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Cited by 51Liver Disease Diagnosis and TreatmentBariatric Surgery and OutcomesPharmacology and Obesity Treatment

MASLD treatment—a shift in the paradigm is imminent

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Machado, Mariana Verdelho·2023·Frontiers in Medicine
DOI 10.3389/fmed.2023.1316284PMC PMC10749497
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Abstract

MASLD prevalence is growing towards the leading cause of end-stage liver disease. Up to today, the most effective treatment is weight loss. Weight loss interventions are moving from lifestyle changes to bariatric surgery or endoscopy, and, more recently, to a new wave of anti-obesity drugs that can compete with bariatric surgery. Liver-targeted therapy is a necessity for those patients who already present liver fibrosis. The field is moving fast, and in the near future, we will testify to a disruptive change in MASLD treatment, similar to the paradigm-shift that occurred for hepatitis C almost one decade ago with direct antiviral agents.

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  • Histological improvement in MASH activity and/or liver fibrosis is the goal of all therapeutics, including lifestyle-based interventions, and remains required prior to drug approval by the FDA.

    “histological improvement in MASH activity and/or liver fibrosis is the goal of all therapeutics, including lifestyle-based interventions, and remains required prior to drug approval by the FDA [25].”

    From Aerobic Exercise Training Leads to MASH Resolution as Defined by the MASH Resolution Index (2026) · cites this paper as [25]

    The “New drugs in development” section (page unavailable) describes MASH resolution or fibrosis improvement as histological endpoints that may support conditional FDA approval. It instead says full FDA approval requires hard clinical outcomes, so it does not support the claim that histological improvement remains required before any drug approval. The Conclusion recommends lifestyle interventions but does not say histological improvement is the goal of all therapeutics. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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References 227 · Cited by 51

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  1. [2]Ciardullo S Carbone M Invernizzi P Perseghin G. Exploring the landscape of steatotic liver disease in the general US population. Liver Int. (2023) 43: 2425– 33. doi: 10.1111/liv.15695 37592856 · DOI
  2. [4]Paik JM Golabi P Younossi Y Srishord M Mishra A Younossi ZM. The growing burden of disability related to nonalcoholic fatty liver disease: data from the global burden of disease 2007-2017. Hepatol Commun. (2020) 4: 1769– 80. doi: 10.1002/hep4.1599, PMID: 33305148 PMC7706296 · DOI
  3. [5]Younossi ZM Stepanova M Ong J Trimble G AlQahtani S Younossi I. Nonalcoholic steatohepatitis is the Most rapidly increasing indication for liver transplantation in the United States. Clin Gastroenterol Hepatol. (2021) 19: 580– 589.e5. doi: 10.1016/j.cgh.2020.05.064, PMID: 32531342 · DOI
  4. [6]Machado MV Diehl AM. Pathogenesis of nonalcoholic steatohepatitis. Gastroenterology. (2016) 150: 1769– 77. doi: 10.1053/j.gastro.2016.02.066, PMID: 26928243 PMC4887389 · DOI
  5. [7]Younossi ZM Stepanova M Younossi Y Golabi P Mishra A Rafiq N. Epidemiology of chronic liver diseases in the USA in the past three decades. Gut. (2020) 69: 564– 8. doi: 10.1136/gutjnl-2019-318813, PMID: 31366455 · DOI
  6. [8]Allen AM Therneau TM Ahmed OT Gidener T Mara KC Larson JJ. Clinical course of non-alcoholic fatty liver disease and the implications for clinical trial design. J Hepatol. (2022) 77: 1237– 45. doi: 10.1016/j.jhep.2022.07.004 35843374 PMC9974107 · DOI
  7. [9]Simon TG Roelstraete B Khalili H Hagström H Ludvigsson JF. Mortality in biopsy-confirmed nonalcoholic fatty liver disease: results from a nationwide cohort. Gut. (2021) 70: 1375– 82. doi: 10.1136/gutjnl-2020-322786, PMID: 33037056 PMC8185553 · DOI · Paper page
  8. [10]Ng CH Lim WH Lim GEH Tan DJH Syn N Muthiah MD. Mortality outcomes by fibrosis stage in nonalcoholic fatty liver disease: A systematic review and Meta-analysis. Clin Gastroenterol Hepatol. (2023) 21: 931– 939.e5. doi: 10.1016/j.cgh.2022.04.014, PMID: 35513235 PMC10792524 · DOI
  9. [11]Allen AM Hicks SB Mara KC Larson JJ Therneau TM. The risk of incident extrahepatic cancers is higher in non-alcoholic fatty liver disease than obesity – A longitudinal cohort study. J Hepatol. (2019) 71: 1229– 36. doi: 10.1016/j.jhep.2019.08.018, PMID: 31470068 PMC6921701 · DOI
  10. [13]Machado MV Marques Vidal P Cortez PH. Hepatic histology in obese patients undergoing bariatric surgery. J Hepatol. (2006) 45: 600– 6. doi: 10.1016/j.jhep.2006.06.013 16899321 · DOI
  11. [14]Machado MV Policarpo S Coutinho J Carvalhana S Leitão J Carvalho A. What is the role of the new index relative fat mass (RFM) in the assessment of nonalcoholic fatty liver disease (NAFLD)? Obes Surg. (2020) 30: 560– 8. doi: 10.1007/s11695-019-04213-8, PMID: 31637670 · DOI
  12. [15]Machado MV. Nonalcoholic fatty liver disease in lean subjects: is it all metabolic-associated fatty liver disease? Hepatoma Res. (2020) 2020: 84. doi: 10.20517/2394-5079.2020.90 · DOI
  13. [16]Romero Gómez M Zelber Sagi S Trenell M. Treatment of NAFLD with diet, physical activity and exercise. J Hepatol. (2017) 67: 829– 46. doi: 10.1016/j.jhep.2017.05.016 28545937 · DOI · Paper page
  14. [20]Machado MV. What should we advise MAFLD patients to eat and drink? Metab Target Organ Damage. (2021) 1: 9. doi: 10.20517/mtod.2021.11 · DOI
  15. [21]Jensen T Abdelmalek MF Sullivan S Nadeau KJ Green M Roncal C. Fructose and sugar: A major mediator of non-alcoholic fatty liver disease. J Hepatol. (2018) 68: 1063– 75. doi: 10.1016/j.jhep.2018.01.019, PMID: 29408694 PMC5893377 · DOI
