title: Adverse events associated with incretin-based drugs in Japanese spontaneous reports: a mixed effects logistic regression model.
abstract: BACKGROUND
  Spontaneous Reporting Systems (SRSs) are passive systems composed of reports of suspected Adverse Drug Events (ADEs), and are used for Pharmacovigilance (PhV), namely, drug safety surveillance. Exploration of analytical methodologies to enhance SRS-based discovery will contribute to more effective PhV. In this study, we proposed a statistical modeling approach for SRS data to address heterogeneity by a reporting time point. Furthermore, we applied this approach to analyze ADEs of incretin-based drugs such as DPP-4 inhibitors and GLP-1 receptor agonists, which are widely used to treat type 2 diabetes.
  
  
  METHODS
  SRS data were obtained from the Japanese Adverse Drug Event Report (JADER) database. Reported adverse events were classified according to the MedDRA High Level Terms (HLTs). A mixed effects logistic regression model was used to analyze the occurrence of each HLT. The model treated DPP-4 inhibitors, GLP-1 receptor agonists, hypoglycemic drugs, concomitant suspected drugs, age, and sex as fixed effects, while the quarterly period of reporting was treated as a random effect. Before application of the model, Fisher's exact tests were performed for all drug-HLT combinations. Mixed effects logistic regressions were performed for the HLTs that were found to be associated with incretin-based drugs. Statistical significance was determined by a two-sided p-value <0.01 or a 99% two-sided confidence interval. Finally, the models with and without the random effect were compared based on Akaike's Information Criteria (AIC), in which a model with a smaller AIC was considered satisfactory.
  
  
  RESULTS
  The analysis included 187,181 cases reported from January 2010 to March 2015. It showed that 33 HLTs, including pancreatic, gastrointestinal, and cholecystic events, were significantly associated with DPP-4 inhibitors or GLP-1 receptor agonists. In the AIC comparison, half of the HLTs reported with incretin-based drugs favored the random effect, whereas HLTs reported frequently tended to favor the mixed model.
  
  
  CONCLUSIONS
  The model with the random effect was appropriate for analyzing frequently reported ADEs; however, further exploration is required to improve the model. The core concept of the model is to introduce a random effect of time. Modeling the random effect of time is widely applicable to various SRS data and will improve future SRS data analyses.
authors.affiliation: Drug Evaluation & Informatics, University of Shizuoka , Shizuoka, Shizuoka , Japan.
authors.forename: Daichi
authors.initials: D
authors.lastname: Narushima
authors.affiliation: Drug Evaluation & Informatics, University of Shizuoka , Shizuoka, Shizuoka , Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Kawasaki
authors.affiliation: Office of Safety II, Pharmaceuticals and Medical Devices Agency , Tokyo , Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Takamatsu
authors.affiliation: Drug Evaluation & Informatics, University of Shizuoka , Shizuoka, Shizuoka , Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamada
keywords: Adverse drug events; Incretin-based drugs; Logistic regression; Spontaneous reporting systems