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.

Healthy diet intervention reverses the progression of NASH through gut microbiota modulation

“…Nevertheless, certain medications, including obeticholic acid (OCA), have displayed favorable outcomes during phase III clinical trials. Nonetheless, some of these drugs encompass several adverse side effects that prevent their clinical application ( 19 , 20 ). Therefore, uncovering alternative strategies for reversing NASH is crucial.…”

Drug targets regulate systemic metabolism and provide new horizons to treat nonalcoholic steatohepatitis

“…For instance, as FXR can regulate the expression of a myriad of genes, the non-selective activation of FXR by canonical agonists (e.g. OCA) generates unwanted side effects, such as pruritus and dyslipidemia in patients with NASH [ 39 ]. Moreover, treatment of FXR agonist cilofexor is positively correlated with elevated IL-31 level and pruritus adverse events in patients with NASH [ 40 ].…”

Changes in m6A in Steatotic Liver Disease

“…There are currently no approved therapeutic agents approved for treating NAFLD or NASH [ 6 ]. The farnesoid X receptor (FXR) agonist obeticholic acid recently failed to gain approval by the Food and Drug Administration for the treatment of NASH, given its side effects [ 7 , 8 ]. NAFLD is associated with obesity-related metabolic changes, i.e., insulin-resistance and type 2 diabetes mellitus (T2DM), and its prevalence is higher in men than premenopausal women [ 9 , 10 ].…”