Comparative risk of fibrosis progression with sodiumglucose cotransporter-2 vs. dipeptidyl peptidase-4 inhibitors in metabolic dysfunction-associated steatotic liver disease and type 2 diabetes mellitus with low-tointermediate fibrosis

Background/Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing cause of cirrhosis and its complications. Given its close association with type 2 diabetes mellitus (T2DM), evaluating whether sodium-glucose cotransporter-2 inhibitors (SGLT2is) can mitigate the progression of liver fibrosis is clinically important. We examined the association between SGLT2i use and liver fibrosis progression in patients diagnosed with MASLD and T2DM. Methods: We conducted a target trial emulation study using a retrospective, active comparator new-user design among adults with MASLD, T2DM, and low-to-intermediate Fibrosis-4 (FIB-4≤2.67) scores who initiated treatment with either SGLT2is or dipeptidyl peptidase-4 inhibitors (DPP-4is) at Mass General Brigham or Asan Medical Center from 2013 to 2023. The primary outcome was the progression to advanced fibrosis (FIB-4>2.67), confirmed on ≥2 occasions within 1 year. The secondary outcome was the development of major adverse liver outcomes (MALO), including incident cirrhosis, decompensation events, hepatocellular carcinoma, or liver transplantation. Results: Among 16,901 eligible patients, 2,571 propensity score-matched pairs were identified with balanced baseline characteristics. During follow-up (median, 3.7 years), fibrosis progression occurred at a rate of 3.46/100 personyears in SGLT2i users and 4.44 in DPP4i users. SGLT2i use was associated with a lower risk of fibrosis progression (HR 0.78, 95% CI 0.67–0.89; P<0.001). No significant difference in MALO incidence was observed. Subgroup analyses showed a consistent association among users of metformin, statins, and aspirin. Conclusions: SGLT2i use was associated with reduced risk of fibrotic progression compared to DPP4i use in adults with MASLD and T2DM.