title: Insulin and other antidiabetic drugs and hepatocellular carcinoma risk: a nested case-control study based on Italian healthcare utilization databases.
abstract: OBJECTIVE
  Insulin and other antidiabetic drugs may modulate hepatocellular carcinoma (HCC) risk in diabetics.
  
  
  METHODS
  We have analyzed the role of various antidiabetic drugs on HCC in a nested case-control study using the healthcare utilization databases of the Lombardy Region in Italy. This included 190 diabetic subjects with a hospital discharge reporting a diagnosis of malignant HCC and 3772 diabetic control subjects matched to each case on sex, age, date at cohort entry, and duration of follow-up.
  
  
  RESULTS
  Increased risks of HCC were found for use of insulin (odds ratio [OR] = 3.73, 95% confidence interval [CI] 2.52-5.51), sulfonylureas (OR = 1.39, 95%CI 0.98-1.99), and repaglinide (OR = 2.12, 95%CI 1.38-3.26), while a reduced risk was found for use of metformin (OR = 0.57, 95%CI 0.41-0.79). The risk of HCC increased with increasing duration of insulin use (OR = 2.52 for <1 year, 5.41 for 1-2 years, and 6.01 for ≥2 years; p for trend < 0.001), while no clear pattern with duration was observed for sulfonylureas, repaglinide, and metformin.
  
  
  CONCLUSIONS
  Our study supports the evidence that patients with diabetes using metformin, and possibly other antidiabetic drugs that increase insulin sensibility, have a reduced risk of HCC, while those using insulin or drugs that increase circulating insulin, such as insulin secretagogues, have an increased risk. Whether these associations are causal, or influenced by different severity of diabetes and/or possible residual bias or misclassification, is still open to discussion.
authors.affiliation: Department of Epidemiology, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Bosetti
authors.affiliation: Department of Statistics, Unit di Biostatistics and Epidemiology, Università Milano-Bicocca, Milan, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Franchi
authors.affiliation: Department of Statistics, Unit di Biostatistics and Epidemiology, Università Milano-Bicocca, Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Nicotra
authors.affiliation: Department of Sciences for the Health Promotion and Mother and Child Care "G. D'Alessandro", Hygiene Section, University of Palermo, Palermo, Italy.
authors.forename: Rosario
authors.initials: R
authors.lastname: Asciutto
authors.affiliation: Unità Organizzativa Governo dei Dati, delle Strategie e Piani del Sistema Sanitario, Regione Lombardia, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Merlino
authors.affiliation: Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: La Vecchia
authors.affiliation: Department of Statistics, Unit di Biostatistics and Epidemiology, Università Milano-Bicocca, Milan, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Corrao
mesh_terms: D000368:Aged; D016022:Case-Control Studies; D015331:Cohort Studies; D016001:Confidence Intervals; D062313:Databases, Pharmaceutical / Q000706:statistics & numerical data*; D011307:Drug Prescriptions / Q000706:statistics & numerical data; D004363:Drug Utilization / Q000706:statistics & numerical data*; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D007328:Insulin / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D007558:Italy / Q000453:epidemiology; D008113:Liver Neoplasms / Q000139:chemically induced / Q000453:epidemiology*; D016015:Logistic Models; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D008875:Middle Aged; D016017:Odds Ratio; D018570:Risk Assessment
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D008687:Metformin
keywords: antidiabetics; diabetes; hepatocellular carcinoma; insulin; metformin; pharmacoepidemiology