Pegbelfermin (BMS-986036), a PEGylated fibroblast growth factor 21 analogue, in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 2a trial
Abstract
Background Pegbelfermin (BMS-986036), a PEGylated human fibroblast growth factor 21 (FGF21) analogue, has previously been shown to improve markers of metabolism and liver fibrosis in obese patients with type 2 diabetes. In this phase 2a study, we aimed to evaluate the safety and efficacy of pegbelfermin in patients with non-alcoholic steatohepatitis.Methods In this multicentre, randomised, double-blind, placebo-controlled, parallel-group, phase 2a study, we recruited adults (aged 21-75 years) with a body-mass index of at least 25 kg/m 2, biopsy-confirmed non-alcoholic steatohepatitis (fibrosis stage 1-3), and a hepatic fat fraction of at least 10% when assessed by magnetic resonance imaging-proton density fat fraction. These patients were enrolled at 17 medical centres in the USA. Eligible patients were stratified by type 2 diabetes status and they were randomly assigned (1:1:1) by a computer-based system to receive subcutaneous injections of placebo once a day, 10 mg pegbelfermin once a day, or 20 mg pegbelfermin once a week, all for 16 weeks. Participants, the study team administering treatment, and investigators analysing outcomes (who were independent of the study team and had no further involvement) were masked to treatment groups. The primary outcomes were safety and the absolute change in hepatic fat fraction after 16 weeks of treatment. All patients who were randomly assigned to groups and received the study drug or placebo were included in the primary analyses. This trial was registered with ClinicalTrials.gov, number NCT02413372.Findings Between May 12, 2015, and Aug 4, 2016, 184 overweight or obese patients with non-alcoholic steatohepatitis were screened for study inclusion. Of these, 95 (52%) patients were excluded because they no longer met study criteria and 80 (43%) patients entered the placebo lead-in phase. After further exclusions, 75 (94%) patients were randomly assigned to groups, received at least one dose of treatment (25 patients to receive 10 mg pegbelfermin once a day; 24 patients to receive 20 mg pegbelfermin once a week, and 26 patients to receive placebo), and were included in the primary analysis. A prespecified interim analysis at week 8 showed a greater than expected change in the primary outcome and supported early closing of patient enrolment, since this analysis indicated that the full planned sample size was not needed. We observed a significant decrease in absolute hepatic fat fraction in the group receiving 10 mg pegbelfermin daily (-6·8% vs -1·3%; p=0·0004) and in the group receiving 20 mg pegbelfermin weekly (-5·2% vs -1·3%; p=0·008) compared with the placebo group. Most adverse events were mild; the most common events were diarrhoea in eight (16%) of 49 patients treated with pegbelfermin and two (8%) of 26 patients treated with placebo and nausea in seven (14%) patients treated with pegbelfermin and two (8%) patients treated with placebo. There were no deaths, discontinuations due to adverse events, or treatment-related serious adverse events.Interpretation Treatment with subcutaneously administered pegbelfermin for 16 weeks was generally well tolerated and significantly reduced hepatic fat fraction in patients with non-alcoholic steatohepatitis. Further study of pegbelfermin is warranted in patients with non-alcoholic steatohepatitis. Additional studies that use liver biopsies would allow for the assessment of pegbelfermin's effects on liver histology. Moreover, further studies should allow assessments of the safety and effectiveness of pegbelfermin in a larger number of patients.Funding Bristol-Myers Squibb.
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In the pegbelfermin study, no histological readouts were available.
“Pegbelfermin showed a reduction in hepatic fat (measured via MRI‐PDFF) and liver transaminases over a 16‐week treatment period as well as an improved lipid profile; [53] however, no histological readouts were available which hampers applicability of the results and warrants further studies on this compound.”
From Current treatment of non‐alcoholic fatty liver disease (2022) · cites this paper as [53]
Pegbelfermin showed a reduction in hepatic fat (measured via MRI-PDFF) and liver transaminases over a 16-week treatment period as well as an improved lipid profile.
“Pegbelfermin showed a reduction in hepatic fat (measured via MRI‐PDFF) and liver transaminases over a 16‐week treatment period as well as an improved lipid profile; [53] however, no histological readouts were available which hampers applicability of the results and warrants further studies on this compound.”
From Current treatment of non‐alcoholic fatty liver disease (2022) · cites this paper as [53]
All FGF21 analogues consistently have a pronounced ability to decrease plasma triglyceride levels, in many cases by as much as ~70%.
“all analogues consistently have a pronounced ability to decrease plasma triglyceride levels, in many cases by as much as ~70% (refs. 81,87–91).”
From Metabolic messengers: FGF21 (2021) · cites this paper as [89]
Two other FGF21 analogues AKR-001 and pegbelfermin have not been found to significantly decrease body weight in people with obesity or type 2 diabetes.
“two other FGF21 analogues, AKR-001 (also known as efruxifermin)88 and pegbelfermin89,90, have not been found to significantly decrease body weight in people with obesity or type 2 diabetes.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [89]
The magnitude of glucose-lowering effects of FGF21 analogues is clearly lower in humans than rodents.
“the magnitude of the glucose-lowering effects of FGF21 analogues is clearly lower in humans than rodents81,87–91, perhaps because of differences in brown adipose tissue metabolism between species65.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [89]
Administration of FGF21 analogues AKR-001 and pegbelfermin in humans with NASH results in marked absolute decreases in liver fat (up to 70%) and significant amelioration of liver fibrosis.
