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 fibrosis.
“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]
The Discussion (page not provided) reports NASH resolution and improved fibrosis with thiazolidinedione therapy, mainly attributable to pioglitazone. The paper does not provide evidence for the sentence’s claims about GLP-1 receptor agonists or metabolic surgery. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIn MASH, treatment with pioglitazone was repeatedly associated with improvements in liver histology, despite a net weight gain of 2-4% of body weight.
“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]
PPARα agonist action on lipid metabolism is driven by stimulation of hepatic fatty acid transport, lipolysis and peroxisomal as well as mitochondrial β-oxidation.
“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]
The Data Sources and Searches section identifies thiazolidinediones as PPAR-γ agonists, and the Discussion addresses their effects on NASH fibrosis. Neither section explains PPARα action on lipid metabolism. Searches for hepatic fatty acid transport, lipolysis, and mitochondrial or peroxisomal β-oxidation found no passage addressing the claimed mechanism. (LLM, conf=0.76)
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Cites
Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA statement
Moher, D., Liberati, A., Tetzlaff, J., Altman, D. G., & for the PRISMA Group (2009) · BMJ · doi:10.1136/bmj.b2535 · Cited by 83,823 · see citing works
Preferred reporting items for systematic reviews and meta-analyses: the PRISMA Statement.
(2009) · PubMed Central · Cited by 44,859 · see citing works
Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement
Moher, D., Liberati, A., Tetzlaff, J., & Altman, D. G. (2009) · Journal of Clinical Epidemiology · doi:10.1016/j.jclinepi.2009.06.005 · Cited by 19,575 · see citing works
EASL–EASD–EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease
(2016) · Journal of Hepatology · doi:10.1016/j.jhep.2015.11.004 · Cited by 4,836 · see citing works
Chalasani, N., Younossi, Z. M., Lavine, J. E., Diehl, A. M., Brunt, E. M., Cusi, K. J., Charlton, M., & Sanyal, A. J. (2012) · Hepatology · doi:10.1002/hep.25762 · Cited by 3,805 · see citing works
Pioglitazone, Vitamin E, or Placebo for Nonalcoholic Steatohepatitis
Sanyal, A. J., Chalasani, N., Kowdley, K. V., McCullough, A., Diehl, A. M., Bass, N. M., Neuschwander-Tetri, B. A., Lavine, J. E., Tonascia, J., Unalp, A., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa0907929 · Cited by 3,327 · see citing works
Angulo, P., Kleiner, D. E., Dam-Larsen, S., Adams, L. A., Bjornsson, E. S., Charatcharoenwitthaya, P., Mills, P. R., Keach, J. C., Lafferty, H. D., Stahler, A., et al. (2015) · Gastroenterology · doi:10.1053/j.gastro.2015.04.043 · Cited by 2,987 · see citing works
Ekstedt, M., Hagström, H., Nasr, P., Fredrikson, M., Stål, P., Kechagias, S., & Hultcrantz, R. (2015) · Hepatology · doi:10.1002/hep.27368 · Cited by 2,287 · see citing works
A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis
Belfort, R., Harrison, S. A., Brown, K., Darland, C., Finch, J., Hardies, J., Balas, B., Gastaldelli, A., Tio, F., Pulcini, J., et al. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa060326 · Cited by 1,827 · see citing works
Wong, R. J., Aguilar, M. E. F., Cheung, R. C., Perumpail, R. B., Harrison, S. A., Younossi, Z. M., & Ahmed, A. (2014) · Gastroenterology · doi:10.1053/j.gastro.2014.11.039 · Cited by 1,821 · see citing works
Musso, G., Gambino, R., Cassader, M., & Pagano, G. (2010) · Annals of Medicine · doi:10.3109/07853890.2010.518623 · Cited by 1,285 · see citing works
Self-citationCusi, K., Orsak, B., Bril, F., Lomonaco, R., Hecht, J., Ortiz-Lopez, C., Tio, F., Hardies, J., Darland, C., Musi, N., et al. (2016) · Annals of Internal Medicine · doi:10.7326/m15-1774 · Cited by 1,024 · see citing works
Musso, G., Gambino, R., Tabibian, J. H., Ekstedt, M., Kechagias, S., Hamaguchi, M., Hultcrantz, R. W., Hagström, H., Yoon, S. K., Charatcharoenwitthaya, P., et al. (2014) · PLoS Medicine · doi:10.1371/journal.pmed.1001680 · Cited by 727 · see citing works
Self-citationAithal, 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. (2008) · Gastroenterology · doi:10.1053/j.gastro.2008.06.047 · Cited by 721 · see citing works
EASL–EASD–EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease
European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), & European Association for the Study of Obesity (EASO) (2016) · Diabetologia · doi:10.1007/s00125-016-3902-y · Cited by 685 · see citing works
Musso, G., Cassader, M., Rosina, F., & Gambino, R. (2012) · Diabetologia · doi:10.1007/s00125-011-2446-4 · Cited by 661 · see citing works
Self-citationRatziu, V., Giral, P., Jacqueminet, S., Charlotte, F., Hartemann–Heurtier, A., Serfaty, L., Podevin, P., Lacorte, J., Bernhardt, C., Bruckert, E., et al. (2008) · Gastroenterology · doi:10.1053/j.gastro.2008.03.078 · Cited by 625 · see citing works
Harnois, D. M. (2009) · Yearbook of Gastroenterology · doi:10.1016/s0739-5930(09)79298-0 · Cited by 505 · see citing works
Sanyal, A. J., MOFRAD, P., Contos, M. J., Sargeant, C., Luketic, V. A., Sterling, R. K., Stravitz, R. T., Shiffman, M. L., Clore, J. N., & Mills, A. S. (2004) · Clinical Gastroenterology and Hepatology · doi:10.1016/s1542-3565(04)00457-4 · Cited by 436 · see citing works
Non-alcoholic steatohepatitis: emerging molecular targets and therapeutic strategies
Musso, G., Cassader, M., & Gambino, R. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2015.3 · Cited by 415 · see citing works
Self-citationRatziu, V., Charlotte, F., Bernhardt, C., Giral, P., Halbron, M., Naour, G. L., Hartemann–Heurtier, A., Bruckert, É., & Poynard, T. (2009) · Hepatology · doi:10.1002/hep.23270 · Cited by 363 · see citing works
Sanyal, A. J., Friedman, S. L., McCullough, A. J., & Dimick‐Santos, L. (2014) · Hepatology · doi:10.1002/hep.27678 · Cited by 355 · see citing works
Brief Communication: The Relationship of Regression of Cirrhosis to Outcome in Chronic Hepatitis C
Mallet, V. O., Gilgenkrantz, H., Serpaggi, J., Verkarre, V., Vallet‐Pichard, A., Fontaine, H., & Pol, S. (2008) · Annals of Internal Medicine · doi:10.7326/0003-4819-149-6-200809160-00006 · Cited by 290 · see citing works
Evolving Frequency and Outcomes of Liver Transplantation Based on Etiology of Liver Disease
Singal, A. K., Guturu, P., Hmoud, B., Kuo, Y.-F., Salameh, H., & Wiesner, R. H. (2013) · Transplantation · doi:10.1097/tp.0b013e31827afb3a · Cited by 278 · see citing works
Fatty Liver and Chronic Kidney Disease: Novel Mechanistic Insights and Therapeutic Opportunities
Musso, G., Cassader, M., Cohney, S. J., Michieli, F. D., Pinach, S., Saba, F., & Gambino, R. (2016) · Diabetes Care · doi:10.2337/dc15-1182 · Cited by 162 · see citing works
Self-citationIdılman, R., Mızrak, D., CORAPCIOGLU, D., Bektaş, M., Doğanay, B., Saykı, M., Çoban, Ş., Erden, E., Soykan, İ., Emral, R., et al. (2008) · Alimentary Pharmacology & Therapeutics · doi:10.1111/j.1365-2036.2008.03723.x · Cited by 119 · see citing works
Efficacy of insulin-sensitizing agents in nonalcoholic fatty liver disease
Omer, Z., Çetinkalp, Ş., Akyıldız, M., Yılmaz, F., Batur, Y., Yılmaz, C., & Akarca, U. S. (2009) · European Journal of Gastroenterology & Hepatology · doi:10.1097/meg.0b013e32832e2baf · Cited by 116 · see citing works
