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

Cheng Han Ng, Ansel Shao Pin Tang, Jieling Xiao, Zhen Yu Wong, Jie Ning Yong, Clarissa E Fu, Rebecca W Zeng, Caitlyn Tan, Gabriel Hong Zhe Wong, Margaret Teng, Douglas Chee, Darren Jun Hao Tan, Kai En Chan, Daniel Q Huang, Nicholas W S Chew, Benjamin Nah, Mohammad S Siddqui, Arun J Sanyal, Mazen Noureddin, Mark Muthiah

Journal: Hepatology communications 2023;7(3):e0005

PMID: 36757421

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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.

Address: MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.; Nottingham University Hospitals NHS Trust, Nottingham, UK.; Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore.; MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.; Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore.; National University Centre for Organ Transplantation, National University Health System, Singapore, Singapore.; MBBS Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.; Department of Cardiology, National University Heart Centre, National University Hospital, Singapore, Singapore.; Division of Gastroenterology, Department of Internal Medicine, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, Virginia, USA.; Houston Research Institute, Houston, Texas, USA.

DOI: 10.1097/HC9.0000000000000005

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MeSH Terms: Humans, Non-alcoholic Fatty Liver Disease, Chenodeoxycholic Acid, Longitudinal Studies, Pruritus