“Administration of the FGF21 analogues AKR-001 (ref. 88) and pegbelfermin89 in humans with NASH results in marked absolute decreases in liver fat (up to 70%) and significant amelioration of liver fibrosis88,89.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [89]
Clinical studies in patients with obesity and type 2 diabetes have found FGF21-analogue administration markedly induces plasma adiponectin levels.
“clinical studies in patients with obesity and type 2 diabetes have found that FGF21-analogue administration markedly induces plasma adiponectin levels81,87–89”
From Metabolic messengers: FGF21 (2021) · cites this paper as [89]
In humans, administration of FGF21 analogues has conflicting effects on bone turnover: PF-05231023 increases markers of bone turnover, whereas AKR-001 and pegbelfermin have not.
“PF-05231023 has been found to increase markers of bone turnover in humans81, whereas AKR-001 (ref. 88) and pegbelfermin89 have not.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [89]
Cites
Design and validation of a histological scoring system for nonalcoholic fatty liver disease†
Kleiner, D. E., Brunt, E. M., Van Natta, M., Behling, C., Contos, M. J., Cummings, O. W., Ferrell, L. D., Liu, Y., Torbenson, M. S., Unalp‐Arida, A., et al. (2005) · Hepatology · doi:10.1002/hep.20701 · Cited by 10,791 · see citing works
Self-citationYounossi, Z. M., Koenig, A. B., Abdelatif, D., Fazel, Y., Henry, L., & Wymer, M. (2016) · Hepatology · doi:10.1002/hep.28431 · Cited by 10,781 · see citing works
Chalasani, N., Younossi, Z., Lavine, J. E., Charlton, M., Cusi, K., Rinella, M., Harrison, S. A., Brunt, E. M., & Sanyal, A. J. (2018) · Hepatology · doi:10.1002/hep.29367 · Cited by 7,239 · see citing works
Self-citationBedogni, G., Bellentani, S., Miglioli, L., Masutti, F., Passalacqua, M., Castiglione, A., & Tiribelli, C. (2006) · BMC Gastroenterology · doi:10.1186/1471-230x-6-33 · Cited by 3,054 · see citing works
Classification and Diagnosis of Diabetes
Fajans, S. S. (1990) · Medical Entomology and Zoology · Cited by 2,356 · see citing works
Nonalcoholic Fatty Liver Disease
Rinella, M. E. (2015) · JAMA · doi:10.1001/jama.2015.5370 · Cited by 2,289 · see citing works
The Fibroblast Growth Factor signaling pathway
Ornitz, D. M., & Itoh, N. (2015) · WIREs Developmental Biology · doi:10.1002/wdev.176 · Cited by 2,050 · see citing works
Xu, A., Wang, Y., Keshaw, H., Xu, L. Y., Lam, K. S. L., & Cooper, G. J. S. (2003) · Journal of Clinical Investigation · doi:10.1172/jci17797 · Cited by 1,298 · see citing works
Xu, A., Wang, Y., Keshaw, H., Xu, L. Y., Lam, K. S. L., & Cooper, G. J. S. (2003) · Journal of Clinical Investigation · doi:10.1172/jci200317797 · Cited by 1,298 · see citing works
Hagström, H., Nasr, P., Ekstedt, M., Hammar, U., Stål, P., Hultcrantz, R., & Kechagias, S. (2017) · Journal of Hepatology · doi:10.1016/j.jhep.2017.07.027 · Cited by 1,067 · see citing works
Fibroblast Growth Factor 21 Corrects Obesity in Mice
Coskun, T., Bina, H. A., Schneider, M. A., Dunbar, J. D., Hu, C. C., Chen, Y., Moller, D. E., & Kharitonenkov, A. (2008) · Endocrinology · doi:10.1210/en.2008-0816 · Cited by 1,031 · see citing works
The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes
Gaich, G., Chien, J. Y., Fu, H., Glass, L. C., Deeg, M. A., Holland, W. L., Kharitonenkov, A., Bumol, T., Schilske, H. K., & Moller, D. E. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.08.005 · Cited by 885 · see citing works
The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21
Kharitonenkov, A., Wroblewski, V. J., Koester, A., Chen, Y.-F., Clutinger, C. K., Tigno, X. T., Hansen, B. C., Shanafelt, A. B., & Etgen, G. J. (2007) · Endocrinology · doi:10.1210/en.2006-1168 · Cited by 738 · see citing works
[Classification and diagnosis of diabetes].
