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First-in-Asian double-blind randomized trial to assess the efficacy and safety of insulin sensitizer in nonalcoholic steatohepatitis patients

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Abstract

Background

The efficacy and safety of insulin sensitizer in Asians with non-alcoholic steatohepatitis (NASH) remain elusive.

Aims

The double-blind, randomized, placebo-controlled trial was conducted aiming to investigate the efficacy and safety of pioglitazone in NASH patients.

Methods

A total of 90 NASH patients (66 males, age = 44.1 ± 12.7 years) were prospectively randomized into oral pioglitazone 30 mg/day (Arm A) or placebo (Arm B) for 24 weeks. The primary endpoint was the efficacy of pioglitazone in reducing inflammation and liver fat at end-of-treatment (EOT). NASH resolution/improvement without fibrosis worsening was also evaluated.

Results

At EOT, there was a significantly decline of alanine aminotransferase (86.9 ± 34.3 to 45.7 ± 35.8 IU/L, p = 0.003) level in Arm A patients. In intention-to-treat analysis among 66 patients who completed paired biopsies, The NAFLD activity score (NAS) of 30 Arm A patients significantly decreased from 4.27 ± 1.14 at baseline to 2.53 ± 1.63 at EOT (p < 0.0001), whereas there was no significant change in patients of Arm B (3.94 ± 1.41 vs 3.94 ± 1.51, p = 1.0). NASH improvement without worsening of fibrosis was achieved in 46.7% (14/30) patients in Arm A, compared to 11.1% (4/36) patients in Arm B (p = 0.002). Liver fat content reduced (20.2 ± 9.0 to 14.3 ± 6.9%, p < 0.0001) on MRI–PDFF in Arm A compared to their counterparts. No significant difference of adverse events occurred between groups.

Conclusions

A 24-week pioglitazone treatment was well-tolerated and effective in improving liver histology and reducing liver steatosis in Asian NASH patients. (ClinicalTrials.gov number: NCT01068444)

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Abbreviations

NAFLD:

Non-alcoholic fatty liver disease

BMI:

Body mass index

MetS:

Metabolic syndrome

T2DM:

Type 2 diabetes mellitus

NASH:

Non-alcoholic steatohepatitis

IR:

Insulin resistance

HCC:

Hepatocellular carcinoma

PPARγ:

Peroxisome proliferator-activated receptor-gamma

TZD:

Thiazolidinediones

FPG:

Fasting plasma glucose

TC:

Total cholesterol

HDL-C:

High-density lipoprotein cholesterol

LDL-C:

Low-density lipoprotein cholesterol

TG:

Triglycerides

UA:

Uric acid

hs-CRP:

High-sensitive C-reactive protein

AST:

Aspartate aminotransferase

ALT:

Alanine aminotransferase

ULN:

Upper limit of normal

EOF:

End-of-follow-up

EOT:

End-of-treatment

AE:

Adverse events

DMC:

Data Monitoring Committee

HOMA-IR:

The homeostasis model assessment method

NAS:

NAFLD activity score

ITT:

Intention-to-treat

FIB-4:

Fibrosis-4

MRI–PDFF:

Magnetic resonance imaging–proton density fat fraction

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Acknowledgements

The authors thank Dr. Yi-Hsin Yang, National Institute of Cancer Research, National Health Research Institutes, Taiwan for data blinding/unblinding processes. The Authors express many thanks for the members of DMC (Dr. Wen-Yu Chang, Dr. Chung-Sheng Lai, Dr. Shi-Jang Shin). This study was supported partly by grants from The Ministry of Science and Technology, Taiwan (MOST 107-2314-B-037-083-MY3), Kaohsiung Medical University (KMU-TC108A04-3, KMU-TC109B05), and Kaohsiung Medical University Hospital (KMUH106-6R08, KMUH107-7R05). The Authors thank China Chemical & Pharmaceutical, Taipei, Taiwan for providing pioglitazone and placebo agents. The authors thank secretary help from Taiwan Liver Research Foundation (TLRF). The foundation did not influence how the study was conducted or the approval of the manuscript.

Funding

This study was supported partly by grants from The Ministry of Science and Technology, Taiwan (MOST 107-2314-B-037-083-MY3), Kaohsiung Medical University (KMU-TC108A04-3, KMU-TC109B05), and Kaohsiung Medical University Hospital (KMUH106-6R08, KMUH107-7R05).

