A diabetologist's perspective of non-alcoholic steatohepatitis (NASH): Knowledge gaps and future directions.
Journal
Liver international : official journal of the International Association for the Study of the Liver
ISSN: 1478-3231
Titre abrégé: Liver Int
Pays: United States
ID NLM: 101160857
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
25
12
2019
accepted:
26
12
2019
entrez:
21
2
2020
pubmed:
23
2
2020
medline:
22
6
2021
Statut:
ppublish
Résumé
There is a close link between steatohepatitis (NASH) and Type 2 diabetes (T2DM). Recently, the American Diabetes Association (ADA) recommended screening for NASH and advanced fibrosis in patients with diabetes and hepatic steatosis or elevated plasma alanine aminotransferase (ALT). This is because as many as ~30% to 40% may have NASH and ~10% to 15% advanced fibrosis. The role of hyperglycemia and the natural history of NASH in diabetes remain poorly understood, as well as which diagnostic algorithm or interventions are most cost-effective. There is significant clinical inertia and most patients today are still not receiving adequate lifestyle intervention or pharmacological treatment with diabetes agents known to be effective against NASH. Lifestyle intervention improves steatohepatitis in proportion to the magnitude of weight loss, but this trend is not as consistent for regression of fibrosis. This limited success supports the need for concomitant pharmacological therapy. Pioglitazone has been shown to consistently induce resolution of NASH in both patients with or without diabetes in a total of 498 participants in five randomized controlled trials (RCTs), but with modest effects on liver fibrosis. Proof-of-concept studies suggest a potential role for GLP-1RAs and SGLT2 inhibitors. Combination therapy is on the horizon. Treating diabetes and NASH with a combination of pioglitazone, GLP-1RAs or SGLT2i, could be a cost-effective strategy to treat both diseases while reducing their high cardiovascular risk. Future combination therapies will likely combine existing diabetes agents with novel NASH-spechfic drugs under development. This review highlights current knowledge gaps and proposes future directions for the treatment of NASH in diabetes.
Substances chimiques
Hypoglycemic Agents
0
Pioglitazone
X4OV71U42S
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
82-88Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Références
Zheng Y, Ley SH, Hu FB. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol. 2018;14:88-98.
Younossi ZM, Golabi P, de Avila L, et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: a systematic review and meta-analysis. J Hepatol. 2019;71:793-801.
Bril F, Ortiz-Lopez C, Lomonaco R, et al. Clinical value of liver ultrasound for the diganosis of nonalcoholic fatty liver disease in overweight and obese patients. Liver Intl. 2015;35:2139-2146.
Younossi Z, Tampi RP, Racila A, et al. Economic and clinical burden of non-alcoholic steatohepatitis (NASH) in patients with type 2 diabetes mellitus (T2DM) in the United States. Diabetes Care (in press). https://doi.org/10.2337/dc19-1113.
Targher G, Lonardo A, Byrne CD. Nonalcoholic fatty liver disease and chronic vascular complications of diabetes mellitus. Nat Rev Endocrinol. 2018;14:99-114.
Bril F, Cusi K. Management of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus: a call to action. Diabetes Care. 2017;40:419-430.
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;67:328-357.
EASL-EASD-EASO Clinical practice guidelines for the management of non-alcoholic fatty liver disease. Diabetologia. 2016;59:1121-1140.
American Diabetes Association. 4. Comprehensive medical evaluation and assessment of comorbidities: standards of medical care in diabetes 2019. Diabetes Care 2019;42(Suppl. 1):S34-S45.
Gastaldelli A, From CK. From NASH to diabetes and from diabetes to NASH: mechanisms and treatment options. JHEP Reports. 2019;1(4):312-328.
Akshintala D, Chugh R, Amer F. Nonalcoholic fatty liver disease: the overlooked complication of type 2 diabetes. In: Feingold KR, Anawalt B, Boyce A, et al, eds. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-2019. PMID: 31310460.
Tilg H, Moschen AR, Roden M. NAFLD and diabetes mellitus. Nat Rev Gastroenterol Hepatol. 2017;14:32-42.
Stefan N, Häring HU, Cusi K. Non-alcoholic fatty liver disease: causes, diagnosis, cardiometabolic consequences, and treatment strategies. Lancet Diabetes Endocrinol. 2019;7:313-324.