Boulin (1953) · PubMed · Cited by 516 · see citing works
Talukdar, S., Zhou, Y., Li, D., Rossulek, M., Dong, J., Somayaji, V., Weng, Y., Clark, R., Lanba, A., Owen, B. M., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.02.001 · Cited by 496 · see citing works
Wei, W., Dutchak, P. A., Wang, X., Ding, X., Wang, X., Bookout, A. L., Goetz, R., Mohammadi, M., Gerard, R. D., Dechow, P. C., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1200797109 · Cited by 426 · see citing works
Harrison, S. A., Rinella, M. E., Abdelmalek, M. F., Trotter, J. F., Paredes, A. H., Arnold, H. L., Kugelmas, M., Bashir, M. R., Jaros, M. J., Ling, L., et al. (2018) · The Lancet · doi:10.1016/s0140-6736(18)30474-4 · Cited by 425 · see citing works
Self-citationXu, J., Stanislaus, S., Chinookoswong, N., Lau, Y. Y., Hager, T., Patel, J., Ge, H., Weiszmann, J., Lu, S.-C., Graham, M., et al. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00348.2009 · Cited by 340 · see citing works
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 277 · see citing works
Plasma adiponectin is decreased in nonalcoholic fatty liver disease
Pagano, C., Soardo, G., Esposito, W., Fallo, F., Basan, L., Donnini, D., Federspil, G., Sechi, L. A., & Vettor, R. (2005) · European Journal of Endocrinology · doi:10.1530/eje.1.01821 · Cited by 257 · see citing works
Charles, E. D., Neuschwander‐Tetri, B. A., Pablo Frias, J., Kundu, S., Luo, Y., Tirucherai, G. S., & Christian, R. (2019) · Obesity · doi:10.1002/oby.22344 · Cited by 257 · see citing works
Self-citationLe, T., Chen, J., Changchien, C., Peterson, M. R., Kono, Y., Patton, H. M., Cohen, B. L., Brenner, D. A., Sirlin, C. B., & Loomba, R. S. (2012) · Hepatology · doi:10.1002/hep.25731 · Cited by 244 · see citing works
Self-citationHarrison, S. A., Rinella, M. E., Abdelmalek, M. F., Jf, T., Paredes, A. H., Arnold, H. L., Kugelmas, M., Bashir, M. R., Jaros, M. J., Li, L., et al. (2018) · Yearbook of pediatric endocrinology · doi:10.1530/ey.15.15.7 · Cited by 188 · see citing works
Self-citationPatel, N. S., Doycheva, I., Peterson, M. R., Hooker, J., Kisselva, T., Schnabl, B., Seki, E., Sirlin, C. B., & Loomba, R. (2015) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2014.08.039 · Cited by 173 · see citing works
Self-citationFundamentals of Toxicologic Pathology
Ross, T. (2010) · Australian Veterinary Journal · doi:10.1111/j.1751-0813.2010.00594.x · Cited by 163 · see citing works
Patel, J. R., Bettencourt, R., Cui, J. Y., Salotti, J., Hooker, J. C., Bhatt, A., Hernandez, C., Nguyen, P., Aryafar, H., Valasek, M. A., et al. (2016) · Therapeutic Advances in Gastroenterology · doi:10.1177/1756283x16656735 · Cited by 163 · see citing works
Self-citationFGF21 reloaded: challenges of a rapidly growing field
Kharitonenkov, A., & Larsen, P. J. (2010) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2010.11.003 · Cited by 147 · see citing works
Kim, A. M., Somayaji, V. R., Dong, J. Q., Rolph, T. P., Weng, Y., Chabot, J. R., Gropp, K. E., Talukdar, S., & Calle, R. A. (2017) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.13023 · Cited by 145 · see citing works
Nielsen, M. J., Veidal, S. S., Karsdal, M. A., Ørsnes‐Leeming, D. J., Vainer, B., Gardner, S. D., Hamatake, R. K., Goodman, Z. D., Schuppan, D., & Patel, K. (2014) · Liver International · doi:10.1111/liv.12700 · Cited by 144 · see citing works
Fang, F., Liu, L., Yang, Y., Tamaki, Z., Wei, J., Marangoni, R. G., Bhattacharyya, S., Summer, R. S., Ye, B., & Varga, J. (2012) · Arthritis Research & Therapy · doi:10.1186/ar4070 · Cited by 110 · see citing works
FGF21-receptor agonists: an emerging therapeutic class for obesity-related diseases
Sonoda, J., Chen, M. Z., & Baruch, A. (2017) · Hormone Molecular Biology and Clinical Investigation · doi:10.1515/hmbci-2017-0002 · Cited by 106 · see citing works
Adiponectin knockout mice on high fat diet develop fibrosing steatohepatitis
Asano, T., Watanabe, K., Kubota, N., Gunji, T., Omata, M., Kadowaki, T., & Ohnishi, S. (2009) · Journal of Gastroenterology and Hepatology · doi:10.1111/j.1440-1746.2009.06039.x · Cited by 101 · see citing works
Dong, J. Q., Rossulek, M. I., Somayaji, V. R., Baltrukonis, D. J., Liang, Y., Hudson, K. J., Hernandez‐Illas, M., & Calle, R. A. (2015) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.12676 · Cited by 100 · see citing works
Adiponectin Agonist ADP355 Attenuates CCl4-Induced Liver Fibrosis in Mice
Kumar, P., Smith, T., Rahman, K., Thorn, N. E., & Anania, F. A. (2014) · PLoS ONE · doi:10.1371/journal.pone.0110405 · Cited by 84 · see citing works
Karsdal, M. A., Henriksen, K., Nielsen, M. J., Byrjalsen, I., Leeming, D. J., Gardner, S. D., Goodman, Z. D., Patel, K., Krag, A. A., Christiansen, C., et al. (2016) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00283.2016 · Cited by 81 · see citing works
Luo, Y., Oseini, A., Gagnon, R., Charles, E. D., Sidik, K., Vincent, R., Collen, R., Idowu, M., Contos, M. J., Mirshahi, F., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-30457-y · Cited by 74 · see citing works
Self-citationNielsen, M. J., Kazankov, K., Leeming, D. J., Karsdal, M. A., Krag, A. A., Francisco Barrera, M., McLeod, D. J., George, J., & Grønbæk, H. (2015) · PLoS ONE · doi:10.1371/journal.pone.0137302 · Cited by 67 · see citing works
Adiponectin Regulation of Stellate Cell Activation via PPARγ-Dependent and -Independent Mechanisms
Shafiei, M. S., Shetty, S., Scherer, P. E., & Rockey, D. C. (2011) · American Journal Of Pathology · doi:10.1016/j.ajpath.2011.02.035 · Cited by 62 · see citing works
NASH Cirrhosis - the New Burden in Liver Transplantation: How Should It Be Managed?
