title: No Decreased Risk of Gastrointestinal Cancers in Users of Metformin in The Netherlands; A Time-Varying Analysis of Metformin Exposure.
abstract: Previous studies on metformin use and gastrointestinal (GI) cancer risk have yielded inconclusive results on metformin's chemoprotective effects. We aimed to evaluate GI cancer risk in users of metformin in The Netherlands using a time-varying approach in a large population-based database. A cohort study was performed using the NCR-PHARMO database. Patients using ≥1 non-insulin antidiabetic drug (NIAD) during 1998 to 2011 were included (N= 57,621). Exposure to NIADs was modeled time-varyingly. Cox regression analysis estimated HRs of GI cancers in current metformin users versus current users of other NIADs. Covariables included age, sex, drugs known to impact cancer risk, history of hospitalization, and starting year of follow-up. A sensitivity analysis was performed, applying a new-user design. Current use of metformin was not associated with a decreased risk of GI cancer [HR, 0.97; 95% confidence interval (CI), 0.82-1.15] or specific GI cancer sites. The sensitivity analysis yielded comparable results. No decreasing trends were observed with increasing cumulative dose of metformin [HR 1.05, 95% CI, 0.85-1.28; HR 0.89, 95% CI, 0.73-1.10; HR 0.96, 95% CI, 0.77-1.19 for dose tertiles low (<405 g), medium (405-999 g), and high (≥999 g)]. In contrast, an increased risk of pancreatic cancer was found in current users of metformin plus insulin (HR, 4.90; 95% CI, 2.64-9.10). In conclusion, no decreased risk of GI cancer was found in current metformin users compared with current users of other NIADs. Variations in the exposure definition of metformin use may be one of the explanations of previously found reduced cancer risks in metformin users.Cancer Prev Res; 10(5); 290-7. ©2017 AACR.
authors.affiliation: Department of Internal Medicine, VieCuri Medical Centre, Venlo, the Netherlands. roy.dejong@maastrichtuniversity.nl.|Division of Gastroenterology and Hepatology, Department of Internal Medicine, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre+, Maastricht, the Netherlands.
authors.forename: Roy G
authors.initials: RG
authors.lastname: de Jong
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Centre+, Maastricht, the Netherlands.|Utrecht Institute for Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, the Netherlands.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Burden
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre+, Maastricht, the Netherlands.
authors.forename: Sander
authors.initials: S
authors.lastname: de Kort
authors.affiliation: PHARMO Institute for Drug Outcomes Research, Utrecht, the Netherlands.
authors.forename: Myrthe P
authors.initials: MP
authors.lastname: van Herk-Sukel
authors.affiliation: Department of Research, Netherlands Comprehensive Cancer Organization, Utrecht, the Netherlands.
authors.forename: Pauline A
authors.initials: PA
authors.lastname: Vissers
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Centre+, Maastricht, the Netherlands.|Utrecht Institute for Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, the Netherlands.|Utrecht Institute for Pharmaceutical Sciences, Division of Pharmacology, Utrecht University, Utrecht, the Netherlands.|Department of Central Hospital Pharmacy, VieCuri Medical Centre, Venlo, the Netherlands.
authors.forename: Paddy K
authors.initials: PK
authors.lastname: Janssen
authors.affiliation: Department of Internal Medicine, Máxima Medical Centre Eindhoven, Eindhoven, the Netherlands.|Division of General Internal Medicine, Department of Internal Medicine, Maastricht University Medical Centre+, Maastricht, the Netherlands.|Department of Health Services Research, CAPHRI School for Public Health and Primary Care, Maastricht University Medical Centre+, Maastricht, the Netherlands.
authors.forename: Harm R
authors.initials: HR
authors.lastname: Haak
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, NUTRIM - School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, the Netherlands.
authors.forename: Ad A
authors.initials: AA
authors.lastname: Masclee
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Centre+, Maastricht, the Netherlands.|Utrecht Institute for Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, the Netherlands.|Department of Health Services Research, CAPHRI School for Public Health and Primary Care, Maastricht University Medical Centre+, Maastricht, the Netherlands.|MRC Life-course Epidemiology Unit, University of Southampton, Southampton, United Kingdom.
authors.forename: Frank
authors.initials: F
authors.lastname: de Vries
authors.affiliation: Department of Epidemiology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre+, Maastricht, the Netherlands.|Department of Clinical Epidemiology, VieCuri Medical Centre, Venlo, the Netherlands.
authors.forename: Maryska L
authors.initials: ML
authors.lastname: Janssen-Heijnen
mesh_terms: D000328:Adult; D000368:Aged; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000453:epidemiology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D009426:Netherlands
chemical_list: D007004:Hypoglycemic Agents; D008687:Metformin