Younossi ZM, Loomba R, Rinella ME, et al. Current and future therapeutic regimens for nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Hepatology. 2018;68:361-371.
Bril F, Kalavalapalli S, Clark VC, et al. Response to pioglitazone in patients with nonalcoholic steatohepatitis with vs without type 2 diabetes. Clin Gastroenterol Hepatol. 2018;16:558-566.
The ACCORD Study Group. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med. 2010;15(363):233-244.
The ACCORD Study Group. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med. 2011;364:818-828.
Rinella ME, Sanyal AJ. Management of NAFLD: a stage-based approach. Nat Rev Gastroenterol Hepatol. 2016;13:196-205.
Castera L, Friedrich-Rust M, Loomba R. Noninvasive assessment of liver disease in patients with nonalcoholic fatty liver disease. Gastroenterology. 2019;156:1264-1281.
Siddiqui MS, Yamada G, Vuppalanchi R, et al. Diagnostic accuracy of noninvasive fibrosis models to detect change in fibrosis stage. Clin Gastroenterol Hepatol. 2019;17:1877-1885.
Anstee QM, Lawitz EJ, Alkhouri N, et al. Noninvasive tests accurately identify advanced fibrosis due to NASH: Baseline data from the STELLAR trials. Hepatology. 2019;70:1521-1530.
Eddowes PJ, Sasso M, Allison M, et al. Accuracy of FibroScan controlled attenuation parameter and liver stiffness measurement in assessing steatosis and fibrosis in patients with nonalcoholic fatty liver disease. Gastroenterology. 2019;156:1717-1730.
Bril F, Millán L, Kalavalapalli S, et al. Use of a metabolomic approach to non-invasively diagnose non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2018;20:1702-1709.
Bril F, Leeming DJ, Karsdal MA, et al. Use of plasma fragments of propeptides of tye III, V, and VI procollagen for the detection of liver fibrosis in type 2 diabetes. Diabetes Care. 2019;42:1348-1351.
Bril F, McPhaul MJ, Caulfield MP, et al. Performance of the SteatoTest, ActiTest, NashTest and FibroTest in a multiethnic cohort of patients with type 2 diabetes mellitus. J Investig Med. 2019;67:303-311.
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. 2019. dc191071. [Epub ahead of print].
Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362:1675-1685.
Bril F, Biernacki DM, Lomonaco R, et al. Role of vitamin E for the treatment of nonalcoholic steatohepatitis in patients with type 2 diabetes: a randomized controlled trial. Diabetes Care. 2019;42:1481-1488.
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.
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.
Aithal GP, Thomas JA, Kaye PV, et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology. 2008;135:1176-1184.
Khan R, Bril F, Cusi K, Newsome PN. Modulation of insulin resistance in NAFLD. Hepatology. 2019;70:711-724.
Cusi K. Incretin-based therapies for the management of nonalcoholic fatty liver diesease in patients with type 2 diabetes. Hepatology. 2019;69:2318-2322.
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.
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;41:1926-1937.
Avgerinos I, Michailidis T, Liakos A, et al. Oral semaglutide for type 2 diabetes: a systematic review and meta-analysis. Diabetes Obes Metab. 2019. https://doi.org/10.1111/dom.13899. [Epub ahead of print].
Giugliano D, Maiorino MI, Bellastella G, Chiodini P, Esposito K. Glycemic control, preexisting cardiovascular disease, and risk of major cardiovascular events in patients with type 2 diabetes mellitus: systematic review with meta-analysis of cardiovascular outcome trials and intensive glucose control trials. J Am Heart Assoc. 2019;18(8):e012356.
Jojima T, Tomotsune T, Iijima T, Akimoto K, Suzuki K, Aso Y. Empagliflozin (an SGLT2 inhibitor), alone or in combination with linagliptin (a DPP-4 inhibitor), prevents steatohepatitis in a novel mouse model of non-alcoholic steatohepatitis and diabetes. Diabetol Metab Syndr. 2016;8:45.
