Treatment options for nonalcoholic steatohepatitis - a safety evaluation

References

• Fazel Y, Koenig AB, Sayiner M, et al. Epidemiology and natural history of non-alcoholic fatty liver disease. Metabolism. 2016;65:1017–1025.
   PubMed Web of Science ®Google Scholar
• Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther. 2011;34:274–285.
   PubMed Web of Science ®Google Scholar
• Charlton MR, Burns JM, Pedersen RA, et al. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology. 2011;141:1249–1253.
   PubMed Web of Science ®Google Scholar
• White DL, Kanwal F, El-Serag HB. Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol. 2012;10:1342–1359 e2.
   PubMed Web of Science ®Google Scholar
• Matteoni CA, Younossi ZM, Gramlich T, et al. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology. 1999;116:1413–1419.
   PubMed Web of Science ®Google Scholar
• Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012;55:2005–2023.
   PubMed Web of Science ®Google Scholar
• Ekstedt M, Hagstrom H, Nasr P, et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology. 2015;61:1547–1554.
   PubMed Web of Science ®Google Scholar
• Carr RM, Oranu A, Khungar V. Nonalcoholic fatty liver disease: pathophysiology and management. Gastroenterol Clin North Am. 2016;45:639–652.
   PubMed Web of Science ®Google Scholar
• Fontana RJ, Seeff LB, Andrade RJ, et al. Standardization of nomenclature and causality assessment in drug-induced liver injury: summary of a clinical research workshop. Hepatology. 2010;52:730–742.
   PubMedGoogle Scholar
• Hoofnagle JH, Van Natta ML, Kleiner DE, et al. Vitamin E and changes in serum alanine aminotransferase levels in patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2013;38:134–143.
   PubMed Web of Science ®Google Scholar
• Prati D, Taioli E, Zanella A, et al. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med. 2002;137:1–10.
   PubMed Web of Science ®Google Scholar
• U.S. Food and Drug Administration. Guidance for industry drug-induced liver injury: premarketing clinical evaluation. 2009.
   Google Scholar
• Robles-Diaz M, Lucena MI, Kaplowitz N, et al. Use of Hy’s law and a new composite algorithm to predict acute liver failure in patients with drug-induced liver injury. Gastroenterology. 2014;147:109–118 e5.
   PubMed Web of Science ®Google Scholar
• Hoofnagle JH, Navarro VJ. Drug-induced liver injury: icelandic lessons. Gastroenterology. 2013;144:1335–1336.
   PubMed Web of Science ®Google Scholar
• Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology. 2010;52:1836–1846.
   PubMed Web of Science ®Google Scholar
• Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology. 1998;114:842–845.
   PubMed Web of Science ®Google Scholar
• Ratziu V, Goodman Z, Sanyal A. Current efforts and trends in the treatment of NASH. J Hepatol. 2015;62:S65–S75.
   PubMed Web of Science ®Google Scholar
• Neuschwander-Tetri BA. Non-alcoholic fatty liver disease. BMC Med. 2017;15:45.
   PubMed Web of Science ®Google Scholar
• Petta S, Gastaldelli A, Rebelos E, et al. Pathophysiology of non alcoholic fatty liver disease. Int J Mol Sci. 2016;17:2082.
   PubMed Web of Science ®Google Scholar
• Cusi K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology. 2012;142:711–725 e6.
   PubMed Web of Science ®Google Scholar
• Promrat K, Kleiner DE, Niemeier HM, et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology. 2010;51:121–129.
   PubMed Web of Science ®Google Scholar
• Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology. 2015;149:367-78 e5; quiz e14-5.
   Web of Science ®Google Scholar
• Liddle RA, Goldstein RB, Saxton J. Gallstone formation during weight-reduction dieting. Arch Intern Med. 1989;149:1750–1753.
   PubMedGoogle Scholar
• Broomfield PH, Chopra R, Sheinbaum RC, et al. Effects of ursodeoxycholic acid and aspirin on the formation of lithogenic bile and gallstones during loss of weight. N Engl J Med. 1988;319:1567–1572.