Panebianco, C., Oben, J. A., Vinciguerra, M., & Pazienza, V. (2016) · Clinical and Experimental Medicine · doi:10.1007/s10238-016-0438-x · Cited by 97 · see citing works
Liver Fibrosis Reversion After Suppression of Hepatitis B Virus
Rockey, D. C. (2016) · Clinics in Liver Disease · doi:10.1016/j.cld.2016.06.003 · Cited by 44 · see citing works
Musso, G., Michieli, F. D., Bongiovanni, D., Parente, R., Framarin, L., Leone, N., Berrutti, M., Gambino, R., Cassader, M., Cohney, S. J., et al. (2016) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2016.08.002 · Cited by 38 · see citing works
Self-citationPioglitazone, Vitamin E, or Placebo for Nonalcoholic Steatohepatitis
Harnois, D. M. (2010) · Yearbook of Gastroenterology · doi:10.1016/s0739-5930(10)79533-7 · Cited by 38 · see citing works
Thiazolidinediones for the Treatment in NASH
Argo, C. K., Iezzoni, J. C., Al‐Osaimi, A. M. S., & Caldwell, S. H. (2009) · Journal of Clinical Gastroenterology · doi:10.1097/mcg.0b013e31818f4fc2 · Cited by 26 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Davies, M. J., Aroda, V. R., Collins, B. S., Gabbay, R. A., Green, J., Maruthur, N. M., Rosas, S. E., Del Prato, S., Mathieu, C., Mingrone, G., et al. (2022) · Diabetes Care · doi:10.2337/dci22-0034 · Cited by 2,104 · see citing works
Davies, M. J., Aroda, V. R., Collins, B. S., Gabbay, R. A., Green, J., Maruthur, N. M., Rosas, S. E., Del Prato, S., Mathieu, C., Mingrone, G., et al. (2022) · Diabetologia · doi:10.1007/s00125-022-05787-2 · Cited by 1,048 · see citing works
Cusi, K., Isaacs, S., Barb, D., Basu, R., Caprio, S., Garvey, W. T., Kashyap, S., Mechanick, J. I., Mouzaki, M., Nadolsky, K., et al. (2022) · Endocrine Practice · doi:10.1016/j.eprac.2022.03.010 · Cited by 1,021 · see citing works
The complex link between NAFLD and type 2 diabetes mellitus - mechanisms and treatments
Targher, G., Corey, K. E., Byrne, C. D., & Roden, M. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-021-00448-y · Cited by 850 · see citing works
Stefan, N., Häring, H., & Cusi, K. J. (2018) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(18)30154-2 · Cited by 848 · see citing works
Targher, G., Byrne, C. D., & Tilg, H. (2020) · Gut · doi:10.1136/gutjnl-2020-320622 · Cited by 848 · see citing works
Metabolic dysfunction-associated steatotic liver disease (MASLD): a state-of-the-art review
Chan, W.-K., Chuah, K.-H., Rajaram, R. B., Lim, L.-L., Ratnasingam, J., & Vethakkan, S. R. (2023) · Journal of Obesity & Metabolic Syndrome · doi:10.7570/jomes23052 · Cited by 776 · see citing works
Type 2 diabetes mellitus in adults: pathogenesis, prevention and therapy
Lu, X., Xie, Q., Pan, X., Zhang, R., Zhang, X., Peng, G., Zhang, Y., Shen, S., & Tong, N. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01951-9 · Cited by 787 · see citing works
NAFLD as a Continuum: From Obesity to Metabolic Syndrome and Diabetes
Godoy-Matos, A. F., Silva Júnior, W. S., & Valerio, C. M. (2020) · Diabetology & Metabolic Syndrome · doi:10.1186/s13098-020-00570-y · Cited by 643 · see citing works
Kanwal, F., Shubrook, J. H., Adams, L. A., Pfotenhauer, K., Wai-Sun Wong, V., Wright, E., Abdelmalek, M. F., Harrison, S. A., Loomba, R., Mantzoros, C. S., et al. (2021) · Gastroenterology · doi:10.1053/j.gastro.2021.07.049 · Cited by 618 · see citing works
Targher, G., Tilg, H., & Byrne, C. D. (2021) · The Lancet Gastroenterology & Hepatology · doi:10.1016/s2468-1253(21)00020-0 · Cited by 586 · see citing works
Dysregulated lipid metabolism links NAFLD to cardiovascular disease
Deprince, A., Haas, J. T., & Staels, B. (2020) · Molecular Metabolism · doi:10.1016/j.molmet.2020.101092 · Cited by 558 · see citing works
Modulation of Insulin Resistance in Nonalcoholic Fatty Liver Disease
