename: Christine
authors.initials: C
authors.lastname: Blasey
authors.forename: Ming T
authors.initials: MT
authors.lastname: Tsuang
authors.forename: Alan F
authors.initials: AF
authors.lastname: Schatzberg
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001569:Benzodiazepines / Q000494:pharmacology / Q000627:therapeutic use*; D001786:Blood Glucose / Q000032:analysis; D001794:Blood Pressure / Q000187:drug effects; D015992:Body Mass Index; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000150:complications* / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D008075:Lipoproteins, HDL / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D000077152:Olanzapine; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D011236:Prediabetic State / Q000139:chemically induced / Q000150:complications; D011237:Predictive Value of Tests; D016032:Randomized Controlled Trials as Topic; D012559:Schizophrenia / Q000150:complications* / Q000188:drug therapy*; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D014150:Antipsychotic Agents; D001786:Blood Glucose; D008075:Lipoproteins, HDL; D010879:Piperazines; D013844:Thiazoles; D001569:Benzodiazepines; C092292:ziprasidone; D000077152:Olanzapine