Safety and tolerability of obeticholic acid in chronic liver disease: a pooled analysis of 1878 individuals.

ABSTRACT

BACKGROUND AND AIMS: Obeticholic acid (OCA) is a farnesoid X receptor agonist used in primary biliary cholangitis (PBC) treatment. Recent studies have expanded OCA use for NASH treatment and results from phase 3 clinical trial have shown beneficial reduction of ≥1 stage of fibrosis with no NASH worsening. However, safety concerns still preside, thus we systematically examine the safety profile of OCA in chronic liver disease. MATERIALS AND METHODS: A search was conducted in Medline and Embase databases for OCA randomized controlled trials in chronic liver disease. Binary events were pooled with Paule-Mandel random effects model and proportional events were examined in a generalized linear mixed model with Clopper-Pearson intervals. RESULTS: A total of 8 studies and 1878 patients were analyzed. There was a 75% [risk ratio (RR) 1.75, 95% CI 1.43-2.15, p < 0.01] increased pruritis risk. OCA increased constipation incidence (RR 1.88, 95% CI 1.45-2.43, p < 0.01), decreased diarrhea (RR 0.62, 95% CI 0.50-0.77, p < 0.01), and increased development of hyperlipidemia (RR 2.69, 95% CI 1.85-3.92, p < 0.01) relative to placebo. Sensitivity analysis in NASH-only studies found a dose-dependent effect with pruritis which increases to RR 3.07 (95% CI 1.74-5.41) at 25 mg. However, up to 9.98% (95% CI 5.01%-18.89%) of NAFLD patients with placebo similarly experience pruritis events. Overall, 16.55% (95% CI 6.47%-36.24%) of patients with NAFLD on OCA experienced pruritis. There was no significant increase in cardiovascular events. CONCLUSIONS: OCA may represent the first pharmacological treatment approved for NASH. However, pruritis, constipation, diarrhea, and hyperlipidemia were major events with evident dose-dependent effect that affect tolerability in NASH. Future long-term studies for longitudinal safety events are required.