Khan, R. S., Bril, F., Cusi, K. J., & Newsome, P. N. (2018) · Hepatology · doi:10.1002/hep.30429 · Cited by 543 · see citing works
Emerging therapeutic approaches for the treatment of NAFLD and type 2 diabetes mellitus
Ferguson, D., & Finck, B. N. (2021) · Nature Reviews Endocrinology · doi:10.1038/s41574-021-00507-z · Cited by 507 · see citing works
Nonalcoholic Fatty Liver Disease and the Heart
Stahl, E. P., Dhindsa, D. S., Lee, S. K., Sandesara, P. B., Chalasani, N., & Sperling, L. S. (2019) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2018.11.050 · Cited by 445 · see citing works
Kim, C.-W., Addy, C., Kusunoki, J., Anderson, N. N., Deja, S., Fu, X., Burgess, S. C., Li, C., Ruddy, M., Chakravarthy, M., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.07.009 · Cited by 419 · see citing works
Stefan, N., Yki‐Järvinen, H., & Neuschwander‐Tetri, B. A. (2024) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(24)00318-8 · Cited by 450 · see citing works
Younossi, Z. M., Loomba, R. S., Rinella, M. E., Bugianesi, E., Marchesini, G., Neuschwander‐Tetri, B. A., Serfaty, L., Negro, F., Caldwell, S. H., Ratziu, V., et al. (2017) · Hepatology · doi:10.1002/hep.29724 · Cited by 361 · see citing works
Cusi, K. J., Abdelmalek, M. F., Apovian, C. M., Balapattabi, K., Bannuru, R. R., Barb, D., Bardsley, J. K., Beverly, E. A., Corbin, K. D., ElSayed, N. A., et al. (2025) · Diabetes Care · doi:10.2337/dci24-0094 · Cited by 396 · see citing works
Musso, G., Cassader, M., Paschetta, E., & Gambino, R. (2018) · Gastroenterology · doi:10.1053/j.gastro.2018.06.031 · Cited by 332 · see citing works
Self-citationMetabolic Dysfunction–Associated Steatotic Liver Disease
Targher, G., Valenti, L., & Byrne, C. D. (2025) · New England Journal of Medicine · doi:10.1056/nejmra2412865 · Cited by 325 · see citing works
PPAR-γ signaling in nonalcoholic fatty liver disease: Pathogenesis and therapeutic targets.
Chen, H., Tan, H.-B., Wan, J., Zeng, Y., Wang, J., Wang, H., & Lu, X. (2023) · Pharmacology and Therapeutics · doi:10.1016/j.pharmthera.2023.108391 · Cited by 292 · see citing works
Nonalcoholic steatohepatitis: the role of peroxisome proliferator-activated receptors
Francque, S., Szabo, G., Abdelmalek, M. F., Byrne, C. D., Cusi, K., Dufour, J.-F., Roden, M., Sacks, F., & Tacke, F. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-020-00366-5 · Cited by 316 · see citing works
Bril, F., Biernacki, D. M., Kalavalapalli, S., Lomonaco, R., Subbarayan, S. K., Lai, J., Tio, F., Suman, A., Orsak, B. K., Hecht, J., et al. (2019) · Diabetes Care · doi:10.2337/dc19-0167 · Cited by 312 · see citing works
Lefere, S., Puengel, T., Hundertmark, J., Penners, C., Frank, A. K., Guillot, A., de Muynck, K., Heymann, F., Adarbes, V., Defrêne, E., et al. (2020) · Journal of Hepatology · doi:10.1016/j.jhep.2020.04.025 · Cited by 310 · see citing works
Tokushige, K., Ikejima, K., Ono, M., Eguchi, Y., Kamada, Y., Itoh, Y., Akuta, N., Yoneda, M., Iwasa, M., Yoneda, M., et al. (2021) · Journal of Gastroenterology · doi:10.1007/s00535-021-01796-x · Cited by 276 · see citing works
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 · see citing works
NAFLD, Insulin Resistance, and Diabetes Mellitus Type 2
Marušić, M., Paić, M., Knobloch, M., & Pršo, A.-M. L. (2021) · Canadian Journal of Gastroenterology and Hepatology · doi:10.1155/2021/6613827 · Cited by 233 · see citing works
Obesity and nonalcoholic fatty liver disease: current perspectives
Sarwar, R., Pierce, N., & Koppe, S. (2018) · Diabetes Metabolic Syndrome and Obesity · doi:10.2147/dmso.s146339 · Cited by 232 · see citing works
The Relationship Between Type 2 Diabetes, NAFLD, and Cardiovascular Risk
