title: Pattern of Onset and Risk Factors for Peripheral Oedema During Vildagliptin Use: Analysis from the Vildagliptin Prescription-Event Monitoring Study in England.
abstract: Clinical trials have identified peripheral oedema (PO) as an adverse event of vildagliptin (an oral anti-diabetic drug [OAD]). A post-marketing study (PMS) was conducted to advance the understanding of vildagliptin use and particular safety concerns identified within the risk-management plan. PMS objectives included comparing the hazards between vildagliptin monotherapy and combination therapy for selected a priori identified risks, including PO.
  
  
  
  This study was a per-protocol supplementary analysis to investigate the pattern of onset and effect of vildagliptin combination therapy on PO risk.
  
  
  
  The PMS used an observational cohort design. OAD exposure, selected risk factors and outcome data were collected from general practitioners in England regarding vildagliptin users for the 6-month period after starting treatment. Data analysis comprised univariate case/non-case analysis, time-to-onset analysis and Cox proportional hazard models to estimate hazard ratios (HR) of PO adjusting for selected patients' baseline characteristics.
  
  
  
  The study cohort included 4828 patients (median age 63 years; interquartile range [IQR] 54-71), 2692 of whom were male (55.8 %). The crude cumulative hazard of PO was 19.09 cases (95 % confidence interval [CI] 13.54-26.10) per 1000 person-years; 50 % of cases occurred during the first 34 days of treatment. A significantly faster time to PO onset was observed in patients prescribed concomitant sulfonylureas versus other treatment combinations (log rank test [LRT] p = 0.0365); in patients with a prior history of PO (LRT p < 0.001), arrhythmia (LRT p = 0.0003) or hypertension (LRT p = 0.0125); and in patients aged ≥60 years (LRT p = 0.0047). Similarly, the case/non-case univariate analysis indicated that patients with PO were older; had a higher prevalence of a history of either arrhythmia, hypertension or PO; and frequently used a sulfonylurea in combination. In the hazard function analysis, only sex and prior PO history had a profound effect on risk of PO after starting vildagliptin. Furthermore, effect modification was observed between sex and prior PO history; in male patients of average age (62 years), the HR was 12.84 (95 % CI 4.96-33.23); in females, it was 1.44 (95 % CI 0.32-6.40).
  
  
  
  In this planned supplementary analysis, the findings suggest that PO occurred most frequently within 1 month after starting treatment with vildagliptin, and previous PO history and male sex in elderly patients were important predictors of this risk. The observation that concomitant use of a sulfonylurea may also increase PO risk early after starting treatment should be taken into consideration if prescribing OADs in combination with vildagliptin.
authors.affiliation: Drug Safety Research Unit, Bursledon Hall, Blundell Lane, Southampton, SO31 1AA, UK. deborah.layton@dsru.org.|Associate Department of the School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK. deborah.layton@dsru.org.
authors.forename: Deborah
authors.identifier: 0000-0002-8557-1376
authors.initials: D
authors.lastname: Layton
authors.affiliation: Drug Safety Research Unit, Bursledon Hall, Blundell Lane, Southampton, SO31 1AA, UK.
authors.forename: Abigail L
authors.initials: AL
authors.lastname: Coughtrie
authors.affiliation: Drug Safety Research Unit, Bursledon Hall, Blundell Lane, Southampton, SO31 1AA, UK.|Medical Affairs, Janssen-Cilag Ltd., High Wycombe, UK.
authors.forename: Naseer
authors.initials: N
authors.lastname: Qayum
authors.affiliation: Drug Safety Research Unit, Bursledon Hall, Blundell Lane, Southampton, SO31 1AA, UK.|Associate Department of the School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK.
authors.forename: Saad A W
authors.initials: SA
authors.lastname: Shakir
mesh_terms: D000218:Adamantane / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D000368:Aged; D015331:Cohort Studies; D004487:Edema / Q000139:chemically induced / Q000453:epidemiology*; D004739:England / Q000453:epidemiology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009570:Nitriles / Q000008:administration & dosage* / Q000009:adverse effects; D000073958:Prescription Drug Monitoring Programs; D011759:Pyrrolidines / Q000008:administration & dosage* / Q000009:adverse effects; D012737:Sex Factors; D000077597:Vildagliptin
chemical_list: D009570:Nitriles; D011759:Pyrrolidines; D000077597:Vildagliptin; D000218:Adamantane