Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Systematic Reviews
Published in: Systematic Reviews 1/2024

Open Access 01-12-2024 | Primary Biliary Cholangitis | Research

Optimal drug regimens for improving ALP biochemical levels in patients with primary biliary cholangitis refractory to UDCA: a systematic review and Bayesian network meta-analysis

Authors: Wei Lin, Jun-xi Wang, Yi-juan Liu

Published in: Systematic Reviews | Issue 1/2024

Login to get access

Abstract

Background

Up to 40% of UDCA-treated patients do not have an adequate clinical response. Farnesoid X receptor agonists, peroxisome proliferator-activated receptor agonists, and fibroblast growth factor 19 analogs were developed as adjunctive therapy. The aim of this network meta-analysis was to compare the efficacy of these drugs as add-on therapy for patients with primary biliary cholangitis (PBC) refractory to UDCA in improving ALP levels.

Methods

We searched PubMed, Embase, Web of Science, and the Cochrane Library for eligible studies until 1 December 2023. Randomized controlled trials, cohort studies, and case–control studies comparing the efficacy of different combination treatments and UDCA monotherapy in UDCA-refractory PBC patients were included in the analysis. Cumulative probability was used to rank the included treatments.

Results

A total of 23 articles were eligible for our network meta-analysis. In terms of improving ALP levels, In terms of improving ALP biochemical levels, bezafibrate combined with UDCA (MD 104.49, 95% CI 60.41, 161.92), fenofibrate combined with UDCA (MD 87.81, 95% CI (52.34, 129.79), OCA combined with UDCA (MD 65.21, 95% CI 8.99, 121.80), seladelpar combined with UDCA (MD 117.39, 95% CI 19.97, 213.95), elafibranor combined with UDCA (MD 140.73, 95% CI 74.34, 209.98), saroglitazar combined with UDCA (MD 132.09, 95% CI 13.99, 247.04) was more effective than UDCA monotherapy. Elafibranor in combination with UDCA was the most likely (32%) to be the optimal drug regimen.