Caussy, C., Aubin, A., & Loomba, R. S. (2021) · Current Diabetes Reports · doi:10.1007/s11892-021-01383-7 · Cited by 246 · see citing works
Mantovani, A., Byrne, C. D., & Targher, G. (2022) · The Lancet Gastroenterology & Hepatology · doi:10.1016/s2468-1253(21)00261-2 · Cited by 230 · see citing works
2021 Clinical Practice Guidelines for Diabetes Mellitus of the Korean Diabetes Association
Hur, K. Y., Moon, M. K., Park, J. S., Kim, S., Lee, S., Yun, J., Baek, J. H., Noh, J., Lee, B., Oh, T. J., et al. (2021) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2021.0156 · Cited by 228 · see citing works
ElSayed, 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 233 · see citing works
Tuleta, I., & Frangogiannis, N. G. (2020) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2020.166044 · Cited by 216 · see citing works
Harrison, S. A., Alkhouri, N., Davison, B. A., Sanyal, A., Edwards, C., Colca, J. R., Lee, B. H., Loomba, R., Cusi, K., Kolterman, O., et al. (2020) · Journal of Hepatology · doi:10.1016/j.jhep.2019.10.023 · Cited by 211 · see citing works
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 222 · see citing works
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 216 · see citing works
Vujkovic, M., Ramdas, S., Lorenz, K. M., Guo, X., Darlay, R., Cordell, H. J., He, J., Gindin, Y., Chung, C., Myers, R. P., et al. (2022) · Nature Genetics · doi:10.1038/s41588-022-01078-z · Cited by 205 · see citing works
Novel therapeutic targets for cholestatic and fatty liver disease
Trauner, M., & Fuchs, C. D. (2022) · Gut · doi:10.1136/gutjnl-2021-324305 · Cited by 204 · see citing works
Treatments for NAFLD: State of Art
Mantovani, A., & Dalbeni, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22052350 · Cited by 202 · see citing works
Nonalcoholic fatty liver disease: Evolving paradigms
Lonardo, A., Nascimbeni, F., Maurantonio, M., Marrazzo, A., Rinaldi, L., & Adinolfi, L. E. (2017) · World Journal of Gastroenterology · doi:10.3748/wjg.v23.i36.6571 · Cited by 197 · see citing works
A 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 194 · see citing works
Combination therapy for non-alcoholic steatohepatitis: rationale, opportunities and challenges
Dufour, J.-F., Caussy, C., & Loomba, R. (2020) · Gut · doi:10.1136/gutjnl-2019-319104 · Cited by 193 · see citing works
Cardiovascular Risk in Non-Alcoholic Fatty Liver Disease: Mechanisms and Therapeutic Implications
Tana, C., Ballestri, S., Ricci, F., Vincenzo, A. D., Ticinesi, A., Gallina, S., Giamberardino, M. A., Cipollone, F., Sutton, R., Vettor, R., et al. (2019) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph16173104 · Cited by 191 · see citing works
Precision medicine in the management of type 2 diabetes
Gloyn, A. L., & Drucker, D. J. (2018) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(18)30052-4 · Cited by 187 · see citing works
Chitturi, S., Wong, V. W., Chan, W., Wong, G. L., Wong, S. K., Sollano, J. D., Ni, Y., Liu, C., Lin, Y., Lesmana, L. A., et al. (2017) · Journal of Gastroenterology and Hepatology · doi:10.1111/jgh.13856 · Cited by 182 · see citing works
Management of non-alcoholic fatty liver disease
Petroni, M. L., Brodosi, L., Bugianesi, E., & Marchesini, G. (2021) · BMJ · doi:10.1136/bmj.m4747 · Cited by 181 · see citing works
Farrell, G. C., Haczeyni, F., & Chitturi, S. (2018) · Advances in Experimental Medicine and Biology · doi:10.1007/978-981-10-8684-7_3 · Cited by 178 · see citing works
Nonalcoholic fatty liver disease as a metabolic disease in humans: A literature review
Cariou, B., Byrne, C. D., Loomba, R. S., & Sanyal, A. J. (2021) · Diabetes Obesity and Metabolism · doi:10.1111/dom.14322 · Cited by 174 · see citing works
Obesity and MASLD: Is weight loss the (only) key to treat metabolic liver disease?