Canbay, A. E., Sowa, J., Syn, W., & Treckmann, J. W. (2016) · Visceral Medicine · doi:10.1159/000446379 · Cited by 31 · see citing works
Leeming, D. J., Grove, J. I., Kaye, P., Hoad, C. L., Francis, S., Nielsen, M. J., Karsdal, M. A., Guha, I. N., & Aithal, G. P. (2017) · Journal of Hepatology · doi:10.1016/s0168-8278(17)30582-2 · Cited by 19 · see citing works
Luo, Y., Krupinski, J., Gao, S.-X., Charles, E. D., & Christian, R. (2018) · Journal of Hepatology · doi:10.1016/s0168-8278(18)31028-6 · Cited by 14 · see citing works
Self-citationLoomba, R. S., Lawitz, E., Ghalib, R. H., Elkhashab, M., Caldwell, S. H., Abdelmalek, M. F., Kowdley, K. V., Xu, R., Chen, G., Djedjos, C. S., et al. (2017) · Journal of Hepatology · doi:10.1016/s0168-8278(17)31811-1 · Cited by 9 · see citing works
Self-citation
Flagged first, then by citations
1 of the 43 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
PPAR control of metabolism and cardiovascular functions
Montaigne, D., Butruille, L., & Staels, B. (2021) · Nature Reviews Cardiology · doi:10.1038/s41569-021-00569-6 · Cited by 960 · 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
Harrison, S. A., Bashir, M. R., Guy, C. D., Zhou, R., Moylan, C. A., Frias, J. P., Alkhouri, N., Bansal, M. B., Baum, S., Neuschwander-Tetri, B. A., et al. (2019) · The Lancet · doi:10.1016/s0140-6736(19)32517-6 · Cited by 802 · see citing works
Self-citationThe endocrine function of adipose tissues in health and cardiometabolic disease
Scheja, L., & Heeren, J. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-019-0230-6 · Cited by 663 · see citing works
Tanase, D. M., Gosav, E. M., Costea, C. F., Ciocoiu, M., Lacatusu, C. M., Maranduca, M. A., Ouatu, A., & Floria, M. (2020) · Journal of Diabetes Research · doi:10.1155/2020/3920196 · Cited by 627 · see citing works
The therapeutic potential of FGF21 in metabolic diseases: from bench to clinic
Geng, L., Lam, K. S. L., & Xu, A. (2020) · Nature Reviews Endocrinology · doi:10.1038/s41574-020-0386-0 · Cited by 607 · 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
Non-alcoholic fatty liver disease: the interplay between metabolism, microbes and immunity
Tilg, H., Adolph, T. E., Dudek, M., & Knolle, P. A. (2021) · Nature Metabolism · doi:10.1038/s42255-021-00501-9 · Cited by 517 · 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
Harrison, S. A., Ruane, P. J., Freilich, B. L., Neff, G., Patil, R., Behling, C. A., Hu, C., Fong, E., de Temple, B., Tillman, E. J., et al. (2021) · Nature Medicine · doi:10.1038/s41591-021-01425-3 · Cited by 368 · see citing works
Self-citationXu, X., Poulsen, K. L., Wu, L., Liu, S., Miyata, T., Song, Q., Wei, Q., Zhao, C., Lin, C., & Yang, J. B. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01119-3 · Cited by 370 · see citing works
Nonalcoholic fatty liver disease (NAFLD) from pathogenesis to treatment concepts in humans
Pafili, K., & Roden, M. (2021) · Molecular Metabolism · doi:10.1016/j.molmet.2020.101122 · Cited by 330 · see citing works
Current treatment of non‐alcoholic fatty liver disease
Paternostro, R., & Trauner, M. (2022) · Journal of Internal Medicine · doi:10.1111/joim.13531 · Cited by 305 · see citing works
Flippo, K. H., & Potthoff, M. J. (2021) · Nature Metabolism · doi:10.1038/s42255-021-00354-2 · Cited by 311 · see citing works
Advancements in the treatment of non-alcoholic fatty liver disease (NAFLD)
Li, R., Zou, J., Ran, W., Qi, X., Chen, Y., Cui, H., & Guo, J. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1087260 · Cited by 338 · see citing works
Treatment of type 2 diabetes: challenges, hopes, and anticipated successes
Nauck, M. A., Wefers, J., & Meier, J. J. (2021) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(21)00113-3 · Cited by 300 · see citing works
Metabolic and Signaling Roles of Ketone Bodies in Health and Disease
Puchalska, P., & Crawford, P. A. (2021) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-111120-111518 · Cited by 290 · see citing works
The role of hepatokines in NAFLD
Stefan, N., Schick, F., Birkenfeld, A. L., Häring, H., & White, M. F. (2023) · Cell Metabolism · doi:10.1016/j.cmet.2023.01.006 · Cited by 282 · see citing works
Therapeutic pipeline in nonalcoholic steatohepatitis
Vuppalanchi, R., Noureddin, M., Alkhouri, N., & Sanyal, A. J. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-020-00408-y · Cited by 278 · see citing works
Self-citationA Dozen Years of Discovery: Insights into the Physiology and Pharmacology of FGF21
