Efficacy and Safety of a Fixed Combination of Glycyrrhizic Acid and Essential Phospholipids in Non-Alcoholic Fatty and Alcoholic Liver Disease: Results from Randomized Placebo-Controlled Trials

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Background. Drug treatment of non-alcoholic fatty and alcoholic liver disease remains an urgent, unsolved problem. Due to the commonality of many pathogenetic mechanisms and predictors of progression, a universal approach to the search for a therapeutic agent can be considered.

Aims — pooled analysis of the results of two multicenter, randomized, double-blind, placebo-controlled studies of a fixed combination of glycyrrhizic acid and essential phospholipids in two dosage forms to study its efficacy and safety in non-alcoholic fatty and alcoholic liver disease, in the presence and absence of predictors of disease progression.

Methods. The pooled analysis included 180 patients with non-alcoholic fatty liver disease (Gepard study) and 120 patients with alcoholic liver disease (Jaguar study). Patients of the main group received a fixed combination of 5.0 g intravenous jet 3 times a week for the first 2 weeks; then — 2 capsules 3 times a day for the next 10 weeks. Patients in the control group received placebo according to the same scheme. The total duration of treatment was 12 weeks in the Gepard study (1 course of stepwise therapy) and 24 weeks in the Jaguar study (2 courses of stepwise therapy). A comparative analysis of the efficacy and safety of a fixed combination and a placebo was carried out, in the presence and absence of predictors of progression, separately for each nosology and in a mixed sample.

Results. In patients with non-alcoholic fatty and alcoholic liver disease who received the fixed combination, in contrast to the placebo group, there was a statistically more significant decrease in the level of biochemical markers of inflammation — alanine aminotransferase, aspartate aminotransferase, adiponectin, and the value of the AktiTest index. There was no negative trend in the NAFLD fibrosis score; more significant positive dynamics of FibroTest is shown. Predictors of disease progression — hyperglycemia, hyperlipidemia, age did not have a negative impact on the results in the study group. The efficacy of the study drug was noted in patients with non-alcoholic fatty liver disease and normal body weight; data were obtained indicating its possible effectiveness with a high activity of the inflammatory process associated with alcoholic liver damage. The frequency of adverse events in the study and control groups was comparable.

Conclusions. Based on a generalized analysis of the results of two studies, promising directions for the study and use of a fixed combination of glycyrrhizic acid and essential phospholipids were identified: non-alcoholic fatty liver disease without obesity, alcoholic steatohepatitis of high activity (as an adjuvant); steatohepatitis of non-alcoholic and alcoholic etiology, combined with hyperglycemia and hyperlipidemia.

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About the authors

Igor V. Maev

A.I. Yevdokimov Moscow State University of Medicine and Dentistry

Email: igormaev@rambler.ru
ORCID iD: 0000-0001-6114-564X
SPIN-code: 1994-0933

MD, PhD, Professor, Academician of the RAS

Russian Federation, Moscow

Alexey O. Bueverov

I.M. Sechenov First Moscow State Medical University (Sechenov University); M.F. Vladimirsky Moscow Regional Research Clinical Institute

Email: kafedra.mse@gmail.com
SPIN-code: 1299-0293

MD, PhD, Associate Professor

Russian Federation, Moscow; Moscow

Artem V. Volnukhin

I.M. Sechenov First Moscow State Medical University (Sechenov University)

Author for correspondence.
Email: volnuhin81@gmail.com
ORCID iD: 0000-0001-5113-2108
SPIN-code: 2700-1986


