title: Observational studies of the association between glucose-lowering medications and cardiovascular outcomes: addressing methodological limitations.
abstract: BACKGROUND
  Recent years have witnessed a growing body of observational literature on the association between glucose-lowering treatments and cardiovascular disease. However, many of the studies are based on designs or analyses that inadequately address the methodological challenges involved.
  
  
  METHODS
  We reviewed recent observational literature on the association between glucose-lowering medications and cardiovascular outcomes and assessed the design and analysis methods used, with a focus on their ability to address specific methodological challenges. We describe and illustrate these methodological issues and their impact on observed associations, providing examples from the reviewed literature. We suggest approaches that may be employed to manage these methodological challenges.
  
  
  RESULTS
  From the evaluation of 81 publications of observational investigations assessing the association between glucose-lowering treatments and cardiovascular outcomes, we identified the following methodological challenges: 1) handling of temporality in administrative databases; 2) handling of risks that vary with time and treatment duration; 3) definitions of the exposure risk window; 4) handling of exposures that change over time; and 5) handling of confounding by indication. Most of these methodological challenges may be suitably addressed through application of appropriate methods.
  
  
  CONCLUSIONS
  Observational research plays an increasingly important role in the evaluation of the clinical effects of diabetes treatment. Implementation of appropriate research methods holds the promise of reducing the potential for spurious findings and the risk that the spurious findings will mislead the medical community about risks and benefits of diabetes medications.
authors.affiliation: Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 1620 Tremont Street (Suite 3030), Boston, MA, 02120, USA, epatorno@partners.org.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Patorno
authors.forename: Amanda R
authors.initials: AR
authors.lastname: Patrick
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Garry
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schneeweiss
authors.forename: Victoria G
authors.initials: VG
authors.lastname: Gillet
authors.forename: Dorothee B
authors.initials: DB
authors.lastname: Bartels
authors.forename: Elvira
authors.initials: E
authors.lastname: Masso-Gonzalez
authors.forename: John D
authors.initials: JD
authors.lastname: Seeger
mesh_terms: D001786:Blood Glucose / Q000187:drug effects; D002318:Cardiovascular Diseases / Q000188:drug therapy*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008962:Models, Theoretical; D012307:Risk Factors
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents