nogrЭкспериментальная и клиническая гастроэнтерологияExperimental and Clinical Gastroenterology1682-8658«Global Media Technologies»10.31146/1682-8658-ecg-169-9-4-10nogr-1186Research ArticleПЕРЕДОВАЯ СТАТЬЯLEADING ARTICLEПредварительные результаты применения дулаглутида у пациентов с неалкогольной жировой болезнью печени (исследование ДЕМОС)Preliminary results of dulaglutide treatment in patients with non-alcoholic fatty liver disease (DEMOS study)БогомоловП. О.BogomolovP. O.

Москва, Россия

Moscow, Russia

БуеверовА. О.BueverovA. O.

Москва, Россия

Moscow, Russia

ДревальА. В.DrevalA. V.

Москва, Россия

Moscow, Russia

НечаеваО. А.NechaevaO. A.

Москва, Россия

Moscow, Russia

МайоровА. Ю.MayorovA. Yu.

Москва, Россия

Moscow, Russia

МишинаЕ. Е.MishinaE. E.

Москва, Россия

Moscow, Russia

ФедосьинаЕ. А.FedosinaE. A.

Москва, Россия

Moscow, Russia

КобловС. В.KoblovS. V.

Москва, Россия

Moscow, Russia

СумцоваО. В.SumtsovaO. V.

Москва, Россия

Moscow, Russia

ДжаллоуА.JallowA.

Москва, Россия

Moscow, Russia

ДубровинаД. А.DubrovinaD. A.

Москва, Россия

Moscow, Russia

ТрошинаЕ. А.TroshinaE. A.

Москва, Россия

Moscow, Russia

КомшиловаК. А.KomshilovaK. A.

Москва, Россия

Moscow, Russia

АраповаМ. В.ArapovaM. V.

Москва, Россия

Moscow, Russia

ВачеишвилиН. Г.VacheishviliN. G.

Москва, Россия

Moscow, Russia

ЛюсинаЕ. О.LiusinaE. O.

Люсина Екатерина Олеговна, Москва, Россия

Ekaterina O. Liusina, Moscow, Russia

eka-lusina@yandex.ruГБУ МЗ МО МОНИКИ им. М. Ф. ВладимирскогоРоссияM. F. Vladimirsky Moscow Regional Research Clinical InstituteRussian FederationГБУ МЗ МО МОНИКИ им. М. Ф. Владимирского; ФГАОУ ВО Первый МГМУ им. И. М. СеченоваРоссияM. F. Vladimirsky Moscow Regional Research Clinical Institute; Sechenov UniversityRussian FederationФГБУ НМИЦ эндокринологии Минздрава РоссииРоссияNational Medical Research Center for EndocrinologyRussian FederationГК ОМСРоссияJSC UMSRussian FederationФГАОУ ВО РНИМУ им. Н. И. Пирогова Минздрава РоссииРоссияPirogov Russian National Research Medical UniversityRussian Federation20192009201909410Copyright © Богомолов П.О., Буеверов А.О., Древаль А.В., Нечаева О.А., Майоров А.Ю., Мишина Е.Е., Федосьина Е.А., Коблов С.В., Сумцова О.В., Джаллоу А., Дубровина Д.А., Трошина Е.А., Комшилова К.А., Арапова М.В., Вачеишвили Н.Г., Люсина Е.О., 20202020Богомолов П.О., Буеверов А.О., Древаль А.В., Нечаева О.А., Майоров А.Ю., Мишина Е.Е., Федосьина Е.А., Коблов С.В., Сумцова О.В., Джаллоу А., Дубровина Д.А., Трошина Е.А., Комшилова К.А., Арапова М.В., Вачеишвили Н.Г., Люсина Е.О.Bogomolov P.O., Bueverov A.O., Dreval A.V., Nechaeva O.A., Mayorov A.Y., Mishina E.E., Fedosina E.A., Koblov S.V., Sumtsova O.V., Jallow A., Dubrovina D.A., Troshina E.A., Komshilova K.A., Arapova M.V., Vacheishvili N.G., Liusina E.O.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.nogr.org/jour/article/view/1186

