Dapagliflozin in Metabolic Dysfunction-Associated Steatotic Liver Disease: Clinical Evidence and Therapeutic Potential.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most common chronic liver disease worldwide, affecting nearly one-third of the global population and disproportionately impacting individuals with type 2 diabetes mellitus (T2DM) and obesity. The disease is driven by complex metabolic disturbances, including insulin resistance (IR), hepatic fat accumulation, oxidative stress, and chronic inflammation, which together promote progression from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, and cirrhosis. Despite the growing burden of MASLD, therapeutic options remain limited and often constrained by cost, accessibility, or tolerability. Dapagliflozin, a sodium-glucose cotransporter-2 inhibitor originally developed for glycemic control in T2DM, has gained attention for its potential hepatoprotective effects. By inducing glucosuria and creating a caloric deficit, dapagliflozin promotes weight reduction, improves insulin sensitivity, and shifts energy metabolism toward fatty acid oxidation. These metabolic effects reduce hepatic de novo lipogenesis, attenuate oxidative stress, and may limit inflammatory pathways involved in MASLD progression. Emerging clinical evidence supports these mechanistic benefits. Prior randomized trials and observational studies have demonstrated improvements in liver enzymes, anthropometric parameters, and metabolic parameters, along with reduction in hepatic fat. Recent biopsy-based evidence, including findings from the DEAN trial, indicates significant improvements in histological endpoints of MASH. Collectively, current data suggest that dapagliflozin may offer a multifaceted therapeutic approach for MASLD by targeting both metabolic and hepatic pathways while providing established cardiovascular and renal benefits. Further large, multicenter trials involving diverse ethnicities, studying key histological endpoints as per regulatory guidance, may confirm these findings and define their role in the evolving treatment landscape of MASLD.