2016, Number 5
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Ann Hepatol 2016; 15 (5)
NASH: A glance at the landscape of pharmacological treatment
Brodosi L, Marchignoli F, Petroni ML, Marchesini G
Language: English
References: 69
Page: 673-681
PDF size: 162.44 Kb.
ABSTRACT
The role of nonalcoholic fatty liver disease, namely nonalcoholic steatohepatitis (NASH), as risk factor for liver- and non-liver-related
morbidity and mortality has been extensively reported. In addition to lifestyle changes, capable of removing the metabolic factors
driving disease progression, there is an urgent need for drugs able to reduce hepatic necroinflammation without worsening of fibrosis.
This goal is considered by regulatory agencies as surrogate marker to define the effectiveness in pharmacological compounds in
NASH, and fast-track approval was granted by the Food and Drug Administration in consideration of disease severity and unmet
medical needs. Several compounds are in the pipeline of pharmaceutical industries and are being studied in phase II trials, but only a
few (obeticholic acid, elafibranor) have started phase III trials. This concise review is intended to offer a systematic analysis of the
most promising therapeutic intervention in NASH. In conclusion, there is reasonable expectation that drug may help curb the burden
of NASH, and we look forward to obtaining solid data on their long-term safety and effectiveness. However, we should not forget
that behavioral interventions remain a mandatory background treatment, able to stop disease progression in compliant overweight/
obese patients, with results that compare favorably with - and add to - the beneficial effects of drug treatment.
REFERENCES
European Association for the Study of the Liver, European Association for the Study of Diabetes, European Association for the Study of Obesity. EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016; 64: 1388-402.
Ekstedt M, Franzen LE, Mathiesen UL, Thorelius L, Holmqvist M, Bodemar G, Kechagias S. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2006; 44: 865-73.
Ekstedt M, Hagstrom H, Nasr P, Fredrikson M, Stal P, Kechagias S, Hultcrantz R. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology 2015; 61: 1547-54.
Sasdelli AS, Brodosi L, Marchesini G. NAFLD-associated hepatocellular carcinoma: a threat to patients with metabolic disorders. Curr Hepatology Rep 2016; 15: 103-12.
Wong RJ, Aguilar M, Cheung R, Perumpail RB, Harrison SA, Younossi ZM, Ahmed A. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology 2015; 148: 547-55.
Piscaglia F, Svegliati-Baroni G, Barchetti A, Pecorelli A, Marinelli S, Tiribelli C, Bellentani S, et al. Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: A multicenter prospective study. Hepatology 2016; 63: 827-38.
Marchesini G, Marzocchi R. Metabolic syndrome and NASH. Clin Liver Dis 2007; 11: 105-17, ix.
Targher G, Day CP, Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med 2010; 363: 1341-50.
Yki-Jarvinen H. Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome. Lancet Diabetes Endocrinol 2014; 2: 901-10.
Lonardo A, Ballestri S, Marchesini G, Angulo P, Loria P. Nonalcoholic fatty liver disease: a precursor of the metabolic syndrome. Dig Liver Dis 2015; 47: 181-90.
Ratziu V, Goodman Z, Sanyal A. Current efforts and trends in the treatment of NASH. J Hepatol 2015; 62: S65-S75.
Sanyal AJ, Friedman SL, McCullough AJ, Dimick-Santos L, American Association for the Study of Liver Diseases, United States Food & Drug Administration. 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. Food and Drug Administration Joint Workshop. Hepatology 2015; 61: 1392-405.
Mazzella N, Ricciardi LM, Mazzotti A, Marchesini G. The role of medications for the management of patients with NAFLD. Clin Liver Dis 2014; 18: 73-89.
Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology 2007; 132: 2131-57.
Henry RR, Buse JB, Sesti G, Davies MJ, Jensen KH, Brett J, Pratley RE. Efficacy of antihyperglycemic therapies and the influence of baseline hemoglobin A(1C): a meta-analysis of the liraglutide development program. Endocr Pract 2011; 17: 906-13.
Ding X, Saxena NK, Lin S, Gupta NA, Anania FA. Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice. Hepatology 2006; 43: 173-81.
Mells JE, Fu PP, Sharma S, Olson D, Cheng L, Handy JA, Saxena NK, 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-G235.
Trevaskis JL, Griffin PS, Wittmer C, Neuschwander-Tetri BA, Brunt EM, Dolman CS, Erickson MR, et al. Glucagon-like peptide- 1 receptor agonism improves metabolic, biochemical, and histopathological indices of nonalcoholic steatohepatitis in mice. Am J Physiol Gastrointest Liver Physiol 2012; 302: G762-G772.
Ben-Shlomo S, Zvibel I, Shnell M, Shlomai A, Chepurko E, Halpern Z, Barzilai N, et al. Glucagon-like peptide-1 reduces hepatic lipogenesis via activation of AMP-activated protein kinase. J Hepatol 2011; 54: 1214-23.
Gupta NA, Mells J, Dunham RM, Grakoui A, Handy J, Saxena NK, Anania FA. 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: 1584-92.
Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, Hazlehurst JM, 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: 679-90.
Pi-Sunyer X, Astrup A, Fujioka K, Greenway F, Halpern A, Krempf M, Lau DC, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med 2015; 373: 11-22.
Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2016.
Hylemon PB, Zhou H, Pandak WM, Ren S, Gil G, Dent P. Bile acids as regulatory molecules. J Lipid Res 2009; 50: 1509-20.
Fiorucci S, Antonelli E, Rizzo G, Renga B, Mencarelli A, Riccardi L, Orlandi S, et al. The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis. Gastroenterology 2004; 127: 1497-512.
Adorini L, Pruzanski M, Shapiro D. Farnesoid X receptor targeting to treat nonalcoholic steatohepatitis. Drug Discov Today 2012; 17: 988-97.
Zhang Y, Kast-Woelbern HR, Edwards PA. Natural structural variants of the nuclear receptor farnesoid X receptor affect transcriptional activation. J Biol Chem 2003; 278: 104-10.
Mudaliar S, Henry RR, Sanyal AJ, Morrow L, Marschall HU, Kipnes M, Adorini L, 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: 574-82 e1.
Zhang Y, Lee FY, Barrera G, Lee H, Vales C, Gonzalez FJ, Willson TM, et al. Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proc Natl Acad Sci U S A 2006; 103: 1006-11.
Zhang Y, Edwards PA. FXR signaling in metabolic disease. FEBS Lett 2008; 582: 10-8.
Watanabe M, Houten SM, Wang L, Moschetta A, Mangelsdorf DJ, Heyman RA, Moore DD, et al. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J Clin Invest 2004; 113: 1408-18.
Savkur RS, Thomas JS, Bramlett KS, Gao Y, Michael LF, Burris TP. Ligand-dependent coactivation of the human bile acid receptor FXR by the peroxisome proliferator-activated receptor gamma coactivator-1alpha. J Pharmacol Exp Ther 2005; 312: 170-8.
Wang YD, Chen WD, Wang M, Yu D, Forman BM, Huang W. Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response. Hepatology 2008; 48: 1632-43.
Beuers U, Gershwin ME, Gish RG, Invernizzi P, Jones DE, Lindor K, Ma X, et al. Changing nomenclature for PBC: from ‘cirrhosis’ to ‘cholangitis’. Gastroenterology 2015; 149: 1627-9.
Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, Chalasani N, 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: 956-65.
Pawlak M, Lefebvre P, Staels B. Molecular mechanism of PPARalpha action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease. J Hepatol 2015; 62: 720-33.
Bojic LA, Huff MW. Peroxisome proliferator-activated receptor delta: a multifaceted metabolic player. Curr Opin Lipidol 2013; 24: 171-7.
Staels B, Rubenstrunk A, Noel B, Rigou G, Delataille P, Millatt LJ, Baron M, 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: 1941-52.
Cariou B, Hanf R, Lambert-Porcheron S, Zair Y, Sauvinet V, Noel B, Flet L, 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: 2923-30.
Cariou B, Staels B. GFT505 for the treatment of nonalcoholic steatohepatitis and type 2 diabetes. Expert Opin Investig Drugs 2014; 23: 1441-8.
Cariou B, Zair Y, Staels B, Bruckert E. Effects of the new dual PPAR alpha/delta agonist GFT505 on lipid and glucose homeostasis in abdominally obese patients with combined dyslipidemia or impaired glucose metabolism. Diabetes Care 2011; 34: 2008-14.
Ratziu V, Harrison SA, Francque S, Bedossa P, Lehert P, Serfaty L, Romero-Gomez M, 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: 1147-59 e5.
Mudaliar S, Polidori D, Zambrowicz B, Henry RR. Sodium-glucose cotransporter inhibitors: effects on renal and intestinal glucose transport: from bench to bedside. Diabetes Care 2015; 38: 2344-53.
Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373: 2117-28.
Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, Johansen OE, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016 (in press).
Yokono M, Takasu T, Hayashizaki Y, Mitsuoka K, Kihara R, Muramatsu Y, Miyoshi S, et al. SGLT2 selective inhibitor ipragliflozin reduces body fat mass by increasing fatty acid oxidation in high-fat diet-induced obese rats. Eur J Pharmacol 2014; 727: 66-74.
Hayashizaki-Someya Y, Kurosaki E, Takasu T, Mitori H, Yamazaki S, Koide K, Takakura S. Ipragliflozin, an SGLT2 inhibitor, exhibits a prophylactic effect on hepatic steatosis and fibrosis induced by choline-deficient l-amino acid-defined diet in rats. Eur J Pharmacol 2015; 754: 19-24.
Lavalle-Gonzalez FJ, Januszewicz A, Davidson J, Tong C, Qiu R, Canovatchel W, Meininger G. Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomised trial. Diabetologia 2013; 56: 2582-92.
Bailey CJ, Gross JL, Pieters A, Bastien A, List JF. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet 2010; 375: 2223-33.