  16. [23]Zhao L Deng C Lin Z Giovannucci E Zhang X. Dietary fats, serum cholesterol and liver Cancer risk: A systematic review and Meta-analysis of prospective studies. Cancers. (2021) 13: 1580. doi: 10.3390/cancers13071580 33808094 PMC8037522 · DOI
  17. [24]Sawada N Inoue M Iwasaki M Sasazuki S Shimazu T Yamaji T. Consumption of n-3 fatty acids and fish reduces risk of hepatocellular carcinoma. Gastroenterology. (2012) 142: 1468– 75. doi: 10.1053/j.gastro.2012.02.018, PMID: 22342990 · DOI
  18. [26]Davis C Bryan J Hodgson J Murphy K. Definition of the Mediterranean diet; a literature review. Nutrition. (2015) 7: 9139– 53. doi: 10.3390/nu7115459 PMC4663587 26556369 · DOI
  19. [29]Kouvari M Boutari C Chrysohoou C Fragkopoulou E Antonopoulou S Tousoulis D. Mediterranean diet is inversely associated with steatosis and fibrosis and decreases ten-year diabetes and cardiovascular risk in NAFLD subjects: results from the ATTICA prospective cohort study. Clin Nutr. (2021) 40: 3314– 24. doi: 10.1016/j.clnu.2020.10.058, PMID: 33234342 · DOI
  20. [30]Becerra-Tomás N Blanco Mejía S Viguiliouk E Khan T Kendall CW Kahleova H. Mediterranean diet, cardiovascular disease and mortality in diabetes: A systematic review and meta-analysis of prospective cohort studies and randomized clinical trials. Crit Rev Food Sci Nutr. (2020) 60: 1207– 27. doi: 10.1080/10408398.2019.1565281 30676058 · DOI · Paper page
  21. [31]Morze J Danielewicz A Przybyłowicz K Zeng H Hoffmann G Schwingshackl L. An updated systematic review and meta-analysis on adherence to mediterranean diet and risk of cancer. Eur J Nutr. (2021) 60: 1561– 86. doi: 10.1007/s00394-020-02346-6 32770356 PMC7987633 · DOI
  22. [32]Kang J Ratamess NA Faigenbaum AD Bush JA Beller N Vargas A. Effect of time-restricted feeding on anthropometric, metabolic, and fitness parameters: A systematic review. J Am Nutr Assoc. (2022) 41: 810– 25. doi: 10.1080/07315724.2021.1958719, PMID: 34491139 · DOI
  23. [33]Sutton EF Beyl R Early KS Cefalu WT Ravussin E Peterson CM. Early time-restricted feeding improves insulin sensitivity, blood pressure, and oxidative stress even without weight loss in men with prediabetes. Cell Metab. (2018) 27: 1212– 1221.e3. doi: 10.1016/j.cmet.2018.04.010, PMID: 29754952 PMC5990470 · DOI · Paper page
  24. [35]Liu D Huang Y Huang C Yang S Wei X Zhang P. Calorie restriction with or without time-restricted eating in weight loss. N Engl J Med. (2022) 386: 1495– 504. doi: 10.1056/NEJMoa2114833 35443107 · DOI · Paper page
  25. [37]Bi H Gan Y Yang C Chen Y Tong X Lu Z. Breakfast skipping and the risk of type 2 diabetes: a meta-analysis of observational studies. Public Health Nutr. (2015) 18: 3013– 9. doi: 10.1017/S1368980015000257 25686619 PMC10271832 · DOI
  26. [38]Rong S Snetselaar LG Xu G Sun Y Liu B Wallace RB. Association of Skipping Breakfast with Cardiovascular and all-Cause Mortality. J Am Coll Cardiol. (2019) 73: 2025– 32. doi: 10.1016/j.jacc.2019.01.065, PMID: 31023424 · DOI
  27. [39]Liu T Wang Y Wang X Liu C Zhang Q Song M. Habitually skipping breakfast is associated with the risk of gastrointestinal cancers: evidence from the Kailuan cohort study. J Gen Intern Med. (2023) 38: 2527– 36. doi: 10.1007/s11606-023-08094-7, PMID: 36869181 PMC10465444 · DOI
  28. [40]Wijarnpreecha K Thongprayoon C Ungprasert P. Coffee consumption and risk of nonalcoholic fatty liver disease: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol. (2017) 29: e8– e12. doi: 10.1097/MEG.0000000000000776, PMID: 27824642 · DOI
  29. [41]Chen YP Lu FB Hu YB Xu LM Zheng MH Hu ED. A systematic review and a dose-response meta-analysis of coffee dose and nonalcoholic fatty liver disease. Clin Nutr. (2019) 38: 2552– 7. doi: 10.1016/j.clnu.2018.11.030 30573353 · DOI · Paper page
  30. [42]Kennedy OJ Roderick P Buchanan R Fallowfield JA Hayes PC Parkes J. Coffee, including caffeinated and decaffeinated coffee, and the risk of hepatocellular carcinoma: a systematic review and dose-response meta-analysis. BMJ Open. (2017) 7: e013739. doi: 10.1136/bmjopen-2016-013739, PMID: 28490552 PMC5730000 · DOI
  31. [43]Xiao Q Sinha R Graubard BI Freedman ND. Inverse associations of total and decaffeinated coffee with liver enzyme levels in National Health and nutrition examination survey 1999-2010. Hepatology. (2014) 60: 2091– 8. doi: 10.1002/hep.27367, PMID: 25124935 PMC4245376 · DOI
  32. [44]Åberg F Puukka P Salomaa V Männistö S Lundqvist A Valsta L. Risks of light and moderate alcohol use in fatty liver disease: follow-up of population cohorts. Hepatology. (2020) 71: 835– 48. doi: 10.1002/hep.30864, PMID: 31323122 · DOI · Paper page
  33. [46]Åberg F Puukka P Salomaa V Männistö S Lundqvist A Valsta L. Combined effects of alcohol and metabolic disorders in patients with chronic liver disease. Clin Gastroenterol Hepatol. (2020) 18: 995– 997.e2. doi: 10.1016/j.cgh.2019.06.036 31255807 · DOI
  34. [48]Åberg F Byrne CD Pirola CJ Männistö V Sookoian S. Alcohol consumption and metabolic syndrome: clinical and epidemiological impact on liver disease. J Hepatol. (2023) 78: 191– 206. doi: 10.1016/j.jhep.2022.08.030, PMID: 36063967 · DOI · Paper page
  35. [49]Jarvis H O'Keefe H Craig D Stow D Hanratty B Anstee QM. Does moderate alcohol consumption accelerate the progression of liver disease in NAFLD? A systematic review and narrative synthesis. BMJ Open. (2022) 12: e049767. doi: 10.1136/bmjopen-2021-049767, PMID: 34983755 PMC8728442 · DOI · Paper page
  36. [51]Ascha MS Hanouneh IA Lopez R Tamimi TAR Feldstein AF Zein NN. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology. (2010) 51: 1972– 8. doi: 10.1002/hep.23527 20209604 · DOI · Paper page
  37. [52]Byambasukh O Zelle D Corpeleijn E. Physical activity, fatty liver, and glucose metabolism over the life course: the lifelines cohort. Am J Gastroenterol. (2019) 114: 907– 15. doi: 10.14309/ajg.0000000000000168, PMID: 30865013 · DOI
  38. [53]Machado MV. Aerobic exercise in the Management of Metabolic Dysfunction Associated Fatty Liver Disease. Diabetes Metab Syndr Obes. (2021) 14: 3627– 45. doi: 10.2147/DMSO.S304357, PMID: 34408459 PMC8364841 · DOI
  39. [54]Haufe S Haas V Utz W Birkenfeld AL Jeran S Böhnke J. Long-lasting improvements in liver fat and metabolism despite body weight regain after dietary weight loss. Diabetes Care. (2013) 36: 3786– 92. doi: 10.2337/dc13-0102, PMID: 23963894 PMC3816862 · DOI
  40. [55]Malespin MH Barritt AS Watkins SE Schoen C Tincopa MA Corbin KD. Weight loss and weight regain in usual clinical practice: results from the TARGET-NASH observational cohort. Clin Gastroenterol Hepatol. (2020) 20: 2393– 5. doi: 10.1016/j.cgh.2021.01.023 33486083 · DOI · Paper page
  41. [57]Mingrone G Panunzi S De Gaetano A Guidone C Iaconelli A Capristo E. Metabolic surgery versus conventional medical therapy in patients with type 2 diabetes: 10-year follow-up of an open-label, single-Centre, randomised controlled trial. Lancet. (2021) 397: 293– 304. doi: 10.1016/S0140-6736(20)32649-0, PMID: 33485454 · DOI · Paper page
  42. [58]Sjöström L Narbro K Sjöström CD Karason K Larsson B Wedel H. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med. (2017) 357: 741– 52. doi: 10.1056/NEJMoa066254 17715408 · DOI · Paper page
  43. [59]Wiggins T Guidozzi N Welbourn R Ahmed AR Markar SR. Association of bariatric surgery with all-cause mortality and incidence of obesity-related disease at a population level: A systematic review and meta-analysis. PLoS Med. (2020) 17: e1003206. doi: 10.1371/journal.pmed.1003206, PMID: 32722673 PMC7386646 · DOI
  44. [61]Lassailly G Caiazzo R Buob D Pigeyre M Verkindt H Labreuche J. Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients. Gastroenterology. (2015) 149: 379– 88. doi: 10.1053/j.gastro.2015.04.014, PMID: 25917783 · DOI · Paper page
  45. [64]Verrastro O Panunzi S Castagneto-Gissey L De Gaetano A Lembo E Capristo E. Bariatric-metabolic surgery versus lifestyle intervention plus best medical care in non-alcoholic steatohepatitis (BRAVES): a multicentre, open-label, randomised trial. Lancet. (2023) 401: 1786– 97. doi: 10.1016/S0140-6736(23)00634-7 37088093 · DOI · Paper page
  46. [67]Yeoh A Wong R Singal AK. The role bariatric surgery and endobariatric therapies in nonalcoholic steatohepatitis. Clin Liver Dis. (2023) 27: 413– 27. doi: 10.1016/j.cld.2023.01.009, PMID: 37024216 · DOI
  47. [69]Baldwin D Chennakesavalu M Gangemi A. Systematic review and meta-analysis of Roux-en-Y gastric bypass against laparoscopic sleeve gastrectomy for amelioration of NAFLD using four criteria. Surg Obes Relat Dis. (2019) 15: 2123– 30. doi: 10.1016/j.soard.2019.09.060, PMID: 31711944 · DOI · Paper page
  48. [70]Pedersen JS Rygg MO Serizawa RR Kristiansen VB Albrechtsen NJW Gluud LL. Effects of Roux-en-Y gastric bypass and sleeve gastrectomy on non-alcoholic fatty liver disease: A 12-month follow-up study with paired liver biopsies. J Clin Med. (2021) 10: 3783. doi: 10.3390/jcm10173783, PMID: 34501231 PMC8432029 · DOI
  49. [71]Seeberg KA Borgeraas H Hofsø D Småstuen MC Kvan NP Grimnes JO. Gastric bypass versus sleeve gastrectomy in type 2 diabetes: effects on hepatic steatosis and fibrosis: A randomized controlled trial. Ann Intern Med. (2022) 175: 74– 83. doi: 10.7326/M21-1962, PMID: 34843380 · DOI
  50. [72]Weingarten TN Swain JM Kendrick ML Charlton MR Schroeder BJ Lee REC. Nonalcoholic steatohepatitis (NASH) does not increase complications after laparoscopic bariatric surgery. Obes Surg. (2021) 21: 1714– 20. doi: 10.1007/s11695-011-0521-z 21948267 · DOI
  51. [73]Bai J Jia Z Chen Y Li Y Zheng S Duan Z. Bariatric surgery is effective and safe for obese patients with compensated cirrhosis: a systematic review and meta-analysis. World J Surg. (2022) 46: 1122– 33. doi: 10.1007/s00268-021-06382-z, PMID: 35275232 · DOI
  52. [74]Heimbach JK Watt KDS Poterucha JJ Ziller NF Cecco SD Charlton MR. Combined liver transplantation and gastric sleeve resection for patients with medically complicated obesity and end-stage liver disease. Am J Transplant. (2013) 13: 363– 8. doi: 10.1111/j.1600-6143.2012.04318.x, PMID: 23137119 · DOI
  53. [77]Jirapinyo P McCarty TR Dolan RD Shah R Thompson CC. Effect of endoscopic bariatric and metabolic therapies on NAFLD: A systematic review and Meta-analysis. Clin Gastroenterol Hepatol. (2022) 20: 511– 524.e1. doi: 10.1016/j.cgh.2021.03.017, PMID: 33727164 · DOI · Paper page
  54. [78]El Haddad A Rammal MO Soweid A Sharara AI Daniel F Rahal MA. Intragastric balloon treatment of obesity: Long-term results and patient satisfaction. Turk J Gastroenterol. (2019) 30: 461– 6. doi: 10.5152/tjg.2019.17877, PMID: 31061001 PMC6505645 · DOI
  55. [80]Hajifathalian K Mehta A Ang B Skaf D Shah SL Saumoy M. Improvement in insulin resistance and estimated hepatic steatosis and fibrosis after endoscopic sleeve gastroplasty. Gastrointest Endosc. (2021) 93: 1110– 8. doi: 10.1016/j.gie.2020.08.023, PMID: 32861753 · DOI · Paper page
  56. [81]Lavín-Alconero L Fernández-Lanas T Iruzubieta-Coz P Arias-Loste MT Rodriguez-Duque JC Rivas C. Efficacy and safety of endoscopic sleeve gastroplasty versus laparoscopic sleeve gastrectomy in obese subjects with NASH: study protocol for a randomized controlled trial (TESLA-NASH study). Trials. (2021) 22: 756. doi: 10.1186/s13063-021-05695-7 34717726 PMC8556907 · DOI
  57. [85]Yabut JM Drucker DJ. Glucagon-like Peptide-1 receptor-based therapeutics for metabolic liver disease. Endocr Rev. (2023) 44: 14– 32. doi: 10.1210/endrev/bnac018, PMID: 35907261 · DOI
  58. [86]Davies MJ Bergenstal R Bode B Kushner RF Lewin A Skjøth TV. Efficacy of Liraglutide for weight loss among patients with type 2 diabetes: the SCALE diabetes randomized clinical trial. JAMA. (2015) 314: 687– 99. doi: 10.1001/jama.2015.9676 26284720 · DOI · Paper page
  59. [88]Armstrong MJ Gaunt P Aithal GP Barton D Hull D Parker R. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet. (2016) 387: 679– 90. doi: 10.1016/S0140-6736(15)00803-X 26608256 · DOI · Paper page
  60. [89]Iqbal J Wu HX Hu N Zhou YH Li L Xiao F. Effect of glucagon-like peptide-1 receptor agonists on body weight in adults with obesity without diabetes mellitus-a systematic review and meta-analysis of randomized control trials. Obes Rev. (2022) 23: e13435. doi: 10.1111/obr.13435, PMID: 35194917 · DOI · Paper page
  61. [90]Xie Z Yang S Deng W Li J Chen J. Efficacy and safety of Liraglutide and Semaglutide on weight loss in people with obesity or overweight: a systematic review. Clin Epidemiol. (2022) 14: 1463– 76. doi: 10.2147/CLEP.S391819, PMID: 36510488 PMC9738168 · DOI · Paper page
  62. [91]Wilding JPH Batterham RL Calanna S Davies M van Gaal LF Lingvay I. Once-weekly Semaglutide in adults with overweight or obesity. N Engl J Med. (2021) 384: 989– 1002. doi: 10.1056/NEJMoa2032183 33567185 · DOI · Paper page
  63. [92]Davies M Færch L Jeppesen OK Pakseresht A Pedersen SD Perreault L. Semaglutide 2·4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet. (2021) 397: 971– 84. doi: 10.1016/S0140-6736(21)00213-0 33667417 · DOI · Paper page
  64. [93]Rubino D Abrahamsson N Davies M Hesse D Greenway FL Jensen C. Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity: the STEP 4 randomized clinical trial. JAMA. (2021) 325: 1414– 25. doi: 10.1001/jama.2021.3224, PMID: 33755728 PMC7988425 · DOI · Paper page
  65. [95]Kadowaki T Isendahl J Khalid U Lee SY Nishida T Ogawa W. Semaglutide once a week in adults with overweight or obesity, with or without type 2 diabetes in an east Asian population (STEP 6): a randomised, double-blind, double-dummy, placebo-controlled, phase 3a trial. Lancet Diabetes Endocrinol. (2022) 10: 193– 206. doi: 10.1016/S2213-8587(22)00008-0 35131037 · DOI · Paper page
  66. [96]Kosiborod MN Bhatta M Davies M Deanfield JE Garvey WT Khalid U. Semaglutide improves cardiometabolic risk factors in adults with overweight or obesity: STEP 1 and 4 exploratory analyses. Diabetes Obes Metab. (2023) 25: 468– 78. doi: 10.1111/dom.14890, PMID: 36200477 PMC10092593 · DOI · Paper page
  67. [100]Newsome PN Buchholtz K Cusi K Linder M Okanoue T Ratziu V. A placebo-controlled trial of subcutaneous Semaglutide in nonalcoholic steatohepatitis. N Engl J Med. (2021) 384: 1113– 24. doi: 10.1056/NEJMoa2028395, PMID: 33185364 · DOI · Paper page
  68. [101]Loomba R Abdelmalek MF Armstrong MJ Jara M Kjær MS Krarup N. Semaglutide 2·4 mg once weekly in patients with non-alcoholic steatohepatitis-related cirrhosis: a randomised, placebo-controlled phase 2 trial. Lancet Gastroenterol Hepatol. (2023) 8: 511– 22. doi: 10.1016/S2468-1253(23)00068-7, PMID: 36934740 PMC10792518 · DOI · Paper page
  69. [102]Rosenstock J Wysham C Frías JP Kaneko S Lee CJ Fernández Landó L. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial. Lancet. (2021) 398: 143– 55. doi: 10.1016/S0140-6736(21)01324-6, PMID: 34186022 · DOI · Paper page
  70. [104]Ludvik B Giorgino F Jódar E Frias JP Fernández Landó L Brown K. Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial. Lancet. (2021) 398: 583– 98. doi: 10.1016/S0140-6736(21)01443-4, PMID: 34370970 · DOI · Paper page
  71. [105]Del Prato S Kahn SE Pavo I Weerakkody GJ Yang Z Doupis J. Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial. Lancet. (2021) 398: 1811– 24. doi: 10.1016/S0140-6736(21)02188-7, PMID: 34672967 · DOI · Paper page
  72. [107]Gastaldelli A Cusi K Landó LF Bray R Brouwers B Rodríguez Á. Effect of tirzepatide versus insulin degludec on liver fat content and abdominal adipose tissue in people with type 2 diabetes (SURPASS-3 MRI): a substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial. Lancet Diabetes Endocrinol. (2022) 10: 393– 406. doi: 10.1016/S2213-8587(22)00070-5, PMID: 35468325 · DOI · Paper page
  73. [108]Hartman ML Sanyal AJ Loomba R Wilson JM Nikooienejad A Bray R. Effects of novel dual GIP and GLP-1 receptor agonist Tirzepatide on biomarkers of nonalcoholic steatohepatitis in patients with type 2 diabetes. Diabetes Care. (2020) 43: 1352– 5. doi: 10.2337/dc19-1892, PMID: 32291277 PMC7245348 · DOI · Paper page
  74. [112]Asano M Sekikawa A Sugeno M Matsuoka O Robertson D Hansen L. Safety/tolerability, efficacy and pharmacokinetics of 600-μg cotadutide in Japanese type 2 diabetes patients with a body mass index of 25 kg/m2 or higher: A phase I, randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. (2023) 25: 2290– 9. doi: 10.1111/dom.15107 37337366 · DOI
  75. [115]Nestor JJ Parkes D Feigh M Suschak JJ Harris MS. Effects of ALT-801, a GLP-1 and glucagon receptor dual agonist, in a translational mouse model of non-alcoholic steatohepatitis. Sci Rep. (2022) 12: 6666. doi: 10.1038/s41598-022-10577-2, PMID: 35461369 PMC9035150 · DOI · Paper page
  76. [116]Harrison SA Tomah S Suschak J Roberts S Yang J He L. Pemvidutide, a GLP-1/glucagon dual receptor agonist significantly reduces liver fat, fibro-inflammation, and body weight in patients with non-alcoholic fatty liver disease: 1 24-week multicenter, randomized, double-blind, placebo-controlled trial. J Hepatol. (2023) 44: 72– 84. doi: 10.1007/s00261-018-1701-2 · DOI
  77. [120]Sanyal A Frias JP Thomas MK Mather KJ Wu Q Du Y. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. (2010) 362: 1675– 85. doi: 10.1056/NEJMoa0907929, PMID: 20427778 PMC2928471 · DOI · Paper page
