Semin Liver Dis 2022; 42(01): 048-060
DOI: 10.1055/s-0041-1732354
Review Article

Novel Antidiabetic Strategies and Diabetologists' Views in Nonalcoholic Steatohepatitis

Sabine Kahl
1   Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
2   German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany
3   Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
,
Jennifer Pützer
1   Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
2   German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany
,
Michael Roden
1   Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
2   German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany
3   Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
› Author Affiliations

Abstract

Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide with high prevalence, especially in individuals with obesity and type 2 diabetes. Among individuals with type 2 diabetes, the severe insulin resistant subgroup has the greatest risk of NAFLD, likely due to dysfunctional adipose tissue mass but also genetic factors, and may progress earlier to inflammatory and profibrotic nonalcoholic steatohepatitis (NASH). NASH has been associated with increased liver-related as well as cardiovascular morbidity and mortality. International diabetes associations recommend certain screening and treatment strategies for NASH in type 2 diabetes, which, however, bear several limitations such as lack of accurate noninvasive diagnostic tools and targeted treatments. Currently, antihyperglycemic drug concepts based on glucagon-like peptide-1 receptor agonists and sodium glucose cotransporter 2 inhibitors offer metabolic as well as cardiorenal benefits and provide treatment options for both hyperglycemia and NASH in type 2 diabetes.



Publication History

Article published online:
21 July 2021

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  • References

  • 1 Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016; 64 (01) 73-84
  • 2 Szczepaniak LS, Nurenberg P, Leonard D. et al. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab 2005; 288 (02) E462-E468
  • 3 Toplak H, Stauber R, Sourij H. EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease: guidelines, clinical reality and health economic aspects. Diabetologia 2016; 59 (06) 1148-1149
  • 4 Dewidar B, Kahl S, Pafili K, Roden M. Metabolic liver disease in diabetes - from mechanisms to clinical trials. Metabolism 2020; 111S: 154299
  • 5 Zaharia OP, Strassburger K, Strom A. et al; German Diabetes Study Group. Risk of diabetes-associated diseases in subgroups of patients with recent-onset diabetes: a 5-year follow-up study. Lancet Diabetes Endocrinol 2019; 7 (09) 684-694
  • 6 Ahlqvist E, Storm P, Käräjämäki A. et al. Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables. Lancet Diabetes Endocrinol 2018; 6 (05) 361-369
  • 7 Mantovani A, Byrne CD, Bonora E, Targher G. Nonalcoholic fatty liver disease and risk of incident type 2 diabetes: a meta-analysis. Diabetes Care 2018; 41 (02) 372-382
  • 8 Tilg H, Moschen AR, Roden M. NAFLD and diabetes mellitus. Nat Rev Gastroenterol Hepatol 2017; 14 (01) 32-42
  • 9 Ziegler D, Strom A, Kupriyanova Y. et al; GDS Group. Association of lower cardiovagal tone and baroreflex sensitivity with higher liver fat content early in type 2 diabetes. J Clin Endocrinol Metab 2018; 103 (03) 1130-1138
  • 10 Younossi ZM, Tampi RP, Racila A. et al. Economic and clinical burden of nonalcoholic steatohepatitis in patients with type 2 diabetes in the U.S. Diabetes Care 2020; 43 (02) 283-289
