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Comparative Efficacy of Drug Interventions on NAFLD Over 24 Weeks: A Traditional and Network Meta-Analysis of Randomized Controlled Trials

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Abstract

Background and Aims

Nonalcoholic fatty liver disease (NAFLD), currently referred to as metabolic dysfunction-associated steatotic liver disease (MASLD), affects approximately 38% of the world’s population, yet no pharmacological therapies have been approved for treatment. We conducted a traditional and network meta-analysis to comprehensively assess the effectiveness of drug regimens on NAFLD, and continued to use the old terminology for consistency.

Methods

Randomized, placebo-controlled trials (RCTs) investigating drug therapy in an adult population diagnosed with NAFLD with or without diabetes mellitus were included. We assessed the quality of RCTs via the Risk of Bias 2 (ROB 2) tool. When I2 < 50%, we chose a random-effects model, otherwise a fixed-effects model was selected. A random effects model was applied in the network meta-analysis. The odds ratio (OR), weighted mean difference (WMD) or standard mean difference (SMD) with 95% confidence interval (CI) were used for outcome evaluation. The primary endpoint was the resolution of nonalcoholic steatohepatitis (NASH) without the worsening of liver fibrosis. Other endpoints included histological findings and metabolic changes. The PROSPERO Registration ID was CRD42023404309.

Results

Thiazolidinediones (TZDs), vitamin E plus pioglitazone, glucagon-like peptide-1 (GLP-1) receptor agonists and fibroblast growth factor-21 (FGF-21) analogue had a higher surface under the cumulative ranking curve (SUCRA = 76.6, 73.0, 72.0 and 71.6) regarding NASH resolution. Improvement of liver fibrosis stage (≥ 1) was observed with obeticholic acid 25 mg/day (OR 2.01, 95% CI 1.35–2.98), lanifibranor 1200 mg/day (OR 2.39, 95% CI 1.19–4.82) and silymarin (OR 4.54, 95% CI 1.18–17.43) in traditional meta-analysis.

Conclusions

The results of the comprehensive analysis suggested hypoglycemic drug therapy as an effective intervention for NAFLD, with or without diabetes mellitus. A prioritized selection of TZDs, vitamin E plus pioglitazone, GLP-1 receptor agonists and FGF-21 analogue may be considered for NASH resolution. Obeticholic acid, lanifibranor and silymarin could be considered for the improvement of liver fibrosis. Each medication was relatively safe compared with placebo.

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Author notes

  1. Yifan Wang, He Yi, and Weixia Sun have contribute equally to this article.

Authors and Affiliations

  1. Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China

    Yifan Wang, He Yi, Weixia Sun, Hekai Yu, Wenxuan Tao & Ling Li

  2. Department of Epidemiology and Biostatistics, School of Public Health, Southeast University, Nanjing, 210009, China

    Xiaojin Yu

  3. Department of Endocrinology, Taizhou Jiangyan Hospital of Traditional Chinese Medicine, Taizhou, 225500, China

    Dianrong Jia

  4. Department of Endocrinology, The Affiliated People’s Hospital of Jiangsu University, Zhenjiang, 212000, China

    Yingzhao Liu

  5. Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA

    Stephen J. Pandol

  6. Basic and Translational Pancreatic Research, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA

    Stephen J. Pandol

  7. Institute of Glucose and Lipid Metabolism, Southeast University, Nanjing, 210009, China

    Ling Li

  8. Department of Clinical Science and Research, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China

    Ling Li

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  3. Weixia Sun
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  4. Hekai Yu
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  5. Wenxuan Tao
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  10. Ling Li
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Corresponding author

Correspondence to Ling Li.

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Funding

This study was funded by National Natural Science Foundation Major International (Regional) Joint Research Program (82320108003), National Natural Science Foundation (82170845, 82000740, 81970717), the Key Research & Development Program (No.BE2022853) and Medical Key Discipline (ZDXK202203) of Jiangsu Province.

Author contributions

Conceptualization and methodology: Yifan Wang, He Yi, Weixia Sun, Hekai Yu, Wenxuan Tao and Ling Li; Data curation, formal analysis, visualization and validation: Yifan Wang, He Yi, Weixia Sun and Xiaojin Yu; Writing–original draft: Yifan Wang, He Yi; Writing–review & editing: Stephen J. Pandol, Dianrong Jia, Yingzhao Liu, Ling Li; Supervision: Weixia Sun, Dianrong Jia, Yingzhao Liu, Ling Li. All authors have accessed and verified the underlying data reported in the manuscript.

Conflict of interest

Yifan Wang has no potential conflicts of interest to declare for this article. He Yi has no potential conflicts of interest to declare for this article. Weixia Sun has no potential conflicts of interest to declare for this article. Hekai Yu has no potential conflicts of interest to declare for this article. Wenxuan Tao has no potential conflicts of interest to declare for this article. Xiaojin Yu has no potential conflicts of interest to declare for this article. Dianrong Jia has no potential conflicts of interest to declare for this article. Yingzhao Liu has no potential conflicts of interest to declare for this article. Stephen J. Pandol has no potential conflicts of interest to declare for this article. Ling Li has no potential conflicts of interest to declare for this article.

Data availability statements

Data are available upon reasonable request.

Code availability

Not applicable.

Ethics approval and patient consent for publication

Not applicable.

Supplementary Information

Below is the link to the electronic supplementary material.

40265_2024_2015_MOESM1_ESM.docx

Supplementary file1 Online Resource 1 This file provides information on effects of drugs on resolution of NASH with no worsening of liver fibrosis, the improvement of liver fibrosis by at least one stage with no worsening of NASH and a comprehensive description of effects of drugs on histology, imaging and serology (DOCX 32 KB)

40265_2024_2015_MOESM2_ESM.docx

Supplementary file2 Online Resource 2 This file depicts league tables of pairwise comparisons of drug therapies for NASH resolution with no worsening of fibrosis and the improvement of liver fibrosis stage (≥1) (DOCX 31 KB)

40265_2024_2015_MOESM3_ESM.docx

Supplementary file3 Online Resource 3 This file depicts risk of bias of RCTs included and provides funnel plots of studies included in the network meta-analyses and tests for inconsistency in network analysis (DOCX 1431 KB)

40265_2024_2015_MOESM4_ESM.docx

Supplementary file4 Online Resource 4 This file provides forest plots of estimates of pharmacological interventions on blood lipids, including low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, and total cholesterol. This file also provides forest plots of estimates of changes in liver fibrosis stage and changes in liver fat content (DOCX 2468 KB)

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Wang, Y., Yi, H., Sun, W. et al. Comparative Efficacy of Drug Interventions on NAFLD Over 24 Weeks: A Traditional and Network Meta-Analysis of Randomized Controlled Trials. Drugs (2024). https://doi.org/10.1007/s40265-024-02015-6

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  • DOI: https://doi.org/10.1007/s40265-024-02015-6

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