title: Comparative safety of diabetes medications and risk of incident invasive breast cancer: a population-based cohort study.
abstract: OBJECTIVE
  Growing evidence suggests that certain commonly used diabetes medications have the potential to differentially alter breast cancer risk. We evaluated the influence of metformin, insulin, and sulfonylureas on risk of incident invasive breast cancer.
  
  
  METHODS
  We conducted a retrospective cohort study of women ≥40 years of age enrolled in a health plan between 1996 and 2011. Ever, current (≤12 months), and duration (<1, 1-2.9, ≥3 years) of diabetes medication use were obtained from pharmacy databases and modeled as time varying. Multivariable Cox proportional hazards models adjusting for potential confounders including screening mammography and body mass index were used to estimate hazard ratios (HRs) and 95% Confidence Intervals (CIs).
  
  
  RESULTS
  Among 10,050 women with diabetes, 57 % used metformin, 43 % used sulfonylureas, 32 % used insulin, and 301 were diagnosed with breast cancer over median follow-up of 6.7 years. Results suggested no significant decreased risk of breast cancer among metformin users (HR 0.86; 95% CI 0.65-1.12). We found no association between increased breast cancer risk and long-acting insulin (HR 0.95; 95% CI 0.51-1.77), but reduced risk with short-/rapid-acting insulin (HR 0.69; 95% CI 0.50-0.94), and suggestion of a dose-response with increasing duration of short-/rapid-acting insulin use (HR 0.87; 95% CI 0.76-1.00). Estimates for sulfonylurea users suggested increased risk with ever use (HR 1.18; 95% CI 0.90-1.53) and with longer durations of use (≥3 years: HR 1.23; 95% CI 0.88-1.73), but confidence intervals included 1.0.
  
  
  CONCLUSIONS
  Our results provide little support for the previously hypothesized decreased risk of breast cancer with metformin use or for an increased risk with insulin use. Implications for possible residual confounding by screening mammography and comorbidity should be considered in breast cancer pharmacoepidemiology studies.
authors.affiliation: Center for Pharmacoepidemiology and Pharmacoeconomic Research, University of Illinois at Chicago, 833 S. Wood St., M/C 871, Chicago, IL, 60612, USA. gcalip@uic.edu.
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Calip
authors.affiliation: Group Health Research Institute, 1730 Minor Ave., Suite 1600, Seattle, WA, 98101, USA.
authors.forename: Onchee
authors.initials: O
authors.lastname: Yu
authors.affiliation: Department of Medicine, University of Washington, 325 9th Ave., Seattle, WA, 98104, USA.
authors.forename: Joann G
authors.initials: JG
authors.lastname: Elmore
authors.affiliation: Group Health Research Institute, 1730 Minor Ave., Suite 1600, Seattle, WA, 98101, USA.|School of Pharmacy, University of Washington, 1959 N.E. Pacific St., H-375, Seattle, WA, 98195, USA.
authors.forename: Denise M
authors.initials: DM
authors.lastname: Boudreau
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000139:chemically induced* / Q000517:prevention & control; D003920:Diabetes Mellitus / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000009:adverse effects*; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D017891:Pharmacoepidemiology; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012307:Risk Factors; D013453:Sulfonylurea Compounds / Q000009:adverse effects*; D013997:Time Factors
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D013453:Sulfonylurea Compounds; D008687:Metformin
keywords: Breast cancer; Diabetes; Insulin; Metformin; Screening mammography; Sulfonylureas