Huttasch, M., Roden, M., & Kahl, S. (2024) · Metabolism · doi:10.1016/j.metabol.2024.155937 · Cited by 169 · see citing works
NAFLD, and cardiovascular and cardiac diseases: Factors influencing risk, prediction and treatment
Targher, G., Corey, K. E., & Byrne, C. D. (2020) · Diabetes & Metabolism · doi:10.1016/j.diabet.2020.101215 · Cited by 170 · see citing works
The Emerging Role of Glucagon-like Peptide-1 Receptor Agonists for the Management of NAFLD
Chavez, C. P., Cusi, K. J., & Kadiyala, S. (2021) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgab578 · Cited by 163 · see citing works
Brunt, E. M., Kleiner, D. E., Wilson, L. A., Sanyal, A. J., Neuschwander‐Tetri, B. A., & for the Nonalcoholic Steatohepatitis Clinical Research Network (2019) · Hepatology · doi:10.1002/hep.30418 · Cited by 154 · see citing works
Tacke, F., & Weiskirchen, R. (2021) · Annals of Translational Medicine · doi:10.21037/atm-20-4354 · Cited by 154 · see citing works
ElSayed, N. A., Aleppo, G., Bannuru, R. R., Bruemmer, D., Collins, B. S., Cusi, K. J., Ekhlaspour, L., Fleming, T. K., Hilliard, M. E., Johnson, E. L., et al. (2023) · Diabetes Care · doi:10.2337/dc24-s004 · Cited by 167 · see citing works
Lipid metabolism in MASLD and MASH: From mechanism to the clinic
Carli, F., Della Pepa, G., Sabatini, S., Vidal Puig, A., & Gastaldelli, A. (2024) · JHEP Reports · doi:10.1016/j.jhepr.2024.101185 · Cited by 147 · see citing works
Wang, J., He, W., Tsai, P.-J., Chen, P.-H., Ye, M., Guo, J., & Su, Z. (2020) · Lipids in Health and Disease · doi:10.1186/s12944-020-01210-0 · Cited by 147 · see citing works
Scheen, A. J. (2019) · Diabetes & Metabolism · doi:10.1016/j.diabet.2019.01.008 · Cited by 146 · see citing works
Metabolic Targets in Nonalcoholic Fatty Liver Disease
Esler, W. P., & Bence, K. K. (2019) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2019.04.007 · Cited by 142 · see citing works
Fougerat, A., Montagner, A., Loiseau, N., Guillou, H., & Wahli, W. (2020) · Cells · doi:10.3390/cells9071638 · Cited by 143 · see citing works
Arab, J. P., Dirchwolf, M., Álvares‐da‐Silva, M. R., Francisco Barrera, M., Benítez, C., Castellanos, M., Castro‐Narro, G., Chávez-Tapia, N. C., Chiodi, D., Cotrim, H. P., et al. (2020) · Annals of Hepatology · doi:10.1016/j.aohep.2020.09.006 · Cited by 142 · see citing works
Tokushige, K., Ikejima, K., Ono, M., Eguchi, Y., Kamada, Y., Itoh, Y., Akuta, N., Yoneda, M., Iwasa, M., Yoneda, M., et al. (2021) · Hepatology Research · doi:10.1111/hepr.13688 · Cited by 145 · see citing works
Omega-3 polyunsaturated fatty acids as a treatment strategy for nonalcoholic fatty liver disease
Jump, D. B., Lytle, K. A., Depner, C. M., & Tripathy, S. (2018) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2017.07.007 · Cited by 142 · see citing works
Mantovani, A., Byrne, C. D., Scorletti, E., Mantzoros, C. S., & Targher, G. (2020) · Diabetes & Metabolism · doi:10.1016/j.diabet.2019.12.007 · Cited by 138 · see citing works
Nonalcoholic Fatty Liver Disease (NAFLD). Mitochondria as Players and Targets of Therapies?
