Obeticholic acid for treatment of NAFLD—A drug in search of a disease

Introduction: Non-alcoholic fatty liver disease (NAFLD) is the hepatic component of the metabolic syndrome. Although the only proven treatments are weight loss, diet, exercise and consumption of coffee, many medications are being investigated for treatment of NAFLD. Aim: To present different aspects of NAFLD as part of the metabolic syndrome and to review some aspects of obeticholic acid (OCA) therapy. Methods: We comment on the REGENERATE trial of OCA for treating NAFLD. Results: This trial (1968 patients with F2-3 fibrosis or F1 fibrosis and ≥ 1 comorbidity) has several limitations. The incidence of pruritus in the OCA group is 22% in the 25 mg dose, 17% in the 10 mg dose and 14% in the placebo group. Pruritus was not rigidly defined and in a trial of elafibranor for NAFLD, only 1% had pruritus in the placebo group. OCA causes hyperlipidaemia; the placebo group had a decrease in cholesterol of 3 mg/dL in the first month vs an increase of 17.8 mg/dL in the 10 mg dose and 23.8 mg/dL in the 25 mg dose group. Since 56% of the patients had diabetes mellitus and 69% had hypertension, this is likely to be detrimental. The interim analysis showed a ‘significant histological improvement’ but there is no data regarding clinical end-points. The issue of changes in lipids was addressed in a separate publication 2 weeks later. Conclusion: The current trials of treatment for NAFLD need to have robust treatment in the placebo groups and address clinical outcomes. At present, it appears to be drugs in search of a disease.