  • 11 de Vries M, Westerink J, Kaasjager KHAH, de Valk HW. Prevalence of nonalcoholic fatty liver disease (NAFLD) in patients with type 1 diabetes mellitus: a systematic review and meta-analysis. J Clin Endocrinol Metab 2020; 105 (12) 3842-3853
  • 12 Perseghin G, Lattuada G, De Cobelli F. et al. Reduced intrahepatic fat content is associated with increased whole-body lipid oxidation in patients with type 1 diabetes. Diabetologia 2005; 48 (12) 2615-2621
  • 13 Gastaldelli A, Cusi K. From NASH to diabetes and from diabetes to NASH: mechanisms and treatment options. JHEP Rep 2019; 1 (04) 312-328
  • 14 Targher G, Corey KE, Byrne CD, Roden M. The complex link between NAFLD and type 2 diabetes mellitus - mechanisms and treatments. Nat Rev Gastroenterol Hepatol 2021; DOI: 10.1038/s41575-021-00448-y. (online ahead of print)
  • 15 Hammarstedt A, Gogg S, Hedjazifar S, Nerstedt A, Smith U. Impaired adipogenesis and dysfunctional adipose tissue in human hypertrophic obesity. Physiol Rev 2018; 98 (04) 1911-1941
  • 16 Roden M, Shulman GI. The integrative biology of type 2 diabetes. Nature 2019; 576 (7785): 51-60
  • 17 Kupriyanova Y, Zaharia OP, Bobrov P. et al. Early changes in hepatic energy metabolism and lipid content in recent-onset type 1 and 2 diabetes mellitus. J Hepatol 2021; 74 (05) 1028-1037
  • 18 Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest 2005; 115 (05) 1343-1351
  • 19 Brown MS, Goldstein JL. Selective versus total insulin resistance: a pathogenic paradox. Cell Metab 2008; 7 (02) 95-96
  • 20 Ter Horst KW, Vatner DF, Zhang D. et al. Hepatic insulin resistance is not pathway selective in humans with nonalcoholic fatty liver disease. Diabetes Care 2021; 44 (02) 489-498
  • 21 Koliaki C, Szendroedi J, Kaul K. et al. Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis. Cell Metab 2015; 21 (05) 739-746
  • 22 Apostolopoulou M, Gordillo R, Koliaki C. et al. Specific hepatic sphingolipids relate to insulin resistance, oxidative stress, and inflammation in nonalcoholic steatohepatitis. Diabetes Care 2018; 41 (06) 1235-1243
  • 23 Gancheva S, Bierwagen A, Kaul K. et al; German Diabetes Study (GDS) Group. Variants in genes controlling oxidative metabolism contribute to lower hepatic atp independent of liver fat content in type 1 diabetes. Diabetes 2016; 65 (07) 1849-1857
  • 24 Szendroedi J, Chmelik M, Schmid AI. et al. Abnormal hepatic energy homeostasis in type 2 diabetes. Hepatology 2009; 50 (04) 1079-1086
  • 25 Dehnad A, Fan W, Jiang JX. et al. AGER1 downregulation associates with fibrosis in nonalcoholic steatohepatitis and type 2 diabetes. J Clin Invest 2020; 130 (08) 4320-4330
  • 26 Trépo E, Valenti L. Update on NAFLD genetics: from new variants to the clinic. J Hepatol 2020; 72 (06) 1196-1209
  • 27 Stender S, Kozlitina J, Nordestgaard BG, Tybjærg-Hansen A, Hobbs HH, Cohen JC. Adiposity amplifies the genetic risk of fatty liver disease conferred by multiple loci. Nat Genet 2017; 49 (06) 842-847
  • 28 Eslam M, Valenti L, Romeo S. Genetics and epigenetics of NAFLD and NASH: clinical impact. J Hepatol 2018; 68 (02) 268-279
  • 29 Brookfield JFQ. Q&A: promise and pitfalls of genome-wide association studies. BMC Biol 2010; 8: 41
  • 30 Zaharia OP, Strassburger K, Knebel B. et al; GDS Group. Role of patatin-like phospholipase domain-containing 3 gene for hepatic lipid content and insulin resistance in diabetes. Diabetes Care 2020; 43 (09) 2161-2168
  • 31 Ando Y, Jou JH. Nonalcoholic fatty liver disease and recent guideline updates. Clin Liver Dis (Hoboken) 2021; 17 (01) 23-28
  • 32 Chalasani N, Younossi Z, Lavine JE. et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology 2018; 67 (01) 328-357
  • 33 Bril F, McPhaul MJ, Caulfield MP. et al. Performance of plasma biomarkers and diagnostic panels for nonalcoholic steatohepatitis and advanced fibrosis in patients with type 2 diabetes. Diabetes Care 2020; 43 (02) 290-297
  • 34 Newsome PN, Sasso M, Deeks JJ. et al. FibroScan-AST (FAST) score for the non-invasive identification of patients with non-alcoholic steatohepatitis with significant activity and fibrosis: a prospective derivation and global validation study. Lancet Gastroenterol Hepatol 2020; 5 (04) 362-373
  • 35 Ciardullo S, Muraca E, Perra S. et al. Screening for non-alcoholic fatty liver disease in type 2 diabetes using non-invasive scores and association with diabetic complications. BMJ Open Diabetes Res Care 2020; 8 (01) e000904
  • 36 American Diabetes Association. 4. Comprehensive Medical Evaluation and Assessment of Comorbidities: Standards of Medical Care in Diabetes-2020 . Diabetes Care 2020; 43 (Suppl. 01) S37-S47
  • 37 Portillo-Sanchez P, Bril F, Maximos M. et al. High prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus and normal plasma aminotransferase levels. J Clin Endocrinol Metab 2015; 100 (06) 2231-2238
  • 38 Geh D, Anstee QM, Reeves HL. NAFLD-associated HCC: progress and opportunities. J Hepatocell Carcinoma 2021; 8: 223-239
  • 39 Wong VW, Chalasani N. Not routine screening, but vigilance for chronic liver disease in patients with type 2 diabetes. J Hepatol 2016; 64 (06) 1211-1213
  • 40 Sanyal AJ, Brunt EM, Kleiner DE. et al. Endpoints and clinical trial design for nonalcoholic steatohepatitis. Hepatology 2011; 54 (01) 344-353
  • 41 Sanyal AJ, Friedman SL, McCullough AJ, Dimick-Santos L. American Association for the Study of Liver Diseases, United States Food and Drug Administration, Food and Drug Administration Joint Workshop. Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: findings and recommendations from an American Association for the Study of Liver Diseases-U.S. Hepatology 2015; 61 (04) 1392-1405
  • 42 Kirk E, Reeds DN, Finck BN, Mayurranjan SM, Patterson BW, Klein S. Dietary fat and carbohydrates differentially alter insulin sensitivity during caloric restriction. Gastroenterology 2009; 136 (05) 1552-1560
  • 43 Koutoukidis DA, Astbury NM, Tudor KE. et al. Association of weight loss interventions with changes in biomarkers of nonalcoholic fatty liver disease: a systematic review and meta-analysis. JAMA Intern Med 2019; 179 (09) 1262-1271
  • 44 Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L. et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology 2015; 149 (02) 367-78.e5 , quiz e14–e15
  • 45 Vilar-Gomez E, Yasells-Garcia A, Martinez-Perez Y. et al. Development and validation of a noninvasive prediction model for nonalcoholic steatohepatitis resolution after lifestyle intervention. Hepatology 2016; 63 (06) 1875-1887
  • 46 Taylor R, Al-Mrabeh A, Zhyzhneuskaya S. et al. Remission of human type 2 diabetes requires decrease in liver and pancreas fat content but is dependent upon capacity for β cell recovery. Cell Metab 2018; 28 (04) 547-556.e3
  • 47 Bacchi E, Negri C, Targher G. et al. Both resistance training and aerobic training reduce hepatic fat content in type 2 diabetic subjects with nonalcoholic fatty liver disease (the RAED2 Randomized Trial). Hepatology 2013; 58 (04) 1287-1295
  • 48 Markova M, Pivovarova O, Hornemann S. et al. Isocaloric diets high in animal or plant protein reduce liver fat and inflammation in individuals with type 2 diabetes. Gastroenterology 2017; 152 (03) 571-585.e8
  • 49 Vangoitsenhoven R, Wilson RL, Cherla DV. et al. Presence of liver steatosis is associated with greater diabetes remission after gastric bypass surgery. Diabetes Care 2021; 44 (02) 321-325