  78. [122]Neuhouser ML Barnett MJ Kristal AR Ambrosone CB King IB Thornquist M. Dietary supplement use and prostate cancer risk in the carotene and retinol efficacy trial. Cancer Epidemiol Biomarkers Prev. (2009) 18: 2202– 6. doi: 10.1158/1055-9965.EPI-09-0013, PMID: 19661078 PMC2733330 · DOI
  79. [123]Miller ER 3rd Pastor Barriuso R Dalal D Riemersma RA Appel LJ Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. (2005) 142: 37– 46. doi: 10.7326/0003-4819-142-1-200501040-00110 15537682 · DOI · Paper page
  80. [124]Leppälä JM Virtamo J Fogelholm R Huttunen JK Albanes D Taylor PR. Controlled trial of alpha-tocopherol and beta-carotene supplements on stroke incidence and mortality in male smokers. Arterioscler Thromb Vasc Biol. (2000) 20: 230– 5. doi: 10.1161/01.ATV.20.1.230, PMID: 10634823 · DOI
  81. [125]Sato K Gosho M Yamamoto T Kobayashi Y Ishii N Ohashi T. Vitamin E has a beneficial effect on nonalcoholic fatty liver disease: a meta-analysis of randomized controlled trials. Nutrition. (2015) 31: 923– 30. doi: 10.1016/j.nut.2014.11.018 26059365 · DOI
  82. [126]Xu R Tao A Zhang S Deng Y Chen G. Association between vitamin E and non-alcoholic steatohepatitis: a meta-analysis. Int J Clin Exp Med. (2015) 8: 3024– 6. PMID: 26064294 PMC4443128
  83. [127]Wang MY Prabahar K Găman MA Zhang JL. Vitamin E supplementation in the treatment on NAFLD: evidence from an umbrella review of meta-analysis on randomized controlled trials. J Dig Dis. (2023) 24: 380– 9. doi: 10.1111/1751-2980.13210 37503812 · DOI
  84. [128]Vilar Gomez E Vuppalanchi R Gawrieh S Ghabril M Saxena R Cummings OW. Vitamin E improves transplant-Free survival and hepatic decompensation among patients with NASH and advanced fibrosis. Hepatology. (2020) 71: 495– 509. doi: 10.1002/hep.30368 30506586 · DOI · Paper page
  85. [130]Bril F Kalavalapalli S Clark VC Lomonaco R Soldevila-Pico C Liu IC. Response to pioglitazone in patients with nonalcoholic steatohepatitis with vs without type 2 diabetes. Clin Gastroenterol Hepatol. (2018) 16: 558– 566.e2. doi: 10.1016/j.cgh.2017.12.001 29223443 · DOI · Paper page
  86. [132]Viscoli CM Inzucchi SE Young LH Insogna KL Conwit R Furie KL. Pioglitazone and risk for bone fracture: safety data from a randomized clinical trial. J Clin Endocrinol Metab. (2017) 102: 914– 22. doi: 10.1210/jc.2016-3237 27935736 PMC5460686 · DOI · Paper page
  87. [133]Tang H Shi W Fu S Wang T Zhai S Song Y. Pioglitazone and bladder cancer risk: a systematic review and meta-analysis. Cancer Med. (2018) 7: 1070– 80. doi: 10.1002/cam4.1354, PMID: 29476615 PMC5911601 · DOI
  88. [134]DeFronzo RA Inzucchi S Abdul-Ghani M Nissen SE. Pioglitazone: the forgotten, cost-effective cardioprotective drug for type 2 diabetes. Diab Vasc Disc Res. (2019) 16: 133– 43. doi: 10.1177/1479164118825376 30706731 · DOI · Paper page
  89. [137]Nesti L Tricò D Mengozzi A Natali A. Rethinking pioglitazone as a cardioprotective agent: a new perspective on an overlooked drug. Cardiovasc Diabetol. (2021) 20: 109. doi: 10.1186/s12933-021-01294-7, PMID: 34006325 PMC8130304 · DOI
  90. [138]Filipova E Uzunova K Kalinov K Vekov T. Pioglitazone and the risk of bladder cancer: a meta-analysis. Diabetes Ther. (2017) 8: 705– 26. doi: 10.1007/s13300-017-0273-4, PMID: 28623552 PMC5544610 · DOI
  91. [139]Wong VW Zelber‐Sagi S Cusi K Carrieri P Wright E Crespo J. Management of NAFLD in primary care settings. Liver Int. (2022) 42: 2377– 89. doi: 10.1111/liv.15404 35986897 · DOI
  92. [140]Jacques V Bolze S Hallakou‐Bozec S Czarnik AW Divakaruni AS Fouqueray P. Deuterium-stabilized (R)-pioglitazone (PXL065) is responsible for pioglitazone efficacy in NASH yet exhibits Little to no PPARγ activity. Hepatol Commun. (2021) 5: 1412– 25. doi: 10.1002/hep4.1723, PMID: 34430785 PMC8369945 · DOI
  93. [141]Harrison SA Thang C Bolze S Dewitt S Hallakou-Bozec S Dubourg J. Evaluation of PXL065 – deuterium-stabilized (R)-pioglitazone in patients with NASH: A phase II randomized placebo-controlled trial (DESTINY-1). J Hepatol. (2023) 78: 914– 25. doi: 10.1016/j.jhep.2023.02.004, PMID: 36804402 · DOI · Paper page
  94. [142]Sinha B Datta D Ghosal S. Meta-analysis of the effects of sodium glucose cotransporter 2 inhibitors in non-alcoholic fatty liver disease patients with type 2 diabetes. JGH Open. (2020) 5: 219– 27. doi: 10.1002/jgh3.12473 33553659 PMC7857274 · DOI
  95. [143]Jin Z Yuan Y Zheng C Liu S Weng H. Effects of sodium-glucose co-transporter 2 inhibitors on liver fibrosis in non-alcoholic fatty liver disease patients with type 2 diabetes mellitus: an updated meta-analysis of randomized controlled trials. J Diabetes Complications. (2023) 37: 108558. doi: 10.1016/j.jdiacomp.2023.108558, PMID: 37499274 · DOI
  96. [146]Ghosal S Sinha B. Exploring the comparative cardiovascular death benefits of sodium-glucose cotransporter 2 inhibitors in type 2 diabetes: a frequentist and Bayesian network meta-analysis-based scoring. Front Endocrinol. (2023) 14: 1168755. doi: 10.3389/fendo.2023.1168755, PMID: 37469980 PMC10353048 · DOI
  97. [147]Riley DR Essa H Austin P Preston F Kargbo I Ibarburu GH. All-cause mortality and cardiovascular outcomes with sodium-glucose co-transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists and with combination therapy in people with type 2 diabetes. Diabetes Obes Metab. (2023) 25: 2897– 909. doi: 10.1111/dom.15185, PMID: 37385958 · DOI
  98. [148]Rinella ME Tacke F Sanyal AJ Anstee QM on behalf of the participants of the AASLD/EASL Workshop. Report on the AASLD/EASL joint workshop on clinical trial endpoints in NAFLD. Hepatology. (2019) 70: 1424– 36. doi: 10.1002/hep.30782 31287572 · DOI
  99. [149]Cheung A Neuschwander‐Tetri BA Kleiner DE Schabel E Rinella M Harrison S. Defining improvement in nonalcoholic steatohepatitis for treatment trial endpoints: recommendations from the liver forum. Hepatology. (2019) 70: 1841– 55. doi: 10.1002/hep.30672, PMID: 31034092 · DOI
  100. [150]Ratziu V Harrison SA Francque S Bedossa P Lehert P Serfaty L. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology. (2016) 150: 1147– 1159.e5. doi: 10.1053/j.gastro.2016.01.038, PMID: 26874076 · DOI · Paper page
  101. [151]Harrison S Ratziu V Dufour JF Kruger C Schattenberg JM Francque S. The dual PPARa/d agonist elafibranor did not achieve resolution of NASH without worsening of fibrosis in adult patients with non-alcoholic steato- hepatitis and significant fibrosis. Hepatology. (2020) 72 Abstract 1730. doi: 10.1002/hep.31579 · DOI
  102. [153]Ratziu V Sanyal AJ Harrison SA Wong VWS Francque S Goodman Z. Cenicriviroc treatment for adults with nonalcoholic steatohepatitis and fibrosis: final analysis of the phase 2b CENTAUR study. Hepatology. (2020) 72: 892– 905. doi: 10.1002/hep.31108 31943293 · DOI · Paper page
  103. [158]Siddiqui MS Parmar D Sheikh F Sarin SK Cisneros L Gawrieh S. Saroglitazar, a dual PPAR α/γ agonist, improves Atherogenic dyslipidemia in patients with non-cirrhotic NAFLD: A pooled analysis. Clin Gastroenterol Hepatol. (2023) 21: 2597– 2605.e2. doi: 10.1016/j.cgh.2023.01.018, PMID: 36731585 · DOI
  104. [160]Krause C Grohs M El Gammal AT Wolter S Lehnert H Mann O. Reduced expression of thyroid hormone receptor β in human nonalcoholic steatohepatitis. Endocr Connect. (2018) 7: 1448– 56. doi: 10.1530/EC-18-0499, PMID: 30496129 PMC6300861 · DOI
  105. [161]Pagadala MR Zein CO Dasarathy S Yerian LM Lopez R McCullough AJ. Prevalence of hypothyroidism in nonalcoholic fatty liver disease. Dig Dis Sci. (2012) 57: 528– 34. doi: 10.1007/s10620-011-2006-2, PMID: 22183820 PMC3922233 · DOI · Paper page
  106. [163]Abdelmalek MF Sanyal AJ Nakajima A Neuschwander-Tetri BA Goodman ZD Lawitz EJ. Pegbelfermin in patients with nonalcoholic steatohepatitis and compensated cirrhosis (FALCON 2): A randomized phase 2b study. Clin Gastroenterol Hepatol. (2023). doi: 10.1016/j.cgh.2023.04.012 37088458 · DOI
  107. [164]Loomba R Lawitz EJ Frias JP Ortiz-Lasanta G Johansson L Franey BB. Safety, pharmacokinetics, and pharmacodynamics of pegozafermin in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 1b/2a multiple-ascending-dose study. Lancet Gastroenterol Hepatol. (2023) 8: 120– 32. doi: 10.1016/S2468-1253(22)00347-8, PMID: 36521501 · DOI · Paper page
  108. [165]Morrison MC Verschuren L Salic K Verheij J Menke A Wielinga PY. Obeticholic acid modulates serum metabolites and gene signatures characteristic of human NASH and attenuates inflammation and fibrosis progression in Ldlr−/−.Leiden mice. Hepatol Commun. (2018) 2: 1513– 32. doi: 10.1002/hep4.1270, PMID: 30556039 PMC6287481 · DOI
  109. [166]Li S Zhuge A Wang K Xia J Wang Q Han S. Obeticholic acid and ferrostatin-1 differentially ameliorate non-alcoholic steatohepatitis in AMLN diet-fed Ob/Ob mice. Front Pharmacol. (2022) 13: 1081553. doi: 10.3389/fphar.2022.1081553, PMID: 36588706 PMC9800415 · DOI
  110. [167]Chaudhuri S Dutta A Das Chakraborty SB. Efficacy and safety of saroglitazar in real-world patients of non-alcoholic fatty liver disease with or without diabetes including compensated cirrhosis: A tertiary care center experience. JGH Open. (2023) 7: 215– 20. doi: 10.1002/jgh3.12878 36968568 PMC10037031 · DOI
  111. [168]Francque S. Saroglitazar for the treatment of NASH: the peroxisome proliferator-activated receptor story Goes on! Hepatology. (2021) 74: 1730– 3. doi: 10.1002/hep.32024, PMID: 34161617 · DOI
  112. [170]Armstrong LE Guo GL. Role of FXR in liver inflammation during nonalcoholic steatohepatitis. Curr Pharmacol Rep. (2017) 3: 92– 100. doi: 10.1007/s40495-017-0085-2, PMID: 28983452 PMC5624538 · DOI
  113. [171]Li L Zhang Q Peng J Jiang C Zhang Y Shen L. Activation of farnesoid X receptor downregulates monocyte chemoattractant protein-1 in murine macrophage. Biochem Biophys Res Commun. (2015) 467: 841– 6. doi: 10.1016/j.bbrc.2015.10.056, PMID: 26474702 · DOI
  114. [172]Sanyal AJ Ratziu V Loomba R Anstee QM Kowdley KV Rinella ME. Results from a new efficacy and safety analysis of the REGENERATE trial of obeticholic acid for treatment of pre-cirrhotic fibrosis due to nonalcoholic steatohepatitis. J Hepatol. (2023) 79: 1110– 20. doi: 10.1016/j.jhep.2023.07.014 37517454 · DOI · Paper page
  115. [173]Francque SM Bedossa P Ratziu V Anstee QM Bugianesi E Sanyal AJ. A randomized, controlled trial of the Pan-PPAR agonist Lanifibranor in NASH. N Engl J Med. (2021) 385: 1. doi: 10.1056/NEJMoa2036205, PMID: 34670042 · DOI · Paper page
  116. [174]Harrison SA Bashir MR Guy CD Zhou R Moylan CA Frias JP. Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. (2019) 394: 2012– 24. doi: 10.1016/S0140-6736(19)32517-6, PMID: 31727409 · DOI · Paper page
  117. [175]Harrison SA Frias JP Neff G Abrams GA Lucas KJ Sanchez W. Safety and efficacy of once-weekly efruxifermin versus placebo in non-alcoholic steatohepatitis (HARMONY): a multicentre, randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Gastroenterol Hepatol. (2023) 8: 1080– 93. doi: 10.1016/S2468-1253(23)00272-8, PMID: 37802088 · DOI · Paper page
  118. [176]Ma K Saha PK Chan L Moore DD. Farnesoid X receptor is essential for normal glucose homeostasis. J Clin Invest. (2006) 116: 1102– 9. doi: 10.1172/JCI25604, PMID: 16557297 PMC1409738 · DOI
  119. [177]Xu W Lu C Zhang F Shao J Yao S Zheng S. Dihydroartemisinin counteracts fibrotic portal hypertension via farnesoid X receptor-dependent inhibition of hepatic stellate cell contraction. FEBS J. (2017) 284: 114– 33. doi: 10.1111/febs.13956, PMID: 27896916 · DOI
  120. [178]Adorini L Trauner M. Miniseries: established pharmacological targets for NASHFXR agonists in NASH treatment. J Hepatol. (2023) 79: 1317– 31. doi: 10.1016/j.jhep.2023.07.034, PMID: 37562746 · DOI
