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Randomized, Placebo-Controlled Trial of Pioglitazone in Nondiabetic Subjects With Nonalcoholic Steatohepatitis
Open accessAbstract
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 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]
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“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]
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“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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Ito, D., Shimizu, S., Inoue, K., Saito, D., Yanagisawa, M., Inukai, K., Akiyama, Y., Morimoto, Y., Noda, M., & Shimada, A. (2017) · Diabetes Care · doi:10.2337/dc17-0518 · Cited by 290
The role of adiponectin in the pathogenesis and treatment of non‐alcoholic fatty liver disease
Pοlyzos, S. A., Kountouras, J., Zavos, C., & Tsiaousi, E. (2009) · Diabetes Obesity and Metabolism · doi:10.1111/j.1463-1326.2009.01176.x · Cited by 282
“Recent evidence suggests the therapeutic efficacy of pioglitazone and rosiglitazone on metabolic and histologic improvement in patients with NASH [124,126,146,166].”
BackgroundPPARs and nonalcoholic fatty liver disease
Liss, K. H. H., & Finck, B. N. (2016) · Biochimie · doi:10.1016/j.biochi.2016.11.009 · Cited by 282
Features, Diagnosis, and Treatment of Nonalcoholic Fatty Liver Disease
Torres, D. M., Williams, C. D., & Harrison, S. A. (2012) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2012.03.011 · Cited by 275
KASL clinical practice guidelines: Management of nonalcoholic fatty liver disease
Kang, S. H., Lee, H. W., Yoo, J., Cho, Y., Kim, S. U., Lee, T. H., Jang, B. K., Ahn, S. B., Ahn, S. B., Kim, H., et al. (2021) · Clinical and Molecular Hepatology · doi:10.3350/cmh.2021.0178 · Cited by 276
Exploration and Development of PPAR Modulators in Health and Disease: An Update of Clinical Evidence
Cheng, H. S., Tan, W., Low, Z. S., Marvalim, C., Lee, J. Y. H., & Tan, N. S. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20205055 · Cited by 282
Current efforts and trends in the treatment of NASH
Ratziu, V., Goodman, Z. D., & Sanyal, A. J. (2015) · Journal of Hepatology · doi:10.1016/j.jhep.2015.02.041 · Cited by 268
“Similar efficacy results were reported in two smaller randomized trials of shorter duration [92,93].”
ResultTreatment options for alcoholic and non-alcoholic fatty liver disease: A review
Singh, S., Osna, N. A., & Kharbanda, K. K. (2017) · World Journal of Gastroenterology · doi:10.3748/wjg.v23.i36.6549 · Cited by 262
Armstrong, M. J., Houlihan, D. D., Rowe, I. A., Clausen, W. H. O., Elbrønd, B., Gough, S. C. L., Tomlinson, J. W., & Newsome, P. N. (2013) · Alimentary Pharmacology & Therapeutics · doi:10.1111/apt.12149 · Cited by 250
Pathogenesis and treatment of non-alcoholic steatohepatitis and its fibrosis
Lee, K., Wu, P.-S., & Lin, H. (2022) · Clinical and Molecular Hepatology · doi:10.3350/cmh.2022.0237 · Cited by 269
Leptin in nonalcoholic fatty liver disease: A narrative review
Polyzos, S. A., Kountouras, J., & Mantzoros, C. S. (2015) · Metabolism · doi:10.1016/j.metabol.2014.10.012 · Cited by 235
“Leptin levels were increased (in parallel with BMI) after pioglitazone treatment in one study [149], without being associated with histological changes.”
BackgroundHeyens, L. J. M., Busschots, D., Koek, G. H., Robaeys, G., & Francque, S. (2021) · Frontiers in Medicine · doi:10.3389/fmed.2021.615978 · Cited by 258
Diabetes and Nonalcoholic Fatty Liver Disease: A Pathogenic Duo
Williams, K., Shackel, N. A., Gorrell, M. D., McLennan, S. V., & Twigg, S. M. (2012) · Endocrine Reviews · doi:10.1210/er.2012-1009 · Cited by 235
Efficacy of Berberine in Patients with Non-Alcoholic Fatty Liver Disease
Yan, H., Xia, M., Wang, Y., Chang, X., Yao, X., Rao, S., Zeng, M., Tu, Y., Feng, R., Jia, W., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0134172 · Cited by 237
“Several pharmacologic interventions have been attempted to treat NAFLD, and the agents targeting insulin resistance such as thiazolidinediones [5,6,7] have yielded promising results.”