  • 50 Moussa O, Ardissino M, Heaton T. et al. Effect of bariatric surgery on long-term cardiovascular outcomes: a nationwide nested cohort study. Eur Heart J 2020; 41 (28) 2660-2667
  • 51 Castagneto-Gissey L, Casella G, Mingrone G. Effect of diet versus gastric bypass on metabolic function in diabetes. N Engl J Med 2020; 383 (24) 2392-2393
  • 52 Yoshino M, Kayser BD, Yoshino J. et al. Effects of diet versus gastric bypass on metabolic function in diabetes. N Engl J Med 2020; 383 (08) 721-732
  • 53 Harris LA, Kayser BD, Cefalo C. et al. Biliopancreatic diversion induces greater metabolic improvement than Roux-en-Y gastric bypass. Cell Metab 2019; 30 (05) 855-864.e3
  • 54 Laursen TL, Hagemann CA, Wei C. et al. Bariatric surgery in patients with non-alcoholic fatty liver disease - from pathophysiology to clinical effects. World J Hepatol 2019; 11 (02) 138-149
  • 55 Tiikkainen M, Häkkinen AM, Korsheninnikova E, Nyman T, Mäkimattila S, Yki-Järvinen H. Effects of rosiglitazone and metformin on liver fat content, hepatic insulin resistance, insulin clearance, and gene expression in adipose tissue in patients with type 2 diabetes. Diabetes 2004; 53 (08) 2169-2176
  • 56 Haukeland JW, Konopski Z, Eggesbø HB. et al. Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial. Scand J Gastroenterol 2009; 44 (07) 853-860
  • 57 Shields WW, Thompson KE, Grice GA, Harrison SA, Coyle WJ. The effect of metformin and standard therapy versus standard therapy alone in nondiabetic patients with insulin resistance and nonalcoholic steatohepatitis (NASH): a pilot trial. Therap Adv Gastroenterol 2009; 2 (03) 157-163
  • 58 Bugianesi E, Gentilcore E, Manini R. et al. A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease. Am J Gastroenterol 2005; 100 (05) 1082-1090
  • 59 Chen HP, Shieh JJ, Chang CC. et al. Metformin decreases hepatocellular carcinoma risk in a dose-dependent manner: population-based and in vitro studies. Gut 2013; 62 (04) 606-615
  • 60 LaMoia TE, Shulman GI. Cellular and molecular mechanisms of metformin action. Endocr Rev 2021; 42 (01) 77-96
  • 61 Poxel Announces Positive Results From Phase SAP. 2a NASH Trial With PXL770, an Oral First-in-Class Direct AMPK Activator. Press Release. 2020
  • 62 Cusi K, Orsak B, Bril F. et al. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial. Ann Intern Med 2016; 165 (05) 305-315
  • 63 Sanyal AJ, Chalasani N, Kowdley KV. et al; NASH CRN. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010; 362 (18) 1675-1685
  • 64 Belfort R, Harrison SA, Brown K. et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006; 355 (22) 2297-2307
  • 65 Bril F, Biernacki DM, Kalavalapalli S. et al. Role of vitamin E for nonalcoholic steatohepatitis in patients with type 2 diabetes: a randomized controlled trial. Diabetes Care 2019; 42 (08) 1481-1488
  • 66 Cusi K. Treatment of patients with type 2 diabetes and non-alcoholic fatty liver disease: current approaches and future directions. Diabetologia 2016; 59 (06) 1112-1120
  • 67 Svegliati-Baroni G, Patrício B, Lioci G, Macedo MP, Gastaldelli A. Gut-pancreas-liver axis as a target for treatment of NAFLD/NASH. Int J Mol Sci 2020; 21 (16) E5820
  • 68 Joy TR, McKenzie CA, Tirona RG. et al. Sitagliptin in patients with non-alcoholic steatohepatitis: a randomized, placebo-controlled trial. World J Gastroenterol 2017; 23 (01) 141-150
  • 69 Cui J, Philo L, Nguyen P. et al. Sitagliptin vs. placebo for non-alcoholic fatty liver disease: a randomized controlled trial. J Hepatol 2016; 65 (02) 369-376