Conclusion

As second-line therapy for UDCA-refractory PBC, PPAR agonists were more effective than any other drugs with other mechanisms in improving ALP biochemical levels, with elafibranor being the best.
Literature
1.
Corpechot C. Primary biliary cirrhosis and bile acids. Clin Res Hepatol Gastroenterol. 2012;36(Suppl 1):S13-20.PubMedCrossRef
2.
Boonstra K, Beuers U, Ponsioen CY. Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: a systematic review. J Hepatol. 2012;56:1181–8.PubMedCrossRef
3.
Suraweera D, Rahal H, Jimenez M, et al. Treatment of primary biliary cholangitis ursodeoxycholic acid non-responders: a systematic review. Liver Int. 2017;37:1877–86.PubMedCrossRef
4.
Kuiper EM, Hansen BE, de Vries RA, et al. Improved prognosis of patients with primary biliary cirrhosis that have a biochemical response to ursodeoxycholic acid. Gastroenterology. 2009;136:1281–7.PubMedCrossRef
5.
Floreani A, Mangini C. Primary biliary cholangitis: Old and novel therapy. Eur J Intern Med. 2018;47:1–5.PubMedCrossRef
6.
Corpechot C, Abenavoli L, Rabahi N, et al. Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis. Hepatology. 2008;48:871–7.PubMedCrossRef
7.
Carbone M, Mells GF, Pells G, et al. Sex and age are determinants of the clinical phenotype of primary biliary cirrhosis and response to ursodeoxycholic acid. Gastroenterology. 2013;144:560-569.e7 quiz e13-4.PubMedCrossRef
8.
Levy C, Peter JA, Nelson DR, et al. Pilot study: fenofibrate for patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid. Aliment Pharmacol Ther. 2011;33:235–42.PubMedCrossRef
9.
Duan W, Ou X, Wang X, et al. Efficacy and safety of fenofibrate add-on therapy for patients with primary biliary cholangitis and a suboptimal response to UDCA. Rev Esp Enferm Dig. 2018;110:557–63.PubMedCrossRef
10.
Cheung AC, Lapointe-Shaw L, Kowgier M, et al. Combined ursodeoxycholic acid (UDCA) and fenofibrate in primary biliary cholangitis patients with incomplete UDCA response may improve outcomes. Aliment Pharmacol Ther. 2016;43:283–93.PubMedCrossRef
11.
Zhang Y, Li S, He L, et al. Combination therapy of fenofibrate and ursodeoxycholic acid in patients with primary biliary cirrhosis who respond incompletely to UDCA monotherapy: a meta-analysis. Drug Des Devel Ther. 2015;9:2757–66.PubMedPubMedCentral
12.
Grigorian AY, Mardini HE, Corpechot C, et al. Fenofibrate is effective adjunctive therapy in the treatment of primary biliary cirrhosis: a meta-analysis. Clin Res Hepatol Gastroenterol. 2015;39:296–306.PubMedCrossRef
13.
Iwasaki S, Ohira H, Nishiguchi S, et al. The efficacy of ursodeoxycholic acid and bezafibrate combination therapy for primary biliary cirrhosis: a prospective, multicenter study. Hepatol Res. 2008;38:557–64.PubMedCrossRef
14.
Agrawal R, Majeed M, Attar BM, et al. Effectiveness of bezafibrate and ursodeoxycholic acid in patients with primary biliary cholangitis: a meta-analysis of randomized controlled trials. Ann Gastroenterol. 2019;32:489–97.PubMedPubMedCentral
15.
Zhang Y, Chen K, Dai W, et al. Combination therapy of bezafibrate and ursodeoxycholic acid for primary biliary cirrhosis: a meta-analysis. Hepatol Res. 2015;45:48–58.PubMedCrossRef
16.
Schattenberg JM, Pares A, Kowdley KV, et al. A randomized placebo-controlled trial of elafibranor in patients with primary biliary cholangitis and incomplete response to UDCA. J Hepatol. 2021;74:1344–54.PubMedCrossRef
17.
Jain MR, Giri SR, Trivedi C, et al. Saroglitazar, a novel PPARα/γ agonist with predominant PPARα activity, shows lipid-lowering and insulin-sensitizing effects in preclinical models. Pharmacol Res Perspect. 2015;3:e00136.PubMedPubMedCentralCrossRef
18.
Vuppalanchi R, Caldwell SH, Pyrsopoulos N, et al. Proof-of-concept study to evaluate the safety and efficacy of saroglitazar in patients with primary biliary cholangitis. J Hepatol. 2022;76:75–85.PubMedCrossRef
19.
Jones D, Boudes PF, Swain MG, et al. Seladelpar (MBX-8025), a selective PPAR-δ agonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid: a double-blind, randomised, placebo-controlled, phase 2, proof-of-concept study. Lancet Gastroenterol Hepatol. 2017;2:716–26.PubMedCrossRef
20.
Sahebkar A, Chew GT, Watts GF. New peroxisome proliferator-activated receptor agonists: potential treatments for atherogenic dyslipidemia and non-alcoholic fatty liver disease. Expert Opin Pharmacother. 2014;15:493–503.PubMedCrossRef
21.
Choi Y-J, Roberts BK, Wang X, et al. Effects of the PPAR-δ agonist MBX-8025 on atherogenic dyslipidemia. Atherosclerosis. 2012;220:470–6.PubMedCrossRef
