Association of SGLT2 Inhibitors with Reduced Hepatocellular Carcinoma Risk in Patients with Type 2 Diabetes

Background and aims: Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are widely prescribed for type 2 diabetes mellitus (T2DM) and may confer hepatoprotective effects. This study investigated their association with hepatocellular carcinoma (HCC) risk compared with other antidiabetic medications. Methods: We conducted a retrospective cohort study using the electronic health records from Mass General Brigham (Boston, USA) and Asan Medical Center (Seoul, Korea) from 2013 to 2024. Adults with T2DM newly initiating SGLT2i, dipeptidyl peptidase-4 inhibitor (DPP4i), glucagon-like peptide-1 receptor agonist (GLP-1RA), or sulfonylureas were included. A 6-month landmark analysis was employed to minimize early event bias. Inverse probability weighting combined with Fine-Gray competing risk models estimated subdistribution hazard ratios (SHRs) for incident HCC, accounting for transplant and death as competing events. Results: After weighting, data from 6,733 SGLT2i, 4,495 GLP-1RA, 23,229 DPP4i, and 17,034 sulfonylurea initiators were analyzed. Over a median follow-up of 3.9 years (277,155 person-years), 623 HCC cases occurred. SGLT2i use was associated with significantly lower HCC risk versus sulfonylureas (SHR 0.44, 95% CI: 0.25–0.79) and DPP4i (SHR 0.53, 95% CI: 0.30–0.93). The comparison with GLP-1RA showed comparable risk (SHR 0.87, 95% CI: 0.40–1.91). Subgroup analyses demonstrated consistent protective associations of SGLT2i in patients ≤65 years, males, and those with chronic liver disease. Sensitivity analyses, including 12-month landmark analysis and adjustments for additional confounders, confirmed robustness of findings. Conclusions: SGLT2 inhibitor therapy was associated with reduced risk of HCC compared with DPP4 inhibitors and sulfonylureas, supporting their potential chemopreventive role in patients with T2DM.