The effect of combined sodium-glucose cotransporter-2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonist (GLP1RA) therapy on colorectal cancer risk in type 2 diabetes mellitus (T2DM) remains uncertain. A target trial emulation published in the Diabetology & Metabolic Syndrome evaluated colon cancer outcomes in patients receiving dual therapy compared with SGLT2i monotherapy.

The analysis used data from the TriNetX Global Collaborative Network between 2017 and 2025 and included adults with T2DM and a history of polypectomy. A new-user design and 180-day landmark analysis were applied to reduce immortal time bias. Patients receiving SGLT2i plus GLP1RA were matched 1:1 with those receiving SGLT2i alone using propensity score matching. The primary outcome was incident colon cancer, and secondary outcomes included colectomy, gastrointestinal cancers, cardiovascular and renal events, and all-cause mortality.

After matching, 28,934 patients were included in each group. Dual therapy was associated with a lower risk of colon cancer compared with SGLT2i alone (HR 0.786; 95% CI 0.671-0.919; P=0.003), corresponding to a 21% relative risk reduction with a number needed to treat 490 over 5 years. Lower risks were also observed for colectomy (HR 0.456), other gastrointestinal cancers (HR 0.690), end-stage renal disease (HR 0.808), major adverse kidney events (HR 0.710), and all-cause mortality (HR 0.658). Negative control outcomes showed no meaningful differences.

A co-primary analysis comparing dual therapy with GLP1RA monotherapy showed a similar association (HR 0.871; P=0.041). These findings indicate that dual therapy was associated with lower colon cancer risk in this population. The observational design supports interpretation as hypothesis-generating, and prospective studies are needed for confirmation.