Background and Aims: Sodium-glucose cotransporter-2 (SGLT2) inhibitors have shown promise in metabolic dysfunction-associated steatotic liver disease (MASLD). This large real-world study aimed to evaluate the effects of SGLT2 inhibitors on MASLD patients’ clinical outcomes and liver-related complications over extended follow-up. Patients and Method: Data were sourced from TriNetX, a global health research platform with de-identified electronic medical records spanning 135 million patients across 112 healthcare organizations worldwide. We included MASLD adults diagnosed according to ICD9/10 criteria. Following propensity score matching based on 34 variables (demographics, comorbidities, laboratory tests and medication history), SGLT2 inhibitor-treated (n = 19,922) patients were compared with non-SGLT2 inhibitor (n = 19,922) cases. Exclusion criteria included baseline improved alanine aminotransferase (ALT) and alkaline phosphatase (ALP) levels > 4 upper normal limit (UNL), baseline advanced liver disease, liver transplant and cancer, past anticoagulation and non-MASLD etiologies. Assessed outcomes included survival, biochemical, hematologic, AFP, metabolic and cardiovascular parameters, progression to advanced liver disease (ALD), synthetic function, and metabolic markers over 1, 5, and 10 years. Results: Following matching, both cohorts were well-balanced across baseline characteristics. After one year, the SGLT2 inhibitor group demonstrated significantly reduced BMI (33.2 ± 6.2 vs. 34.1 ± 6.5 kg/m², p < 0.001), improved ALT (40.3 ± 31.5 vs. 48.3 ± 41.2 U/L, p < 0.001), and better glycemic control (HbA1c 7.35 ± 1.51% vs. 7.93 ± 1.72%, p < 0.001). The SGLT2 inhibitor group showed higher 10-year survival rates (95.00% vs. 88.69%, p < 0.001), fewer cardiovascular events (10.19% vs. 11.80%, p < 0.001), and markedly reduced progression to advanced liver disease (6.90% vs. 14.15%, p < 0.001). These benefits were consistent across clinical, laboratory, and medication-defined ALD categories. Notably, rates of hepatic decompensation events were significantly lower with SGLT2 inhibitor therapy. Conclusions: In this large real-world cohort, SGLT2 inhibitor use in MASLD patients was associated with significantly improved long-term survival, cardiovascular, and liver-related outcomes over 10 years of follow-up. These benefits likely result from combined metabolic improvements, anti-inflammatory effects, and direct hepatoprotective mechanisms. SGLT2 inhibitors represent a promising therapeutic strategy for improving outcomes in MASLD.

Introduction: Semaglutide (SEMA) has shown potential benefits in metabolic dysfunction-associated steatotic liver disease (MASLD). This large real-world study aimed to evaluate the effects of SEMA on MASLD patients’ clinical outcomes and liver-related complications. Results: Following propensity score matching based on 34 variables (demographics, comorbidities, laboratory tests, and medication history), SEMA-treated (n = 19,112) patients were compared with non-SEMA (n = 19,112) cases. Both cohorts were well-balanced, except for higher BMI in the SEMA group (36.60 ± 6.25 vs. 34.89 ± 6.84 kg/m²). After one year, the SEMA group demonstrated ~one BMI point reduction but maintained significantly higher BMI (35.51 ± 6.34 vs. 34.11 ± 6.64, p < 0.001). LDL, triglycerides, and HbA1c levels significantly improved with SEMA, as evidenced by decreased rates of poor metabolic markers (31.13% vs. 34.32%, p < 0.001). The SEMA-treated patients demonstrated significantly higher survival, lower cardiovascular risk, and reduced progression to advanced liver disease compared to controls. Discussion: In this large real-world cohort, SEMA use in MASLD patients was associated with significantly improved 1-year survival, cardiovascular, and liver-related outcomes. These benefits appear to result primarily from metabolic improvements and anti-inflammatory effects. Materials and Methods: Data were sourced from TriNetX, a global health research platform with de-identified electronic medical records spanning 135 million patients across 112 healthcare organizations worldwide. We included MASLD adults diagnosed according to ICD9 criteria. Assessed outcomes included survival, biochemical, hematologic, AFP, metabolic and cardiovascular parameters, advanced liver disease (ALD), synthetic function, and metabolic markers. Conclusions: Semaglutide may serve as an effective therapeutic strategy to improve outcomes in MASLD.