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

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.