В открытое наблюдательное проспективное когортное исследование включено 65 пациентов с неалкогольной жировой болезнью печени (НАЖБП), средний возраст 54,8 ± 10,5 лет. На момент включения в исследование 45 пациентов имели сахарный диабет 2-го типа (СД-2) и получали метформин в рамках сахароснижающей терапии; остальные 20 пациентов получали терапию метформином для профилактики СД-2 в рамках метаболического синдрома. Проведен курс лечения агонистом рецептора глюкагоноподобного пептида-1 пролонгированного действия дулаглутидом в виде подкожных еженедельных инъекций. В группе пациентов с СД-2 препарат вводился в дозе 0,75 мг первые 2 инъекции, следующие 24 недели в дозе 1,5 мг. В группе пациентов без СД-2 препарат вводился в дозе 0,75 мг первые 4 инъекции, затем доза была увеличена до 1,5 мг. Общая продолжительность наблюдения составила 26 недель. На фоне терапии в обеих группах больных отмечено статистически значимое уменьшение массы тела, ИМТ, окружности талии, уровней глюкозы и HbA1c, индексов инсулинорезистентности, активности АЛТ и ГГТ, а также уменьшение индекса стеатоза печени и снижение медианы плотности печени по данным эластографии. Таким образом, терапия дулаглутидом у пациентов с НАЖБП обусловливает значимое снижение массы тела, улучшение показателей углеводного и липидного обмена, а также уменьшение биохимических маркеров активности стеатогепатита.

65 patients with nonalcoholic fatty liver disease (NAFLD) were included in open-label observative prospective cohort study. Mean age was 54.8 ± 10.5 y. o. All patients were treated with metformin before and during the study. All patients were treated by GLP-1 receptor agonist dulaglutide subcutaneously weekly 26 weeks. Patients of group with type 2 diabetes were treated with dulaglutide 0.75 mg weekly 2 weeks, than 1.5 weekly 24 weeks. Patients of group without diabetes were treated by dulaglutide 0.75 mg weekly 4 weeks, than 1.5 weekly 22 weeks. Both groups of patients were demonstrated significant reduce of body weight, BMI, waist circumference, glucose, HbA1c, insulin resistance indexes, transaminases and gamma-glutamyltranspeptidase activity. Fatty liver index and liver stiff ness also decreased after treatment. We can conclude that dulaglutide treatment in NAFLD patients decreases body wieight, improves glucose and lipid metabolism and decreases inflammatory activity of steatohepatitis.