   PubMed Web of Science ®Google Scholar
• Yancy WS Jr., Olsen MK, Guyton JR, et al. A low-carbohydrate, ketogenic diet versus a low-fat diet to treat obesity and hyperlipidemia: a randomized, controlled trial. Ann Intern Med. 2004;140:769–777.
   PubMed Web of Science ®Google Scholar
• Chen TY, Smith W, Rosenstock JL, et al. A life-threatening complication of Atkins diet. Lancet. 2006;367:958.
   PubMed Web of Science ®Google Scholar
• Wong VW, Chan RS, Wong GL, et al. Community-based lifestyle modification programme for non-alcoholic fatty liver disease: a randomized controlled trial. J Hepatol. 2013;59:536–542.
   PubMed Web of Science ®Google Scholar
• de Almeida SR, Rocha PR, Sanches MD, et al. Roux-en-Y gastric bypass improves the nonalcoholic steatohepatitis (NASH) of morbid obesity. Obes Surg. 2006;16:270–278.
   PubMed Web of Science ®Google Scholar
• Hafeez S, Ahmed MH. Bariatric surgery as potential treatment for nonalcoholic fatty liver disease: a future treatment by choice or by chance? J Obes. 2013;2013:839275.
   PubMedGoogle Scholar
• Lassailly G, Caiazzo R, Buob D, et al. Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients. Gastroenterology. 2015;149:379–388; quiz e15–6.
   Web of Science ®Google Scholar
• Mattar SG, Velcu LM, Rabinovitz M, et al. Surgically-induced weight loss significantly improves nonalcoholic fatty liver disease and the metabolic syndrome. Ann Surg. 2005;242:610–617; discussion 618-20.
   PubMed Web of Science ®Google Scholar
• Higa KD, Boone KB, Ho T. Complications of the laparoscopic Roux-en-Y gastric bypass: 1,040 patients–what have we learned? Obes Surg. 2000;10:509–513.
   PubMed Web of Science ®Google Scholar
• Rasmussen JJ, Fuller W, Ali MR. Marginal ulceration after laparoscopic gastric bypass: an analysis of predisposing factors in 260 patients. Surg Endosc. 2007;21:1090–1094.
   PubMed Web of Science ®Google Scholar
• Lalor PF, Tucker ON, Szomstein S, et al. Complications after laparoscopic sleeve gastrectomy. Surg Obes Relat Dis. 2008;4:33–38.
   PubMed Web of Science ®Google Scholar
• Buchwald H, Oien DM. Metabolic/bariatric surgery worldwide 2011. Obes Surg. 2013;23:427–436.
   PubMed Web of Science ®Google Scholar
• Force ABET, Sullivan S, Kumar N, et al. ASGE position statement on endoscopic bariatric therapies in clinical practice. Gastrointest Endosc. 2015;82:767–772.
   PubMed Web of Science ®Google Scholar
• Lee YM, Low HC, Lim LG, et al. Intragastric balloon significantly improves nonalcoholic fatty liver disease activity score in obese patients with nonalcoholic steatohepatitis: a pilot study. Gastrointest Endosc. 2012;76:756–760.
   PubMed Web of Science ®Google Scholar
• Mui WL, Ng EK, Tsung BY, et al. Impact on obesity-related illnesses and quality of life following intragastric balloon. Obes Surg. 2010;20:1128–1132.
   PubMed Web of Science ®Google Scholar
• U.S. Food and Drug Administration. Summary of safety and effectiveness data (SSED) - ORBERA™ Intragastric Balloon System. 2015.
   Google Scholar
• Force ABET, Committee AT, Abu Dayyeh BK, et al. ASGE bariatric endoscopy task force systematic review and meta-analysis assessing the ASGE PIVI thresholds for adopting endoscopic bariatric therapies. Gastrointest Endosc. 2015;82:425–438 e5.
   PubMed Web of Science ®Google Scholar
• Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362:1675–1685.
   PubMed Web of Science ®Google Scholar
• Kowdley KV, Wilson LA, Van Natta ML, et al. Efficacy and safety of vitamin E in nonalcoholic steatohepatitis patients with and without diabetes: pooled analysis from the PIVENS and FLINT NIDDK NASH CRN Trials. Hepatology. 2015;62:1387–1397.
