1. Kevin Ma, MD

Among patients with type 2 diabetes mellitus (T2DM), treatment with sodium-glucose cotransporter-2 inhibitors (SGLT2i) has been shown to significantly reduce the risk of several solid organ tumors compared to dipeptidyl peptidase 4 inhibitors (DPP4i). This study aimed to investigate the impact of SGLT2i treatment on the incidence of gastrointestinal cancers in patients with T2DM. This population-based cohort study included adult patients with T2DM in the United States initiating SGLT2i and DPP4i between 2013 and 2023. Propensity score matching was performed to balance baseline covariates between two cohorts. Primary outcomes assessed were new-onset gastrointestinal cancers, including malignancies of the esophagus, stomach, small intestine, colon, rectum, anus, liver, bile duct, gallbladder, and pancreas. Hazard ratios (HRs) and log-rank tests were derived using Cox proportional hazards regression models. Subgroup analyses stratified by sex and age were also conducted. A total of 460,216 SGLT2i initiators and 748,385 DPP4i initiators were included. After propensity score matching, SGLT2i initiators demonstrated a significantly lower risk of new-onset digestive organ cancer compared to those initiating DPP4i (HR= 0.609, 95% CI=0.575-0.646, log-rank p<0.001), including gastric cancer (HR=0.545, 95% CI=0.448-0.661, log-rank p<0.001), liver and intrahepatic bile duct cancer (HR=0.643, 95% CI=0.570-0.725, log-rank p<0.001) and colon cancer (HR=0.533, 95% CI=0.483-0.588, log-rank p<0.001). Consistent findings were observed in subgroup analyses stratified by sex and age, for which treatment with SGLT2i was associated with a significantly reduced risk of gastrointestinal malignancies compared to DPP4i among females (HR=0.648, 95% CI=0.592, 0.709, log-rank p<0.001) and males (HR=0.567, 95% CI=0.526-0.612, log-rank p<0.001), and among patients aged between 40 and 59 years, as well as those aged over 60 years. In conclusion, patients with T2DM treated with SGLT2i presented with a significantly lower risk of gastrointestinal cancers. Clinical trials are warranted to validate the safety of SGLT2i in patients with malignancies.