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Authors and Affiliations

  1. Hepatobiliary Division and Hepatitis Center, Department of Internal Medicine, Kaohsiung Medical University Hospital, 100 Tzyou Road, Kaohsiung, Taiwan

    Jee-Fu Huang, Chia-Yen Dai, Chung-Feng Huang, Pei-Chien Tsai, Ming-Lun Yeh, Po-Yau Hsu, Nai-Jen Hou, Ching-I Huang, Po-Cheng Liang, Yi-Hung Lin, Chih-Wen Wang, Ming-Yen Hsieh, Shinn-Chern Chen, Zu-Yau Lin, Ming-Lung Yu & Wan-Long Chuang

  2. Graduate Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    Jee-Fu Huang, Chia-Yen Dai, Chung-Feng Huang, Ming-Lun Yeh, Po-Yau Hsu, Ming-Lung Yu & Wan-Long Chuang

  3. Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    Jee-Fu Huang, Chia-Yen Dai, Chung-Feng Huang, Ming-Lun Yeh, Ching-I Huang, Shinn-Chern Chen, Zu-Yau Lin, Ming-Lung Yu & Wan-Long Chuang

  4. Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan

    Jee-Fu Huang & Ming-Lung Yu

  5. Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

    Jee-Fu Huang, Nai-Jen Hou & Ming-Yen Hsieh

  6. Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, Taiwan

    Shiu-Feng Huang

  7. Department of Anatomic Pathology, Linko Chang Gung Memorial Hospital, Taoyuan, Taiwan

    Shiu-Feng Huang

  8. Division of Gastroenterology, Department of Internal Medicine, Taitung Mackay Memorial Hospital, Taitung, Taiwan

    Ming-Jong Bair

  9. Mackay Medical College, New Taipei City, Taiwan

    Ming-Jong Bair

Authors
  1. Jee-Fu Huang
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Contributions

Conception and design: J-FH, M-LY, C-YD, C-FH, W-LC. Acquisition of data: J-FH, C-YD, C-FH, M-JB, S-CC, M-LY, N-JH, C-IH, P-CL, Y-HL, C-WW, M-YH, S-CC, Z-YL. Data analysis and interpretation: J-FH, P-CT, C-FH, C-YD, P-YH, S-FH, W-LC, M-LY. Manuscript drafting and critical revising: J-FH, P-CT, M-LY, W-LC.

Corresponding authors

Correspondence to Ming-Lung Yu or Wan-Long Chuang.

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Conflict of interest

Jee-Fu Huang: Consultant of Roche, BMS, Gilead, Merck, Sysmex, Pharmaessential, Polaris, and Instylla. Speaker for Abbvie, BMS, Gilead, Merck, Sysmex, and Roche. Chia-Yen Dai: Consultant of Abbvie and Roche; Speaker for Abbvie, Gilead, and Roche. Chung-Feng Huang: Speaker for Abbvie, BMS, Bayer, Gilead, Merck, and Roche. Ming-Lung Yu: Research grant from Abbott, BMS, Merck, and Gilead; Consultant of Abbvie, Abbott, Ascletis, BMS, Merck, Gilead, and Roche; Speaker for Abbvie, Abbott, BMS, Merck, Gilead, and IPSEN. Wan-Long Chuang: Consultant of Gilead, AbbVie, BMS, and PharmaEssentia; Speaker for Gilead, AbbVie, BMS, and PharmaEssentia.

Ethics approval

The Institutional Review Board of the Kaohsiung Medical University Hospital approved the study.

Consent to participate

The trial was conducted in compliance with the Declaration of Helsinki and the Good Clinical Practice guidelines of the International Conference on Harmonization. Written informed consent for interview, anthropomorphic measurements, blood sampling, liver biopsies and medical record review were obtained from patients.

Consent for publication

All authors contributed to the interpretation of the data and reviewed and approved the manuscript.

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Huang, JF., Dai, CY., Huang, CF. et al. First-in-Asian double-blind randomized trial to assess the efficacy and safety of insulin sensitizer in nonalcoholic steatohepatitis patients. Hepatol Int 15, 1136–1147 (2021). https://doi.org/10.1007/s12072-021-10242-2

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