22.
Wong KA, Bahar R, Liu CH, et al. Current treatment options for primary biliary cholangitis. Clin Liver Dis. 2018;22:481–500.PubMedCrossRef
23.
24.
Hirschfield GM, Mason A, Luketic V, et al. Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology. 2015;148:751-61.e8.PubMedCrossRef
25.
Nevens F, Andreone P, Mazzella G, et al. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med. 2016;375:631–43.PubMedCrossRef
26.
Kowdley KV, Luketic V, Chapman R, et al. A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis. Hepatology. 2018;67:1890–902.PubMedCrossRef
27.
Mayo MJ, Wigg AJ, Leggett BA, et al. NGM282 for treatment of patients with primary biliary cholangitis: a multicenter, randomized, double-blind, placebo-controlled trial. Hepatol Commun. 2018;2:1037–50.PubMedPubMedCentralCrossRef
28.
Jones D, Boudes PF, Swain MG, et al. Seladelpar (MBX-8025), a selective PPAR-delta agonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid: a double-blind, randomised, placebo-controlled, phase 2, proof-of-concept study. Lancet Gastroenterol Hepatol. 2017;2:716–26.PubMedCrossRef
29.
Bowlus CL, Galambos MR, Aspinall RJ, et al. A phase II, randomized, open-label, 52-week study of seladelpar in patients with primary biliary cholangitis. J Hepatol. 2022;77:353–64.
30.
Hirschfield GM, Beuers U, Kupcinskas L, et al. A placebo-controlled randomised trial of budesonide for primary biliary cholangitis following an insufficient response to UDCA. J Hepatol. 2021;74:321–9.
31.
32.
33.
Dias S, Welton NJ, Caldwell DM, et al. Checking consistency in mixed treatment comparison meta-analysis. Stat Med. 2010;29:932–44.PubMedCrossRef
34.
Cipriani A, Higgins JP, Geddes JR, et al. Conceptual and technical challenges in network meta-analysis. Ann Intern Med. 2013;159:130–7.PubMedCrossRef
35.
Brooks SP, Gelman A. General methods for monitoring convergence of iterative simulations. J Comput Graph Stat. 1998;7:434–55.
36.
37.
Luo D, Wan X, Liu J, et al. Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range. Stat Methods Med Res. 2018;27:1785–805.PubMedCrossRef
38.
Wan X, Wang W, Liu J, et al. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol. 2014;14:135.PubMedPubMedCentralCrossRef
39.
Corpechot C, Chazouilleres O, Rousseau A, et al. A placebo-controlled trial of bezafibrate in primary biliary cholangitis. N Engl J Med. 2018;378:2171–81.PubMedCrossRef
40.
Hosonuma K, Sato K, Yamazaki Y, et al. A prospective randomized controlled study of long-term combination therapy using ursodeoxycholic acid and bezafibrate in patients with primary biliary cirrhosis and dyslipidemia. Am J Gastroenterol. 2015;110:423–31.PubMedCrossRef
41.
Takeuchi Y, Ikeda F, Fujioka S, et al. Additive improvement induced by bezafibrate in patients with primary biliary cirrhosis showing refractory response to ursodeoxycholic acid. J Gastroenterol Hepatol. 2011;26:1395–401.PubMedCrossRef
42.
Itakura J, Izumi N, Nishimura Y, et al. Prospective randomized crossover trial of combination therapy with bezafibrate and UDCA for primary biliary cirrhosis. Hepatol Res. 2004;29:216–22.PubMedCrossRef
43.
Kanda T, Yokosuka O, Imazeki F, et al. Bezafibrate treatment: a new medical approach for PBC patients? J Gastroenterol. 2003;38:573–8.PubMedCrossRef
44.
Nakai S, Masaki T, Kurokohchi K, et al. Combination therapy of bezafibrate and ursodeoxycholic acid in primary biliary cirrhosis: a preliminary study. Am J Gastroenterol. 2000;95:326–7.PubMedCrossRef
45.
46.
Wang L, Sun K, Tian A, et al. Fenofibrate improves GLOBE and UK-PBC scores and histological features in primary biliary cholangitis. Minerva Med. 2022;113:974–82.
47.
Li C, Zheng K, Chen Y, et al. A randomized, controlled trial on fenofibrate in primary biliary cholangitis patients with incomplete response to ursodeoxycholic acid. Ther Adv Chronic Dis. 2022;13:20406223221114200.PubMedPubMedCentralCrossRef
48.
Ding D, Guo G, Liu Y, et al. Efficacy and safety of fenofibrate addition therapy in patients with cirrhotic primary biliary cholangitis with incomplete response to ursodeoxycholic acid. Hepatol Commun. 2022;6:3487–95.PubMedPubMedCentralCrossRef
49.
Ding D, Ren P, Guo G, et al. Fenofibrate normalizes alkaline phosphatase and improves long-term outcomes in patients with advanced primary biliary cholangitis refractory to ursodeoxycholic acid. Gastroenterol Hepatol. 2023;46:692–701.PubMedCrossRef
50.
