ArticleClinical epidemiology2021
Avoiding Time-Related Biases: A Feasibility Study on Antidiabetic Drugs and Pancreatic Cancer Applying the Parametric g-Formula to a Large German Healthcare Database.
Article in Clinical epidemiology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers, 1 of them a synthesis that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
3 citing papers in PubMed, 1 synthesis or guideline pooled it, 7 citations in OpenAlex.
- Reporting of Observational Studies Explicitly Aiming to Emulate Randomized Trials: A Systematic Review.JAMA network open · 2023Pooled it
- Target trial emulation studies in oncology: a comprehensive analysis.The oncologist · 2026Article
- Methodologies for the Emulation of Biomarker-Guided Trials Using Observational Data: A Systematic Review.Journal of personalized medicine · 2025Review
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
purposeInvestigating intended or unintended effects of sustained drug use is of high clinical relevance but remains methodologically challenging. This feasibility study aims to evaluate the usefulness of the parametric g-formula within a target trial for application to an extensive healthcare database in order to address various sources of time-related biases and time-dependent confounding. PATIENTS AND
methodsBased on the German Pharmacoepidemiological Research Database (GePaRD), we estimated the pancreatic cancer incidence comparing two hypothetical treatment strategies for type 2 diabetes mellitus (T2DM), i.e., (A) sustained metformin monotherapy vs (B) combination therapy with DPP-4 inhibitors after one year metformin monotherapy. We included 77,330 persons with T2DM who started metformin therapy at baseline between 2005 and 2011. Key aspects for avoiding time-related biases and time-dependent confounding were the emulation of a target trial over a 7-year follow-up period and application of the parametric g-formula.
resultsOver the 7-year follow-up period, 652 out of the 77,330 study subjects had a diagnosis of pancreatic cancer. Assuming no unobserved confounding, we found evidence that the metformin/DPP-4i combination therapy increased the risk of pancreatic cancer compared to a sustained metformin monotherapy (risk ratio: 1.47; 95% bootstrap CI: 1.07-1.94). The risk ratio decreased in sensitivity analyses addressing protopathic bias.
conclusionWhile protopathic bias could not fully be ruled out, and computational challenges necessitated compromises in the analysis, the g-formula and target trial emulation proved useful: Self-inflicted biases were avoided, observed time-varying confounding was adjusted for, and the estimated risks have a clear causal interpretation.
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