   Google Scholar
• Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 2015;385:956–965.
   PubMed Web of Science ®Google Scholar
• Lavine JE, Schwimmer JB, Van Natta ML, et al. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA. 2011;305:1659–1668.
   PubMed Web of Science ®Google Scholar
• Miller ER 3rd, Pastor-Barriuso R, Dalal D, et al. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005;142:37–46.
   PubMed Web of Science ®Google Scholar
• Rimm EB, Stampfer MJ, Ascherio A, et al. Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med. 1993;328:1450–1456.
   PubMed Web of Science ®Google Scholar
• Klein EA, Thompson IM Jr., Tangen CM, et al. Vitamin E and the risk of prostate cancer: the selenium and vitamin E cancer prevention trial (SELECT). JAMA. 2011;306:1549–1556.
   PubMed Web of Science ®Google Scholar
• Poulsen L, Siersbaek M, Mandrup S. PPARs: fatty acid sensors controlling metabolism. Semin Cell Dev Biol. 2012;23:631–639.
   PubMed Web of Science ®Google Scholar
• Cheang WS, Tian XY, Wong WT, et al. The peroxisome proliferator-activated receptors in cardiovascular diseases: experimental benefits and clinical challenges. Br J Pharmacol. 2015;172:5512–5522.
   PubMed Web of Science ®Google Scholar
• Liang F, Wang F, Zhang S, et al. Peroxisome proliferator activated receptor (PPAR)alpha agonists inhibit hypertrophy of neonatal rat cardiac myocytes. Endocrinology. 2003;144:4187–4194.
   PubMed Web of Science ®Google Scholar
• Moore KJ, Rosen ED, Fitzgerald ML, et al. The role of PPAR-gamma in macrophage differentiation and cholesterol uptake. Nat Med. 2001;7:41–47.
   PubMed Web of Science ®Google Scholar
• Braissant O, Foufelle F, Scotto C, et al. Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. Endocrinology. 1996;137:354–366.
   PubMed Web of Science ®Google Scholar
• Pawlak M, Lefebvre P, Staels B. Molecular mechanism of PPAR-alpha action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease. J Hepatol. 2015;62:720–733.
   PubMed Web of Science ®Google Scholar
• Cariou B, Hanf R, Lambert-Porcheron S, et al. Dual peroxisome proliferator-activated receptor alpha/delta agonist GFT505 improves hepatic and peripheral insulin sensitivity in abdominally obese subjects. Diabetes Care. 2013;36:2923–2930.
   PubMed Web of Science ®Google Scholar
• Staels B, Rubenstrunk A, Noel B, et al. Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology. 2013;58:1941–1952.
   PubMed Web of Science ®Google Scholar
• Ratziu V, Harrison SA, Francque S, et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-alpha and -delta, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology. 2016;150:1147–1159 e5.
   PubMed Web of Science ®Google Scholar
• Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, et al. Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone. Hepatology. 2003;38:1008–1017.
   PubMed Web of Science ®Google Scholar
• Belfort R, Harrison SA, Brown K, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006;355:2297–2307.
   PubMed Web of Science ®Google Scholar
• Boettcher E, Csako G, Pucino F, et al. Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2012;35:66–75.
   PubMed Web of Science ®Google Scholar
• 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;165:305–315.
   PubMed Web of Science ®Google Scholar
• Friedland SN, Leong A, Filion KB, et al. The cardiovascular effects of peroxisome proliferator-activated receptor agonists. Am J Med. 2012;125:126–133.
   PubMed Web of Science ®Google Scholar
• Pai V, Paneerselvam A, Mukhopadhyay S, et al. A multicenter, prospective, randomized, double-blind study to evaluate the safety and efficacy of saroglitazar 2 and 4 mg compared to pioglitazone 45 mg in diabetic dyslipidemia (PRESS V). J Diabetes Sci Technol. 2014;8:132–141.
   PubMedGoogle Scholar
• Jani RH, Pai V, Jha P, et al. A multicenter, prospective, randomized, double-blind study to evaluate the safety and efficacy of Saroglitazar 2 and 4 mg compared with placebo in type 2 diabetes mellitus patients having hypertriglyceridemia not controlled with atorvastatin therapy (PRESS VI). Diabetes Technol Ther. 2014;16:63–71.
