NAFLD is the most common liver disorder in the USA. NASH is an advanced form of NAFLD and a leading cause of end-stage liver disease and indication for liver transplantation. Insulin resistance and inflammation underlie the pathogenesis of the disease. This double-blind, randomized, placebo-controlled, multicenter study aimed to determine the effect of oral insulin in patients with NASH 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. At screening and after 12 weeks of treatment, liver fat content was measured by MRI-PDFF and liver fibrosis and steatosis levels by FibroScan®. No severe drug-related adverse events were reported during the study. After 12 weeks of treatment, mean percent reductions in whole-liver (-11.2±22.8% vs. -6.5±15.3%, respectively) and liver segment 3 (-11.7±21.1% vs. +0.1±17.3%, respectively) fat content were higher in the insulin as compared to the placebo arm. Patients receiving insulin showed a median -1.1 kPa and -21.0 dB/m reduction from baseline fibrosis and steatosis levels, respectively. In comparison, placebo-treated patients showed median increases of 0.3 kPa and 13.0 dB/m, respectively. At Week 12, HbA1c levels decreased by a mean -0.27±1.3% in the oral insulin cohort and increased by a mean 0.23±0.73% in the placebo cohort. Mean percent changes from baseline ALT and AST levels were -0.1±30.4% and -0.8±28.6%, respectively, in the oral insulin arm and 3.0±26.7% and 13.4±46.6%, respectively, in the placebo arm. Over the treatment period, mean total cholesterol, HDL, LDL, and triglycerides levels were consistently lower than baseline in the active arm and higher than baseline in the placebo arm. The results of this feasibility study support the safety and potential therapeutic effect of orally delivered insulin on liver fibrosis, fat accumulation, and inflammatory processes.


Y.Ishay: None. J.M.Neutel: None. Y.Kolben: None. R.Gelman: None. O.Sneh arbib: None. O.Lopez: None. R.Sotolongo: None. Y.Ilan: None. M.Kidron: Employee; Oramed Pharmaceuticals.

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