Russian Federation, bld. 4, 11, Rossolimo str., Moscow, 119991


  1. Toshikuni N, Tsuchishima M, Fukumura A, et al. Associations of Fatty Liver Disease with Hypertension, Diabetes, and Dyslipidemia: Comparison between Alcoholic and Nonalcoholic Steatohepatitis. Gastroenterol Res Pract. 2017;2017:9127847. doi: https://doi.org/10.1155/2017/9127847
  2. Ress C., Kaser S. Mechanisms of intrahepatic triglyceride accumulation. World J Gastroenterol. 2016;22(4):1664–1673. doi: https://doi.org/10.3748/wjg.v22.i4.1664
  3. Younossi ZM, Koenig AB, Abdelatif D, et al. Global Epidemiology of Nonalcoholic Fatty Liver Disease-Meta-Analytic Assessment of Prevalence, Incidence and Outcomes. Hepatology. 2016;64(1):73–84. doi: https://doi.org/10.1002/hep.28431
  4. Ofosua A, Ramaia D, Reddy M. Non-alcoholic fatty liver disease: controlling an emerging epidemic, challenges, and future directions. Ann Gastroenterol. 2018;31(3):288–295. doi: https://doi.org/10.20524/aog.2018.0240
  5. Ивашкин В.Т., Драпкина О.М., Маев И.В., и др. Распространенность неалкогольной жировой болезни печени у пациентов амбулаторно-поликлинической практики в Российской Федерации: результаты исследования DIREG 2 // Российский журнал гастроэнтерологии, гепатологии, колопроктологии. — 2015. — № 6. — С. 31–41. [Ivashkin VT, Drapkina OM, Maev IV, et al. Prevalence of non-alcoholic fatty liver disease in outpatient patients in the Russian Federation: results of the DIREG 2 study. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2015;(6):31–41. (In Russ.)]
  6. Mann RE, Smart RG, Govoni R. The Epidemiology of Alcoholic Liver Disease. Alcohol Res Health. 2003;27(3):209–219.
  7. Сернов С.П., Лифшиц В.Б., Субботина В.Г., и др. Эпидемиология алкогольной болезни печени // Саратовский научно-медицинский журнал. — 2009. — Т. 5 — № 4. — С. 564–568. [Sernov SP, Lifshits VB, Subbotina VG, et al. Epidemiology of alcoholic liver disease. Saratov Journal of Medical Scientific Research. 2009;5(4):564–568. (In Russ.)]
  8. Комова А. Г., Маевская М. В., Ивашкин В. Т. Распространенность диффузных заболеваний печени в Москве // Клинические перспективы гастроэнтерологии, гепатологии. — 2014. — № 5. — С. 3–8. [Komova AG, Mayevskaya MV, Ivashkin VT. The prevalence of diffuse liver diseases in Moscow. Clinical perspectives of gastroenterology, hepatology. 2014;5:3–8. (In Russ.)]
  9. Prado V, Caballería J, Vargas V, et al. Alcoholic hepatitis: How far are and where are we going? Ann Hepatol. 2016;15(4):463–473.
  10. Osna NA, Donohue TM Jr, Kharbanda KK. Alcoholic Liver Disease: Pathogenesis and Current Management. Alcohol Res. 2017;38(2):147–161.
  11. Yu J, Marsh S, Hu J, et al. The Pathogenesis of Nonalcoholic Fatty Liver Disease: Interplay between Diet, Gut Microbiota, and Genetic Background. Gastroenterol Res Pract. 2016;2016:2862173. doi: http://doi.org/10.1155/2016/2862173
  12. Katsarou A, Moustakas II, Pyrina I, et al. Metabolic inflammation as an instigator of fibrosis during nonalcoholic fatty liver disease. World J Gastroenterol. 2020;26(17):1993–2011. doi: https://doi.org/10.3748/wjg.v26.i17.1993
  13. Singh S, Osna NA, Kharbanda KK. Treatment options for alcoholic and non-alcoholic fatty liver disease: A review. World J Gastroenterol. 2017;23(36):6549–6570. doi: https://doi.org/10.3748/wjg.v23.i36.6549
