Comparative Evaluation of the Effects of Oral Anti-hyperglycemic Agents and an Ayurvedic Hepatoprotective Agent in a Rat Model of Non-alcoholic Fatty Liver Disease (NAFLD).

Introduction Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic liver disease characterized by the accumulation of triglycerides (TG) in the liver, and histopathological findings include simple fatty liver, steato-hepatitis, fibrosis, and ultimately cirrhosis. Our study assessed the efficacy of oral anti-hyperglycemic agents (glimepiride, vildagliptin, and dapagliflozin) and an ayurvedic medicine (Liv52) in an induced MASLD rat model both biochemically and histopathologically. Materials and methods It was a pre-clinical experimental study whereby Sprague-Dawley rats (n = 36, male = female, 18-20 weeks old, weight 150-180 g) acclimatized in an animal house facility (12-hour light/dark cycle) were used. Baseline total cholesterol (TC), TG, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) enzyme-linked immunosorbent assay (ELISA) was done, and then, all animals were divided into six groups (M = F) of six rats each (negative control - only high-fat diet, glimepiride group, vildagliptin group, dapagliflozin group, Liv52 group, and positive control - pioglitazone group, respectively) and fed with high-fat diet and water ad libitum for six weeks. Repeat TC, TG, AST, and ALT estimations were done to confirm model induction. Thereafter, each group was given its pertinent drug for four weeks by oral gavage along with a high-fat diet + water ad libitum. Final TC, TG, AST, and ALT estimations were done followed by the sacrifice of all rats, liver isolation, and histopathological examination for the NAFLD activity score (NAS). Results High-fat diet administration led to deranged TC, AST, and ALT values in the Sprague-Dawley rats, thereby confirming model induction. The glimepiride group exhibited reduced AST, ALT, and NAS along with increased TC and TG levels. The vildagliptin group exhibited reduced TC, AST, ALT, and NAS along with increased TG levels. The dapagliflozin group exhibited reduced TC, TG, and AST along with increased ALT levels and no change in NAS. The Liv52 group exhibited reduced TC and NAS along with increased TG and AST levels and no changes in ALT levels. Also, four rats of the Liv52 group died within a week of dosing, and their liver histopathology showed focal necrosis, inflammation, and congestion. Finally, the pioglitazone group (positive control) exhibited reduced TC, AST, and NAS along with increased TG and ALT levels. Conclusion We conclude that glimepiride, which exhibited AST and ALT reductions along with a four-point NAS reduction, offers itself as a promising drug candidate for human clinical trials for MASLD. Vildagliptin, which exhibited TC, AST, and ALT reductions but a less promising one-point NAS reduction, can also be tried in human clinical trials for MASLD.