   PubMed Web of Science ®Google Scholar
• Liao HW, Saver JL, Wu YL, et al. Pioglitazone and cardiovascular outcomes in patients with insulin resistance, pre-diabetes and type 2 diabetes: a systematic review and meta-analysis. BMJ Open. 2017;7:e013927.
   PubMed Web of Science ®Google Scholar
• Levin D, Bell S, Sund R, et al. Pioglitazone and bladder cancer risk: a multipopulation pooled, cumulative exposure analysis. Diabetologia. 2015;58:493–504.
   PubMed Web of Science ®Google Scholar
• Lewis JD, Habel LA, Quesenberry CP, et al. Pioglitazone use and risk of bladder cancer and other common cancers in persons with diabetes. JAMA. 2015;314:265–277.
   PubMed Web of Science ®Google Scholar
• Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med. 2016;374:1321–1331.
   PubMed Web of Science ®Google Scholar
• Dongiovanni P, Petta S, Mannisto V, et al. Statin use and non-alcoholic steatohepatitis in at risk individuals. J Hepatol. 2015;63:705–712.
   PubMed Web of Science ®Google Scholar
• Ekstedt M, Franzen LE, Mathiesen UL, et al. Statins in non-alcoholic fatty liver disease and chronically elevated liver enzymes: a histopathological follow-up study. J Hepatol. 2007;47:135–141.
   PubMed Web of Science ®Google Scholar
• Loomba R, Sirlin CB, Ang B, et al. Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (MOZART trial). Hepatology. 2015;61:1239–1250.
   PubMed Web of Science ®Google Scholar
• Araya J, Rodrigo R, Pettinelli P, et al. Decreased liver fatty acid delta-6 and delta-5 desaturase activity in obese patients. Obesity (Silver Spring). 2010;18:1460–1463.
   PubMed Web of Science ®Google Scholar
• Puri P, Baillie RA, Wiest MM, et al. A lipidomic analysis of nonalcoholic fatty liver disease. Hepatology. 2007;46:1081–1090.
   PubMed Web of Science ®Google Scholar
• Zhang MJ, Spite M. Resolvins: anti-inflammatory and proresolving mediators derived from omega-3 polyunsaturated fatty acids. Annu Rev Nutr. 2012;32:203–227.
   PubMed Web of Science ®Google Scholar
• Sanyal AJ, Abdelmalek MF, Suzuki A, et al. No significant effects of ethyl-eicosapentanoic acid on histologic features of nonalcoholic steatohepatitis in a phase 2 trial. Gastroenterology. 2014;147:377–384 e1.
   PubMed Web of Science ®Google Scholar
• Argo CK, Patrie JT, Lackner C, et al. Effects of n-3 fish oil on metabolic and histological parameters in NASH: a double-blind, randomized, placebo-controlled trial. J Hepatol. 2015;62:190–197.
   PubMed Web of Science ®Google Scholar
• Dobrzyn P, Dobrzyn A, Miyazaki M, et al. Stearoyl-CoA desaturase 1 deficiency increases fatty acid oxidation by activating AMP-activated protein kinase in liver. Proc Natl Acad Sci USA. 2004;101:6409–6414.
   PubMed Web of Science ®Google Scholar
• Dobrzyn A, Ntambi JM. Stearoyl-CoA desaturase as a new drug target for obesity treatment. Obes Rev. 2005;6:169–174.
   PubMed Web of Science ®Google Scholar
• Safadi R, Konikoff FM, Mahamid M, et al. The fatty acid-bile acid conjugate Aramchol reduces liver fat content in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2014;12:2085–2091 e1.
   PubMed Web of Science ®Google Scholar
• Cohen DE, Anania FA, Chalasani N, et al. An assessment of statin safety by hepatologists. Am J Cardiol. 2006;97:77C–81C.
   PubMed Web of Science ®Google Scholar
• Athyros VG, Tziomalos K, Gossios TD, et al. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis. Lancet. 2010;376:1916–1922.
   PubMed Web of Science ®Google Scholar
• Watanabe M, Houten SM, Wang L, et al. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J Clin Invest. 2004;113:1408–1418.
