Lower Incidence of Gastrointestinal Cancers in Sodium Glucose Co-Transporter-2 Inhibitor-Treated Patients With Type 2 Diabetes Mellitus: A Population-Based Cohort Study in the United States

Introduction: The relationship between T2DM and cancer has been a topic of interest, with studies showing that hyperglycemic patients associated with higher risks of developing cancers, including colorectal, hepatocellular, and endometrial cancer. The use of antidiabetic medications such as metformin and GLP-1RA has been explored in relation to cancer incidence. Yet, the effect of SGLT2i on gastrointestinal (GI) cancer incidence remains unclear. Our study aims to assess the association between SGLT2i and various GI cancers in patients with T2DM compared to other oral antidiabetic drugs. Methods: A population-based cohort study including patients with T2DM from 92 hospitals across the US was conducted from 2013 to 2023. Inclusion criteria were patients with T2DM who newly initiated treatment with SGLT2i, DPP4i, or GLP-1RA. Patients with a history of T1DM or malignancies were excluded. Propensity score matching was applied to account for confounding factors. The primary outcome was the occurrence of digestive organ cancers, including esophageal, gastric, small intestinal, colorectal, rectal, anal, hepatic, biliary, and gallbladder malignancies. Kaplan-Meier analysis and log-rank tests were used to compare the outcomes across cohorts, while hazard ratios and corresponding 95% CIs were calculated via the Cox proportional regression model. Results: A total of 718,276 first line SGLT2i initiators matched to 1,159,112 DPP4i initiators diagnosed with T2DM were included in the study. Among these, 5,072 incidents of colon cancer were identified, with 1,789 (0.25%) occurring in SGLT2i groups and 3,283 (0.46%) in DPP4i group after matching. Colon cancer was the most commonly observed digestive organ malignancy, followed by hepatic and intrahepatic bile duct cancer. SGLT2i initiators demonstrated a significantly reduced risk of the new-onset of all composite digestive organ cancer compared to those using DPP4i (HR, 0.85; 95% CI, 0.82 to 0.88), including gastric cancer (HR, 0.84; 95% CI, 0.74 to 0.945, P=0.005), liver and intrahepatic bile duct cancer (HR, 0.87; 95% CI, 0.81 to 0.95) and colon cancer (HR, 0.781; 95% CI, 0.74 to 0.83, P< 0.001). Conclusion: The study showed a notable reduction in the risk of developing various GI cancers in individuals with T2DM who received SGLT2i, compared to those treated with DPP4i or GLP-1RA. These findings emphasize the therapeutic potential of SGLT2i in preventing GI malignancies in T2DM patients. Additional clinical trials are needed to further investigate their applications.