Ciaula, A. D., Passarella, S., Shanmugam, H., Noviello, M., Bonfrate, L., Wang, D. Q. ‐., & Portincasa, P. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22105375 · Cited by 133 · see citing works
Metabolic Spectrum of Liver Failure in Type 2 Diabetes and Obesity: From NAFLD to NASH to HCC
Kim, H.-M., Lee, D. S., An, T. H., Park, H., Kim, W. K., Bae, K., & Oh, K. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22094495 · Cited by 130 · see citing works
Non‐alcoholic fatty liver disease and type 2 diabetes: An update
Lee, C., Lui, D. T. W., & Lam, K. S. (2022) · Journal of Diabetes Investigation · doi:10.1111/jdi.13756 · Cited by 132 · see citing works
Pioglitazone for NAFLD Patients With Prediabetes or Type 2 Diabetes Mellitus: A Meta-Analysis
Lian, J., & Fu, J. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.615409 · Cited by 124 · see citing works
2023 Clinical Practice Guidelines for Diabetes Mellitus of the Korean Diabetes Association
Choi, J. H., Lee, K. A., Moon, J. H., Chon, S., Kim, D. J., Kim, H. J., Kim, N. H., Seo, J. A., Kim, M. K., Lim, J. H., et al. (2023) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2023.0282 · Cited by 129 · see citing works
Byrne, C. D., & Targher, G. (2021) · Diabetes Obesity and Metabolism · doi:10.1111/dom.14484 · Cited by 122 · see citing works
Metabolic dysfunction-associated steatotic liver disease and the heart
Driessen, S., Francque, S., Anker, S. D., Cabezas, M. C., Grobbee, D. E., Tushuizen, M. E., & Holleboom, A. G. (2023) · Hepatology · doi:10.1097/hep.0000000000000735 · Cited by 125 · see citing works
Nogueira, J. P., & Cusi, K. J. (2024) · Diabetes Spectrum · doi:10.2337/dsi23-0013 · Cited by 126 · see citing works
Risk of Heart Failure in Patients With Nonalcoholic Fatty Liver Disease
Mantovani, A., Byrne, C. D., Benfari, G., Bonapace, S., Simon, T. G., & Targher, G. (2022) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2021.11.007 · Cited by 114 · see citing works
Dixon, E. D., Nardo, A. D., Claudel, T., & Trauner, M. A. (2021) · Genes · doi:10.3390/genes12050645 · Cited by 113 · see citing works
Treating NASH by targeting peroxisome proliferator-activated receptors
Staels, B., Butruille, L., & Francque, S. (2023) · Journal of Hepatology · doi:10.1016/j.jhep.2023.07.004 · Cited by 110 · see citing works
Alqahtani, S. A., & Schattenberg, J. M. (2021) · Clinical Interventions in Aging · doi:10.2147/cia.s295524 · Cited by 113 · see citing works
Weiskirchen, R., Weiskirchen, S., & Tacke, F. (2018) · F1000Research · doi:10.12688/f1000research.14841.1 · Cited by 105 · see citing works
Steatosis in Liver Transplantation: Current Limitations and Future Strategies
Linares, I., Hamar, M., Selzner, N., & Selzner, M. (2018) · Transplantation · doi:10.1097/tp.0000000000002466 · Cited by 104 · see citing works
Modulation of Fibroblasts in Conjunctival Wound Healing
Zada, M., Pattamatta, U., & White, A. J. R. (2017) · Ophthalmology · doi:10.1016/j.ophtha.2017.08.028 · Cited by 103 · see citing works
Handelsman, Y., Butler, J., Bakris, G. L., DeFronzo, R. A., Fonarow, G. C., Green, J. B., Grunberger, G., Januzzi, J. L., Klein, S., Kushner, P. R., et al. (2023) · Journal of Diabetes and its Complications · doi:10.1016/j.jdiacomp.2022.108389 · Cited by 105 · see citing works
The role of ChREBP in carbohydrate sensing and NAFLD development
Régnier, M., Carbinatti, T., Parlati, L., Benhamed, F., & Postic, C. (2023) · Nature Reviews Endocrinology · doi:10.1038/s41574-023-00809-4 · Cited by 101 · see citing works
Gastaldelli, A., Sabatini, S., Carli, F., Gaggini, M., Bril, F., Belfort‐DeAguiar, R., Positano, V., Barb, D., Kadiyala, S., Harrison, S., et al. (2021) · Liver International · doi:10.1111/liv.15005 · Cited by 101 · see citing works
Diabesity and antidiabetic drugs
Pappachan, J. M., Fernandez, C. J., & Chacko, E. C. (2018) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2018.10.004 · Cited by 98 · see citing works
