title: Prolonged use of human insulin increases breast cancer risk in Taiwanese women with type 2 diabetes.
abstract: BACKGROUND
  Human insulin is commonly used to treat hyperglycemia in patients with diabetes, but its potential link with female breast cancer is under debate. This study investigated whether human insulin use might be associated with breast cancer risk in Taiwanese women with type 2 diabetes.
  
  
  METHODS
  The reimbursement databases of all Taiwanese diabetic patients from 1996 to 2009 were retrieved from the National Health Insurance. An entry date was set at 1 January 2004 and a total of 482,033 women with type 2 diabetes were followed up for breast cancer incidence until the end of 2009. Incidences for ever-users, never-users and subgroups of human insulin exposure (using tertile cutoffs of time since starting insulin, cumulative dose and cumulative duration of insulin) were calculated and the adjusted hazard ratios were estimated by Cox regression. The potential risk modification by concomitant treatment with metformin, statin and angiotensin converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB) was also evaluated.
  
  
  RESULTS
  There were 59,798 ever-users and 422,235 never-users of human insulin, with respective numbers of incident breast cancer of 559 (0.93 %) and 4,711 (1.12 %), and respective incidence of 207.9 and 215.1 per 100,000 person-years. The overall adjusted hazard ratio (95 % confidence interval) did not show a significant association with insulin [1.033 (0.936-1.139)]. However, patients in the third tertiles of dose-response parameters might show a significantly higher risk of breast cancer while compared to never-users: 1.185 (1.026-1.368), 1.260 (1.096-1.450) and 1.257 (1.094-1.446) for ≥67 months for time since starting insulin, ≥39,000 units for cumulative dose of insulin, and ≥21.8 months for cumulative duration of insulin, respectively. Additional analyses suggested that the breast cancer risk associated with human insulin use might be beneficially modified by concomitant use of metformin, statin and ACEI/ARB.
  
  
  CONCLUSIONS
  This study discloses a significantly higher risk of breast cancer associated with prolonged use of human insulin. The increased risk of breast cancer associated with human insulin use may be modified by medications such as metformin, statin and ACEI/ARB.
authors.affiliation: Department of Internal Medicine, National Taiwan University College of Medicine, No. 7 Chung-Shan South Road, Taipei, 100, Taiwan. ccktsh@ms6.hinet.net.|Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. ccktsh@ms6.hinet.net.
authors.forename: Chin-Hsiao
authors.initials: CH
authors.lastname: Tseng
mesh_terms: D001943:Breast Neoplasms / Q000139:chemically induced* / Q000453:epidemiology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects; D015994:Incidence; D000068880:Isophane Insulin, Human / Q000008:administration & dosage / Q000009:adverse effects*; D008875:Middle Aged; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013624:Taiwan / Q000453:epidemiology
chemical_list: D007004:Hypoglycemic Agents; D000068880:Isophane Insulin, Human