Avoiding Time-Related Biases: A Feasibility Study on Antidiabetic Drugs and Pancreatic Cancer Applying the Parametric g-Formula to a Large German Healthcare Database

• Published in: Clinical epidemiology 2021-01, Vol.13, p.1027-1038
• Main Authors: Börnhorst, Claudia, Reinders, Tammo, Rathmann, Wolfgang, Bongaerts, Brenda, Haug, Ulrike, Didelez, Vanessa, Kollhorst, Bianca
• Format: Article
• Language: English
• Subjects: Analysis; Antidiabetics; Cancer; Cancer therapies; Cardiovascular disease; Clinical medicine; Diabetes; Diabetes therapy; Drug dosages; Drug therapy; electronic health data; Epidemiology; Feasibility studies; Glucose; Health insurance; Hypoglycemic agents; Kidney diseases; Liver diseases; Medical screening; Oncology, Experimental; Online databases; Original Research; Pancreatic cancer; parametric g-formula; Substance abuse treatment; target trial emulation; time-dependent confounding; time-related bias; Type 2 diabetes; type-2 diabetes mellitus
• ISSN: 1179-1349; 1179-1349
• DOI: 10.2147/CLEP.S328342

Investigating 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. Based 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. Over 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. While 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.