  14. Abenavoli L, Di Renzo L, Guzzi PH, et al. Non-alcoholic fatty liver disease severity, central fat mass and adinopectin: a close relationship. Clujul Med. 2015;88(4):489–493. doi: https://doi.org/10.15386/cjmed-595
  15. Kartik J, Kohli A, Manch R, et al. Alcoholic Liver Disease High Risk or Low Risk for Developing Hepatocellular Carcinoma? Clin Liver Dis. 2016;20:563–580. doi: https://doi.org/10.1016/j.cld.2016.02.012
  16. Liangpunsakul S, Puri P, Shah V, et al. Effects of Age, Sex, Body Weight, and Quantity of Alcohol. Clin Gastroenterol Hepatol. 2016;14(12):1831–1838.e3. doi: https://doi.org/10.1016/j.cgh.2016.05.041
  17. Valenti L, Bugianesi E, Pajvani U, et al. Nonalcoholic fatty liver disease: cause or consequence of type 2 diabetes? Liver Int. 2016;11(36):1563–1579. doi: https://doi.org/10.1111/liv.13185
  18. Hagström H. Alcohol Consumption in Concomitant Liver Disease: How Much is Too Much? Curr Hepatol Rep. 2017;16(2):152–157. doi: https://doi.org/10.1007/s11901-017-0343-0
  19. Буеверов А.О., Богомолов П.О. Враг, способный стать другом // Медицинский совет. Гастроэнтерология. – 2018. — № 6. – С. 104-112. [Bueverov AO, Bogomolov PO. An enemy who can become a friend. Medical advice. Gastroenterology. 2018;6:104–112. (In Russ.)]
  20. Ивашкин В.Т., Бакулин И.Г., Богомолов П.О., и др. Результаты многоцентрового двойного слепого рандомизированного плацебоконтролируемого пострегистрационного (IV фаза) клинического исследования «Гепард» (PHG-M2/P02-12), проведенного с целью оценки эффективности и безопасности комбинированного препарата глицирризиновой кислоты и эссенциальных фосфолипидов (Фосфоглив) при неалкогольной жировой болезни печени // Российский журнал гастроэнтерологии, гепатологии, колопроктологии. — 2017. — Т. 27. — № 2. — С. 34–43. [Ivashkin VT, Bakulin IG, Bogomolov PO, et al. Results of a multicenter, double-blind, randomized placebo-controlled post-registration (phase IV) clinical study “Gepard” (PHG-M2 / P02-12), conducted to assess the efficacy and safety of a combined preparation of glycyrrhizic acid and essential phospholipids (Phosphogliv) in non-alcoholic fatty disease liver. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2017;2(27):34–43. (In Russ.)]
  21. Бакулин И.Г., Бохан Н.А., Богомолов П.О. и др. Результаты двойного слепого, рандомизированного, плацебо-контролируемого, многоцентрового пострегистрационного клинического исследования (IV фаза) по изучению эффективности и безопасности препарата Фосфоглив в терапии пациентов с алкогольной болезнью печени «Ягуар» (PHG-M2/ P03-12) // Российский журнал гастроэнтерологии, гепатологии, колопроктологии. —2017. — Т. 28. — № 3. — С. 57–68. [Bakulin IG, Bokhan NA, Bogomolov PO, et al. Results of a double-blind, randomized, placebo-controlled, multicenter post-marketing clinical study (phase IV) to study the efficacy and safety of Phosphogliv in the treatment of patients with alcoholic liver disease “Jaguar” (PHG-M2/P03-12). Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2017;3(28):57–68. (In Russ.)]
  22. Двойрин В.В., Клименков А.А. Методика контролируемых клинических испытаний. — М.: Медицина, 1985. — 144 с. [Dvoirin VV, Klimenkov AA. Methodology for controlled clinical trials. Moscow: Medicine; 1985. 144 p. (In Russ.)]
