Sodium–Glucose Cotransporter 2 Inhibitor Use and Risk of Liver-Related Events in Patients With Type 2 Diabetes: A Meta-analysis of Observational Cohort Studies
Alessandro Mantovani, Riccardo Morandin, Maria Giovanna Lando, Veronica Fiorio, Grazia Pennisi, Salvatore Petta, Norbert Stefan, Herbert Tilg, Christopher D. Byrne, Giovanni Targher
Abstract
BACKGROUND: There is uncertainty regarding effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors on the risk of major adverse liver-related outcomes (MALOs). PURPOSE: We performed a meta-analysis of observational cohort studies to quantify the magnitude of the association between SGLT2 inhibitor use and risk of developing MALOs for people with type 2 diabetes mellitus (T2DM). DATA SOURCES: We systematically reviewed three large electronic databases from inception to January 2025. STUDY SELECTION: We included active-comparator, new-user cohort studies with comparison of SGLT2 inhibitors versus other glucose-lowering medications in patients with T2DM. DATA EXTRACTION: The primary outcome was incidence rate of MALOs defined as a composite of hepatic decompensation events, hepatocellular carcinoma, liver transplantation, or liver-related deaths. Secondary outcomes included each of the above as individual events. Meta-analysis was performed with random-effects models. DATA SYNTHESIS: We identified eight cohort studies with aggregate data on 626,104 patients with T2DM (397,806 SGLT2 inhibitor new users and 228,298 new users of other glucose-lowering agents). During a median of 2.7 years, SGLT2 inhibitor use was associated with significantly lower risk of MALOs (random-effects hazard ratio 0.83, 95% CI 0.72-0.95; I2 = 83.1%) and liver-related deaths (0.64, 0.50-0.82; I2 = 0%). The significant risk reduction in MALOs was observed in comparisons of SGLT2 inhibitors with dipeptidyl peptidase 4 inhibitors, metformin, or pioglitazone but not glucagon-like peptide 1 receptor agonists. Sensitivity analyses did not modify these results. A funnel plot did not show significant publication bias. LIMITATIONS: Observational design of the cohort studies and high level of heterogeneity are the main limitations. CONCLUSIONS: SGLT2 inhibitor use was associated with lower risk of MALOs for patients with T2DM.