Hepatic and metabolic effects of SGLT2 inhibitors in type 2 diabetes and MASLD assessed by metabolomic and lipidomic analysis

Abstract

Sodium–glucose cotransporter-2 (SGLT-2) inhibitors show promising hepatic benefits in patients with metabolic dysfunction–associated steatotic liver disease (MASLD); however, their effects on underlying metabolic mechanisms remain unclear. This study included 29 patients with type 2 diabetes mellitus (T2DM) and MASLD who initiated SGLT-2 inhibitor therapy. Hepatic fat content was assessed using advanced ultrasound techniques, including tissue attenuation imaging (TAI) and tissue scatter distribution imaging (TSI). Biochemical analyses, gas chromatography–mass spectrometry (GC–MS) based metabolomics, and liquid chromatography–mass spectrometry (LC–MS)–based lipidomics were performed at baseline and after six months of treatment. Treatment resulted in significant reductions in hepatic fat fraction (17.0 ± 5.5% to 13.7 ± 5.9%, p = 0.002), glycated hemoglobin (HbA1c; p < 0.001), and body mass index (BMI; p < 0.001). Metabolomic analysis identified 17 significantly altered metabolites, predominantly amino acids (β-alanine, glycine, valine, and isoleucine), with enrichment of aminoacyl-transfer RNA (tRNA) biosynthesis and adenosine triphosphate–binding cassette (ABC) transporter pathways. Lipidomic profiling revealed remodeling of 492 lipid species, particularly phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, and triacylglycerol subclasses. SGLT 2 inhibitor therapy improved hepatic steatosis and induced metabolic remodeling in patients with T2DM and MASLD. Integrated metabolomic and lipidomic analyses suggest hepatic benefits beyond glycemic control, involving amino acid and lipid metabolic pathways.