  23. Angulo P, Hui JM, Marchesini G, et al. The NAFLD fibrosis score: A noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45(4):846–854. doi: https://doi.org/10.1002/hep.21496
  24. Лазебник Л.Б., Голованова Е.В., Туркина С.В., и др. Неалкогольная жировая болезнь печени у взрослых: клиника, диагностика, лечение. Рекомендации для терапевтов, третья версия // Экспериментальная и клиническая гастроэнтерология. — 2021. Т. 185. — № 1. — С. 4–52. [Lazebnik LB, Golovanova EV, Turkina SV, et al. Non-alcoholic fatty liver disease in adults: clinic, diagnostics, treatment. Guidelines for therapists, third version. Eksperimental’naya i klinicheskaya gastroenterologiya. 2021;185(1):4–52. (In Russ.)] doi: https://doi.org/10.31146/1682-8658-ecg-185-1-4-52
  25. Naveau S, Gaudé G, Asnacios A, et al. Diagnostic and prognostic values of noninvasive biomarkers of fibrosis in patients with alcoholic liver disease. Hepatology. 2009;49(1):97–105. doi: https://doi.org/10.1002/hep.22576
  26. Poynard T, Imbert-Bismut F, Munteanu M, et al. Overview of the diagnostic value of biochemical markers of liver fibrosis (FibroTest, HCV FibroSure) and necrosis (ActiTest) in patients with chronic hepatitis C. Comp Hepatol. 2004;3(1):8. doi: https://doi.org/10.1186/1476-5926-3-8
  27. Лазебник Л.Б., Голованова Е.В., Еремина Е.Ю., и др. Алкогольная болезнь печени (АБП) у взрослых // Экспериментальная и клиническая гастроэнтерология. — 2020. — Т. 174. — № 2. — С. 4–28. [Lazebnik LB, Golovanova EV, Eremina EYu, et al. Alcoholic liver disease (ABD) in adults. Eksperimental’naya i klinicheskaya gastroenterologiya. 2020; 174(2):4–28. (In Russ.)] doi: https://doi.org/10.31146/1682-8658-ecg-174-2-4-28
  28. Hughes E, Hopkins LJ, Parker R. Survival from alcoholic hepatitis has not improved over time. PLoS One. 2018;13(2):e0192393. doi: https://doi.org/10.1371/journal.pone.0192393
  29. Takei H, Baba Y, Hisatsune A, et al. Glycyrrhizin inhibits interleukin-8 production and nuclear factor-kappaB activity in lung epithelial cells, but not through glucocorticoid receptors. J Pharmacol Sci. 2008;106(3):460–468. doi: https://doi.org/10.1254/jphs.fp0072378
  30. Yoh T, Nakashima T, Sumida Y, et al. Effects of glycyrrhizin on glucocorticoid signaling pathway in hepatocytes. Dig Dis Sci. 2002;47(8):1775–1781. doi: https://doi.org/10.1023/a:1016492527927
  31. Sun X-P, Shi R-R, Yuan X-Q. Effect of glycyrrhizin on expression of TNF-α, IL-1 and IL-6 in adjuvant arthritis rat. Heilongjiang Medicine and Pharmacy. 2011 [Electronic resource]. Available from: https://en.cnki.com.cn/Article_en/CJFDTOTAL-KXJY201101015.htm
  32. Matsui S, Matsumoto H, Sonoda Y, et al. Glycyrrhizin and related compounds down-regulate production of inflammatory chemokines IL-8 and eotaxin 1 in a human lung fibroblast cell line. Int Immunopharmacol. 2004;4(13):1633–1644. doi: https://doi.org/10.1016/j.intimp.2004.07.023
  33. Yuan H, Ji W-S, Wu K-X, et al. Anti-inflammatory effect of Diammonium Glycyrrhizinate in a rat model of ulcerative colitis. World J Gastroenterol. 2006;12(28):4578–4581. doi: https://doi.org/10.3748/wjg.v12.i28.4578
  34. Raphael TJ, Kuttan G. Effect of naturally occurring triterpenoids ursolic acid and glycyrrhizic acid on the cell-mediated immune responses of metastatic tumor-bearing animals. Immunopharmacol Immunotoxicol. 2008;30(2):243–255. doi: https://doi.org/10.1080/08923970701675044
