The association between sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and cancer risk in type 2 diabetes mellitus (T2DM) patients remains controversial. This study aimed to investigate whether SGLT-2i use is associated with a reduced risk of overall or site-specific cancer. Using the Shenzhen Public Health Data Platform, we emulated a target trial with an active-comparator, new-user design. Dipeptidyl peptidase-4 inhibitors (DPP-4i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) were used as reference medications. Hazard ratios (HRs) and 95% confidence intervals (CIs) were assessed using overlapping weighting-based Cox proportional hazards models. The cohort included 134,481 patients when using DPP-4i as comparator. During a median follow-up of 1.8 years, 1848 (2.2%) and 1557 (3.0%) cancer cases were identified among SGLT-2i and DPP-4i users. After adjusting for confounders, SGLT-2i was associated with a lower risk of overall cancer compared with DPP-4i (HR: 0.91; 95% CI: 0.85-0.98). A negative association was observed for site-specific cancers, including lung (HR: 0.84; 95% CI: 0.72-0.98) and thyroid cancer (HR: 0.76; 95% CI: 0.61-0.96). In the comparison between SGLT-2i and GLP-1RA, 3371 (2.58%) cancer cases occurred. After adjustment, no significant difference in overall cancer risk was observed between SGLT-2i and GLP-1RA users (HR: 1.03; 95% CI: 0.85-1.25). SGLT-2i was associated with a reduced risk of lung and thyroid cancers compared with DPP-4i, while no statistically significant difference was observed relative to GLP-1RA. These findings provide supportive evidence for the safety of SGLT-2i regarding carcinogenic risk and suggest its potential role in cancer prevention strategies among T2DM patients.