  • 70 Macauley M, Hollingsworth KG, Smith FE. et al. Effect of vildagliptin on hepatic steatosis. J Clin Endocrinol Metab 2015; 100 (04) 1578-1585
  • 71 Petit JM, Cercueil JP, Loffroy R. et al. Effect of liraglutide therapy on liver fat content in patients with inadequately controlled type 2 diabetes: the Lira-NAFLD study. J Clin Endocrinol Metab 2017; 102 (02) 407-415
  • 72 Yan J, Yao B, Kuang H. et al. Liraglutide, sitagliptin, and insulin glargine added to metformin: the effect on body weight and intrahepatic lipid in patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease. Hepatology 2019; 69 (06) 2414-2426
  • 73 Armstrong MJ, Gaunt P, Aithal GP. et al; LEAN trial team. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 2016; 387 (10019): 679-690
  • 74 Pratley RE, Aroda VR, Lingvay I. et al; SUSTAIN 7 investigators. Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial. Lancet Diabetes Endocrinol 2018; 6 (04) 275-286
  • 75 Lingvay I, Desouza CV, Lalic KS. et al. A 26-week randomized controlled trial of semaglutide once daily versus liraglutide and placebo in patients with type 2 diabetes suboptimally controlled on diet and exercise with or without metformin. Diabetes Care 2018; 41 (09) 1926-1937
  • 76 Newsome PN, Buchholtz K, Cusi K. et al. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis. N Engl J Med 2021; 384 (12) 1113-1124
  • 77 Rinella ME, Tacke F, Sanyal AJ, Anstee QM. participants of the AASLD/EASL Workshop. Report on the AASLD/EASL joint workshop on clinical trial endpoints in NAFLD. J Hepatol 2019; 71 (04) 823-833
  • 78 Kahl S, Gancheva S, Straßburger K. et al. Empagliflozin effectively lowers liver fat content in well-controlled type 2 diabetes: a randomized, double-blind, phase 4, placebo-controlled trial. Diabetes Care 2020; 43 (02) 298-305
  • 79 Latva-Rasku A, Honka M-J, Kullberg J. et al. The SGLT2 inhibitor dapagliflozin reduces liver fat but does not affect tissue insulin sensitivity: a randomized, double-blind, placebo-controlled study with 8-week treatment in type 2 diabetes patients. Diabetes Care 2019; 42 (05) 931-937
  • 80 Lai LL, Vethakkan SR, Nik Mustapha NR, Mahadeva S, Chan WK. Empagliflozin for the treatment of nonalcoholic steatohepatitis in patients with type 2 diabetes mellitus. Dig Dis Sci 2020; 65 (02) 623-631
  • 81 Akuta N, Kawamura Y, Fujiyama S. et al. SGLT2 inhibitor treatment outcome in nonalcoholic fatty liver disease complicated with diabetes mellitus: the long-term effects on clinical features and liver histopathology. Intern Med 2020; 59 (16) 1931-1937
  • 82 Grant PJ, Cosentino F. The 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: new features and the ‘Ten Commandments’ of the 2019 Guidelines are discussed by Professor Peter J. Grant and Professor Francesco Cosentino, the Task Force chairmen. Eur Heart J 2019; 40 (39) 3215-3217
  • 83 Zinman B, Bhosekar V, Busch R. et al. Semaglutide once weekly as add-on to SGLT-2 inhibitor therapy in type 2 diabetes (SUSTAIN 9): a randomised, placebo-controlled trial. Lancet Diabetes Endocrinol 2019; 7 (05) 356-367
  • 84 Jabbour SA, Frías JP, Ahmed A. et al. Efficacy and safety over 2 years of exenatide plus dapagliflozin in the DURATION-8 study: a multicenter, double-blind, phase 3, randomized controlled trial. Diabetes Care 2020; 43 (10) 2528-2536
  • 85 Gastaldelli A, Repetto E, Guja C. et al. Exenatide and dapagliflozin combination improves markers of liver steatosis and fibrosis in patients with type 2 diabetes. Diabetes Obes Metab 2020; 22 (03) 393-403
