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

doi:10.1097/HC9.0000000000000005

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

Houston Methodist

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

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.

Original language	English (US)
Pages (from-to)	E0005
Journal	Hepatology Communications
Volume	7
Issue number	3
DOIs	https://doi.org/10.1097/HC9.0000000000000005
State	Published - Mar 1 2023

Keywords

Humans
Non-alcoholic Fatty Liver Disease/drug therapy
Chenodeoxycholic Acid/adverse effects
Longitudinal Studies
Pruritus/drug therapy

ASJC Scopus subject areas

Hepatology

Access to Document

10.1097/HC9.0000000000000005

Cite this

Ng, C. H., Tang, A. S. P., Xiao, J., Wong, Z. Y., Yong, J. N., Fu, C. E., Zeng, R. W., Tan, C., Wong, G. H. Z., Teng, M., Chee, D., Tan, D. J. H., Chan, K. E., Huang, D. Q., Chew, N. W. S., Nah, B., Siddqui, M. S., Sanyal, A. J., Noureddin, M., & Muthiah, M. (2023). Safety and tolerability of obeticholic acid in chronic liver disease: A pooled analysis of 1878 individuals. Hepatology Communications, 7(3), E0005. https://doi.org/10.1097/HC9.0000000000000005

Ng, CH, Tang, ASP, Xiao, J, Wong, ZY, Yong, JN, Fu, CE, Zeng, RW, Tan, C, Wong, GHZ, Teng, M, Chee, D, Tan, DJH, Chan, KE, Huang, DQ, Chew, NWS, Nah, B, Siddqui, MS, Sanyal, AJ, Noureddin, M & Muthiah, M 2023, 'Safety and tolerability of obeticholic acid in chronic liver disease: A pooled analysis of 1878 individuals', Hepatology Communications, vol. 7, no. 3, pp. E0005. https://doi.org/10.1097/HC9.0000000000000005

@article{fd70607358a14f41a69203acab122ac8,

title = "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.",

keywords = "Humans, Non-alcoholic Fatty Liver Disease/drug therapy, Chenodeoxycholic Acid/adverse effects, Longitudinal Studies, Pruritus/drug therapy",

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

year = "2023",

month = mar,

day = "1",

doi = "10.1097/HC9.0000000000000005",

language = "English (US)",

volume = "7",

pages = "E0005",

journal = "Hepatology Communications",

issn = "2471-254X",

publisher = "Lippincott Williams and Wilkins",

number = "3",

}

TY - JOUR

T1 - Safety and tolerability of obeticholic acid in chronic liver disease

T2 - A pooled analysis of 1878 individuals

AU - Ng, Cheng Han

AU - Tang, Ansel Shao Pin

AU - Xiao, Jieling

AU - Wong, Zhen Yu

AU - Yong, Jie Ning

AU - Fu, Clarissa E.

AU - Zeng, Rebecca W.

AU - Tan, Caitlyn

AU - Wong, Gabriel Hong Zhe

AU - Teng, Margaret

AU - Chee, Douglas

AU - Tan, Darren Jun Hao

AU - Chan, Kai En

AU - Huang, Daniel Q.

AU - Chew, Nicholas W.S.

AU - Nah, Benjamin

AU - Siddqui, Mohammad S.

AU - Sanyal, Arun J.

AU - Noureddin, Mazen

AU - Muthiah, Mark

PY - 2023/3/1

Y1 - 2023/3/1

N2 - 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.

AB - 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.

KW - Humans

KW - Non-alcoholic Fatty Liver Disease/drug therapy

KW - Chenodeoxycholic Acid/adverse effects

KW - Longitudinal Studies

KW - Pruritus/drug therapy

UR - http://www.scopus.com/inward/record.url?scp=85157992662&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85157992662&partnerID=8YFLogxK

U2 - 10.1097/HC9.0000000000000005

DO - 10.1097/HC9.0000000000000005

M3 - Article

C2 - 36757421

AN - SCOPUS:85157992662

SN - 2471-254X

VL - 7

SP - E0005

JO - Hepatology Communications

JF - Hepatology Communications

IS - 3

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this