Oral Insulin Alleviates Liver Fibrosis and Reduces Liver Steatosis in Patients With Metabolic Dysfunction-associated Steatohepatitis and Type 2 Diabetes: Results of Phase II Randomized, Placebo-controlled Feasibility Clinical Trial

Abstract

Background and AimsMetabolic dysfunction-associated steatohepatitis (MASH) is an advanced form of NAFLD and a leading cause of end-stage liver disease and transplantation. Insulin resistance and inflammation underlie the pathogenesis of the disease. MethodsThis double-blind, randomized, placebo-controlled, multicenter feasibility clinical trial aimed to determine the safety of ORMD-0801 in patients with MASH and T2DM. Patients were treated twice daily for 12 weeks with an 8 mg insulin (n=21) or placebo (n=11) capsule. Safety was monitored throughout the study. MRI-PDFF assessed liver fat content, and Fibroscan® measured liver fibrosis and steatosis levels at screening and after 12 weeks of treatment. ResultsNo severe drug-related adverse events were reported during the study. After 12 weeks of treatment, mean percent reductions in whole-liver (-11.2% vs. -6.5%, respectively) and liver segment 3 (-11.7% vs. +0.1%, respectively) fat content was higher in the insulin than in the placebo arm. Patients receiving insulin showed a median -1.2 kPa and -21.0 dB/m reduction from baseline fibrosis and steatosis levels, respectively, while placebo-treated patients showed median increases of 0.3 kPa and 13.0 dB/m, respectively. At Week 12, oral insulin was associated with a mean of 0.27% reduction and placebo with a 0.23% increase from baseline HbA1c levels. Mean percent changes from baseline alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels were -10% and -0.8%, respectively, in the oral insulin and 3.0% and 13.4%, in the placebo arm. ConclusionThe results of this feasibility study support the safety and potential therapeutic effect of orally delivered insulin on liver fibrosis, fat accumulation, and inflammatory processes (NIH Clinical Trials No. NCT04618744).