BackgroundNonalcoholic fatty liver disease in women with polycystic ovary syndrome
Paschou, S. Α., Pοlyzos, S. A., Anagnostis, P. G., Goulis, D. G., Kanaka‐Gantenbein, C., Lambrinoudaki, I. V., Georgopoulos, N. A., & Vryonidou, A. (2019) · Endocrine · doi:10.1007/s12020-019-02085-7 · Cited by 233
Nonalcoholic fatty liver disease in adults: current concepts in etiology, outcomes, and management
Marjot, T., Moolla, A., Cobbold, J. F., Hodson, L., & Tomlinson, J. W. (2020) · Endocrine Reviews · doi:10.1210/endrev/bnz009 · Cited by 228
Pioglitazone: side effect and safety profile
Shah, P., & Mudaliar, S. R. D. (2010) · Expert Opinion on Drug Safety · doi:10.1517/14740331003623218 · Cited by 226
“There is growing data now that non-alcoholic fatty liver diseasemay even be a hepaticmanifestation of Type 2 diabetes and in recent studies, the administration of pioglitazone has been associated with metabolic and histologic improvements in diabetic and non-diabetic study patients with nonalcoholic steatohepatitis [3…”
BackgroundElSayed, N. A., Aleppo, G., Aroda, V. R., Bannuru, R. R., Brown, F. M., Bruemmer, D., Collins, B. S., Cusi, K. J., Hilliard, M. E., Isaacs, D. M., et al. (2022) · Diabetes Care · doi:10.2337/dc23-s004 · Cited by 242
Recent advances in nonalcoholic fatty liver disease
Cheung, O., & Sanyal, A. J. (2009) · Current Opinion in Gastroenterology · doi:10.1097/mog.0b013e3283294a18 · Cited by 217
Mantovani, A., Byrne, C. D., & Targher, G. (2022) · The Lancet Gastroenterology & Hepatology · doi:10.1016/s2468-1253(21)00261-2 · Cited by 230
ElSayed, N. A., McCoy, R. G., Aleppo, G., Bajaj, M. S., Balapattabi, K., Beverly, E. A., Early, K. B., Bruemmer, D., Cusi, K. J., Echouffo-Tcheugui, J. B., et al. (2024) · Diabetes Care · doi:10.2337/dc25-s004 · Cited by 226
Non-alcoholic fatty liver disease: What the clinician needs to know
Machado, M. V. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i36.12956 · Cited by 215
Non-alcoholic fatty liver disease: pathophysiological concepts and treatment options
Grander, C., Grabherr, F., & Tilg, H. (2023) · Cardiovascular Research · doi:10.1093/cvr/cvad095 · Cited by 236
Non-alcoholic fatty liver disease: A patient guideline
Francque, S. M., Marchesini, G., Kautz, A., Walmsley, M., Dorner, R., Lazarus, J. V., Zelber-Sagi, S., Hallsworth, K., Busetto, L., Frühbeck, G., et al. (2021) · JHEP Reports · doi:10.1016/j.jhepr.2021.100322 · Cited by 264
Treatments for NAFLD: State of Art
Mantovani, A., & Dalbeni, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22052350 · Cited by 244
Watanabe, S., Hashimoto, E., Ikejima, K., Uto, H., Ono, M., Sumida, Y., Seike, M., Takei, Y., Takehara, T., Tokushige, K., et al. (2015) · Hepatology Research · doi:10.1111/hepr.12511 · Cited by 197
Non‐alcoholic fatty liver disease from pathogenesis to management: an update
Musso, G., Gambino, R., & Cassader, M. (2009) · Obesity Reviews · doi:10.1111/j.1467-789x.2009.00657.x · Cited by 200
Nonalcoholic fatty liver disease
Erickson, S. K. (2009) · Journal of Lipid Research · doi:10.1194/jlr.r800089-jlr200 · Cited by 194
“A variety of drugs such as the statins [for review see (44)], the glitazones [(45, 46) and references therein], and other modalities [for recent comprehensive review, see (47)] have been studied.”
BackgroundA role of peroxisome proliferator‐activated receptor γ in non‐alcoholic fatty liver disease
Skat‐Rørdam, J., Ipsen, D. H., Lykkesfeldt, J., & Tveden‐Nyborg, P. (2018) · Basic & Clinical Pharmacology & Toxicology · doi:10.1111/bcpt.13190 · Cited by 197
Marchisello, S., Pino, A. D., Scicali, R., Urbano, F., Piro, S., Purrello, F., & Rabuazzo, A. M. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20081948 · Cited by 202
Negi, C. K., Babica, P., Bajard, L., Vašků, J. B., & Tarantino, G. (2021) · Metabolism · doi:10.1016/j.metabol.2021.154925 · Cited by 196
The Role of Metformin in the Management of NAFLD
Mazza, A., Fruci, B., Garinis, G. A., Giuliano, S., Malaguarnera, R., & Belfiore, A. (2011) · Experimental Diabetes Research · doi:10.1155/2012/716404 · Cited by 189
“An improvement in fibrosis was seen only in one of the small four studies mentioned above [41].”
BackgroundNonalcoholic fatty liver disease: A comprehensive review of a growing epidemic
Hassan, K. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i34.12082 · Cited by 192
Metadata
- 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 › Hepatology › 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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