   PubMed Web of Science ®Google Scholar
• Calkin AC, Tontonoz P. Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR. Nat Rev Mol Cell Biol. 2012;13:213–224.
   PubMed Web of Science ®Google Scholar
• Cipriani S, Mencarelli A, Palladino G, et al. FXR activation reverses insulin resistance and lipid abnormalities and protects against liver steatosis in Zucker (fa/fa) obese rats. J Lipid Res. 2010;51:771–784.
   PubMed Web of Science ®Google Scholar
• Verbeke L, Farre R, Trebicka J, et al. Obeticholic acid, a farnesoid X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats. Hepatology. 2014;59:2286–2298.
   PubMed Web of Science ®Google Scholar
• Ali AH, Lindor KD. Obeticholic acid for the treatment of primary biliary cholangitis. Expert Opin Pharmacother. 2016;17:1809–1815.
   PubMed Web of Science ®Google Scholar
• Nevens F, Andreone P, Mazzella G, et al. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med. 2016;375:631–643.
   PubMed Web of Science ®Google Scholar
• Hirschfield GM, Mason A, Luketic V, et al. Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology. 2015;148:751–761 e8.
   PubMed Web of Science ®Google Scholar
• Williamson RM, Price JF, Glancy S, et al. Prevalence of and risk factors for hepatic steatosis and nonalcoholic Fatty liver disease in people with type 2 diabetes: the edinburgh type 2 diabetes study. Diabetes Care. 2011;34:1139–1144.
   PubMed Web of Science ®Google Scholar
• 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;100:2231–2238.
   Web of Science ®Google Scholar
• Mells JE, Fu PP, Sharma S, et al. Glp-1 analog, liraglutide, ameliorates hepatic steatosis and cardiac hypertrophy in C57BL/6J mice fed a Western diet. Am J Physiol Gastrointest Liver Physiol. 2012;302:G225–35.
   PubMed Web of Science ®Google Scholar
• Lee J, Hong SW, Chae SW, et al. Exendin-4 improves steatohepatitis by increasing Sirt1 expression in high-fat diet-induced obese C57BL/6J mice. PLoS One. 2012;7:e31394.
   PubMed Web of Science ®Google Scholar
• Armstrong MJ, Gaunt P, Aithal GP, 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;387:679–690.
   PubMed Web of Science ®Google Scholar
• Bjerre Knudsen L, Madsen LW, Andersen S, et al. Glucagon-like Peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation. Endocrinology. 2010;151:1473–1486.
   PubMed Web of Science ®Google Scholar
• U.S. Food and Drug Administration. Postmarket drug safety information for patients and providers - Victoza (liraglutide). 2010.
   Google Scholar
• Sun F, Wu S, Guo S, et al. Impact of GLP-1 receptor agonists on blood pressure, heart rate and hypertension among patients with type 2 diabetes: A systematic review and network meta-analysis. Diabetes Res Clin Pract. 2015;110:26–37.
   PubMed Web of Science ®Google Scholar
• Henao-Mejia J, Elinav E, Jin C, et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature. 2012;482:179–185.
   PubMed Web of Science ®Google Scholar
• Adar T, Ben Ya’acov A, Lalazar G, et al. Oral administration of immunoglobulin G-enhanced colostrum alleviates insulin resistance and liver injury and is associated with alterations in natural killer T cells. Clin Exp Immunol. 2012;167:252–260.
   PubMed Web of Science ®Google Scholar
• Struff WG, Sprotte G. Bovine colostrum as a biologic in clinical medicine: a review–Part II: clinical studies. Int J Clin Pharmacol Ther. 2008;46:211–225.
   PubMed Web of Science ®Google Scholar
• Mizrahi M, Shabat Y, Ben Ya’acov A, et al. Alleviation of insulin resistance and liver damage by oral administration of Imm124-E is mediated by increased Tregs and associated with increased serum GLP-1 and adiponectin: results of a phase I/II clinical trial in NASH. J Inflamm Res. 2012;5:141–150.
