- 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).

- 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.

- We included 11,726 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.

- 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.