Reduced risks of colorectal cancer with GLP-1RAs in type 2 diabetes: A nationwide cohort study using a target trial emulation framework - 11/08/25

Doi : 10.1016/j.diabet.2025.101695

Chih-Chien Wu ^a,^b, Chien-Chou Su ^c, Yu-Ching Chang ^d, Pei-Ting Lee ^e,^f, Yi-Chia Su ^d,^e,^g,^h,^⁎
^a Division of Colorectal Surgery, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
^b Department of Surgery, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
^c Clinical Innovation and Research Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
^d Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
^e Department of Pharmacy, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
^f Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan
^g Department of Pharmacy, School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
^h Department of Nursing, Shu-Zen Junior College of Medicine and Management, Kaohsiung, Taiwan

^⁎Correspondence to: Yi-Chia Su, Department of Pharmacy, Kaohsiung Veterans General Hospital, No. 386, Dazhong 1st Rd., Zuoying Dist., Kaohsiung City 813414, TaiwanDepartment of PharmacyKaohsiung Veterans General HospitalNo. 386, Dazhong 1st Rd., Zuoying Dist.Kaohsiung City813414Taiwan

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Abstract

Aim

- Type 2 diabetes (T2D) is associated with increased risk of colorectal cancer (CRC). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) may reduce CRC risk compared to insulin therapy; however, current evidence is controversial. We aimed to evaluate the association between CRC and the use of GLP-1RAs and long-acting insulins (LAIs).

Methods

- This target trial emulation employed nationwide data from a Taiwanese T2D cohort. We identified new GLP-1RA and LAI users from 2013 to 2021, and applied propensity score (PS) matching to ensure comparable baseline characteristics. The primary outcome was CRC. Follow-up lasted until outcome occurrence, death, or study end in 2022, whichever came first. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to assess the association between treatment and outcomes. Sensitivity analyses—including stabilized inverse probability weighting, time-dependent survival analysis, E-values, and negative control outcome analyses—were conducted to test the robustness of findings.

Results

- We included 11726 PS-matched pairs of GLP-1RA and LAI users and found no significant baseline disparities between cohorts. Compared to LAIs, GLP-1RAs were associated with significantly reduced CRC risk (HR [95% CI]: 0.66 [0.48–0.92]), with the association limited to the rectum (HR: 0.53 [0.28–0.92]) but not observed in the right- or left-sided colon (right, HR: 0.69 [0.41–1.19]; left, HR: 0.77 [0.44–1.33]). These findings were consistent across sensitivity analyses and among patients with varying baseline characteristics.

Conclusion

- Among patients with T2D requiring injectable glucose-lowering agents, GLP-1RA use, compared to LAIs, was associated with reduced CRC risk, particularly in the rectum.

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Keywords : Colorectal cancer risk, Glucose-lowering agents, Glucagon-like peptide-1 receptor agonists, Long-acting insulins, Type 2 diabetes

Abbreviations : CI, CRC, GLA, GLP-1RA, HR, IPTW, ITT, LAI, NHIRD, PS, RCT, SMD, T2D, TCR