  121. [179]Calkin AC Tontonoz P. Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR. Nat Rev Mol Cell Biol. (2012) 13: 213– 24. doi: 10.1038/nrm3312, PMID: 22414897 PMC3597092 · DOI · Paper page
  122. [180]Henriksson E Andersen B. FGF19 and FGF21 for the treatment of NASH-two sides of the same coin? Differential and overlapping effects of FGF19 and FGF21 from mice to human. Front Endocrinol. (2020) 11: 601349. doi: 10.3389/fendo.2020.601349, PMID: 33414764 PMC7783467 · DOI
  123. [181]Rodrigues PM Afonso MB Simão AL Carvalho CC Trindade A Duarte A. miR-21 ablation and obeticholic acid ameliorate nonalcoholic steatohepatitis in mice. Cell Death Dis. (2017) 8: e2748. doi: 10.1038/cddis.2017.172, PMID: 28406477 PMC5477590 · DOI
  124. [183]Neuschwander-Tetri BA Loomba R Sanyal AJ Lavine JE Van Natta ML Abdelmalek MF. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. (2015) 385: 956– 65. doi: 10.1016/S0140-6736(14)61933-4, PMID: 25468160 PMC4447192 · DOI · Paper page
  125. [184]Siddiqui MS Van Natta ML Connelly MA Vuppalanchi R Neuschwander-Tetri BA Tonascia J. Impact of obeticholic acid on the lipoprotein profile in patients with non-alcoholic steatohepatitis. J Hepatol. (2020) 72: 25– 33. doi: 10.1016/j.jhep.2019.10.006, PMID: 31634532 PMC6920569 · DOI
  126. [185]Pockros PJ Fuchs M Freilich B Schiff E Kohli A Lawitz EJ. CONTROL: A randomized phase 2 study of obeticholic acid and atorvastatin on lipoproteins in nonalcoholic steatohepatitis patients. Liver Int. (2019) 39: 2082– 93. doi: 10.1111/liv.14209, PMID: 31402538 · DOI
  127. [186]John BV Schwartz K Levy C Dahman B Deng Y Martin P. Impact of Obeticholic acid exposure on decompensation and mortality in primary biliary cholangitis and cirrhosis. Hepatol Commun. (2021) 5: 1426– 36. doi: 10.1002/hep4.1720, PMID: 34430786 PMC8369937 · DOI · Paper page
  128. [188]Tran CP Kim JJ Feld JJ Wong WW. Cost-effectiveness of obeticholic acid for the treatment of non-alcoholic steatohepatitis: an early economic evaluation. Can Liver J. (2021) 4: 360– 9. doi: 10.3138/canlivj-2021-0011 35989894 PMC9235126 · DOI
  129. [190]Ratziu V Rinella ME Neuschwander-Tetri BA Lawitz E Denham D Kayali Z. EDP-305 in patients with NASH: A phase II double-blind placebo-controlled dose-ranging study. J Hepatol. (2022) 76: 506– 17. doi: 10.1016/j.jhep.2021.10.018, PMID: 34740705 · DOI · Paper page
  130. [191]Patel K Harrison SA Elkhashab M Trotter JF Herring R Rojter SE. Cilofexor, a nonsteroidal FXR agonist, in patients with noncirrhotic NASH: A phase 2 randomized controlled trial. Hepatology. (2020) 72: 58– 71. doi: 10.1002/hep.31205, PMID: 32115759 · DOI · Paper page
  131. [192]Sanyal AJ Lopez P Lawitz EJ Lucas KJ Loeffler J Kim W. Tropifexor for nonalcoholic steatohepatitis: an adaptive, randomized, placebo-controlled phase 2a/b trial. Nat Med. (2023) 29: 392– 400. doi: 10.1038/s41591-022-02200-8, PMID: 36797481 PMC9941046 · DOI
  132. [193]Naoumov NV Brees D Loeffler J Chng E Ren Y Lopez P. Digital pathology with artificial intelligence analyses provides greater insights into treatment-induced fibrosis regression in NASH. J Hepatol. (2022) 77: 1399– 409. doi: 10.1016/j.jhep.2022.06.018, PMID: 35779659 · DOI · Paper page
  133. [194]Anstee QM Lucas KJ Francque S Abdelmalek MF Sanyal AJ Ratziu V. Tropifexor plus cenicriviroc combination versus monotherapy in non-alcoholic steatohepatitis: results from the phase 2b TANDEM study. Hepatology. (2023) 78: 1223– 39. doi: 10.1097/HEP.0000000000000439, PMID: 37162151 PMC10521801 · DOI
  134. [195]Loomba R Noureddin M Kowdley KV Kohli A Sheikh A Neff G. Combination therapies including Cilofexor and Firsocostat for bridging fibrosis and cirrhosis attributable to NASH. Hepatology. (2021) 73: 625– 43. doi: 10.1002/hep.31622, PMID: 33169409 · DOI · Paper page
  135. [196]Alkhouri N Herring R Kabler H Kayali Z Hassanein T Kohli A. Safety and efficacy of combination therapy with semaglutide, cilofexor and firsocostat in patients with NASH: A randomised, open-label phase II trial. J Hepatol. (2022) 77: 607– 18. doi: 10.1016/j.jhep.2022.04.003, PMID: 35439567 · DOI · Paper page
  136. [197]Staels B Butruille L Francque S. Treating NASH by targeting peroxisome proliferator-activated receptors. J Hepatol. (2023) 79: 1302– 16. doi: 10.1016/j.jhep.2023.07.004, PMID: 37459921 · DOI
  137. [198]Wettstein G Luccarini JM Poekes L Faye P Kupkowski F Adarbes V. The new-generation pan-peroxisome proliferator-activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis. Hepatol Commun. (2017) 1: 524– 37. doi: 10.1002/hep4.1057 29404476 PMC5678909 · DOI
  138. [200]Siddiqui MS Idowu MO Parmar D Borg BB Denham D Loo NM. A phase 2 double blinded, randomized controlled trial of Saroglitazar in patients with nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. (2021) 19: 2670– 2. doi: 10.1016/j.cgh.2020.10.051, PMID: 33152542 · DOI
  139. [202]Bohinc BN Michelotti G Xie G Pang H Suzuki A Guy CD. Repair-related activation of hedgehog signaling in stromal cells promotes intrahepatic hypothyroidism. Endocrinology. (2014) 155: 4591– 601. doi: 10.1210/en.2014-1302 25121996 PMC4256825 · DOI
  140. [204]Kannt A Wohlfart P Madsen AN Veidal SS Feigh M Schmoll D. Activation of thyroid hormone receptor-β improved disease activity and metabolism independent of body weight in a mouse model of non-alcoholic steatohepatitis and fibrosis. Br J Pharmacol. (2021) 178: 2412– 23. doi: 10.1111/bph.15427, PMID: 33655500 · DOI
  141. [205]Harrison SA Bashir M Moussa SE McCarty K Pablo Frias J Taub R. Effects of Resmetirom on noninvasive endpoints in a 36-week phase 2 active treatment extension study in patients with NASH. Hepatol Commun. (2021) 5: 573– 88. doi: 10.1002/hep4.1657, PMID: 33860116 PMC8034581 · DOI · Paper page
