Table 2.

The most researched antidiabetic drugs on sphingolipid metabolism and their potential connection to MASLD*.

Drug		Therapeutic action	Sphingolipid metabolism		MASLD impact
			Experimental	Clinical
Metformin		Suppressed liver gluconeogenesis, decreased intestinal absorption of glucose, and improved insulin sensitivity (125).	Promotes mitochondrial β-oxidation, decreasing ceramides and diacylglycerol levels (76, 126, 127).	Reduced levels of 3 ceramides and 4 sphingomyelins in subjects with PCOS. Orally, 4 week progression from 500 mg/day to 1500 mg/day, dose continued during 7 weeks (128). Decreased the levels of S1P after a single oral dose of 500 mg metformin (129).	Reduction of ceramides redirecting FA metabolism from energy storage to expenditure. Human hepatocytes were treated with 1 mM metformin (127). May reduce the incidence and death rate of NASH-related HCC (130).
Thiazolidinediones	Pioglitazone	Improved insulin sensitivity and binding to the peroxisome proliferator-activated receptor gamma (PPARγ) (125).	Reduction in certain ceramide species (C22:1, C23:0) and intrahepatic diacylglycerol. Orally through diet supplemented with pioglitazone (0.01%) (131). No changes in ceramides in subjects with T2D and obesity. Pioglitazone was administered orally for 2 or 7 weeks (2.5 mg/kg) (132, 133).	Reduced ceramide concentrations in individuals with metabolic syndrome. Pioglitazone orally administered (45mg/day) (134). No changes in ceramides in subjects with T2D and obesity but increased saturation of FA within cell membrane lipids. Pioglitazone was administered orally for 6 months (45mg/day) (132).	Improvement in individual histologic scores, adipose tissue, hepatic, and muscle insulin sensitivity (125).
	Rosiglitazone		No changes in ceramide levels. Mice were fed rosiglitazone mixed with chow diet (200 mg/kg chow) for 20 or 28 days, or (50 ppm) for 8 weeks, respectively (135, 136).	Limited evidence; further research needed.	Improvement of steatosis correlated with a reduction of transaminase level improvement in insulin sensitivity. No results on ballooning and fibrosis (125).
GLP-1 receptor agonists	Liraglutide	Enhanced glucose-dependent insulin secretion; inhibition of glucagon release from the pancreas (125).	Prevents accumulation of C16 and C24-ceramides. Liraglutide was infused via micro-osmotic pump (0.1 µl/h) (137).	Reductions in ceramides, hexocyl-ceramides, phosphatidylcholines, and triglycerides. Liraglutide was administered orally at a starting dose of 0.6 mg/day and up to 1.8 mg/day maintenance-dose during 26 weeks (138). Reduction in specific ceramides associated with CVD risk (C16 Cer and C24:1 Cer). Liraglutide was administered orally (1.8 mg/day) during 12 weeks (139).	Prevention of ceramide accumulation in cardiac progenitor cells, and displayed anti-steatotic effects. 31% reduction of hepatic steatosis (125). Significant reductions in ceramides (18:0, 18:1, 19:0, 24:1 and 26:1) and decreased liver fat content (p=0.0005). Subjects receives liraglutide (1.2 mg/day) for 6 months (140).
	Exenatide		Decrease in diacylglycerols and ceramides. Mice were daily injected with exenatide for 8 weeks (30 µg/kg of body weight) (141).		Reduced steatosis, significantly decreased NASH-related biomarkers (ALT, AST, GGT). Improved fibrosis score (NFS, APRI score but not FIB-4). Exenatide was given orally at a dose of 10 μg per day the first 4 weeks, and continued up to 6 months at 20 μg per day (142). Decrease in ceramides. Downregulation in hepatic lipogenic genes and genes involved in inflammation and fibrosis (141).
SGLT2 inhibitors	Empagliflozin	Increased glucagon levels, reduced renal reabsorption of glucose increasing its excretion (125).	Reduced SM, ceramide, S1P, and neutral CDase activity in diabetic rats. Empagliflozin was daily administered (30 mg/kg) during 4 weeks (143).	Change in sphingosine/ceramide metabolism via neutral CDase in individuals with T2D. Subjects received empagliflozin (25 mg/day) for 4 weeks (144).	Reduction in BMI, cholesterol, GGT, ballooning, and fibrosis. Improvement in liver steatosis and serum ALT level (125). Lowered hepatic lactosylceramides (LCER 16:0, 18:0). Mice received oral empagliflozin for 12 weeks 10 mg/kg/day) (145)
GIP and GLP-1 receptor agonist	Tirzepatide	Stimulated insulin release from the pancreas and increased adiponectin levels (146).	Limited evidence; further research needed.	Reduced levels of individual saturated ceramides and sphingomyelins; increased levels of individual unsaturated sphingomyelins and conjugated ceramides. Subjects received subcutaneously doses of tirzepatide (1, 5, 10, 15 mg) once a week for 26 weeks (147).	Significantly decreased NASH-related biomarkers (ALT, cytokeratin-18, procollagen III) and increased adiponectin in patients with T2D. Patients received subcutaneously doses of tirzepatide (1, 5, 10, 15 mg) once a week for 26 weeks (148).

MASLD, metabolic associated steatotic liver disease FA, fatty acids; NAFLD, non-alcoholic fatty liver disease; HCC, hepatocellular carcinoma; CVD, cardiovascular disease; T2D, type 2 diabetes; BMI, body mass index; GGT, gamma-glutamyl transferase; ALT, alanine aminotransferase; GIP, gastric inhibitory polypeptide.

*When indicated, the current terms MASH/MASLD that appear in this table were used instead of the traditional terms NASH/NAFLD.