Background: The mortality of colorectal cancer remains high despite the development of novel anti-neoplastic agents. Preclinical studies have shown that colorectal cancer upregulates the expression of sodium-glucose cotransporter 2 (SGLT2) channels and inhibition of these channels by SGLT2 inhibitors (SGLT2i) reduces tumor proliferation. We aimed to investigate the impact of SGLT2i on the outcome of patients with colorectal cancer. Methods: We conducted a retrospective cohort study by including all adult patients with colorectal adenocarcinoma and type 2 diabetes mellitus in two tertiary centers in Taiwan. SGLT2i and non-SGLT2i patients were matched 1:1 based on age, sex, and cancer stage. The primary outcome was overall survival (OS) and progression-free survival (PFS), and the secondary outcomes were previously reported serious adverse events associated with the use of SGLT2i. Results: We identified 1347 patients with colorectal cancer and type 2 diabetes mellitus, from which 92 patients in the SGLT2i cohort were matched to the non-SGLT2i cohort. Compared to non-SGLT2i recipients, SGLT2i recipients had a higher rate of OS (5-year OS: 86.2% [95% CI: 72.0-93.5] vs. 62.3% [95% CI: 50.9-71.8], p = 0.013) and PFS (5-year PFS: 76.6% [95% CI: 60.7-86.7] vs. 57.0% [95% CI: 46.2-66.4], p = 0.021). In Cox proportional hazard analyses, the use of SGLT2i was associated with a 50-70% reduction in the risk of all-cause mortality and disease progression. The rate of cancer-associated mortality was lower in the SGLT2i group (7% vs. 21%, p = 0.005). SGLT2i were not associated with an increased risk of sepsis, hypoglycemia, or acute kidney injury. We did not detect any cases of urosepsis or diabetic ketoacidosis in the SGLT2i group. Conclusions: The use of SGLT2i was associated with a higher rate of survival in colorectal cancer patients with diabetes mellitus.

^aAdjusted for age, sex, cancer stage, Eastern Cooperative Oncology Group (ECOG) Performance Status, chemotherapy regimen, radiotherapy, hypertension, hyperlipidemia, chronic kidney disease, and chronic obstructive pulmonary disease.