Risk of Hepatic Events Associated with Sodium-glucose cotransporter-2 Inhibitors in Patients with Type 2 Diabetes: A Nationwide Cohort Study

Background: Data from several randomized trials have shown that sodium-glucose co-transporter 2 (SGLT2) inhibitors may have promising effects on early-stage liver disease (eg, fibrosis). However, the hepatic benefits of SGLT2 inhibitors for advanced liver diseases in patients with type 2 diabetes (T2D) is yet to be addressed and warrants further research.

Objectives: To estimate the risk of hepatic events associated with the use of SGLT2 inhibitor versus dipeptidyl peptidase-4 (DPP4) inhibitors in patients with T2D.

Methods: We conducted an active comparator, new user cohort by using the nationwide health insurance claims data of South Korea. We included patients with T2D who were newly prescribed a SGLT2 inhibitor or a DPP4 inhibitor between 1 Sep 2014 and 31 Dec 2020. Patients were followed from the date of initiation of study drugs until the earliest of occurrence of a hepatic event, treatment discontinuation/switching, all-cause death, or end of study period (31 Dec 2020). The primary outcome was major hepatic events, a composite end point comprised of liver-cause death, liver failure, and hepatic decompensation events. The secondary outcomes were the individual components of the primary outcome, liver cirrhosis, and all-cause death. We estimated hazard ratios (HR) with 95% confidence intervals (CI) using Cox proportional hazard models within the propensity score-matched cohort.

Results: After 1:1 propensity score matching, we identified 228,754 patients with a mean age of 54.0 years and 58.9% male. Use of SGLT2 inhibitors, as compared with DPP4 inhibitors, was associated with a 43% decreased risk of major hepatic events (HR 0.57, 95% CI 0.45-0.72). The HRs for the secondary outcomes showed similar findings with 0.65 (0.52-0.82) for compensated liver cirrhosis, 0.56 (0.44-0.71) for hepatic decompensation events, 0.34 (0.11-1.09) for liver transplant, 0.64 (0.37-1.11) for liver-cause death and 0.63 (0.56-0.72) for all-cause death. Subgroup analyses showed no statistically significant findings when stratified on the history of baseline chronic liver disease, insulin use, and thiazolidinedione use. Our main findings remained robust in a sensitivity analysis that a subset of patients with laboratory test results (HR 0.66, 0.49-0.74).

Conclusions: In this nationwide cohort study, SGLT2 inhibitors were significantly associated with lower risks of major hepatic events, hepatic decompensation events, and decompensated liver cirrhosis, suggesting potential hepatic benefits among patients with type 2 diabetes. Given that T2D is a risk factor for liver disease, our findings provide real-world evidence for SGLT2 inhibitors to be considered as a therapeutic option to prevent or delay hepatic deterioration among patients with T2D.