неалкогольная жировая болезнь печенидулаглутидлечениеnonalcoholic fatty liver diseasedulaglutidetreatmentНаучная работа выполнена в рамках реализации научной программы, поддержанной грантом Российского научного фонда (проект № 17–15–01475)ReferencesSayiner M, Koenig A, Henry L, Younossi ZM. Epidemiology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis in the United States and the rest of the world. Clin Liver Dis. 2016; 20:205–214.Sayiner M, Koenig A, Henry L, Younossi ZM. Epidemiology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis in the United States and the rest of the world. Clin Liver Dis. 2016; 20:205–214.Bellentani S. Th e epidemiology of nonalcoholic fatty liver disease. Liver Int. 2017; 37(Suppl 1):81–84.Bellentani S. Th e epidemiology of nonalcoholic fatty liver disease. Liver Int. 2017; 37(Suppl 1):81–84.Lucas C, Lucas G, Lucas N, Krzowska-Firych J, Tomasiewicz K. A systematic review of the present and future of non-alcoholic fatty liver disease. Clin Exp Hepatol. 2018 Sep;4(3):165–174. doi: 10.5114/ceh.2018.78120.Lucas C, Lucas G, Lucas N, Krzowska-Firych J, Tomasiewicz K. A systematic review of the present and future of non-alcoholic fatty liver disease. Clin Exp Hepatol. 2018 Sep;4(3):165–174. doi: 10.5114/ceh.2018.78120.Estes C, Anstee QM, Arias-Loste MT. Modeling NAFLD Disease Burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016–2030. J Hepatol. 2018 Jun 7. pii: S0168–8278(18)32121–4.Estes C, Anstee QM, Arias-Loste MT. Modeling NAFLD Disease Burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016–2030. J Hepatol. 2018 Jun 7. pii: S0168–8278(18)32121–4.Adams LA, Anstee QM, Tilg H, Targher G. Nonalcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases. Gut. 2017; 66:1138–1153.Adams LA, Anstee QM, Tilg H, Targher G. Nonalcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases. Gut. 2017; 66:1138–1153.Santoleri D, Titchenell PM. Resolving the paradox of hepatic insulin resistance. Cell Mol Gastroenterol Hepatol. 2018; https://doi.org/10.1016/j.jcmgh.2018.10.016.Santoleri D, Titchenell PM. Resolving the paradox of hepatic insulin resistance. Cell Mol Gastroenterol Hepatol. 2018; https://doi.org/10.1016/j.jcmgh.2018.10.016.Lambert JE, Ramos-Roman MA, Browning JD, Parks EJ. Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease. Gastroenterology. 2014;146:726–735.Lambert JE, Ramos-Roman MA, Browning JD, Parks EJ. Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease. Gastroenterology. 2014;146:726–735.Rouabhia S, Milic N, Abenavoli L. Metformin in the treatment of non-alcoholic fatty liver disease: safety, efficacy and mechanism. Expert Rev Gastroenterol Hepatol. 2014 May;8(4):343–9. doi: 10.1586/17474124.2014.894880.Rouabhia S, Milic N, Abenavoli L. Metformin in the treatment of non-alcoholic fatty liver disease: safety, efficacy and mechanism. Expert Rev Gastroenterol Hepatol. 2014 May;8(4):343–9. doi: 10.1586/17474124.2014.894880.Zhu X., Yan H., Xia M., Chang X., Xu X., Wang L., et al. Metformin attenuates triglyceride accumulation in HepG2 cells through decreasing stearyl-coenzyme A desaturase 1 expression. Lipids Health Dis. 2018;17:114. doi: 10.1186/s12944–018–0762–0.Zhu X., Yan H., Xia M., Chang X., Xu X., Wang L., et al. Metformin attenuates triglyceride accumulation in HepG2 cells through decreasing stearyl-coenzyme A desaturase 1 expression. Lipids Health Dis. 2018;17:114. doi: 10.1186/s12944–018–0762–0.Lin M. J., Dai W., Scott M. J., Li R., Zhang Y. Q., Yang Y., Chen L. Z., Huang X. S. Metformin improves nonalcoholic fatty liver disease in obese mice via down-regulation of apolipoprotein A5 as part of the AMPK/LXRα signaling pathway. Oncotarget. 2017;8:108802–108809.Lin M. J., Dai W., Scott M. J., Li R., Zhang Y. Q., Yang Y., Chen L. Z., Huang X. S. Metformin improves nonalcoholic fatty liver disease in obese mice via down-regulation of apolipoprotein A5 as part of the AMPK/LXRα signaling pathway. Oncotarget. 2017;8:108802–108809.Zhou J, Massey S, Story D, Li L. Metformin: an old drug with new applications. Int J Mol Sci. 2018 Sep 21;19(10). pii: E2863. doi: 10.3390/ijms19102863.Zhou J, Massey S, Story D, Li L. Metformin: an old drug with new applications. Int J Mol Sci. 2018 Sep 21;19(10). pii: E2863. doi: 10.3390/ijms19102863.Kanoski SE, Hayes MR, Skibicka KP. GLP-1 and weight loss: unraveling the diverse neural circuitry. Am J Physiol Regul Integr Comp Physiol. 2016 May 15;310(10): R885–95. doi: 10.1152/ajpregu.00520.2015.Kanoski SE, Hayes MR, Skibicka KP. GLP-1 and weight loss: unraveling the diverse neural circuitry. Am J Physiol Regul Integr Comp Physiol. 2016 May 15;310(10): R885–95. doi: 10.1152/ajpregu.00520.2015.Романцова Т. И. Аналог глюкагоноподобного пептида-1 лираглутид (Саксенда®): механизм действия, эффективность в лечении ожирения. Ожирение и метаболизм. 2018;15(1):3–11. doi: 10.14341/omet201813–11Romantsova T. I. Gglucagon-like peptide-1 analogue liraglutide (Saxenda®): mechanism of action, efficacy for the treatment of obesity. Obesity and metabolism. 2018, vol. 15, no.1, pp. 3–11. doi: 10.14341/omet201813–11Liu J, Wang G, Jia Y, et al. GLP-1 receptor agonists: effects on the progression of non-alcoholic fatty liver disease. Diabetes Metab Res Rev. 2015;31:329–335.Liu J, Wang G, Jia Y, et al. GLP-1 receptor agonists: effects on the progression of non-alcoholic fatty liver disease. Diabetes Metab Res Rev. 2015;31:329–335.Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet. 2016 Feb 13;387(10019):679–90. doi: 10.1016/S0140–6736(15)00803-X.Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet. 2016 Feb 13;387(10019):679–90. doi: 10.1016/S0140–6736(15)00803-X.Khoo J, Hsiang J, Taneja R, Law NM, Ang TL. Comparative effects of liraglutide 3 mg vs structured lifestyle modifi cation on body weight, liver fat and liver function in obese patients with non-alcoholic fatty liver disease: A pilot randomized trial. Diabetes Obes Metab. 2017 Dec;19(12):1814–1817. doi: 10.1111/dom.13007.Khoo J, Hsiang J, Taneja R, Law NM, Ang TL. Comparative effects of liraglutide 3 mg vs structured lifestyle modifi cation on body weight, liver fat and liver function in obese patients with non-alcoholic fatty liver disease: A pilot randomized trial. Diabetes Obes Metab. 2017 Dec;19(12):1814–1817. doi: 10.1111/dom.13007.Tian F, Zheng Z, Zhang D, He S, Shen J. Efficacy of liraglutide in treating type 2 diabetes mellitus complicated with non-alcoholic fatty liver disease. Biosci Rep. 2018 Dec 21;38(6). pii: BSR20181304. doi: 10.1042/BSR20181304.Tian F, Zheng Z, Zhang D, He S, Shen J. Efficacy of liraglutide in treating type 2 diabetes mellitus complicated with non-alcoholic fatty liver disease. Biosci Rep. 2018 Dec 21;38(6). pii: BSR20181304. doi: 10.1042/BSR20181304.Dutour A, Abdesselam I, Ancel P, Kober F, Mrad G, Darmon P, et al. Exenatide decreases liver fat content and epicardial adipose tissue in patients with obesity and type 2 diabetes: a prospective randomized clinical trial using magnetic resonance imaging and spectroscopy. Diabetes Obes Metab. 2016 Sep;18(9):882–91. doi: 10.1111/dom.12680.Dutour A, Abdesselam I, Ancel P, Kober F, Mrad G, Darmon P, et al. Exenatide decreases liver fat content and epicardial adipose tissue in patients with obesity and type 2 diabetes: a prospective randomized clinical trial using magnetic resonance imaging and spectroscopy. Diabetes Obes Metab. 2016 Sep;18(9):882–91. doi: 10.1111/dom.12680.Seko Y, Sumida Y, Tanaka S, Mori K, Taketani H, Ishiba H, et al. Effect of 12-week dulaglutide therapy in Japanese patients with biopsy-proven non-alcoholic fatty liver disease and type 2 diabetes mellitus. Hepatol Res. 2017 Oct;47(11):1206–1211. doi: 10.1111/hepr.12837.Seko Y, Sumida Y, Tanaka S, Mori K, Taketani H, Ishiba H, et al. Effect of 12-week dulaglutide therapy in Japanese patients with biopsy-proven non-alcoholic fatty liver disease and type 2 diabetes mellitus. Hepatol Res. 2017 Oct;47(11):1206–1211. doi: 10.1111/hepr.12837.Cusi K, Sattar N, García-Pérez LE, Pavo I, Yu M, Robertson KE, et al. Dulaglutide decreases plasma aminotransferases in people with Type 2 diabetes in a pattern consistent with liver fat reduction: a post hoc analysis of the AWARD programme. Diabet Med. 2018 Oct;35(10):1434–1439. doi: 10.1111/dme.13697Cusi K, Sattar N, García-Pérez LE, Pavo I, Yu M, Robertson KE, et al. Dulaglutide decreases plasma aminotransferases in people with Type 2 diabetes in a pattern consistent with liver fat reduction: a post hoc analysis of the AWARD programme. Diabet Med. 2018 Oct;35(10):1434–1439. doi: 10.1111/dme.13697Christou GA, Katsiki N, Blundell J, Fruhbeck G, Kiortsis DN. Semaglutide as a promising antiobesity drug. Obes Rev. 2019 Feb 15. doi: 10.1111/obr.12839.Christou GA, Katsiki N, Blundell J, Fruhbeck G, Kiortsis DN. Semaglutide as a promising antiobesity drug. Obes Rev. 2019 Feb 15. doi: 10.1111/obr.12839.Bedogni G, Bellentani S, Miglioli L, et al. The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterol. 2006;6:33.Bedogni G, Bellentani S, Miglioli L, et al. The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterol. 2006;6:33.McPherson S, Hardy T, Dufour JF, et al. Age as a confounding factor for the accurate non-Invasive diagnosis of advanced NAFLD fibrosis. Am J Gastroenterol. 2017;112(5):740–751.McPherson S, Hardy T, Dufour JF, et al. Age as a confounding factor for the accurate non-Invasive diagnosis of advanced NAFLD fibrosis. Am J Gastroenterol. 2017;112(5):740–751.Ndrepepa G, Kastrati A. Gamma-glutamyl transferase and cardiovascular disease. Ann Transl Med. 2016 Dec;4(24):481. doi: 10.21037/atm.2016.12.27Ndrepepa G, Kastrati A. Gamma-glutamyl transferase and cardiovascular disease. Ann Transl Med. 2016 Dec;4(24):481. doi: 10.21037/atm.2016.12.27Alexander KS, Zakai NA, Lidofsky SD, Callas PW, Judd SE, Tracy RP, Cushman M. Non-alcoholic fatty liver disease, liver biomarkers and stroke risk: The reasons for geographic and racial differences in stroke cohort. PLoS One. 2018 Mar 12;13(3): e0194153. doi: 10.1371/journal.pone.0194153. eCollection 2018. PMID: 29529073.Alexander KS, Zakai NA, Lidofsky SD, Callas PW, Judd SE, Tracy RP, Cushman M. Non-alcoholic fatty liver disease, liver biomarkers and stroke risk: The reasons for geographic and racial differences in stroke cohort. PLoS One. 2018 Mar 12;13(3): e0194153. doi: 10.1371/journal.pone.0194153. eCollection 2018. PMID: 29529073.

The authors declare that there are no conflicts of interest present.