Abstract

Background: The effects of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) on liver and renal outcomes in patients with type 2 diabetes mellitus (T2DM) were demonstrated in recent trials. However, the magnitude of benefits associated with underlying metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear. We aimed to explore the risk of adverse liver and renal outcomes in patients with MASLD and T2DM taking SGLT-2i vs. dipeptidyl peptidase-4 inhibitors (DPP-4i) and glucagon-like peptide-1 receptor agonists (GLP-1RA).

Methods: We conducted a population-based, multicenter cohort study with consecutive patients diagnosed with MASLD (without cirrhosis) and T2DM using the TriNeTx dataset. Cohort entry was defined as the date of the first-ever prescription for one of the drugs of interest (SGLT-2i, GLP-1RA, or DPP-4i) during the study period. We used a lag of 6 months for all exposures to minimize protopathic bias. We performed a 1:1 propensity score matching (PSM) to reduce confounding effects. The primary outcomes were defined as the first incidence of cirrhosis, the composite outcome of hepatic decompensation events, and hepatocellular carcinoma (HCC). Secondary outcomes included composite outcome of chronic kidney disease (CKD), composite endpoint of a severe stage of CKD (stages 4-5), and need for hemodialysis. We conducted secondary mad sensitivity analyses to assess the robustness of our findings. The outcomes were estimated using a Cox proportional hazards model with hazard ratios (HR) and 95% confidence intervals (CI).

Results: In this cohort, 47890 patients received SGLT-2i, and 45160 patients receiving DPP4i were included as controls. After PSM, 43758 patients were followed for a median of 1.9 years. For sensitivity analysis, 59205 were included in the GLP-1RA group. Compared with DPP4i use, SGLT-2i use was associated with a lower risk of incident cirrhosis (HR, 1.01), hepatic decompensation (HR 1.03), and HCC (HR 1.07). Similarly, secondary outcomes composite CKD, severe stages of CKD, and need for hemodialysis. The SGLT2i group was non-inferior to the GLP-1RA group in terms of liver outcomes: the incidence of cirrhosis (HR 1.0),, hepatic decompensation (HR 0.99) and HCC(HR 0.89) was similar compared with the SGLT-2i group. Sensitivity analysis showed a similar magnitude to the primary and secondary analyses.

Conclusion: In patients with MASLD and T2DM, SGLT-2i use was associated with significantly reduced risks of adverse liver and renal outcomes compared with DPP4i. SGLT-2i was not inferior to GLP1-RA for adverse liver outcomes but showed a significantly lower incidence.