Pharmacotherapeutic Impact on Nonalcoholic Steatohepatitis Histology: A Systematic Review and Network Meta-analysis

Overview

Journal J Clin Exp Hepatol

Publisher Elsevier

Specialty Gastroenterology

Date 2022 Jul 11

PMID 35814516

Authors

Alexander J Kovalic

Affiliations

Soon will be listed here.

Abstract

Background: Due to lack of targeted treatment options and inconsistent utilization of histologic endpoints among clinical trials, identifying efficacious pharmacotherapies for nonalcoholic steatohepatitis [NASH] has proven challenging.

Methods: A thorough systematic review and frequentist random-effects network meta-analysis was performed across all randomized clinical trials reporting a pharmacotherapeutic intervention on biopsy-proven NASH. Primary outcomes were based on the most current, up-to-date recommended histologic endpoints.

Results: A total of 40 RCTs were identified including 6593 total patients. The most effective and statistically significant treatment interventions for minimum two-point improvement in NAFLD Activity Score were aldafermin 1 mg [RR 7.69, 95% CI 2.00; 29.57], vitamin E 800 IU in combination with pioglitazone 45 mg [RR 3.38, 95% CI 1.88; 6.07], pioglitazone 45 mg [RR 3.29, 95% CI 1.74; 6.22], vitamin E 800 IU [RR 2.06, 95% CI 1.33; 3.18], resmetirom 80 mg [RR 1.74, 95% CI 1.03; 2.94], obeticholic acid 25 mg [RR 1.63, 95% CI 1.32; 2.01], and obeticholic acid 10 mg [RR 1.31, 95% CI 1.02; 1.67]). The most robust pharmacotherapies for NASH resolution without worsening fibrosis were found to be aldafermin 1 mg [RR 5.77, 95% CI 1.48; 22.51], pioglitazone 45 mg [RR 2.65, 95% CI 1.43; 4.91], vitamin E 800 IU in combination with pioglitazone 45 mg [RR 2.64, 95% CI 1.36; 5.12], pioglitazone 30 mg [RR 2.46, 95% CI 1.56; 3.88], vitamin E 800 IU [RR 1.90, 95% CI 1.20; 3.00], and obeticholic acid 25 mg [RR 1.52, 95% CI 1.03; 2.23]). Obeticholic acid had a significant improvement on fibrosis. Multiple interventions were found to improve individual histologic scores across secondary outcome analyses and are detailed below.

Conclusion: This novel systematic review and network meta-analysis represents the most comprehensive investigation to date regarding the pharmacotherapeutic options for biopsy-proven NASH using current recommended histologic endpoints.

Citing Articles

Efficacy and safety of the FGF19 analog aldafermin for the treatment of nonalcoholic steatohepatitis: a GRADE assessed systematic review and meta-analysis.

Ali M, Rehman O, Talha M, Fatima E, Fatima L, Zain A Ann Med Surg (Lond). 2024; 86(12):7072-7081.

PMID: 39649867 PMC: 11623846. DOI: 10.1097/MS9.0000000000002649.

Efficacy and safety of resmetirom among patients with non-alcoholic steatohepatitis: a systematic review and meta-analysis.

Mazhar S, Azhar A, Khan A, Shakil G, Kumari S, Devi D Ann Med Surg (Lond). 2024; 86(9):5447-5454.

PMID: 39239031 PMC: 11374252. DOI: 10.1097/MS9.0000000000002314.

Comparison of glucagon-like peptide-1 receptor agonists and thiazolidinediones on treating nonalcoholic fatty liver disease: A network meta-analysis.

Park M, Kim H, Kim M, Kim K Clin Mol Hepatol. 2023; 29(3):693-704.

PMID: 36907574 PMC: 10366812. DOI: 10.3350/cmh.2022.0330.

Management of metabolic-associated fatty liver disease: The diabetology perspective.

Jeeyavudeen M, Khan S, Fouda S, Pappachan J World J Gastroenterol. 2023; 29(1):126-143.

PMID: 36683717 PMC: 9850951. DOI: 10.3748/wjg.v29.i1.126.

Effects of Maternal Gut Microbiota-Targeted Therapy on the Programming of Nonalcoholic Fatty Liver Disease in Dams and Fetuses, Related to a Prenatal High-Fat Diet.

Yu H, Sheen J, Hou C, Lin I, Huang L, Tain Y Nutrients. 2022; 14(19).

PMID: 36235659 PMC: 9573493. DOI: 10.3390/nu14194004.

