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Thiazolidinediones and Advanced Liver Fibrosis in Nonalcoholic Steatohepatitis: A Meta-analysis
Open accessAbstract
Importance: Nonalcoholic steatohepatitis (NASH) is projected to be the leading cause of liver transplantation by 2020. Advanced fibrosis (stage F3-F4) on liver biopsy independently predicts all-cause and liver-related mortality in NASH. There are no known efficacious treatments for advanced fibrosis related to NASH. Thiazolidinedione therapy has been extensively evaluated in NASH, and new randomized clinical trials (RCTs) of its efficacy have been completed. Objective: To synthesize the evidence about the association of thiazolidinedione therapy with advanced liver fibrosis in NASH. Data Sources: MEDLINE, Ovid MEDLINE In-Process, Cochrane Library, EMBASE, clinicaltrials.gov, PubMed, and Scopus databases (without language restrictions), as well as other registries and scientific meeting presentations, from database inception through August 15, 2016. Study Selection: Randomized clinical trials evaluating the effect of thiazolidinedione therapy on histologic features of the liver in biopsy-proven NASH. Data Extraction and Synthesis: Two investigators extracted study data independently and in duplicate and rated the risk of bias using the Cochrane Risk of Bias Tool. Main Outcomes and Measures: The primary outcome was a dichotomous improvement in advanced fibrosis on liver biopsy, defined as an improvement in fibrosis stage from F3-F4 to F0-F2. Secondary outcomes were at least a 1-point improvement in fibrosis of any stage and NASH resolution. This meta-analysis also evaluated adverse effects of thiazolidinedione therapy, including weight gain, lower limb edema, congestive heart failure, bone fractures, cancer, and anemia. With the use of random-effects models, dichotomous variables are presented as odds ratios (ORs) with 95% CIs, and continuous variables are presented as weighted mean differences with 95% CIs. Results: This study analyzed 8 RCTs (5 evaluating pioglitazone use and 3 evaluating rosiglitazone maleate use) enrolling 516 patients with biopsy-proven NASH for a duration of 6 to 24 months. Among all studies combined, thiazolidinedione therapy was associated with improved advanced fibrosis (OR, 3.15; 95% CI, 1.25-7.93; P = .01; I2 = 0%), fibrosis of any stage (OR, 1.66; 95% CI, 1.12-2.47; P = .01; I2 = 0%), and NASH resolution (OR, 3.22; 95% CI, 2.17-4.79; P < .001; I2 = 0%). Analyses restricted to RCTs enrolling patients without diabetes yielded similar results for improvement in advanced fibrosis (OR, 2.95; 95% CI, 1.04-10.90; P = .02; I2 = 0%), improvement in fibrosis of any stage (OR, 1.76; 95% CI, 1.02-3.03; P = .02; I2 = 0%), and NASH resolution (OR, 3.40; 95% CI, 1.95-5.93; P < .001; I2 = 0%). All effects were accounted for by pioglitazone use. Weight gain and lower limb edema occurred more frequently with thiazolidinedione therapy (initial body weight +2.70%; 95% CI, 1.96%-4.34%; P = .001). The small sample size of included RCTs prevented evaluation of more serious adverse effects of thiazolidinedione therapy. Conclusions and Relevance: Pioglitazone use improves advanced fibrosis in NASH, even in patients without diabetes. Whether this finding translates to improvement in risk for clinical outcomes requires further study.
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“Pioglitazone therapy, GLP-1 RA therapy, and metabolic surgery have all been shown to reduce NASH activity; pioglitazone therapy and metabolic surgery may also improve hepatic fi brosis (188,292 -298).”
From Management of Hyperglycemia in Type 2 Diabetes, 2022. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) (2022) · cites this paper as [293]
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“In MASH, treatment with pioglitazone, the most prescribed PPARγ agonistic drug over the last decades, was repeatedly associated with improvements in liver histology, despite a net weight gain of 2-4 % of body weight (Table 1) [176,177].”
From Obesity and MASLD: Is weight loss the (only) key to treat metabolic liver disease? (2024) · cites this paper as [176]
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“PPARα agonist action on lipid metabolism is driven by stimulation of hepatic fatty acid transport, lipolysis and peroxisomal as well as mitochondrial β-oxidation [172].”
From Obesity and MASLD: Is weight loss the (only) key to treat metabolic liver disease? (2024) · cites this paper as [172]
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Metadata
- Authors
- Musso, G., Cassader, M., Paschetta, E., & Gambino, R.
- Affiliations
- Ospedale Humanitas Gradenigo (IT)
- University of Turin (IT)
- Corresponding author
- Musso, Giovanni
- Venue
- JAMA Internal Medicine
- Publisher
- American Medical Association (AMA)
- Published
- 2017-05-01
- Volume
- 177
- Issue
- 5
- Pages
- 633
- ISSN
- 2168-6106 (ISSN-L)
- PMC
- PMC5470366
- OpenAlex
- W2593506275
- Cited by
- 449
- References
- 31
- Citations by year
- 2026: 37 · 2025: 49 · 2024: 45 · 2023: 69 · 2022: 58 · 2021: 66 · 2020: 39 · 2019: 33 · 2018: 32 · 2017: 18
- FWCI
- 26.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Internal Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- thiazolidinediones, nonalcoholic steatohepatitis, advanced liver fibrosis, pioglitazone, rosiglitazone, NASH resolution, adverse drug reactions, weight gain, congestive heart failure, anemia, drug safety, liver transplantation risk, risk of bias assessment, risk of bias
- MeSH terms
- Pioglitazone, Diabetes Mellitus, Type 2, Humans, Hypoglycemic Agents, Treatment Outcome, Disease Progression, Thiazolidinediones, Non-alcoholic Fatty Liver Disease, Protective Factors
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