Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis
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Background & aims Nonalcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease for which there is limited therapy available. Insulin sensitizing, anti-inflammatory, and antifibrotic properties of thiazolidinediones support their use in treating NASH. We have evaluated pioglitazone in the treatment of nondiabetic patients with NASH.Methods We randomized 74 nondiabetic patients (45 men; median age, 54 y) with histologically proven NASH to 12 months of standard diet, exercise, and either placebo or pioglitazone (30 mg/day). Sixty-one patients (30 placebo, 31 pioglitazone) had liver biopsies both at the beginning and the end of the study.Results Compared with placebo, pioglitazone therapy was associated with an increase in weight (mean change, -0.55 vs +2.77 kg; P = .04) and a reduction in glucose (+0.4 vs -0.1 mmol/L; P = .02), HbA1c (+0.16% vs -0.18%; P = .006), insulin C peptide level (+42 vs -78 pmol/L; P = .02), alanine aminotransferase level (-10.9 vs -36.2 u/L; P = .009), gamma-glutamyltransferase level (-9.4 vs -41.2 u/L; P = .002), and ferritin (-11.3 vs -90.5 microg/L; P = .01). Histologic features including hepatocellular injury (P = .005), Mallory-Denk bodies (P = .004), and fibrosis (P = .05) were reduced in patients treated with pioglitazone compared with those in the placebo group.Conclusions Pioglitazone therapy over a 12-month period in nondiabetic subjects with NASH resulted in improvements in metabolic and histologic parameters, most notably liver injury and fibrosis. Larger extended trials are justified to assess the long-term efficacy of pioglitazone in this patient group.
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A meta-analysis of 8 RCTs in people with biopsy-proven MASH concluded that pioglitazone was associated with improvement of MASH and reversal of fibrosis, irrespective of presence of type 2 diabetes.
“A meta-analysis of 8 RCTs in people with biopsy-proven MASH concluded that pioglitazone was not only associated with the improvement of MASH but also reversal of fibrosis, irrespective of the presence of type 2 diabetes [178].”
From Obesity and MASLD: Is weight loss the (only) key to treat metabolic liver disease? (2024) · cites this paper as [178]
The Discussion (page not supplied) reports that this trial found reduced liver injury and fibrosis after 12 months of pioglitazone in nondiabetic patients with NASH. The source is one randomized trial, not a meta-analysis of eight RCTs, and it does not establish fibrosis reversal irrespective of type 2 diabetes status. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn nondiabetic patients with MASH, 12-month pioglitazone treatment significantly reduced hepatocellular injury, Mallory-Denk bodies, and fibrosis compared with placebo.
“Histological analysis revealed significant reductions in hepatocellular injury, Mallory–Denk bodies, and fibrosis compared with placebo.”
From Strategies to promote liver fibrosis amelioration with involvement of restorative macrophages (2026) · cites this paper as [203]
In several RCTs, pioglitazone has been shown to improve histological features of steatohepatitis, without a clear effect on fibrosis regression even after prolonged (3-year) therapy.
“In several RCTs, pioglitazone, a thiazolidinedione which mainly activates peroxisome proliferator-activated receptor (PPAR) c , has been shown to improve histological features of steatohepatitis, 372,418 -420 without a clear effect on fi brosis regression even after prolonged (3-year) therapy.”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [418]
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- Authors
- Aithal, G. P., Thomas, J. A., Kaye, P. V., Lawson, A., Ryder, S. D., Spendlove, I., Austin, A. S., Freeman, J. G., Morgan, L., & Webber, J.
- Affiliations
- Nottingham University Hospitals NHS Trust (GB)
- University of Nottingham (GB)
- Royal Derby Hospital (GB)
- University Hospitals Birmingham NHS Foundation Trust (GB)
- Corresponding author
- Aithal, Guruprasad P.
- ORCID
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2008-10
- Volume
- 135
- Issue
- 4
- Pages
- 1176-1184
- ISSN
- 0016-5085 (ISSN-L)
- OpenAlex
- W2151490108
- Cited by
- 721
- References
- 39
- Citations by year
- 2026: 15 · 2025: 33 · 2024: 34 · 2023: 38 · 2022: 51 · 2021: 54 · 2020: 48 · 2019: 35 · 2018: 34 · 2017: 36 · 2016: 45 · 2015: 42 · 2014: 40 · 2013: 38 · 2012: 35
- FWCI
- 35.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Keywords
- pioglitazone, nonalcoholic steatohepatitis, thiazolidinediones, non-diabetic patients, liver fibrosis, liver histopathology, insulin sensitivity, insulin resistance, hepatocyte injury, Mallory-Denk bodies, alanine aminotransferase, ferritin, weight change, glycemic control
- MeSH terms
- Pioglitazone, Adult, Aged, Alkaline Phosphatase, Fatty Liver, Female, Humans, Hypoglycemic Agents, Insulin, Liver, Liver Cirrhosis, Male, Middle Aged, Patient Dropouts, Placebos, Treatment Outcome, Thiazolidinediones, Adipokines
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