  35. Moro T, Shimoyama Y, Kushida M, et al. Glycyrrhizin and its metabolite inhibit Smad3-mediated type I collagen gene transcription and suppress experimental murine liver fibrosis. Life Sci. 2008;83(15–16): 531–539. doi: https://doi.org/10.1016/j.lfs.2008.07.023
  36. Gao H-X, Shao S-H, Wang G-Q. Research progress of Radix Glycyrrhizae. J Jinggangshan Med Coll. 2004;5(11):8–11.
  37. Hajiaghamohammadi AA, Ziaee A, Samimi R. the efficacy of licorice root extract in decreasing transaminase activities in non-alcoholic fatty liver disease: a randomized controlled clinical trial. Phytother Res. 2012;26(9):1381–1384. doi: https://doi.org/10.1002/ptr.3728
  38. Chigurupati H, Auddy B, Biyani M, et al. Hepatoprotective Effects of a Proprietary Glycyrrhizin Product during Alcohol Consumption: A Randomized, Double-Blind, Placebo-Controlled, Crossover Study. Phytother Res. 2016;30(12):1943–1953. doi: https://doi.org/10.1002/ptr.5699
  39. Wei M, Liang-Zhu Y, Li W, et al. Effects of Compound Glycyrrhizin on Liver Function in Patients with Alcoholic Liver Disease: a Meta-analysis. China Pharmacy. 2013;24(12). doi: https://doi.org/10.6039/j.issn.1001-0408.2013.12.22
  40. Вьючнова Е.С., Маев И.В., Бабина С.М. Эффективность эссенциальных фосфолипидов в лечении больных с неалкогольным стеатогепатитом // Клинические перспективы гастроэнтерологии, гепатологии. — 2010. — № 3. — С. 3–11. [Vyuchnova ES, Maev IV, Babina SM. The effectiveness of essential phospholipids in the treatment of patients with non-alcoholic steatohepatitis. Klinicheskiye perspektivy gastroenterologii, gepatologii. 2010;3:3–11. (In Russ.)]
  41. Никитин И.Г., Байкова И.Е., Волынкина В.М., и др. Опыт использования глицирризиновой кислоты в лечении пациентов с алкогольной болезнью печени // Российский журнал гастроэнтерологии, гепатологии, колопроктологии. — 2009. — Т. 19. — № 1. — С. 53–58. [Nikitin IG, Baykova IE, Volynkina VM, et al. Experience of using glycyrrhizic acid in the treatment of patients with alcoholic liver disease. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2009;1:53–58. (In Russ.)]
  42. Мехтиев С.Н. Перспективы комплексной терапии больных алкогольной болезнью печени с выраженными стадиями фиброза // ЭФ. Гастроэнтерология. — 2011. — № 2. — C. 15–22. [Mekhtiev SN. Prospects for complex therapy of patients with alcoholic liver disease with severe stages of fibrosis. EF. Gastroenterologiya. 2011;(2):15–22. (In Russ.)]
  43. Manns MP, Wedemeyer H, Singer A, et al. Glycyrrhizin in patients who failed previous interferon alpha-based therapies: biochemical and histological effects after 52 weeks. J Viral Hepat. 2012;19(8):537–546. doi: https://doi.org/10.1111/j.1365-2893.2011.01579.x
  44. Буеверов А.О., Богомолов П.О. Неалкогольная жировая болезнь печени без ожирения: проблема, ожидающая решения // Терапевтический архив. — 2017. — Т. 89. — № 12. – С. 226–232. [Bueverov AO, Bogomolov PO. Nonalcoholic fatty liver disease without obesity: the problem to be solved. Terapevticheskii Arkhiv. 2017;89(12):226–232. (In Russ.)] doi: https://doi.org/10.17116/terarkh20178912226-232

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