Kliewer, S. A., & Mangelsdorf, D. J. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.01.004 · Cited by 273 · see citing works
Harrison, S. A., Frias, J. P., Neff, G., Abrams, G. A., Lucas, K. J., Sanchez, W., Gogia, S., Sheikh, M. Y., Behling, C., Bedossa, P., et al. (2023) · The Lancet Gastroenterology & Hepatology · doi:10.1016/s2468-1253(23)00272-8 · Cited by 276 · see citing works
Self-citationPathogenesis 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 260 · see citing works
Nonalcoholic Fatty Liver Disease
Zhao, Y.-C., Zhao, G., Chen, Z., She, Z., Cai, J., & Li, H. (2019) · Hypertension · doi:10.1161/hypertensionaha.119.13419 · Cited by 244 · see citing works
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 · see citing works
Ni, Y., Qian, L., Siliceo, S. L., Long, X., Nychas, E., Liu, Y., Ismaiah, M. J., Leung, H., Zhang, L., Gao, Q., et al. (2023) · Cell Metabolism · doi:10.1016/j.cmet.2023.08.002 · Cited by 231 · see citing works
Ratziu, V., de Guevara, L., Safadi, R., Poordad, F., Fuster, F., Flores-Figueroa, J., Arrese, M., Fracanzani, A. L., Ben Bashat, D., Lackner, K., et al. (2021) · Nature Medicine · doi:10.1038/s41591-021-01495-3 · Cited by 222 · see citing works
Self-citationImmunological mechanisms and therapeutic targets of fatty liver diseases
Wang, H., Mehal, W. Z., Nagy, L. E., & Rotman, Y. (2020) · Cellular and Molecular Immunology · doi:10.1038/s41423-020-00579-3 · Cited by 222 · see citing works
Liver Fibrosis: Therapeutic Targets and Advances in Drug Therapy
Tan, Z., Sun, H., Xue, T., Gan, C., Liu, H., Xie, Y., Yao, Y., & Ye, T. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.730176 · Cited by 220 · see citing works
NAFLD and NASH: etiology, targets and emerging therapies
Wei, S., Wang, L., Evans, P. C., & Xu, S. (2024) · Drug Discovery Today · doi:10.1016/j.drudis.2024.103910 · Cited by 216 · see citing works
Nakajima, A., Eguchi, Y., Yoneda, M., Imajo, K., Tamaki, N., Suganami, H., Nojima, T., Tanigawa, R., Iizuka, M., Iida, Y., et al. (2021) · Alimentary Pharmacology & Therapeutics · doi:10.1111/apt.16596 · Cited by 213 · see citing works
Self-citationTillman, E. J., & Rolph, T. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.601290 · Cited by 209 · see citing works
Epidemiology, Pathogenesis, Diagnosis and Emerging Treatment of Nonalcoholic Fatty Liver Disease
Makri, E. S., Goulas, A., & Pοlyzos, S. A. (2020) · Archives of Medical Research · doi:10.1016/j.arcmed.2020.11.010 · Cited by 205 · see citing works
Collagen biology and non‐invasive biomarkers of liver fibrosis
Karsdal, M. A., Daniels, S. J., Holm Nielsen, S., Bager, C., Rasmussen, D. G. K., Loomba, R., Surabattula, R., Villesen, I. F., Luo, Y., Shevell, D., et al. (2020) · Liver International · doi:10.1111/liv.14390 · Cited by 197 · see citing works
Self-citationNovel 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
Sharpton, S. R., Schnabl, B., Knight, R., & Loomba, R. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2020.11.010 · Cited by 194 · see citing works
Self-citationCombination 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
Self-citationNegi, C. K., Babica, P., Bajard, L., Vašků, J. B., & Tarantino, G. (2021) · Metabolism · doi:10.1016/j.metabol.2021.154925 · Cited by 193 · see citing works
Parlati, L., Régnier, M., Guillou, H., & Postic, C. (2021) · JHEP Reports · doi:10.1016/j.jhepr.2021.100346 · Cited by 190 · see citing works
Therapeutic Landscape for NAFLD in 2020
Neuschwander‐Tetri, B. A. (2020) · Gastroenterology · doi:10.1053/j.gastro.2020.01.051 · Cited by 183 · see citing works
Self-citationManagement 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
Harrison, S. A., Rolph, T., Knott, M., & Dubourg, J. (2024) · Journal of Hepatology · doi:10.1016/j.jhep.2024.04.034 · Cited by 176 · see citing works
Self-citationObesity 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
Microbiota changes and intestinal microbiota transplantation in liver diseases and cirrhosis
Bajaj, J. S., & Khoruts, A. (2020) · Journal of Hepatology · doi:10.1016/j.jhep.2020.01.017 · Cited by 170 · see citing works
Going Back to the Biology of FGF21: New Insights
Lewis, J. E., Ebling, F. J. P., Samms, R. J., & Tsintzas, K. (2019) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2019.05.007 · Cited by 164 · see citing works
Tacke, F., & Weiskirchen, R. (2021) · Annals of Translational Medicine · doi:10.21037/atm-20-4354 · Cited by 154 · see citing works
Multicenter Validation of Association Between Decline in MRI‐PDFF and Histologic Response in NASH