References

Singh S, Khera R, Allen A, Murad M, Loomba R . Comparative effectiveness of pharmacological interventions for nonalcoholic steatohepatitis: A systematic review and network meta-analysis. Hepatology. 2015; 62(5):1417-32. DOI: 10.1002/hep.27999. View

Harrison S, Abdelmalek M, Caldwell S, Shiffman M, Diehl A, Ghalib R . Simtuzumab Is Ineffective for Patients With Bridging Fibrosis or Compensated Cirrhosis Caused by Nonalcoholic Steatohepatitis. Gastroenterology. 2018; 155(4):1140-1153. DOI: 10.1053/j.gastro.2018.07.006. View

Hutton B, Salanti G, Caldwell D, Chaimani A, Schmid C, Cameron C . The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann Intern Med. 2015; 162(11):777-84. DOI: 10.7326/M14-2385. View

Rinella M, Tacke F, Sanyal A, Anstee Q . Report on the AASLD/EASL Joint Workshop on Clinical Trial Endpoints in NAFLD. Hepatology. 2019; 70(4):1424-1436. DOI: 10.1002/hep.30782. View

Salanti G, Ades A, Ioannidis J . Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial. J Clin Epidemiol. 2010; 64(2):163-71. DOI: 10.1016/j.jclinepi.2010.03.016. View

Sterne J, Savovic J, Page M, Elbers R, Blencowe N, Boutron I . RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019; 366:l4898. DOI: 10.1136/bmj.l4898. View

Papakonstantinou T, Nikolakopoulou A, Higgins J, Egger M, Salanti G . CINeMA: Software for semiautomated assessment of the confidence in the results of network meta-analysis. Campbell Syst Rev. 2023; 16(1):e1080. PMC: 8356302. DOI: 10.1002/cl2.1080. View

Puhan M, Schunemann H, Murad M, Li T, Brignardello-Petersen R, Singh J . A GRADE Working Group approach for rating the quality of treatment effect estimates from network meta-analysis. BMJ. 2014; 349:g5630. DOI: 10.1136/bmj.g5630. View

Nikolakopoulou A, Higgins J, Papakonstantinou T, Chaimani A, Del Giovane C, Egger M . CINeMA: An approach for assessing confidence in the results of a network meta-analysis. PLoS Med. 2020; 17(4):e1003082. PMC: 7122720. DOI: 10.1371/journal.pmed.1003082. View

10.

Cotter T, Rinella M . Nonalcoholic Fatty Liver Disease 2020: The State of the Disease. Gastroenterology. 2020; 158(7):1851-1864. DOI: 10.1053/j.gastro.2020.01.052. View

11.

Younossi Z, Stepanova M, Rafiq N, Makhlouf H, Younoszai Z, Agrawal R . Pathologic criteria for nonalcoholic steatohepatitis: interprotocol agreement and ability to predict liver-related mortality. Hepatology. 2011; 53(6):1874-82. DOI: 10.1002/hep.24268. View

12.

Rucker G, Schwarzer G . Ranking treatments in frequentist network meta-analysis works without resampling methods. BMC Med Res Methodol. 2015; 15:58. PMC: 4521472. DOI: 10.1186/s12874-015-0060-8. View

13.

Sanyal A, Brunt E, Kleiner D, Kowdley K, Chalasani N, Lavine J . Endpoints and clinical trial design for nonalcoholic steatohepatitis. Hepatology. 2011; 54(1):344-53. PMC: 4014460. DOI: 10.1002/hep.24376. View

14.

Brignardello-Petersen R, Bonner A, Alexander P, Siemieniuk R, Furukawa T, Rochwerg B . Advances in the GRADE approach to rate the certainty in estimates from a network meta-analysis. J Clin Epidemiol. 2017; 93:36-44. DOI: 10.1016/j.jclinepi.2017.10.005. View

15.

Ekstedt M, Hagstrom H, Nasr P, Fredrikson M, Stal P, Kechagias S . Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology. 2014; 61(5):1547-54. DOI: 10.1002/hep.27368. View

16.

DerSimonian R, Laird N . Meta-analysis in clinical trials. Control Clin Trials. 1986; 7(3):177-88. DOI: 10.1016/0197-2456(86)90046-2. View

17.

Kleiner D, Bedossa P . Liver histology and clinical trials for nonalcoholic steatohepatitis-perspectives from 2 pathologists. Gastroenterology. 2015; 149(6):1305-8. DOI: 10.1053/j.gastro.2015.09.015. View

18.

Luo D, Wan X, Liu J, Tong T . Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range. Stat Methods Med Res. 2016; 27(6):1785-1805. DOI: 10.1177/0962280216669183. View

19.

Kleiner D, Brunt E, Van Natta M, Behling C, Contos M, Cummings O . Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005; 41(6):1313-21. DOI: 10.1002/hep.20701. View

20.

Sheka A, Adeyi O, Thompson J, Hameed B, Crawford P, Ikramuddin S . Nonalcoholic Steatohepatitis: A Review. JAMA. 2020; 323(12):1175-1183. DOI: 10.1001/jama.2020.2298. View