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

Authors
 Hyun-Soo Zhang  ;  Yeunsoo Yang  ;  Sunmi Lee  ;  Sohee Park  ;  Chung Mo Nam  ;  Sun Ha Jee 
Citation
 INTERNATIONAL JOURNAL OF COLORECTAL DISEASE, Vol.37(8) : 1827-1834, 2022-08 
Journal Title
INTERNATIONAL JOURNAL OF COLORECTAL DISEASE
ISSN
 0179-1958 
Issue Date
2022-08
MeSH
Bias ; Colorectal Neoplasms* / complications ; Colorectal Neoplasms* / epidemiology ; Diabetes Mellitus, Type 2* / complications ; Diabetes Mellitus, Type 2* / drug therapy ; Diabetes Mellitus, Type 2* / epidemiology ; Humans ; Hypoglycemic Agents / adverse effects ; Incidence ; Metformin* / therapeutic use ; Risk Factors
Keywords
Bias (epidemiology) ; Chemoprevention ; Colorectal neoplasms ; Metformin ; Pharmacoepidemiology
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.
Full Text
https://link.springer.com/article/10.1007/s00384-022-04212-9
DOI
10.1007/s00384-022-04212-9
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Preventive Medicine (예방의학교실) > 1. Journal Papers
4. Graduate School of Public Health (보건대학원) > Graduate School of Public Health (보건대학원) > 1. Journal Papers
Yonsei Authors
Nam, Chung Mo(남정모) ORCID logo https://orcid.org/0000-0003-0985-0928
Park, So Hee(박소희) ORCID logo https://orcid.org/0000-0001-8513-5163
Jee, Sun Ha(지선하) ORCID logo https://orcid.org/0000-0001-9519-3068
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/193418
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