Loomba, R. S., Neuschwander‐Tetri, B. A., Sanyal, A. J., Chalasani, N., Diehl, A. M., Terrault, N. A., Kowdley, K. V., Dasarathy, S., Kleiner, D. E., Behling, C. A., et al. (2020) · Hepatology · doi:10.1002/hep.31121 · Cited by 151 · see citing works
Self-citationFGF21: A Novel Regulator of Glucose and Lipid Metabolism and Whole-Body Energy Balance
Szczepańska, E., & Gietka‐Czernel, M. (2022) · Hormone and Metabolic Research · doi:10.1055/a-1778-4159 · Cited by 155 · see citing works
Lonardo, A., Mantovani, A., Lugari, S., & Targher, G. (2020) · Annals of Hepatology · doi:10.1016/j.aohep.2020.03.001 · Cited by 150 · see citing works
New developments in the biology of fibroblast growth factors
Ornitz, D. M., & Itoh, N. (2022) · WIREs Mechanisms of Disease · doi:10.1002/wsbm.1549 · Cited by 143 · see citing works
Portincasa, P., Khalil, M., Mahdi, L., Perniola, V., Idone, V., Graziani, A., Baffy, G., & Ciaula, A. D. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25115640 · Cited by 152 · see citing works
Li, X. (2019) · Frontiers of Medicine · doi:10.1007/s11684-019-0711-y · Cited by 139 · see citing works
Current and emerging pharmacological options for the treatment of nonalcoholic steatohepatitis
Pοlyzos, S. A., Kang, E. S., Boutari, C., Rhee, E., & Mantzoros, C. S. (2020) · Metabolism · doi:10.1016/j.metabol.2020.154203 · Cited by 139 · see citing works
Current status, problems, and perspectives of non-alcoholic fatty liver disease research
Tanaka, N., Kimura, T., Fujimori, N., Nagaya, T., Komatsu, M., & Tanaka, E. (2019) · World Journal of Gastroenterology · doi:10.3748/wjg.v25.i2.163 · Cited by 139 · see citing works
Fibroblast growth factor 21 in non-alcoholic fatty liver disease
Tucker, B., Li, H., Long, X., Rye, K., & Ong, K. L. (2019) · Metabolism · doi:10.1016/j.metabol.2019.153994 · Cited by 132 · see citing works
Breakthroughs in therapies for NASH and remaining challenges
Ratziu, V., Francque, S., & Sanyal, A. (2022) · Journal of Hepatology · doi:10.1016/j.jhep.2022.04.002 · Cited by 132 · see citing works
Self-citationNonalcoholic 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
Kaufman, A., Abuqayyas, L., Denney, W. S., Tillman, E. J., & Rolph, T. (2020) · Cell Reports Medicine · doi:10.1016/j.xcrm.2020.100057 · Cited by 131 · see citing works
Evolving Role for Pharmacotherapy in NAFLD/NASH
Attia, S. L., Softic, S., & Mouzaki, M. (2020) · Clinical and Translational Science · doi:10.1111/cts.12839 · Cited by 130 · see citing works
The Race to Bash NASH: Emerging Targets and Drug Development in a Complex Liver Disease
Romero, F. A., Jones, C. T., Xu, Y., Fenaux, M., & Halcomb, R. L. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01701 · Cited by 126 · see citing works
Targeting FGF21 in cardiovascular and metabolic diseases: from mechanism to medicine
Tan, H., Tong, Y. A., Chen, Z., Wu, W., Xu, S., & Weng, J. (2022) · International Journal of Biological Sciences · doi:10.7150/ijbs.73936 · Cited by 119 · see citing works
EDP-305 in patients with NASH: a phase II double-blind placebo-controlled dose-ranging study
Ratziu, V., Rinella, M. E., Neuschwander-Tetri, B. A., Lawitz, E., Denham, D., Kayali, Z., Sheikh, A., Kowdley, K. V., Desta, T., Elkhashab, M., et al. (2022) · Journal of Hepatology · doi:10.1016/j.jhep.2021.10.018 · Cited by 123 · see citing works
Self-citationLoomba, R. S., Morgan, E. S., Watts, L. M., Xia, S., Hannan, L. A., Geary, R. S., Baker, B. F., & Bhanot, S. (2020) · The Lancet. Gastroenterology & hepatology · doi:10.1016/s2468-1253(20)30186-2 · Cited by 117 · see citing works
Self-citationMetabolic Changes of Hepatocytes in NAFLD
Lu, Q., Tian, X., Wu, H., Huang, J., Li, M., Mei, Z., Zhou, L., Xie, H., & Zheng, S. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.710420 · Cited by 113 · see citing works
From NAFLD to MAFLD: Definition, Pathophysiological Basis and Cardiovascular Implications
Boccatonda, A., Andreetto, L., D’Ardes, D., Cocco, G., Rossi, I., Vicari, S., Schiavone, C., Cipollone, F., & Guagnano, M. T. (2023) · Biomedicines · doi:10.3390/biomedicines11030883 · Cited by 113 · see citing works
Abdelmalek, M. F., Sanyal, A. J., Nakajima, A., Neuschwander‐Tetri, B. A., Goodman, Z. D., Lawitz, E., Harrison, S. A., Jacobson, I. M., Imajo, K., Gunn, N., et al. (2023) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2023.04.012 · Cited by 113 · see citing works
