title: Insulin glargine use and breast cancer risk: Associations with cumulative exposure.
abstract: BACKGROUND
  This study was aimed to assess the risk of breast cancer associated with exposure to insulin glargine in women with type 2 diabetes and evaluate whether the pattern of risk concurs with the hypothesized trend of an increase in risk with longer duration of use, taking into account previous cumulative exposure to other types of insulin.
  
  
  METHODS
  We performed a restrospective cohort study (2002-2013) in the Clinical Practice Research Datalink among adult female patients with a first ever insulin prescription (n = 12 468). Time-dependent exposure measures were used to assess associations with duration of use of: (1) other insulin types before glargine was first prescribed (i.e. among switchers); and (2) of glargine during follow-up. Analyses were performed separately for insulin-naïve glargine users and patients switched to glargine. Cox proportional hazards models were used to derive p-trends, hazard ratios (HR) and 95% confidence intervals (CI) for breast cancer associated with glargine use.
  
  
  RESULTS
  During 66 151 person years, 186 breast cancer cases occurred; 76 in glargine users (3.0/1000 years) and 110 in users of other insulins (2.7/1000 years). Among insulin-naïve women, no association with cumulative glargine use was observed (p-trend = 0.91), even after ≥5 years (HR = 1.06, 95% CI 0.48-2.33). Among switchers, a linear trend with years of prior exposure to other insulins was found (p-trend = 0.02). An increased risk was observed in glargine users with extensive (>3 years) past exposure to other insulins (HR = 3.17, 95% CI 1.28-7.84). A non-significant trend with cumulative glargine exposure was found among switchers (p-trend = 0.24).
  
  
  CONCLUSIONS
  Exposure to glargine was not associated with an increased breast cancer risk in insulin-naïve patients. Exposure to other insulins prior to the start of glargine appears to be relevant when studying breast cancer risk associated with glargine use.
authors.affiliation: a Utrecht Institute for Pharmaceutical Sciences, Utrecht University , The Netherlands ;
authors.forename: Paul J H L
authors.initials: PJ
authors.lastname: Peeters
authors.affiliation: a Utrecht Institute for Pharmaceutical Sciences, Utrecht University , The Netherlands ;
authors.forename: Marloes T
authors.initials: MT
authors.lastname: Bazelier
authors.affiliation: a Utrecht Institute for Pharmaceutical Sciences, Utrecht University , The Netherlands ;
authors.forename: Hubert G M
authors.initials: HG
authors.lastname: Leufkens
authors.affiliation: b School of Health Sciences, University of Tampere , Tampere , Finland ;
authors.forename: Anssi
authors.initials: A
authors.lastname: Auvinen
authors.affiliation: a Utrecht Institute for Pharmaceutical Sciences, Utrecht University , The Netherlands ;|c Health eResearch Centre, Farr Institute for Health Informatics Research, University of Manchester , Manchester , UK ;
authors.forename: Tjeerd P
authors.initials: TP
authors.lastname: van Staa
authors.affiliation: a Utrecht Institute for Pharmaceutical Sciences, Utrecht University , The Netherlands ;|d Medical Center Maastricht and School for Public Health and Primary Care (CAPHRI), Maastricht University , Maastricht , The Netherlands ;|e MRC Lifecourse Epidemiology Unit, University of Southampton , Southampton , UK ;|f Department of Clinical Pharmacy and Toxicology , Maastricht University Medical Center , Maastricht , The Netherlands.
authors.forename: Frank
authors.initials: F
authors.lastname: de Vries
authors.affiliation: a Utrecht Institute for Pharmaceutical Sciences, Utrecht University , The Netherlands ;
authors.forename: Marie L
authors.initials: ML
authors.lastname: De Bruin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000139:chemically induced* / Q000453:epidemiology; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects*; D000069036:Insulin Glargine / Q000009:adverse effects*; D008875:Middle Aged; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012307:Risk Factors; D006113:United Kingdom / Q000453:epidemiology
chemical_list: D007004:Hypoglycemic Agents; D000069036:Insulin Glargine