  142. [206]Harrison SA Bedossa P Guy C Schattenberg J Loomba R Taub R. Primary results from MAESTRO-NASH a pivotal phase 3 52-week serial liver biopsy study in 966 patients with NASH and fibrosis. J Hepatol. (2023) 78: 401– 6. doi: 10.1016/S0168-8278(23)00440-336115636 · DOI
  143. [207]Tillman EJ Rolph T. FGF21: an emerging therapeutic target for non-alcoholic steatohepatitis and related metabolic diseases. Front Endocrinol. (2020) 11: 601290. doi: 10.3389/fendo.2020.601290, PMID: 33381084 PMC7767990 · DOI
  144. [210]Loomba R Sanyal AJ Nakajima A Neuschwander-Tetri BA Goodman ZD Harrison SA. Pegbelfermin in patients with nonalcoholic steatohepatitis and stage 3 fibrosis (FALCON 1): A randomized phase 2b study. Clin Gastroenterol Hepatol. (2023). doi: 10.1016/j.cgh.2023.04.011 37088457 · DOI
  145. [212]Alisi A Ceccarelli S Panera N Prono F Petrini S de Stefanis C. Association between serum atypical fibroblast growth factors 21 and 19 and pediatric nonalcoholic fatty liver disease. PLoS One. (2013) 8: e67160. doi: 10.1371/journal.pone.0067160, PMID: 23840612 PMC3694051 · DOI
  146. [213]Nicholes K Guillet S Tomlinson E Hillan K Wright B Frantz GD. A mouse model of hepatocellular carcinoma: ectopic expression of fibroblast growth factor 19 in skeletal muscle of transgenic mice. Am J Pathol. (2002) 160: 2295– 307. doi: 10.1016/S0002-9440(10)61177-7, PMID: 12057932 PMC1850847 · DOI · Paper page
  147. [214]Chen Z Jiang L Liang L Koral K Zhang Q Zhao L. The role of fibroblast growth factor 19 in hepatocellular carcinoma. Am J Pathol. (2021) 191: 1180– 92. doi: 10.1016/j.ajpath.2021.04.014, PMID: 34000282 PMC8351122 · DOI
  148. [215]Zhou M Wang X Phung V Lindhout DA Mondal K Hsu J-Y. Separating Tumorigenicity from bile acid regulatory activity for endocrine hormone FGF19. Cancer Res. (2014) 74: 3306– 16. doi: 10.1158/0008-5472.CAN-14-0208 24728076 · DOI · Paper page
  149. [217]Zhou M Learned RM Rossi SJ DePaoli AM Tian H Ling L. Engineered FGF19 eliminates bile acid toxicity and lipotoxicity leading to resolution of steatohepatitis and fibrosis in mice. Hepatol Commun. (2017) 1: 1024– 42. doi: 10.1002/hep4.1108, PMID: 29404440 PMC5721409 · DOI · Paper page
  150. [218]Luo J Ko B Elliott M Zhou M Lindhout DA Phung V. A nontumorigenic variant of FGF19 treats cholestatic liver diseases. Sci Transl Med. (2014) 6: 247ra100. doi: 10.1126/scitranslmed.3009098 25080475 · DOI
  151. [219]Harrison SA Rossi SJ Paredes AH Trotter JF Bashir MR Guy CD. NGM282 improves liver fibrosis and histology in 12 weeks in patients with nonalcoholic steatohepatitis. Hepatology. (2020) 71: 1198– 212. doi: 10.1002/hep.30590, PMID: 30805949 PMC7187438 · DOI · Paper page
  152. [220]Harrison SA Neff G Guy CD Bashir MR Paredes AH Frias JP. Efficacy and safety of Aldafermin, an engineered FGF19 analog, in a randomized, double-blind, placebo-controlled trial of patients with nonalcoholic steatohepatitis. Gastroenterology. (2021) 160: 219– 231.e1. doi: 10.1053/j.gastro.2020.08.004, PMID: 32781086 · DOI · Paper page
  153. [221]Harrison SA Abdelmalek MF Neff G Gunn N Guy CD Alkhouri N. Aldafermin in patients with non-alcoholic steatohepatitis (ALPINE 2/3): a randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Gastroenterol Hepatol. (2022) 7: 603– 16. doi: 10.1016/S2468-1253(22)00017-6, PMID: 35325622 · DOI
  154. [222]Loomba R Kayali Z Noureddin M Ruane P Lawitz EJ Bennett M. GS-0976 reduces hepatic steatosis and fibrosis markers in patients with nonalcoholic fatty liver disease. Gastroenterology. (2018) 155: 1463– 1473.e6. doi: 10.1053/j.gastro.2018.07.027, PMID: 30059671 PMC6318218 · DOI · Paper page
  155. [223]Loomba R Mohseni R Lucas KJ Gutierrez JA Perry RG Trotter JF. TVB-2640 (FASN inhibitor) for the treatment of nonalcoholic steatohepatitis: FASCINATE-1, a randomized, placebo-controlled phase 2a trial. Gastroenterology. (2021) 161: 1475– 86. doi: 10.1053/j.gastro.2021.07.025, PMID: 34310978 · DOI · Paper page
  156. [225]Safadi R Konikoff FM Mahamid M Zelber-Sagi S Halpern M Gilat T. The fatty acid-bile acid conjugate Aramchol reduces liver fat content in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. (2014) 12: 2085– 2091.e1. doi: 10.1016/j.cgh.2014.04.038, PMID: 24815326 · DOI
  157. [227]Chalasani N Abdelmalek MF Garcia-Tsao G Vuppalanchi R Alkhouri N Rinella M. Effects of Belapectin, an inhibitor of Galectin-3, in patients with nonalcoholic steatohepatitis with cirrhosis and portal hypertension. Gastroenterology. (2020) 158: 1334– 1345.e5. doi: 10.1053/j.gastro.2019.11.296, PMID: 31812510 · DOI · Paper page
  158. [228]Lindén D Romeo S. Therapeutic opportunities for the treatment of NASH with genetically validated targets. J Hepatol. (2023) 79: 1056– 64. doi: 10.1016/j.jhep.2023.05.007, PMID: 37207913 · DOI

Authors
Machado, M. V.
Affiliations
University of Lisbon (PT)
Corresponding author
Machado, Mariana Verdelho
ORCID
Machado, Mariana Verdelho
Venue
Frontiers in Medicine
Publisher
Frontiers Media SA
Published
2023-12-11
Volume
10
Pages
1316284-1316284
ISSN
2296-858X (ISSN-L)
DOI
10.3389/fmed.2023.1316284
PMC
PMC10749497
OpenAlex
W4389560817
Cited by
51
References
227
Citations by year
2026: 8 · 2025: 30 · 2024: 13
FWCI
1.99
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, other-oa)
Topics
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Surgery › Bariatric Surgery and Outcomes
  • Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
Keywords
non-alcoholic fatty liver disease, weight loss interventions, bariatric surgery, endoscopic weight loss, anti-obesity drugs, liver fibrosis, end-stage liver disease

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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