Dohmen K, Tanaka H, Haruno M. Effectiveness of fenofibrate in comparison to bezafibrate for patients with asymptomatic primary biliary cirrhosis. Fukuoka Igaku Zasshi. 2013;104:350–61.PubMed
51.
Kjærgaard K, Frisch K, Sørensen M, et al. Obeticholic acid improves hepatic bile acid excretion in patients with primary biliary cholangitis. J Hepatol. 2021;74:58–65.PubMedCrossRef
52.
Kowdley KV, Bowlus CL, Levy C, et al. Efficacy and safety of elafibranor in primary biliary cholangitis. N Engl J Med. 2023. Online ahead of print.
53.
Hirschfield GM, Shiffman ML, Gulamhusein A, et al. Seladelpar efficacy and safety at 3 months in patients with primary biliary cholangitis: ENHANCE, a phase 3, randomized, placebo-controlled study. Hepatology. 2023;78:397–415.PubMedCrossRef
54.
Hirschfield GM, Gershwin ME. The immunobiology and pathophysiology of primary biliary cirrhosis. Annu Rev Pathol. 2013;8:303–30.PubMedCrossRef
55.
Örnolfsson KT, Lund SH, Olafsson S, et al. Biochemical response to ursodeoxycholic acid among PBC patients: a nationwide population-based study. Scand J Gastroenterol. 2019;54:609–16.PubMedCrossRef
56.
Lammers WJ, van Buuren HR, Hirschfield GM, et al. Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis: an international follow-up study. Gastroenterology. 2014;147:1338-49.e5 quiz e15.PubMedCrossRef
57.
Murillo Perez CF, Harms MH, Lindor KD, et al. Goals of treatment for improved survival in primary biliary cholangitis: treatment target should be bilirubin within the normal range and normalization of alkaline phosphatase. Am J Gastroenterol. 2020;115:1066–74.PubMedCrossRef
58.
59.
Reig A, Álvarez-Navascués C, Vergara M, et al. Obeticholic acid and fibrates in primary biliary cholangitis: comparative effects in a multicentric observational study. Am J Gastroenterol. 2021;116:2250–7.PubMedCrossRef
60.
Smets L, Verbeek J, Korf H, et al. Improved markers of cholestatic liver injury in patients with primary biliary cholangitis treated with obeticholic acid and bezafibrate. Hepatology. 2021;73:2598–600.PubMedCrossRef
61.
Soret PA, Lam L, Carrat F, et al. Combination of fibrates with obeticholic acid is able to normalise biochemical liver tests in patients with difficult-to-treat primary biliary cholangitis. Aliment Pharmacol Ther. 2021;53:1138–46.PubMedCrossRef
62.
Myers Robert P, Swain Mark G, Lee Samuel S, et al. B-cell depletion with rituximab in patients with primary biliary cirrhosis refractory to ursodeoxycholic acid. Am J Gastroenterol. 2013;108:933–41.
63.
Wolfhagen FH, van Hoogstraten HJ, van Buuren HR, et al. Triple therapy with ursodeoxycholic acid, prednisone and azathioprine in primary biliary cirrhosis: a 1-year randomized, placebo-controlled study. J Hepatol. 1998;29:736–42.PubMedCrossRef
64.
Fang YQ, Lv DX, Jia W, et al. Case-control study on prednisolone combined with ursodeoxycholic acid and azathioprine in pure primary biliary cirrhosis with high levels of immunoglobulin G and transaminases: efficacy and safety analysis. Medicine (Baltimore). 2014;93:e104.PubMedCrossRef
Metadata
Title
Optimal drug regimens for improving ALP biochemical levels in patients with primary biliary cholangitis refractory to UDCA: a systematic review and Bayesian network meta-analysis
Authors
Wei Lin
Jun-xi Wang
Yi-juan Liu
Publication date
01-12-2024
Publisher
BioMed Central
Published in
Systematic Reviews / Issue 1/2024
Electronic ISSN: 2046-4053
DOI
https://doi.org/10.1186/s13643-024-02460-0

Other articles of this Issue 1/2024

Systematic Reviews 1/2024 Go to the issue

Protocol

Mechanisms behind gender transformative approaches targeting adolescent pregnancy in low- and middle-income countries: a realist synthesis protocol

Protocol

Personal growth initiative across the life span: a systematic review protocol of quantitative studies using the Personal Growth Initiative Scale-II

Research

A systematic review and meta-analysis on the effects of ill health and health shocks on labour supply

Correction

Correction: Patient‑reported outcome (PRO) instruments used in patients undergoing adoptive cell therapy (ACT) for the treatment of cancer: a systematic review

Methodology

Natural language processing (NLP) to facilitate abstract review in medical research: the application of BioBERT to exploring the 20-year use of NLP in medical research

Protocol

Barriers and enablers to the implementation of patient-reported outcome and experience measures (PROMs/PREMs): protocol for an umbrella review