Nishimura N, Kitade M, Noguchi R, et al. Ipragliflozin, a sodiumglucose cotransporter 2 inhibitor, ameliorates the development of liver fibrosis in diabetic Otsuka long-Evans Tokushima fatty rats. J Gastroenterol. 2016;51:1141-1149.
Ohta A, Kato H, Ishii S, et al. Ipragliflozin, a sodium glucose cotransporter 2 inhibitor, reduces intrahepatic lipid content and abdominal visceral fat volume in patients with type 2 diabetes. Expert Opin Pharmacother. 2017;18:1433-1438.
Shibuya T, Fushimi N, Kawai M, et al. Luseogliflozin improves liver fat deposition compared to metformin in type 2 diabetes patients with non-alcoholic fattyliver disease: a prospective randomized controlled pilot study. Diabetes Obes Metab. 2018;20:438-442.
Kuchay MS, Krishan S, Mishra SK, et al. Effect of empagliflozin on liver fat in patients with type 2 diabetes and nonalcoholic fatty liver disease: a randomized controlled trial (E-LIFT Trial). Diabetes Care. 2018;41:1801-1808.
Bolinder J, Ljunggren Ö, Kullberg J, et al. Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin. J Clin Endocrinol Metab. 2012;97:1020-1031.
Eriksson JW, Lundkvist P, Jansson P-A, et al. Effects of dapagliflozin and n-3 carboxylic acids on non-alcoholic fatty liver disease in people with type 2 diabetes: a double-blind randomised placebo-controlled study. Diabetologia. 2018;61:1923-1934.
Cusi K, Bril F, Barb D, et al. Effect of canagliflozin treatment on hepatic triglyceride content and glucose metabolism in patients with type 2 diabetes. Diabetes Obes Metab. 2019;21:812-821.
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;42:931-937.
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. 2019. dc190641. [Epub ahead of print].
Bril F, Barb D, Lomonaco R, Lai J, Cusi K. Change in hepatic fat content measured by MRI does not predict treatment-induced histological improvement of steatohepatitis. J Hepatol. 2019: S0168-8278(19)30584-7. [Epub ahead of print].
Akuta N, Kawamura Y, Watanabe C, et al. Impact of sodium glucose cotransporter 2 inhibitor on histological features and glucose metabolism of non-alcoholic fatty liver disease complicated by diabetes mellitus. Hepatol Res. 2019;49:531-539.
Seko Y, Nishikawa T, Umemura A, et al. Efficacy and safety of canagliflozin in type 2 diabetes mellitus patients with biopsy-proven nonalcoholic steatohepatitis classified as stage 1-3 fibrosis. Diabetes Metab Syndr Obes. 2018;11:835-843.
Lai LL, Vethakkan SR, Nik Mustapha NR, Mahadeva S, Chan W-K. Empagliflozin for the treatment of nonalcoholic steatohepatitis in patients with type 2 diabetes mellitus. Dig Dis Sci. 2019 https://doi.org/10.1007/s10620-019-5477-1. [Epub ahead of print].
Smits MM, Tonneijck L, Muskiet MHA, et al. Twelve week liraglutide or sitagliptin does not affect hepatic fat in type 2 diabetes: a randomised placebo-controlled trial. Diabetologia. 2016;59:2588-2593.
Vanderheiden A, Harrison LB, Warshauer JT, et al. Mechanisms of action of liraglutide in patients with type 2 diabetes treated with high-dose nsulin. J Clin Endocrinol Metab. 2016;101:1798-1806.
Frøssing S, Nylander M, Chabanova E, et al. Effect of liraglutide on ectopic fat in polycystic ovary syndrome: a randomized clinical trial. Diabetes Obes Metab. 2018;20:215-218.
Cui J, Philo L, Nguyen P, et al. Sitagliptin vs. placebo for non-alcoholic fatty liver disease: a randomized controlled trial. J Hepatology. 2016;65:369-376.
Joy TR, McKenzie CA, Tirona RG, et al. Sitagliptin in patients with non-alcoholic steatohepatitis: a randomized, placebo-controlled trial. World J Gastroenterol. 2017;23:141-150.
Macauley M, Hollingsworth KG, Smith FE, et al. Effect of vildagliptin on hepatic steatosis. J Clin Endocrinol Metab. 2015;100:1578-1585.