Metformin use is not associated with colorectal cancer incidence in type-2 diabetes patients: evidence from methods that avoid immortal time bias

Abstract

Purpose: Immortal time bias (ITB) continues to distort many observational studies on metformin use and cancer risk. Our objective was to employ three statistical methods proven to avoid ITB and compare their results to that of a naïve time-fixed analysis in order to provide further evidence of metformin's association, or none thereof, with colorectal cancer (CRC) incidence.

Methods: A total of 41,533 Korean subjects with newly diagnosed type-2 diabetes in 2005-2015 were selected from a prospectively maintained cohort (median follow-up of 6.3 years). Time-to-CRC incidence was regressed upon metformin use (yes/no, average prescription days/year) using time-dependent Cox, landmark, nested case-control, and time-fixed Cox analyses. Other CRC risk factors were included to adjust for possible confounding.

Results: Neither metformin ever-use nor average metformin prescription days/year was associated with incident CRC hazard in time-dependent Cox, landmark, and nested case-control analyses with HR (95% CI) of 0.88 (0.68-1.13), 0.86 (0.65-1.12), and 1.10 (0.86-1.40) for metformin ever-use, and 0.97 (0.90-1.04), 0.95 (0.88-1.04), and 1.02 (0.95-1.10) for average metformin prescription days/year, respectively. In contrast, time-fixed Cox regression showed a falsely exaggerated protective effect of metformin on CRC incidence.

Conclusion: The association between metformin use and subsequent CRC incidence was statistically nonsignificant after accounting for time-related biases such as ITB. Previous studies that avoided these biases and meta-analyses of RCTs on metformin and cancer incidence were in agreement with our results. A definitive, large-scale RCT is needed to clarify this topic, and future observational studies should be explicit in avoiding ITB and other time-related biases.