  • 86 Harreiter J, Just I, Leutner M. et al. Combined exenatide and dapagliflozin has no additive effects on reduction of hepatocellular lipids despite better glycaemic control in patients with type 2 diabetes mellitus treated with metformin: EXENDA, a 24-week, prospective, randomized, placebo-controlled pilot trial. Diabetes Obes Metab 2021; 23 (05) 1129-1139
  • 87 Armstrong MJ, Hull D, Guo K. et al. Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis. J Hepatol 2016; 64 (02) 399-408
  • 88 Chino Y, Samukawa Y, Sakai S. et al. SGLT2 inhibitor lowers serum uric acid through alteration of uric acid transport activity in renal tubule by increased glycosuria. Biopharm Drug Dispos 2014; 35 (07) 391-404
  • 89 Lee YS, Park MS, Choung JS. et al. Glucagon-like peptide-1 inhibits adipose tissue macrophage infiltration and inflammation in an obese mouse model of diabetes. Diabetologia 2012; 55 (09) 2456-2468
  • 90 Xu L, Nagata N, Chen G. et al. Empagliflozin reverses obesity and insulin resistance through fat browning and alternative macrophage activation in mice fed a high-fat diet. BMJ Open Diabetes Res Care 2019; 7 (01) e000783
  • 91 Mantovani A, Petracca G, Beatrice G, Csermely A, Lonardo A, Targher G. Glucagon-like peptide-1 receptor agonists for treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: an updated meta-analysis of randomized controlled trials. Metabolites 2021; 11 (02) 73
  • 92 Vahl TP, Tauchi M, Durler TS. et al. Glucagon-like peptide-1 (GLP-1) receptors expressed on nerve terminals in the portal vein mediate the effects of endogenous GLP-1 on glucose tolerance in rats. Endocrinology 2007; 148 (10) 4965-4973
  • 93 Seo D, Faintuch BL, Aparecida de Oliveira E, Faintuch J. Pancreas and liver uptake of new radiolabeled incretins (GLP-1 and Exendin-4) in models of diet-induced and diet-restricted obesity. Nucl Med Biol 2017; 49: 57-64
  • 94 Gupta NA, Mells J, Dunham RM. et al. Glucagon-like peptide-1 receptor is present on human hepatocytes and has a direct role in decreasing hepatic steatosis in vitro by modulating elements of the insulin signaling pathway. Hepatology 2010; 51 (05) 1584-1592
  • 95 Svegliati-Baroni G, Saccomanno S, Rychlicki C. et al. Glucagon-like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signalling alteration induced by a high-fat diet in nonalcoholic steatohepatitis. Liver Int 2011; 31 (09) 1285-1297
  • 96 Rakipovski G, Rolin B, Nøhr J. et al. The GLP-1 analogs liraglutide and semaglutide reduce atherosclerosis in ApoE−/− and LDLr−/− mice by a mechanism that includes inflammatory pathways. JACC Basic Transl Sci 2018; 3 (06) 844-857
  • 97 Romero-Gómez M, Zelber-Sagi S, Trenell M. Treatment of NAFLD with diet, physical activity and exercise. J Hepatol 2017; 67 (04) 829-846
  • 98 Press Release. Accessed on July 14, 2021 at: https://investor.lilly.com/news-releases/news-release-details/lillys-tirzepatide-significantly-reduced-a1c-and-body-weight
  • 99 Hartman ML, Sanyal AJ, Loomba R. et al. 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 (06) 1352-1355
  • 100 Mathiesen DS, Bagger JI, Bergmann NC. et al. The effects of dual GLP-1/GIP receptor agonism on glucagon secretion-a review. Int J Mol Sci 2019; 20 (17) E4092
  • 101 Mullard A. FDA rejects NASH drug. Nat Rev Drug Discov 2020; 19 (08) 501
  • 102 Younossi ZM, Ratziu V, Loomba R. et al; REGENERATE Study Investigators. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 2019; 394 (10215): 2184-2196
  • 103 Eaton JE, Vuppalanchi R, Reddy R, Sathapathy S, Ali B, Kamath PS. Liver injury in patients with cholestatic liver disease treated with obeticholic acid. Hepatology 2020; 71 (04) 1511-1514
