Efficacy of Luseogliflozin Added to Semaglutide in Patients With Metabolic Dysfunction-Associated Steatohepatitis and Type 2 Diabetes Mellitus: A Randomised, Open-Label Trial.

AIMS: Type 2 diabetes drives the progression of metabolic dysfunction-associated steatohepatitis (MASH). We evaluated whether antidiabetic therapy, specifically adding sodium-glucose cotransporter 2 (SGLT2) inhibitor to a glucagon-like peptide-1 receptor agonist (GLP-1RA), improves liver histology in adults with biopsy-proven MASH and type 2 diabetes. MATERIALS AND METHODS: In this 52-week, open-label, randomised, parallel-group trial in Japan, adults with biopsy-confirmed MASH and type 2 diabetes received semaglutide plus luseogliflozin or semaglutide alone at antidiabetic doses. Paired liver biopsies at baseline and Week 52 were evaluated by blinded pathologists. Primary histological endpoints included resolution of MASH without worsening fibrosis, ≥ 1-point improvement in the non-alcoholic fatty liver disease (NAFLD) activity score without worsening fibrosis and ≥ 1-stage improvement in fibrosis without worsening MASH. RESULTS: Sixty participants were randomised (combination, n = 24; monotherapy, n = 36). At Week 52, all histological endpoints numerically favoured combination therapy. Resolution of MASH without worsening fibrosis occurred in 34.9% versus 19.4%, ≥ 1-point improvement in the NAFLD activity score (NAS) in 75.5% versus 55.6% and ≥ 1-stage fibrosis improvement in 26.9% versus 13.9%. In the pre-specified per-protocol analysis, ≥ 1-point improvement in the NAS was nominally significant. Combination therapy reduced body weight, glycated haemoglobin levels, aminotransferase levels and FibroScan-derived liver stiffness. CONCLUSIONS: In the pre-specified full analysis set, combination therapy at antidiabetic doses did not significantly improve pre-specified histological endpoints compared with monotherapy. In the pre-specified per-protocol analysis, a nominal improvement in the NAS was observed. Combination therapy improved body weight, glycemic control, aminotransferase levels and liver stiffness, with no new safety concerns identified. TRIAL REGISTRATION: UMIN Clinical Trials Registry (UMIN-CTR): UMIN000045003; Japan Registry of Clinical Trials (jRCT): jRCTs061210009.