Association of dual SGLT-2 inhibitor and GLP-1 receptor agonist therapy with colon cancer risk in post-polypectomy patients with diabetes: a target trial emulation

Patients with type 2 diabetes mellitus (T2DM) have an elevated risk of colorectal cancer. SGLT-2 inhibitors and GLP-1 receptor agonists have demonstrated potential anticancer properties through distinct mechanisms. However, the association of combination therapy with colon cancer risk remains unknown. We conducted a target trial emulation using the TriNetX Global Collaborative Network (2017–2025). Adults with T2DM and a history of polypectomy receiving dual therapy (SGLT-2 inhibitor plus GLP-1 receptor agonist) were compared with SGLT-2 inhibitor monotherapy using 1:1 propensity score matching without replacement. A new-user design and 180-day landmark analysis were employed to address immortal time bias. The primary outcome was incident colon cancer. Secondary outcomes included colectomy, other gastrointestinal cancers, cardiovascular events, renal outcomes, and all-cause mortality. Bonferroni correction was applied for multiple secondary comparisons (α = 0.05/11 = 0.0045). After propensity score matching, 28,934 patients were included in each group. Dual therapy was associated with a lower risk of colon cancer compared with SGLT-2 inhibitor alone (HR 0.786, 95% CI 0.671–0.919; P = 0.003), representing a 21% relative risk reduction (NNT = 490 over 5 years). Significant reductions were also observed in 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, supporting study validity. In post-polypectomy T2DM patients, dual therapy was associated with a 21% lower risk of colon cancer versus SGLT-2 inhibitor monotherapy. Co-primary analysis demonstrated this association also persisted when comparing dual therapy against GLP-1 receptor agonist monotherapy alone (HR 0.871; P = 0.041), indicating additive chemopreventive effects of the combination warranting prospective investigation.