SGLT2 inhibitors and the risk of hepatocellular carcinoma in patients with MASLD and Type 2 diabetes

Background: - Hepatocellular carcinoma (HCC) is increasingly driven by non-viral causes, especially metabolic dysfunction–associated steatotic liver disease (MASLD), which is common in type 2 diabetes mellitus (T2D). No pharmacologic agent is currently approved for HCC chemoprevention. Objective: - To evaluate the association between sodium–glucose cotransporter-2 inhibitor (SGLT2i) use and risks of HCC and all-cause mortality in patients with MASLD and T2D. Design: - Multinational, retrospective cohort study using the TriNetX federated electronic health record network (2005–2025). Adults aged 18–90 years with non-viral MASLD and pre-existing T2D were identified. We applied a 1-year washout, used an active-comparator design, and performed 1:1 propensity score matching. Adjusted hazard ratios (aHRs) were estimated with Cox models. Results: - After matching, 93,930 SGLT2i users were compared with 93,930 active comparators with excellent covariate balance. Median follow-up was 3.24 years (IQR 1.72–5.09) in the SGLT2i group and 3.25 years (IQR 1.72–5.08) in comparators. HCC occurred in 43 (0.05 %) SGLT2i users vs 74 (0.08 %) comparators (aHR 0.43; 95 % CI 0.29–0.63). All-cause mortality was 5.32 % vs 10.50 % (aHR 0.34; 95 % CI 0.33–0.35). Results were consistent across subgroups and sensitivity analyses, including time-anchored landmark analyses. Risk reductions were also observed for liver fibrosis/cirrhosis and hepatic nodules. Conclusions: - Among patients with MASLD and T2D, SGLT2 inhibitor use was associated with lower risks of HCC and all-cause mortality compared with active comparators. While residual confounding cannot be excluded, these findings support prospective evaluation of SGLT2 inhibitors for liver-related risk reduction in this population.