Drug-induced liver injury in obesity and nonalcoholic fatty liver disease
Allard, J., Guillou, D. L., Begriche, K., & Fromenty, B. (2019) · Advances in pharmacology · doi:10.1016/bs.apha.2019.01.003 · Cited by 98 · see citing works
Fujii, H., Imajo, K., Yoneda, M., Nakahara, T., Hyogo, H., Takahashi, H., Hara, T., Tanaka, S., Sumida, Y., Eguchi, Y., et al. (2019) · Journal of Gastroenterology and Hepatology · doi:10.1111/jgh.14595 · Cited by 94 · see citing works
Pοlyzos, S. A., Kechagias, S., & Tsochatzis, E. A. (2021) · Alimentary Pharmacology & Therapeutics · doi:10.1111/apt.16575 · Cited by 92 · see citing works
Huo, T., Zhao, X., Cheng, Z., Wei, J., Zhu, M., Dou, X., & Jiao, N. (2023) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2023.11.021 · Cited by 92 · see citing works
Ciardullo, S., Muraca, E., Vergani, M., Invernizzi, P., & Perseghin, G. (2023) · Gastroenterology report · doi:10.1093/gastro/goae029 · Cited by 90 · see citing works
Handelsman, Y., Anderson, J. E., Bakris, G. L., Ballantyne, C. M., Bhatt, D. L., Bloomgarden, Z. T., Bozkurt, B., Budoff, M. J., Butler, J., Cherney, D. Z. I., et al. (2024) · Metabolism · doi:10.1016/j.metabol.2024.155931 · Cited by 93 · see citing works
Alqahtani, S. A., & Schattenberg, J. M. (2021) · Dove Medical Press (Taylor and Francis Group) · Cited by 85 · see citing works
Gastaldelli, A., Repetto, E., Guja, C., Hardy, E., Han, J., Jabbour, S. A., & Ferrannini, E. (2019) · Diabetes Obesity and Metabolism · doi:10.1111/dom.13907 · Cited by 81 · see citing works
Management of NAFLD in primary care settings
Wong, V. W., Zelber‐Sagi, S., Cusi, K. J., Carrieri, P., Wright, E. E., Crespo, J., & Lazarus, J. V. (2022) · Liver International · doi:10.1111/liv.15404 · Cited by 82 · see citing works
PPAR-Targeted Therapies in the Treatment of Non-Alcoholic Fatty Liver Disease in Diabetic Patients
Lange, N. F., Graf, V., Caussy, C., & Dufour, J. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23084305 · Cited by 80 · see citing works
Francque, S., Bédossa, P., Abdelmalek, M. F., Anstee, Q. M., Bugianesi, E., Ratziu, V., Huot-Marchand, P., Bruno, S., Junien, J., Broqua, P., et al. (2020) · Contemporary Clinical Trials · doi:10.1016/j.cct.2020.106170 · Cited by 78 · see citing works
Cusi, K. J., Alkhouri, N., Harrison, S. A., Fouqueray, P., Moller, D. E., Hallakou‐Bozec, S., Bolze, S., Grouin, J., Megnien, S. J., Dubourg, J., et al. (2021) · The Lancet. Gastroenterology & hepatology · doi:10.1016/s2468-1253(21)00300-9 · Cited by 78 · see citing works
Galiero, R., Caturano, A., Vetrano, E., Cesaro, A., Rinaldi, L., Salvatore, T., Marfella, R., Sardu, C., Moscarella, E., Gragnano, F., et al. (2021) · Reviews in Cardiovascular Medicine · doi:10.31083/j.rcm2203082 · Cited by 82 · see citing works
Dongiovanni, P., Meroni, M., Baselli, G., Bassani, G. A., Rametta, R., Pietrelli, A., Maggioni, M., Facciotti, F., Trunzo, V., Badiali, S., et al. (2017) · Clinical Science · doi:10.1042/cs20170175 · Cited by 77 · see citing works
NAFLD and Cardiovascular Diseases: Epidemiological, Mechanistic and Therapeutic Considerations
Niederseer, D., Wernly, B., Aigner, E. S., Stickel, F., & Datz, C. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10030467 · Cited by 82 · see citing works
Ivashkin, V. T., Maevskaya, M. V., Жаркова, М. С., Kotovskaya, Y. V., Ткачева, О. Н., Troshina, E. A., Shestakova, M. V., Maev, I. V., Breder, V. V., Geyvandova, N. I., et al. (2022) · Russian Journal of Gastroenterology Hepatology Coloproctology · doi:10.22416/1382-4376-2022-32-4-104-140 · Cited by 77 · see citing works
A critical review of endpoints for non-cirrhotic NASH therapeutic trials
Ratziu, V. (2018) · Journal of Hepatology · doi:10.1016/j.jhep.2017.12.001 · Cited by 74 · see citing works
- 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 · 2016: 2
- 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 › Epidemiology › 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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