  • 104 Press Release. Intercept receives complete response letter from FDA for obeticholic acid for the treatment of fibrosis due to NASH. Accessed on July 14, 2021 at: https://ir.interceptpharma.com/news-releases/news-release-details/intercept-receives-complete-response-letter-fda-obeticholic-acid
  • 105 Neuschwander-Tetri BA, Loomba R, Sanyal AJ. et al; NASH Clinical Research Network. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 2015; 385 (9972): 956-965
  • 106 Mudaliar S, Henry RR, Sanyal AJ. et al. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 2013; 145 (03) 574.e1-582.e1
  • 107 Stanley TL, Feldpausch MN, Oh J. et al. Effect of tesamorelin on visceral fat and liver fat in HIV-infected patients with abdominal fat accumulation: a randomized clinical trial. JAMA 2014; 312 (04) 380-389
  • 108 Stanley TL, Fourman LT, Feldpausch MN. et al. Effects of tesamorelin on non-alcoholic fatty liver disease in HIV: a randomised, double-blind, multicentre trial. Lancet HIV 2019; 6 (12) e821-e830
  • 109 Clemmons DR, Miller S, Mamputu JC. Safety and metabolic effects of tesamorelin, a growth hormone-releasing factor analogue, in patients with type 2 diabetes: a randomized, placebo-controlled trial. PLoS One 2017; 12 (06) e0179538
  • 110 Harrison SA, Bashir MR, Guy CD. et al. Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 2019; 394 (10213): 2012-2024
  • 111 Inventiva announces design of Phase III clinical trial with lanifibranor in NASH. Accessed on July 14, 2021 at: https://www.globenewswire.com/news-release/2021/01/05/2153793/0/en/Inventiva-announces-design-of-Phase-III-clinical-trial-with-lanifibranor-in-NASH.html
  • 112 Inventiva's lanifibranor meets the primary and key secondary endpoints in the Phase IIb NATIVE clinical trial in non-alcoholic steatohepatitis (NASH). Accessed on July 14, 2021 at: https://www.globenewswire.com/news-release/2020/06/15/2048284/0/en/Inventiva-s-lanifibranor-meets-the-primary-and-key-secondary-endpoints-in-the-Phase-IIb-NATIVE-clinical-trial-in-non-alcoholic-steatohepatitis-NASH.html
  • 113 Alkhouri NHR, Kabler H, Kayali Z. et al. Late breaker: orals. J Hepatol 2020; 73: S114-S122
  • 114 Falutz J, Potvin D, Mamputu JC. et al. Effects of tesamorelin, a growth hormone-releasing factor, in HIV-infected patients with abdominal fat accumulation: a randomized placebo-controlled trial with a safety extension. J Acquir Immune Defic Syndr 2010; 53 (03) 311-322
  • 115 Villicev CM, Freitas FR, Aoki MS. et al. Thyroid hormone receptor beta-specific agonist GC-1 increases energy expenditure and prevents fat-mass accumulation in rats. J Endocrinol 2007; 193 (01) 21-29
  • 116 Sargeant JA, Henson J, King JA, Yates T, Khunti K, Davies MJ. A review of the effects of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors on lean body mass in humans. Endocrinol Metab (Seoul) 2019; 34 (03) 247-262
  • 117 Abdul-Ghani M, Migahid O, Megahed A. et al. Combination therapy with exenatide plus pioglitazone versus basal/bolus insulin in patients with poorly controlled type 2 diabetes on sulfonylurea plus metformin: the Qatar study. Diabetes Care 2017; 40 (03) 325-331
  • 118 Han E, Lee YH, Lee BW, Kang ES, Cha BS. Ipragliflozin additively ameliorates non-alcoholic fatty liver disease in patients with type 2 diabetes controlled with metformin and pioglitazone: a 24-week randomized controlled trial. J Clin Med 2020; 9 (01) E259
  • 119 Scheen AJ. Sodium-glucose cotransporter type 2 inhibitors for the treatment of type 2 diabetes mellitus. Nat Rev Endocrinol 2020; 16 (10) 556-577
  • 120 Hædersdal S, Lund A, Nielsen-Hannerup E. et al. The role of glucagon in the acute therapeutic effects of SGLT2 inhibition. Diabetes 2020; 69 (12) 2619-2629