Self-citationLoomba, R. S., Sanyal, A. J., Nakajima, A., Neuschwander‐Tetri, B. A., Goodman, Z. D., Harrison, S. A., Lawitz, E., Gunn, N., Imajo, K., Ravendhran, N., et al. (2023) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2023.04.011 · Cited by 111 · see citing works
Self-citationsiRNA- and miRNA-based therapeutics for liver fibrosis
Zhao, Z., Lin, C., & Cheng, K. (2019) · Translational research · doi:10.1016/j.trsl.2019.07.007 · Cited by 105 · see citing works
Loomba, R., Lawitz, E. J., Frias, J. P., Ortiz-Lasanta, G., Johansson, L., Franey, B. B., Morrow, L., Rosenstock, M., Hartsfield, C. L., Chen, C.-Y., et al. (2023) · The Lancet Gastroenterology & Hepatology · doi:10.1016/s2468-1253(22)00347-8 · Cited by 106 · see citing works
Self-citationThe 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
The Molecular Mechanisms of Liver Fibrosis and Its Potential Therapy in Application
Zhang, D., Zhang, Y., & Sun, B. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232012572 · Cited by 102 · see citing works
Nanodrug with ROS and pH Dual‐Sensitivity Ameliorates Liver Fibrosis via Multicellular Regulation
Lin, L., Gong, H., Li, R., Huang, J., Cai, M., Lan, T., Huang, W., Guo, Y., Zhou, Z., An, Y., et al. (2020) · Advanced Science · doi:10.1002/advs.201903138 · Cited by 101 · see citing works
Nuclear receptors linking metabolism, inflammation, and fibrosis in nonalcoholic fatty liver disease
Puengel, T., Liu, H., Guillot, A., Heymann, F., Tacke, F., & Peiseler, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23052668 · Cited by 95 · see citing works
The role of FGF21 and its analogs on liver associated diseases
Falamarzi, K., Malekpour, M., Tafti, M. F., Azarpira, N., Behboodi, M., & Zarei, M. (2022) · Frontiers in Medicine · doi:10.3389/fmed.2022.967375 · Cited by 94 · see citing works
Henriksson, E., & Andersen, B. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.601349 · Cited by 95 · see citing works
Treatment of liver fibrosis: Past, current, and future
Zhang, C., Liu, S., & Yang, M. J. (2023) · World Journal of Hepatology · doi:10.4254/wjh.v15.i6.755 · Cited by 97 · see citing works
Baruch, A., Wong, C., Chinn, L. W., Vaze, A., Sonoda, J., Gelzleichter, T., Chen, S., Lewin-Koh, N., Morrow, L., Dheerendra, S., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2012073117 · Cited by 95 · see citing works
Current Options and Future Directions for NAFLD and NASH Treatment
Zhang, C., & Yang, M. J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22147571 · Cited by 94 · see citing works
Targeting FGF21 for the Treatment of Nonalcoholic Steatohepatitis
Zarei, M., Pizarro‐Delgado, J., Barroso, E., Palomer, X., & Vázquez‐Carrera, M. (2020) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2019.12.005 · Cited by 92 · see citing works
FGF21 in obesity and cancer: New insights
Lu, W., Li, X., & Luo, Y. (2020) · Cancer Letters · doi:10.1016/j.canlet.2020.11.026 · Cited by 92 · see citing works
Self-citationCiardullo, S., Muraca, E., Vergani, M., Invernizzi, P., & Perseghin, G. (2023) · Gastroenterology report · doi:10.1093/gastro/goae029 · Cited by 90 · see citing works
SOMAscan Proteomics Identifies Serum Biomarkers Associated With Liver Fibrosis in Patients With NASH
Luo, Y., Wadhawan, S., Greenfield, A., Decato, B. E., Oseini, A. M., Collen, R., Shevell, D. E., Thompson, J., Jarai, G., Charles, E. D., et al. (2021) · Hepatology Communications · doi:10.1002/hep4.1670 · Cited by 87 · see citing works
Self-citationGilroy, C. A., Capozzi, M. E., Varanko, A. K., Tong, J., D’Alessio, D. A., Campbell, J. E., & Chilkoti, A. (2020) · Science Advances · doi:10.1126/sciadv.aaz9890 · Cited by 86 · see citing works
New drugs for NAFLD: lessons from basic models to the clinic
Reimer, K. C., Wree, A., Roderburg, C., & Tacke, F. (2019) · Hepatology International · doi:10.1007/s12072-019-10001-4 · Cited by 83 · see citing works
Ajmera, V. H., Liu, A., Singh, S., Yachoa, G., Ramey, M., Bhargava, M., Zamani, A., Lopez, S. J., Mangla, N., Bettencourt, R., et al. (2019) · Hepatology · doi:10.1002/hep.30974 · Cited by 84 · see citing works
Self-citationLiu, C., Schönke, M., Zhou, E., Li, Z., Kooijman, S., Boon, M. R., Larsson, M., Wallenius, K., Dekker, N., Barlind, L., et al. (2021) · Cardiovascular Research · doi:10.1093/cvr/cvab076 · Cited by 81 · see citing works
Genetic Code Expansion: Inception, Development, Commercialization
Manandhar, M., Chun, E., & Romesberg, F. E. (2021) · Journal of the American Chemical Society · doi:10.1021/jacs.0c11938 · Cited by 83 · see citing works
FGF19 and FGF21: In NASH we trust
