Glucose-lowering medications and the risk of cancer: A methodological review of studies based on real-world data

Diabetes Obes Metab. 2019 Sep;21(9):2029-2038. doi: 10.1111/dom.13766. Epub 2019 May 29.


Aim: To review the methodology of observational studies examining the association between glucose-lowering medications and cancer to identify the most common methodological challenges and sources of bias.

Methods: We searched PubMed systematically to identify observational studies on glucose-lowering medications and cancer published between January 2000 and January 2016. We assessed the design and analytical methods used in each study, with a focus on their ability to achieve study validity, and further evaluated the prevalence of major methodological choices over time.

Results: Of 155 studies evaluated, only 26% implemented a new-user design, 41% used an active comparator, 33% implemented a lag or latency period, and 51% adjusted for diabetes duration. Potential for immortal person-time bias was identified in 63% of the studies; 55% of the studies adjusted for variables measured during the follow-up without appropriate statistical methods. Aside from a decreasing trend in adjusting for variables measured during the follow-up, we observed no trends in methodological choices over time.

Conclusions: The prevalence of well-known design and analysis flaws that may lead to biased results remains high among observational studies on glucose-lowering medications and cancer, limiting the conclusions that can be drawn from these studies. Avoiding known pitfalls could substantially improve the quality and validity of real-world evidence in this field.

Keywords: bias; cancer; epidemiological methods; glucose-lowering medications; review.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Systematic Review

MeSH terms

  • Diabetes Mellitus / drug therapy*
  • Humans
  • Hypoglycemic Agents / adverse effects*
  • Neoplasms / chemically induced
  • Neoplasms / epidemiology*
  • Observational Studies as Topic
  • Prevalence


  • Hypoglycemic Agents