   PubMedGoogle Scholar
• Dulai PS, Singh S, Patel J, et al. Increased risk of mortality by fibrosis stage in non-alcoholic fatty liver disease: systematic review and meta-analysis. Hepatology. 2017;65:1557–1565.
   PubMed Web of Science ®Google Scholar
• Barry-Hamilton V, Spangler R, Marshall D, et al. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat Med. 2010;16:1009–1017.
   PubMed Web of Science ®Google Scholar
• Mehal WZ, Iredale J, Friedman SL. Scraping fibrosis: expressway to the core of fibrosis. Nat Med. 2011;17:552–553.
   PubMed Web of Science ®Google Scholar
• Loomba R, Lawitz E, Mantry PS. GS-4997, an inhibitor of Apoptosis Signal-Regulating Kinase (ASK1), alone or in combination with simtuzumab for the treatment of nonalcoholic steatohepatitis (NASH): a randomized, phase 2 trial. Abstract LB-3. Presented at: the Liver Meeting; Boston (MA); 2016.
   Google Scholar
• Benson AB 3rd, Wainberg ZA, Hecht JR, et al. A phase II randomized, double-blind, placebo-controlled study of simtuzumab or Placebo in combination with gemcitabine for the first-line treatment of pancreatic adenocarcinoma. Oncologist. 2017;22:241–e15.
   PubMed Web of Science ®Google Scholar
• Raghu G, Brown KK, Collard HR, et al. Efficacy of simtuzumab versus placebo in patients with idiopathic pulmonary fibrosis: a randomised, double-blind, controlled, phase 2 trial. Lancet Respir Med. 2017;5:22–32.
   PubMed Web of Science ®Google Scholar
• Meissner EG, McLaughlin M, Matthews L, et al. Simtuzumab treatment of advanced liver fibrosis in HIV and HCV-infected adults: results of a 6-month open-label safety trial. Liver Int. 2016;36:1783–1792.
   PubMed Web of Science ®Google Scholar
• Barreyro FJ, Holod S, Finocchietto PV, et al. The pan-caspase inhibitor Emricasan (IDN-6556) decreases liver injury and fibrosis in a murine model of non-alcoholic steatohepatitis. Liver Int. 2015;35:953–966.
   PubMed Web of Science ®Google Scholar
• Shiffman M, Freilich B, Vuppalanchi R, et al. A Placebo-controlled, multicenter, double-blind, randomised trial of emricasan in subjects with non-alcoholic fatty liver disease (NAFLD) and raised transaminases. J Hepatology. 2015;62:S282.
   Web of Science ®Google Scholar
• Chiang SH, Bazuine M, Lumeng CN, et al. The protein kinase IKKepsilon regulates energy balance in obese mice. Cell. 2009;138:961–975.
   PubMed Web of Science ®Google Scholar
• Reilly SM, Chiang SH, Decker SJ, et al. An inhibitor of the protein kinases TBK1 and IKK-varepsilon improves obesity-related metabolic dysfunctions in mice. Nat Med. 2013;19:313–321.
   PubMed Web of Science ®Google Scholar
• Friedman S, Sanyal A, Goodman Z, et al. Efficacy and safety study of cenicriviroc for the treatment of non-alcoholic steatohepatitis in adult subjects with liver fibrosis: CENTAUR Phase 2b study design. Contemp Clin Trials. 2016;47:356–365.
   PubMed Web of Science ®Google Scholar
• Baghdasaryan A, Claudel T, Gumhold J, et al. Dual farnesoid X receptor/TGR5 agonist INT-767 reduces liver injury in the Mdr2-/- (Abcb4-/-) mouse cholangiopathy model by promoting biliary HCO(-)(3) output. Hepatology. 2011;54:1303–1312.
   PubMed Web of Science ®Google Scholar
• Fernandes P, Hashiguchi T, Fujii M, et al. Anti-NASH effects of solithromycin in NASH-HCC mouse model. Gastroenterology. 2014;146:S145–S146.
   Web of Science ®Google Scholar
• Targher G, Bertolini L, Rodella S, et al. Nonalcoholic fatty liver disease is independently associated with an increased incidence of cardiovascular events in type 2 diabetic patients. Diabetes Care. 2007;30:2119–2121.
   PubMed Web of Science ®Google Scholar