Nonalcoholic fatty liver disease (NAFLD) and subsequent nonalcoholic steatohepatitis are leading causes of chronic liver disease, with disease progression directly associated with insulin resistance and T2DM. In light of the common risk factors, pathogenesis and complications with T2DM, direct insulin intervention has been suggested for T2DM patients with NAFLD. Recently, salient metabolic effects of oral insulin have been suggested, owing to first pass metabolism and local insulin availability and concentration in liver fat cells. This pilot study assessed the safety, tolerability and early effects on liver fat content of an oral insulin formulation (ORMD-0801), preprandially administered once-daily (2x8 mg capsules) for 12 consecutive weeks, to 8 T2DM patients with NASH. The 12-week ORMD-0801 treatment proved safe and tolerable in all patients, with no serious or severe adverse events recorded throughout the study period. The 12-week treatment induced a mean -6.9±6.8% reduction in liver fat content (sign test p value: 0.035), as measured by magnetic resonance imaging proton density fat fraction (MRI-PDFF). In parallel, concentrations of gamma-glutamyltransferase (GGTP), a key marker of chronic hepatitis, were significantly lower after 12 weeks of treatment as compared to baseline (-14.6±13.1 U/L; sign test p value: 0.008), as were fasting insulin levels (-96.5±206.0 pmol/L; sign test p value: 0.035). Taken together, these preliminary observations suggest a palliative effect of oral insulin on NASH in T2DM patients, as shown by reductions in liver fat content and chronic hepatitis. These encouraging findings will require further validation in large-scale, randomized clinical trials.


M. Kidron: Employee; Self; Oramed Pharmaceuticals. Stock/Shareholder; Self; Oramed Pharmaceuticals. S. Perles: Employee; Spouse/Partner; Haddassah Medical Center. Employee; Self; Oramed Pharmaceuticals. R. Kaloti: None. R. Ghantous: None. S.F. Sandouka: None. Y. Malaabi: None. R. Safadi: None.

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