Nakano S, Katsuno K, Isaji M, Nagasawa T, Buehrer B, Walker S, Wilkison WO, et al. Remogliflozin etabonate improves fatty liver disease in diet-induced obese male mice. J Clin Exp Hepatol 2015; 5: 190-8.
Wilkinson W, Cheatham B, Walker S. Remogliflozin etabonate reduces insulin resistance and liver function enzymes: role for treatment of NASH. J Hepatol 2015; 62: S211.
Barry-Hamilton V, Spangler R, Marshall D, McCauley S, Rodriguez HM, Oyasu M, Mikels A, et al. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat Med 2010; 16: 1009-17.
Hong F, Chou H, Friedman SL. Significant anti-fibrootic activity of cenicriviroc, a dual CCR2/CCR5 antagonist, in a rat model of thioacetamide-induced liver fibrosis and cirrhosis. Hepatology 2013; 58: 1381A-2A.
Lefebvre E, Moyle G, Reshef R, Richman LP, Thompson M, Hong F, Chou HL, et al. Antifibrotic effects of the dual CCR2/ CCR5 antagonist cenicriviroc in animal models of liver and kidney fibrosis. PLoS One 2016; 11: e0158156.
Thompson M, Saag M, DeJesus E, Gathe J, Lalezari J, Landay AL, Cade J, et al. A 48-week randomized phase 2b study evaluating cenicriviroc versus efavirenz in treatmentnaive HIV-infected adults with C-C chemokine receptor type 5-tropic virus. AIDS 2016; 30: 869-78.
Lefebvre E, Gottwald M, Lasseter K, Chang W, Willett M, Smith PF, Somasunderam A, et al. Pharmacokinetics, safety, and CCR2/CCR5 antagonist activity of cenicriviroc in participants with mild or moderate hepatic impairment. Clin Transl Sci 2016; 9: 139-48.
Konikoff FM, Gilat T. Effects of fatty acid bile acid conjugates (FABACs) on biliary lithogenesis: potential consequences for non-surgical treatment of gallstones. Curr Drug Targets Immune Endocr Metabol Disord 2005; 5: 171-5.
Dobrzyn A, Dobrzyn P, Lee SH, Miyazaki M, Cohen P, Asilmaz E, Hardie DG, et al. Stearoyl-CoA desaturase-1 deficiency reduces ceramide synthesis by downregulating serine palmitoyltransferase and increasing beta-oxidation in skeletal muscle. Am J Physiol Endocrinol Metab 2005; 288: E599- E607.
Goldiner I, van der Velde AE, Vandenberghe KE, van Wijland MA, Halpern Z, Gilat T, Konikoff FM, et al. ABCA1-dependent but apoA-I-independent cholesterol efflux mediated by fatty acid-bile acid conjugates (FABACs). Biochem J 2006; 396: 529-36.
Zhang Z, Dales NA, Winther MD. Opportunities and challenges in developing stearoyl-coenzyme A desaturase-1 inhibitors as novel therapeutics for human disease. J Med Chem 2014; 57: 5039-56.
Safadi R, Konikoff FM, Mahamid M, Zelber-Sagi S, Halpern M, Gilat T, Oren R, 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: 2085-91 e1.
Henderson NC, Mackinnon AC, Farnworth SL, Poirier F, Russo FP, Iredale JP, Haslett C, et al. Galectin-3 regulates myofibroblast activation and hepatic fibrosis. Proc Natl Acad Sci U S A 2006; 103: 5060-5.
Thomas C, Gioiello A, Noriega L, Strehle A, Oury J, Rizzo G, Macchiarulo A, et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab 2009; 10: 167-77.
McMahan RH, Wang XX, Cheng LL, Krisko T, Smith M, El Kasmi K, Pruzanski M, et al. Bile acid receptor activation modulates hepatic monocyte activity and improves nonalcoholic fatty liver disease. J Biol Chem 2013; 288: 11761-70.
Marchesini G, Petta S, Dalle Grave R. Diet, weight loss, and liver health in nonalcoholic fatty liver disease: Pathophysiology, evidence, and practice. Hepatology 2016; 63: 2032-43.
Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres- Gonzalez A, Gra-Oramas B, Gonzalez-Fabian L, Friedman SL, et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology 2015; 149: 367-78 e5; quiz e14-5.
Steven S, Hollingsworth KG, Al-Mrabeh A, Avery L, Aribisala B, Caslake M, Taylor R. Very-low-calorie diet and 6 months of weight stability in type 2 diabetes: pathophysiologic changes in responders and nonresponders. Diabetes Care 2016; 39: 808-15.
Centis E, Moscatiello S, Bugianesi E, Bellentani S, Fracanzani AL, Calugi S, Petta S, et al. Stage of change and motivation to healthier lifestyle in non-alcoholic fatty liver disease. J Hepatol 2013; 58: 771-7.
Marchesini G, Trovati M. Type 2 diabetes and the Naaman syndrome. Diabetes Care 2003; 26: 3195.