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

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

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Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Science, Aetion Inc., Boston, Massachusetts.
Optum Epidemiology, Boston, Massachusetts.



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.


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.


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.


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.


bias; cancer; epidemiological methods; glucose-lowering medications; review

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