Talukdar, S., & Kharitonenkov, A. (2020) · Molecular Metabolism · doi:10.1016/j.molmet.2020.101152 · Cited by 82 · see citing works
Long, M. T., Gandhi, S., & Loomba, R. S. (2020) · Metabolism · doi:10.1016/j.metabol.2020.154259 · Cited by 79 · see citing works
Self-citationFrancque, 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
Self-citationCheung, A. C., Neuschwander‐Tetri, B. A., Kleiner, D. E., Schabel, E., Rinella, M. E., Harrison, S. A., Ratziu, V., Sanyal, A. J., Loomba, R. S., Megnien, S. J., et al. (2019) · Hepatology · doi:10.1002/hep.30672 · Cited by 77 · see citing works
Self-citationYueh, M., He, F., Chen, C., Vu, C., Tripathi, A., Knight, R. D., Karin, M., Chen, S., & Tukey, R. H. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2017129117 · Cited by 77 · see citing works
Dysregulation of Lipid and Glucose Metabolism in Nonalcoholic Fatty Liver Disease
Bhat, N., & Mani, A. (2023) · Nutrients · doi:10.3390/nu15102323 · Cited by 76 · see citing works
Steatotic Liver Disease: Pathophysiology and Emerging Pharmacotherapies
Kokkorakis, M., Muzurović, E. M., Volčanšek, Š., Chakhtoura, M., Hill, M. A., Mikhailidis, D. P., & Mantzoros, C. S. (2024) · Pharmacological Reviews · doi:10.1124/pharmrev.123.001087 · Cited by 77 · see citing works
Fibrosis in Chronic Liver Disease: An Update on Diagnostic and Treatment Modalities
Manka, P. P., Zeller, A. C., & Syn, W. (2019) · Drugs · doi:10.1007/s40265-019-01126-9 · Cited by 77 · see citing works
Orosomucoid 2 maintains hepatic lipid homeostasis through suppression of de novo lipogenesis
Zhou, B., Luo, Y., Ji, N., Hu, C., & Lu, Y. (2022) · Nature Metabolism · doi:10.1038/s42255-022-00627-4 · Cited by 75 · see citing works
Self-citationThe potential function and clinical application of FGF21 in metabolic diseases
Chen, Z., Yang, L., Liu, Y., Huang, P., Song, H., & Zheng, P. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.1089214 · Cited by 72 · see citing works
Rader, D. J., Maratos-Flier, E., Nguyen, A., Hom, D., Ferriere, M., Li, Y., Kompa, J., Martic, M., Hinder, M., Basson, C. T., et al. (2022) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgab624 · Cited by 72 · see citing works
Liu, C., Schönke, M., Spoorenberg, B., Lambooij, J. M., van der Zande, H. J. P., Zhou, E., Tushuizen, M. E., Andréasson, A., Park, A., Oldham, S. N., et al. (2023) · eLife · doi:10.7554/elife.83075 · Cited by 72 · see citing works
Probiotic culture supernatant improves metabolic function through FGF21-adiponectin pathway in mice
Liu, Q., Liu, Y., Li, F., Gu, Z., Liu, M., Shao, T., Zhang, L., Zhou, G., Pan, C., He, L., et al. (2019) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2019.108256 · Cited by 73 · see citing works
The hepatic lipidome: From basic science to clinical translation
ten Hove, M., Pater, L. V., Storm, G., Weiskirchen, S., Weiskirchen, R., Lammers, T., & Bansal, R. (2020) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.06.027 · Cited by 71 · see citing works
- Authors
- Sanyal, A., Charles, E. D., Neuschwander-Tetri, B. A., Loomba, R., Harrison, S. A., Abdelmalek, M. F., Lawitz, E. J., Halegoua-DeMarzio, D., Kundu, S., Noviello, S., Luo, Y., & Christian, R.
- Affiliations
- Virginia Commonwealth University (US)
- Bristol-Myers Squibb (United States) (US)
- University of California San Diego (US)
- Pinnacle Clinical Research (US)
- Duke University (US)
- The University of Texas at San Antonio Health Science Center (US)
- Thomas Jefferson University (US)
- Corresponding author
- Charles, Edgar D
- ORCID
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2018-12
- Volume
- 392
- Issue
- 10165
- Pages
- 2705-2717
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- OpenAlex
- W2905440332
- Cited by
- 550
- References
- 43
- Citations by year
- 2026: 40 · 2025: 52 · 2024: 87 · 2023: 82 · 2022: 76 · 2021: 83 · 2020: 91 · 2019: 36 · 2018: 1 · 2012: 1
- FWCI
- 41.22
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Lancet (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- PEGylation, nonalcoholic steatohepatitis, hepatic fat fraction, liver fibrosis, obesity, type 2 diabetes, drug safety, drug efficacy, subcutaneous injection, liver disease treatment
- MeSH terms
- Adult, Diabetes Mellitus, Type 2, Double-Blind Method, Drug Administration Schedule, Female, Fibroblast Growth Factors, Humans, Injections, Subcutaneous, Male, Middle Aged, Obesity, Polyethylene Glycols, Non-alcoholic Fatty Liver Disease
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