title: Risk factors for adverse symptoms during dipeptidyl peptidase-IV inhibitor therapy: a questionnaire-based study carried out by the Japan Pharmaceutical Association Drug Event Monitoring project in Kumamoto Prefecture.
abstract: BACKGROUND
  Meta-analyses of randomized clinical trials have reported that dipeptidyl peptidase IV (DPP-4) inhibitors are well tolerated and that the incidence of hypoglycemia with the use of DPP-4 inhibitors is similar to that observed with placebos. However, in general, provider-oriented methods using medical record reviews offer lower rates of non-serious, symptomatic adverse drug reactions (ADRs) than patient-oriented methods. Moreover, severe hypoglycemia occurred in three clinical trials using sitagliptin, but in two of these trials this phenomenon has been previously described only in the drug application data in the US.
  
  
  OBJECTIVE
  The aim of this study was to assess the profile of patient-reported symptomatic ADRs under DPP-4 inhibitor therapy and to detect risk factors for hypoglycemic and non-hypoglycemic adverse symptoms in daily clinical practice.
  
  
  METHODS
  We analyzed a subpopulation of participants in the Drug Event Monitoring (DEM) project of the Japan Pharmaceutical Association. An anonymous survey was conducted in February 2012 to assess the self-perception of adverse symptoms during a median 28 (4-88) days after the last prescription of DPP-4 inhibitors by means of interviews of pharmacists using structured questionnaires.
  
  
  RESULTS
  A total of 864 males and 686 females were included. The prescribed DPP-4 inhibitors included sitagliptin (75.4 %), alogliptin (15.5 %), vildagliptin (8.8 %) and linagliptin (0.3 %). Mild hypoglycemic symptoms were reported by 34 individuals (2.2 %) receiving monotherapy of sitagliptin (10/402) or alogliptin (3/65), or combination therapy of sitagliptin (15/767) or alogliptin (6/176) with other hypoglycemic agents. In the multiple regression model, hypoglycemic symptoms were found to be significantly associated with liver disease, female sex and alcohol consumption more than three times per week. Non-hypoglycemic symptoms were reported by 57 individuals (3.7 %), the most common symptoms of which were gastrointestinal symptoms (2.1 %). Combination therapy was only found to be associated with nonhypoglycemic symptoms.
  
  
  CONCLUSIONS
  The present study suggested that hypoglycemic symptoms under therapy with sitagliptin or alogliptin may be associated with liver disease, female sex and alcohol consumption, all of which are potentially capable of leading to poor gluconeogenesis because they decrease the counter-regulatory hormonal responses to hypoglycemia.
authors.affiliation: Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1, Oe-honmachi, Kumamoto, 862-0973, Japan.
authors.forename: Ayami
authors.initials: A
authors.lastname: Kajiwara
authors.forename: Junji
authors.initials: J
authors.lastname: Saruwatari
authors.forename: Misaki
authors.initials: M
authors.lastname: Sakata
authors.forename: Kazunori
authors.initials: K
authors.lastname: Morita
authors.forename: Ayana
authors.initials: A
authors.lastname: Kita
authors.forename: Kentaro
authors.initials: K
authors.lastname: Oniki
authors.forename: Masato
authors.initials: M
authors.lastname: Yamamura
authors.forename: Motoji
authors.initials: M
authors.lastname: Murase
authors.forename: Haruo
authors.initials: H
authors.lastname: Koda
authors.forename: Seisuke
authors.initials: S
authors.lastname: Hirota
authors.forename: Tadao
authors.initials: T
authors.lastname: Ishizuka
authors.forename: Kazuko
authors.initials: K
authors.lastname: Nakagawa
mesh_terms: D016907:Adverse Drug Reaction Reporting Systems; D000368:Aged; D000428:Alcohol Drinking / Q000009:adverse effects; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced* / Q000453:epidemiology; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D007564:Japan; D008107:Liver Diseases / Q000150:complications; D008297:Male; D012307:Risk Factors; D012737:Sex Factors; D012957:Societies, Pharmaceutical; D011795:Surveys and Questionnaires
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents