Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Emerging therapeutic approaches for the treatment of NAFLD and type 2 diabetes mellitus

Nature Reviews Endocrinology volume 17, pages 484–495 (2021)Cite this article

Subjects

Abstract

Non-alcoholic fatty liver disease (NAFLD) has emerged as the most prevalent liver disease in the world, yet there are still no approved pharmacological therapies to prevent or treat this condition. NAFLD encompasses a spectrum of severity, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). Although NASH is linked to an increased risk of hepatocellular carcinoma and cirrhosis and has now become the leading cause of liver failure-related transplantation, the majority of patients with NASH will ultimately die as a result of complications of type 2 diabetes mellitus (T2DM) and cardiometabolic diseases. Importantly, NAFLD is closely linked to obesity and tightly interrelated with insulin resistance and T2DM. Thus, targeting these interconnected conditions and taking a holistic attitude to the treatment of metabolic disease could prove to be a very beneficial approach. This Review will explore the latest relevant literature and discuss the ongoing therapeutic options for NAFLD focused on targeting intermediary metabolism, insulin resistance and T2DM to remedy the global health burden of these diseases.

Key points

  • Non-alcoholic fatty liver disease (NAFLD) has become the most common liver disease globally, yet there are currently no approved therapies.

  • While NAFLD progression to non-alcoholic steatohepatitis is becoming the leading cause of end-stage liver failure, the leading causes of death in patients with NAFLD are complications of cardiometabolic disease.

  • A tight relationship exists between NAFLD, insulin resistance and type 2 diabetes mellitus.

  • It is likely that developing therapeutics that target both NAFLD and cardiometabolic risk factors might be extremely beneficial.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The pathological spectrum of NAFLD.
Fig. 2: Role of insulin resistance in NAFLD.
Fig. 3: Targeting of intermediary metabolism for NAFLD therapy.

Similar content being viewed by others

References

  1. Younossi, Z. M. et al. Global epidemiology of nonalcoholic fatty liver disease — Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 64, 73–84 (2016).

    Article  PubMed  Google Scholar 

  2. Younossi, Z. M. et al. The economic and clinical burden of nonalcoholic fatty liver disease in the United States and Europe. Hepatology 64, 1577–1586 (2016).

    Article  PubMed  Google Scholar 

  3. Vilar-Gomez, E. et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology 149, 367–378 (2015).

    Article  PubMed  Google Scholar 

  4. Chalasani, N. et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology 67, 328–357 (2018).

    Article  PubMed  Google Scholar 

  5. Younossi, Z. M. et al. Epidemiology of chronic liver diseases in the USA in the past three decades. Gut 69, 564–568 (2020).

    Article  PubMed  Google Scholar 

  6. Lonardo, A. et al. Sex differences in nonalcoholic fatty liver disease: state of the art and identification of research gaps. Hepatology 70, 1457–1469 (2019).

    Article  CAS  PubMed  Google Scholar 

  7. Yang, J. D. et al. Gender and menopause impact severity of fibrosis among patients with nonalcoholic steatohepatitis. Hepatology 59, 1406–1414 (2014).

    Article  CAS  PubMed  Google Scholar 

  8. DiStefano, J. K. NAFLD and NASH in postmenopausal women: implications for diagnosis and treatment. Endocrinology 161, bqaa134 (2020).

    Article  PubMed  Google Scholar 

  9. Sanyal, A. J. et al. The natural history of advanced fibrosis due to nonalcoholic steatohepatitis: data from the simtuzumab trials. Hepatology 70, 1913–1927 (2019).

    Article  CAS  PubMed  Google Scholar 

  10. Sheka, A. C. et al. Nonalcoholic steatohepatitis: a review. JAMA 323, 1175–1183 (2020).

    Article  CAS  PubMed  Google Scholar 

  11. Younossi, Z. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat. Rev. Gastroenterol. Hepatol. 15, 11–20 (2018).

    Article  PubMed  Google Scholar 

  12. Ivanics, T., Abreu, P., De Martin, E. & Sapisochin, G. Changing trends in liver transplantation: challenges and solutions. Transplantation 105, 743–756 (2021).

    Article  PubMed  Google Scholar 

  13. Donnelly, K. L. et al. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J. Clin. Invest. 115, 1343–1351 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Fabbrini, E. et al. Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease. Gastroenterology 134, 424–431 (2008).

    Article  CAS  PubMed  Google Scholar 

  15. Korenblat, K. M., Fabbrini, E., Mohammed, B. S. & Klein, S. Liver, muscle, and adipose tissue insulin action is directly related to intrahepatic triglyceride content in obese subjects. Gastroenterology 134, 1369–1375 (2008).

    Article  CAS  PubMed  Google Scholar 

  16. Smith, G. I. et al. Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease. J. Clin. Invest. 130, 1453–1460 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lambert, J. E., Ramos-Roman, M. A., Browning, J. D. & Parks, E. J. Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease. Gastroenterology 146, 726–735 (2014).

    Article  CAS  PubMed  Google Scholar 

  18. Samuel, V. T. & Shulman, G. I. Nonalcoholic fatty liver disease as a nexus of metabolic and hepatic diseases. Cell Metab. 27, 22–41 (2018).

    Article  CAS  PubMed  Google Scholar 

  19. Koliaki, C. Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis. Cell Metab. 21, 739–746 (2015).

    Article  CAS  PubMed  Google Scholar 

  20. Cable, E. E. et al. Reduction of hepatic steatosis in rats and mice after treatment with a liver-targeted thyroid hormone receptor agonist. Hepatology 49, 407–417 (2009).

    Article  CAS  PubMed  Google Scholar 

  21. Cheng, H. S. et al. Exploration and development of PPAR modulators in health and disease: an update of clinical evidence. Int. J. Mol. Sci. 20, 5055 (2019).

    Article  CAS  PubMed Central  Google Scholar 

  22. McCommis, K. S. et al. Targeting the mitochondrial pyruvate carrier attenuates fibrosis in a mouse model of nonalcoholic steatohepatitis. Hepatology 65, 1543–1556 (2017).

    Article  CAS  PubMed  Google Scholar 

  23. Petersen, M. C. & Shulman, G. I. Mechanisms of insulin action and insulin resistance. Physiol. Rev. 98, 2133–2223 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Samuel, V. T. & Shulman, G. I. Nonalcoholic fatty liver disease, insulin resistance, and ceramides. N. Eng. J. Med. 381, 1866–1869 (2019).

    Article  Google Scholar 

  25. Rinella, M. E. Nonalcoholic fatty liver disease: a systematic review. JAMA 313, 2263–2273 (2015).

    Article  CAS  PubMed  Google Scholar 

  26. Marra, F. & Svegliati-Baroni, G. Lipotoxicity and the gut-liver axis in NASH pathogenesis. J. Hepatol. 68, 280–295 (2018).

    Article  CAS  PubMed  Google Scholar 

  27. Kubes, P. & Jenne, C. Immune responses in the liver. Ann. Rev. Immunol. 36, 247–277 (2018).

    Article  CAS  Google Scholar 

  28. Tsuchida, T. & Friedman, S. L. Mechanisms of hepatic stellate cell activation. Nat. Rev. Gastroenterol. Hepatol. 14, 397–411 (2017).

    Article  CAS  PubMed  Google Scholar 

  29. Schwabe, R. F., Tabas, I. & Pajvani, U. B. Mechanisms of fibrosis development in nonalcoholic steatohepatitis. Gastroenterology 158, 1913–1928 (2020).

    Article  CAS  PubMed  Google Scholar 

  30. Angulo, P. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 149, 389–397 (2015).

    Article  PubMed  Google Scholar 

  31. Taylor, R. S. et al. Association between fibrosis stage and outcomes of patients with nonalcoholic fatty liver disease: a systematic review and meta-analysis. Gastroenterology 58, 1611–1625 (2020).

    Article  Google Scholar 

  32. Rinella, M. E., Tacke, F., Sanyal, A. J. & Anstee, Q. M. Report on the AASLD/EASL joint workshop on clinical trial endpoints in NAFLD. J. Hepatol. 71, 823–833 (2019).

    Article  PubMed  Google Scholar 

  33. Davison, B. A. et al. Suboptimal reliability of liver biopsy evaluation has implications for randomized clinical trials. J. Hepatol. 73, 1322–1332 (2020).

    Article  CAS  PubMed  Google Scholar 

  34. Cotter, T. G. & Rinella, M. Nonalcoholic fatty liver disease 2020: the state of the disease. Gastroenterology 158, 1851–1864 (2020).

    Article  CAS  PubMed  Google Scholar 

  35. Zheng, Y., Ley, S. H. & Hu, F. B. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat. Rev. Endocrinol. 14, 88–98 (2018).

    Article  PubMed  Google Scholar 

  36. Kleiner, D. E. et al. Association of histologic disease activity with progression of nonalcoholic fatty liver disease. JAMA Netw. Open. 2, e1912565 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Alexander, M. et al. Risks and clinical predictors of cirrhosis and hepatocellular carcinoma diagnoses in adults with diagnosed NAFLD: real-world study of 18 million patients in four European cohorts. BMC Med. 17, 95 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Yang, J. D. et al. Diabetes is associated with increased risk of hepatocellular carcinoma in patients with cirrhosis from nonalcoholic fatty liver disease. Hepatology 71, 907–916 (2020).

    Article  CAS  PubMed  Google Scholar 

  39. Lomonaco, R. et al. Metabolic impact of nonalcoholic steatohepatitis in obese patients with type 2 diabetes. Diabetes Care 39, 632–638 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Musso, G. et al. Nonalcoholic steatohepatitis versus steatosis: adipose tissue insulin resistance and dysfunctional response to fat ingestion predict liver injury and altered glucose and lipoprotein metabolism. Hepatology 56, 933–942 (2012).

    Article  CAS  PubMed  Google Scholar 

  41. De Silva, N. M. G. et al. Liver function and risk of type 2 diabetes: bidirectional mendelian randomization study. Diabetes 68, 1681–1691 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Mantovani, A., Byrne, C. D., Bonora, E. & Targher, G. Nonalcoholic fatty liver disease and risk of incident type 2 diabetes: a meta-analysis. Diabetes Care 41, 372–382 (2018).

    Article  CAS  PubMed  Google Scholar 

  43. Younossi, Z. M. et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: a systematic review and meta-analysis. J. Hepatol. 71, 793–801 (2019).

    Article  PubMed  Google Scholar 

  44. Cusi, K. Time to include nonalcoholic steatohepatitis in the management of patients with type 2 diabetes. Diabetes Care 43, 275–279 (2020).

    Article  PubMed  Google Scholar 

  45. Noureddin, M. et al. Screening for non-alcoholic fatty liver disease in persons with type 2 diabetes in the U.S. is cost effective: a comprehensive cost-utility analysis. Gastroenterology 159, 1985–1987 (2020).

    Article  PubMed  Google Scholar 

  46. Low Wang, C. C., Hess, C. N., Hiatt, W. R. & Goldfine, A. B. Clinical update: cardiovascular disease in diabetes mellitus: atherosclerotic cardiovascular disease and heart failure in type 2 diabetes mellitus — mechanisms, management, and clinical considerations. Circulation 133, 2459–2502 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Selvin, E. et al. Glycated hemoglobin, diabetes, and cardiovascular risk in nondiabetic adults. N. Eng. J. Med. 362, 800–811 (2010).

    Article  CAS  Google Scholar 

  48. Ghosh-Swaby, O. R. et al. Glucose-lowering drugs or strategies, atherosclerotic cardiovascular events, and heart failure in people with or at risk of type 2 diabetes: an updated systematic review and meta-analysis of randomised cardiovascular outcome trials. Lancet Diabetes Endocrinol. 8, 418–435 (2020).

    Article  CAS  PubMed  Google Scholar 

  49. Byrne, C. D. & Targher, G. NAFLD as a driver of chronic kidney disease. J. Hepatol. 72, 785–801 (2020).

    Article  PubMed  Google Scholar 

  50. Vilar-Gomez, E. et al. Improvement in liver histology due to lifestyle modification is independently associated with improved kidney function in patients with non-alcoholic steatohepatitis. Aliment. Pharmacol. Ther. 45, 332–344 (2017).

    Article  CAS  PubMed  Google Scholar 

  51. Eslam, M., Sanyal, A. J. & George, J. MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease. Gastroenterology 158, 1999–2014 (2020).

    Article  CAS  PubMed  Google Scholar 

  52. Tilg, H. & Effenberger, M. From NAFLD to MAFLD: when pathophysiology succeeds. Nat. Rev. Gastroenterol. Hepatol. 17, 387–388 (2020).

    Article  PubMed  Google Scholar 

  53. Younossi, Z. M. et al. From NAFLD to MAFLD: implications of a premature change in terminology. Hepatology 73, 1194–1198 (2021).

    Article  PubMed  Google Scholar 

  54. Gimeno, R. E., Briere, D. A. & Seeley, R. J. Leveraging the gut to treat metabolic disease. Cell Metab. 31, 679–698 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Young, A. A. et al. Glucose-lowering and insulin-sensitizing actions of exendin-4: studies in obese diabetic (ob/ob, db/db) mice, diabetic fatty Zucker rats, and diabetic rhesus monkeys (Macaca mulatta). Diabetes 48, 1026–1034 (1999).

    Article  CAS  PubMed  Google Scholar 

  56. Tølbøl, K. S. et al. Metabolic and hepatic effects of liraglutide, obeticholic acid and elafibranor in diet-induced obese mouse models of biopsy-confirmed nonalcoholic steatohepatitis. World J. Gastroenterol. 24, 179–194 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Dutour, A. 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. 18, 882–891 (2016).

    Article  CAS  PubMed  Google Scholar 

  58. Armstrong, M. J. et al. Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis. J. Hepatol. 64, 399–408 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Armstrong, M. J. et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 387, 679–690 (2016).

    Article  CAS  PubMed  Google Scholar 

  60. Newsome, P. et al. Effect of semaglutide on liver enzymes and markers of inflammation in subjects with type 2 diabetes and/or obesity. Aliment. Pharmacol. Ther. 50, 193–203 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Newsome, P. N. et al. A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis. N. Eng. J. Med. 384, 1113–1124 (2021).

    Article  CAS  Google Scholar 

  62. Muller, T. D. et al. Glucagon-like peptide 1 (GLP-1). Mol. Metab. 30, 72–130 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Ferrannini, E. Sodium-glucose co-transporters and their inhibition: clinical physiology. Cell Metab. 26, 27–38 (2017).

    Article  CAS  PubMed  Google Scholar 

  64. Watt, M. J., Miotto, P. M., De Nardo, W. & Montgomery, M. K. The liver as an endocrine organ-linking NAFLD and insulin resistance. Endocr. Rev. 40, 1367–1393 (2019).

    Article  PubMed  Google Scholar 

  65. Williams, K. H. et al. Circulating dipeptidyl peptidase-4 activity correlates with measures of hepatocyte apoptosis and fibrosis in non-alcoholic fatty liver disease in type 2 diabetes mellitus and obesity: a dual cohort cross-sectional study. J. Diabetes 7, 809–819 (2015).

    Article  CAS  PubMed  Google Scholar 

  66. Kawakubo, M. et al. Dipeptidyl peptidase-4 inhibition prevents nonalcoholic steatohepatitis-associated liver fibrosis and tumor development in mice independently of its anti-diabetic effects. Sci. Rep. 10, 983 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Cui, J. et al. Sitagliptin vs. placebo for non-alcoholic fatty liver disease: a randomized controlled trial. J. Hepatol. 65, 369–376 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Joy, T. R. et al. Sitagliptin in patients with non-alcoholic steatohepatitis: a randomized, placebo-controlled trial. World J. Gastroenterol. 23, 141–150 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Gross, B., Pawlak, M., Lefebvre, P. & Staels, B. PPARs in obesity-induced T2DM, dyslipidaemia and NAFLD. Nat. Rev. Endocrinol. 13, 36–49 (2017).

    Article  CAS  PubMed  Google Scholar 

  70. Mayerson, A. B. et al. The effects of rosiglitazone on insulin sensitivity, lipolysis, and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes. Diabetes 51, 797 (2002).

    Article  CAS  PubMed  Google Scholar 

  71. Galli, A. et al. Antidiabetic thiazolidinediones inhibit collagen synthesis and hepatic stellate cell activation in vivo and in vitro. Gastroenterology 122, 1924–1940 (2002).

    Article  CAS  PubMed  Google Scholar 

  72. Musso, G., Cassader, M., Paschetta, E. & Gambino, R. Thiazolidinediones and advanced liver fibrosis in nonalcoholic steatohepatitis: a meta-analysis. JAMA Inter. Med. 177, 633–640 (2017).

    Article  Google Scholar 

  73. Nissen, S. E. & Wolski, K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N. Eng. J. Med. 356, 2457–2471 (2007).

    Article  CAS  Google Scholar 

  74. Hickson, R. P., Cole, A. L. & Dusetzina, S. B. Implications of removing rosiglitazone’s black box warning and restricted access program on the uptake of thiazolidinediones and dipeptidyl peptidase-4 inhibitors among patients with type 2 diabetes. J. Manag. Care Spec. Pharm. 25, 72–79 (2019).

    PubMed  PubMed Central  Google Scholar 

  75. Lehmann, J. M. et al. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J. Biol. Chem. 270, 12953–12956 (1995).

    Article  CAS  PubMed  Google Scholar 

  76. Ratziu, V. et al. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial. Gastroenterology 135, 100–110 (2008).

    Article  CAS  PubMed  Google Scholar 

  77. Neuschwander-Tetri, B. A., Brunt, E. M., Wehmeier, K. R., Oliver, D. & Bacon, B. R. Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone. Hepatology 38, 1008–1017 (2003).

    Article  CAS  PubMed  Google Scholar 

  78. Juurlink, D. N. et al. Adverse cardiovascular events during treatment with pioglitazone and rosiglitazone: population based cohort study. BMJ 339, b2942 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Belfort, R. et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N. Eng. J. Med. 355, 2297–2307 (2006).

    Article  CAS  Google Scholar 

  80. Sanyal, A. J. et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N. Engl. J. Med. 362, 1675–1685 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Cusi, K. et al. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus a randomized trial. Ann. Inter. Med. 165, 305–315 (2016).

    Article  Google Scholar 

  82. Boettcher, E., Csako, G., Pucino, F., Wesley, R. & Loomba, R. Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis. Aliment. Pharmacol. Ther. 35, 66–75 (2012).

    Article  CAS  PubMed  Google Scholar 

  83. Kawaguchi-Suzuki, M., Bril, F., Kalavalapalli, S., Cusi, K. & Frye, R. F. Concentration-dependent response to pioglitazone in nonalcoholic steatohepatitis. Aliment. Pharmacol. Ther. 46, 56–61 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Kawaguchi-Suzuki, M. et al. A genetic score associates with pioglitazone response in patients with non-alcoholic steatohepatitis. Front. Pharmacol. 9, 752 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Colca, J. R. et al. Identification of a mitochondrial target of thiazolidinedione insulin sensitizers (mTOT)–relationship to newly identified mitochondrial pyruvate carrier proteins. PLoS One 8, e61551 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Heerspink, H. J., Perkins, B. A., Fitchett, D. H., Husain, M. & Cherney, D. Z. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications. Circulation 134, 752–772 (2016).

    Article  CAS  PubMed  Google Scholar 

  87. Tahara, A., Takasu, T., Yokono, M., Imamura, M. & Kurosaki, E. Characterization and comparison of SGLT2 inhibitors: part 3. Effects on diabetic complications in type 2 diabetic mice. Eur. J. Pharmacol. 809, 163–171 (2017).

    Article  CAS  PubMed  Google Scholar 

  88. Cusi, K. et al. Effect of canagliflozin treatment on hepatic triglyceride content and glucose metabolism in patients with type 2 diabetes. Diabetes Obes. Metab. 21, 812–821 (2019).

    Article  CAS  PubMed  Google Scholar 

  89. Latva-Rasku, A. 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 42, 931–937 (2019).

    Article  CAS  PubMed  Google Scholar 

  90. Shimizu, M. et al. Evaluation of the effects of dapagliflozin, a sodium-glucose co-transporter-2 inhibitor, on hepatic steatosis and fibrosis using transient elastography in patients with type 2 diabetes and non-alcoholic fatty liver disease. Diabetes Obes. Metab. 21, 285–292 (2019).

    Article  CAS  PubMed  Google Scholar 

  91. Kahl, S. 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 43, 298–305 (2020).

    Article  CAS  PubMed  Google Scholar 

  92. Kuchay, M. S. 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 41, 1801–1808 (2018).

    Article  CAS  PubMed  Google Scholar 

  93. Bajaj, H. S. et al. SGLT2 inhibitors and incretin agents: associations with alanine aminotransferase activity in type 2 diabetes. Diabetes Metab. 44, 493–499 (2018).

    Article  CAS  PubMed  Google Scholar 

  94. Ueda, P. et al. Sodium glucose cotransporter 2 inhibitors and risk of serious adverse events: nationwide register based cohort study. BMJ 363, k4365 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Loomba, R. 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 61, 1239–1250 (2015).

    Article  CAS  PubMed  Google Scholar 

  96. Li, P. et al. Hematopoietic-derived galectin-3 causes cellular and systemic insulin resistance. Cell 167, 973–984 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Wang, Z., Park, H. & Bae, E. J. Efficacy of evogliptin and cenicriviroc against nonalcoholic steatohepatitis in mice: a comparative study. Korean J. Physiol. Pharmacol. 23, 459–466 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Ahmad, T. R. & Haeusler, R. A. Bile acids in glucose metabolism and insulin signalling — mechanisms and research needs. Nat. Rev. Endocrinol. 15, 701–712 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Puri, P. et al. The presence and severity of nonalcoholic steatohepatitis is associated with specific changes in circulating bile acids. Hepatology 67, 534–548 (2018).

    Article  CAS  PubMed  Google Scholar 

  100. Beraza, N. et al. Nor-ursodeoxycholic acid reverses hepatocyte-specific nemo-dependent steatohepatitis. Gut 60, 387–396 (2011).

    Article  CAS  PubMed  Google Scholar 

  101. Traussnigg, S. et al. Norursodeoxycholic acid versus placebo in the treatment of non-alcoholic fatty liver disease: a double-blind, randomised, placebo-controlled, phase 2 dose-finding trial. Lancet Gastroenterol. Hepatol. 4, 781–793 (2019).

    Article  PubMed  Google Scholar 

  102. Zhang, Y. et al. Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proc. Natl Acad. Sci. USA 103, 1006–1011 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Watanabe, M. Lowering bile acid pool size with a synthetic farnesoid X receptor (FXR) agonist induces obesity and diabetes through reduced energy expenditure. J. Biol. Chem. 286, 26913–26920 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Mudaliar, S. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 145, 574–582 (2013).

    Article  CAS  PubMed  Google Scholar 

  105. Neuschwander-Tetri, B. A. et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 385, 956–965 (2015).

    Article  CAS  PubMed  Google Scholar 

  106. Younossi, Z. M. et al. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 394, 2184–2196 (2019).

    Article  CAS  PubMed  Google Scholar 

  107. Loomba, R. et al. Multicenter validation of association between decline in MRI-PDFF and histologic response in nonalcoholic steatohepatitis. Hepatology 72, 1219–1229 (2020).

    Article  CAS  PubMed  Google Scholar 

  108. Loomba, R. et al. Factors associated with histologic response in adult patients with nonalcoholic steatohepatitis. Gastroenterology 156, 88–95 (2019).

    Article  PubMed  Google Scholar 

  109. Hernandez, E. D. et al. Tropifexor-mediated abrogation of steatohepatitis and fibrosis is associated with the antioxidative gene expression profile in rodents. Hepatol. Commun. 3, 1085–1097 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. An, P. et al. A novel non-bile acid FXR agonist EDP-305 potently suppresses liver injury and fibrosis without worsening of ductular reaction. Liver Int. 40, 1655–1669 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Patel, K. et al. Cilofexor, a nonsteroidal FXR agonist, in patients with noncirrhotic NASH: a phase 2 randomized controlled trial. Hepatology 72, 58–71 (2020).

    Article  CAS  PubMed  Google Scholar 

  112. Fang, S. et al. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat. Med. 21, 159–165 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Staels, 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 58, 1941–1952 (2013).

    Article  CAS  PubMed  Google Scholar 

  114. Cariou, B. et al. Dual peroxisome proliferator-activated receptor α/δ agonist GFT505 improves hepatic and peripheral insulin sensitivity in abdominally obese subjects. Diabetes Care 36, 2923–2930 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Ratziu, V. et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology 150, 1147–1159 (2016).

    Article  CAS  PubMed  Google Scholar 

  116. Genfit. GENFIT: Announces Results from Interim Analysis of RESOLVE-IT Phase 3 Trial of Elafibranor in Adults with NASH and Fibrosis https://ir.genfit.com/news-releases/news-release-details/genfit-announces-results-interim-analysis-resolve-it-phase-3 (2020).

  117. Wettstein, G. et al. The new-generation pan-peroxisome proliferator-activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis. Hepatol. Commun. 1, 524–537 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Inventiva. Inventiva’s lanifibranor meets the primary and key secondary endpoints in the Phase IIb NATIVE clinical trial in non-alcoholic steatohepatitis (NASH) https://inventivapharma.com/inventivas-lanifibranor-meets-the-primary-and-key-secondary-endpoints-in-the-phase-iib-native-clinical-trial-in-non-alcoholic-steatohepatitis-nash/ (2020).

  119. Jain, M. R. et al. Dual PPARα/γ agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models. Liver Int. 38, 1084–1094 (2018).

    Article  CAS  PubMed  Google Scholar 

  120. Jain, N. et al. Effect of a dual PPAR α/γ agonist on insulin sensitivity in patients of type 2 diabetes with hypertriglyceridemia- randomized double-blind placebo-controlled trial. Sci. Rep. 9, 19017 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Sinha, R. A., Singh, B. K. & Yen, P. M. Direct effects of thyroid hormones on hepatic lipid metabolism. Nat. Rev. Endocrinol. 14, 259–269 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Wikström, L. et al. Abnormal heart rate and body temperature in mice lacking thyroid hormone receptor alpha 1. EMBO J. 17, 455–461 (1998).

    Article  PubMed  PubMed Central  Google Scholar 

  123. Harrison, S. A. et al. Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 394, 2012–2024 (2019).

    Article  CAS  PubMed  Google Scholar 

  124. Zhou, J. et al. A liver-specific thyromimetic, vk2809, decreases hepatosteatosis in glycogen storage disease type Ia. Thyroid 29, 1158–1167 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Loomba, R. et al. VK2809, a novel liver-directed thyroid receptor beta agonist, significantly reduces liver fat with both low and high doses in patients with non-alcoholic fatty liver disease: a phase 2 randomized, placebo-controlled trial. J. Hepatol. 70, e150–e151 (2019).

    Article  Google Scholar 

  126. Kim, C. W. et al. Acetyl CoA carboxylase inhibition reduces hepatic steatosis but elevates plasma triglycerides in mice and humans: a bedside to bench investigation. Cell Metab. 26, 394–406 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Harriman, G. et al. Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats. Proc. Natl Acad. Sci. USA 113, E1796–E1805 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Loomba, R. et al. GS-0976 reduces hepatic steatosis and fibrosis markers in patients with nonalcoholic fatty liver disease. Gastroenterology 155, 1463–1473 (2018).

    Article  CAS  PubMed  Google Scholar 

  129. Lawitz, E. J. et al. Acetyl-CoA carboxylase inhibitor GS-0976 for 12 weeks reduces hepatic de novo lipogenesis and steatosis in patients with nonalcoholic steatohepatitis. Clin. Gastroenterol. Hepatol. 16, 1983–1991 (2018).

    Article  CAS  PubMed  Google Scholar 

  130. Esler, W. et al. Partial inhibition of de novo lipogenesis with the acetyl-CoA carboxylase inhibitor PF-05221304 does not increase circulating triglycerides in humans and is sufficient to lower steatosis in rats. J. Hepatol. 70, e69 (2019).

    Article  Google Scholar 

  131. Amin, N. et al. PF-05221304 (PF’1304), a liver-targeted acetylcoa carboxylase inhibitor (ACCI), in adults with nonalcoholic fatty liver disease (NAFLD) demonstrates robust reductions in liver fat and alt-phase 2a, dose-ranging study. Hepatology 70 (Suppl. 1), 21A–22A (2019).

    Google Scholar 

  132. Wu, M. et al. Antidiabetic and antisteatotic effects of the selective fatty acid synthase (FAS) inhibitor platensimycin in mouse models of diabetes. Proc. Natl Acad. Sci. USA 108, 5378–5383 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Syed-Abdul, M. M. et al. First-in-class fatty acid synthase inhibitor TVB-2640 reduces hepatic de novo lipogenesis in males with metabolic abnormalities. Hepatology 72, 103–118 (2020).

    Article  CAS  PubMed  Google Scholar 

  134. Sagimet. Sagimet announces positive topline results in 12-week nash phase 2 clinical trial of FASN inhibitor TVB-2640 https://sagimet.com/sagimet-announces-positive-topline-results-in-12-week-nash-phase-2-clinical-trial-of-fasn-inhibitor-tvb-2640/ (2020).

  135. Aljohani, A. M., Syed, D. N. & Ntambi, J. M. Insights into stearoyl-CoA desaturase-1 regulation of systemic metabolism. Trends Endocrinol. Metab. 28, 831–842 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Kotronen, A. et al. Hepatic stearoyl-CoA desaturase (SCD)-1 activity and diacylglycerol but not ceramide concentrations are increased in the nonalcoholic human fatty liver. Diabetes 58, 203–208 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Gutiérrez-Juárez, R. et al. Critical role of stearoyl-CoA desaturase-1 (SCD1) in the onset of diet-induced hepatic insulin resistance. J. Clin. Invest. 116, 1686–1695 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Iruarrizaga-Lejarreta, M. et al. Role of Aramchol in steatohepatitis and fibrosis in mice. Hepatol. Commun. 1, 911–927 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Safadi, R. et al. The fatty acid-bile acid conjugate Aramchol reduces liver fat content in patients with nonalcoholic fatty liver disease. Clin. Gastroenterol. Hepatol. 12, 2085–2091 (2014).

    Article  CAS  PubMed  Google Scholar 

  140. Ratziu, V., Ladron-De-Guevara, L., Safadi, R. & Poordad, F. One-year results of the global phase 2b randomized placebo-controlled arrest trial of aramchol, a stearoyl CoA desaturase inhibitor, in patients with nash. Hepatology 68, 1448A–1449A (2018).

    Google Scholar 

  141. Yen, C. L. E., Stone, S. J., Koliwad, S., Harris, C. & Farese, R. V. Jr DGAT enzymes and triacylglycerol biosynthesis. J. Lipid Res. 49, 2283–2301 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Yamaguchi, K. et al. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology 45, 1366–1374 (2007).

    Article  CAS  PubMed  Google Scholar 

  143. Gluchowski, N. L. et al. Hepatocyte deletion of triglyceride-synthesis enzyme acyl CoA: diacylglycerol acyltransferase 2 reduces steatosis without increasing inflammation or fibrosis in mice. Hepatology 70, 1972–1985 (2019).

    Article  CAS  PubMed  Google Scholar 

  144. Loomba, R. et al. An international, randomized, placebo-controlled phase 2 trial demonstrates novel effects of DGAT2 antisense inhibition in reducing steatosis without causing hypertriglyceridemia in T2DM patients. J. Hepatol. 70, e67–e68 (2019).

    Article  Google Scholar 

  145. Loomba, R. et al. Novel antisense inhibition of diacylglycerol O-acyltransferase 2 for treatment of non-alcoholic fatty liver disease: a multicentre, double-blind, randomised, placebo-controlled phase 2 trial. Lancet Gastroenterol. Hepatol. 5, 829–838 (2020).

    Article  PubMed  Google Scholar 

  146. Saxena, A., Chidsey, K., Somayaji, V., Ogden, A. & Duvvuri, S. Diacylglycerol acyltransferase 2 (DGAT2) inhibitor PF-06865571 reduces liver fat by MRI-PDFF after 2 weeks in adults with NAFLD. Hepatology 70 (Suppl. 1), 1260A (2019).

    Google Scholar 

  147. Jang, C. et al. The small intestine shields the liver from fructose-induced steatosis. Nat. Metab. 2, 586–593 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Andres-Hernando, A. et al. Deletion of fructokinase in the liver or in the intestine reveals differential effects on sugar-induced metabolic dysfunction. Cell Metab. 32, 117–127 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Softic, S. et al. Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling. J. Clin. Invest. 127, 4059–4074 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Calle, R., Bergman, A., Somayaji, V., Chidsey, K. & Kazierad, D. PS-110 Ketohexokinase inhibitor PF-06835919 administered for 6 weeks reduces whole liver fat as measured by magnetic resonance imaging-proton density fat fraction in subjects with non-alcoholic fatty liver disease. J. Hepatol. 70, e69–e70 (2019).

    Article  Google Scholar 

  151. Bricker, D. K. et al. A mitochondrial pyruvate carrier required for pyruvate uptake in yeast, Drosophila, and humans. Science 337, 96–100 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. McCommis, K. S. et al. Loss of mitochondrial pyruvate carrier 2 in the liver leads to defects in gluconeogenesis and compensation via pyruvate-alanine cycling. Cell Metab. 22, 682–694 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Harrison, S. A. et al. Insulin sensitizer MSDC-0602K in non-alcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase IIb study. J. Hepatol. 72, 613–626 (2020).

    Article  CAS  PubMed  Google Scholar 

  154. Degirolamo, C., Sabbà, C. & Moschetta, A. Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23. Nat. Rev. Drug. Discov. 15, 51–69 (2016).

    Article  CAS  PubMed  Google Scholar 

  155. Fu, L. et al. Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes. Endocrinology 145, 2594–2603 (2004).

    Article  CAS  PubMed  Google Scholar 

  156. Harrison, S. A. et al. NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 391, 1174–1185 (2018).

    Article  CAS  PubMed  Google Scholar 

  157. Luo, J. et al. A nontumorigenic variant of FGF19 treats cholestatic liver diseases. Sci. Transl. Med. 6, 247ra100 (2014).

    Article  PubMed  Google Scholar 

  158. Rinella, M. E. et al. Rosuvastatin improves the FGF19 analogue NGM282-associated lipid changes in patients with non-alcoholic steatohepatitis. J. Hepatol. 70, 735–744 (2019).

    Article  CAS  PubMed  Google Scholar 

  159. Harrison, S. A. et al. NGM282 improves liver fibrosis and histology in 12 weeks in patients with nonalcoholic steatohepatitis. Hepatology 71, 1198–1212 (2020).

    Article  CAS  PubMed  Google Scholar 

  160. Chavez, A. O. et al. Circulating fibroblast growth factor-21 is elevated in impaired glucose tolerance and type 2 diabetes and correlates with muscle and hepatic insulin resistance. Diabetes Care 32, 1542–1546 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Fisher, F. M. et al. Obesity is a fibroblast growth factor 21 (FGF21)-resistant state. Diabetes 59, 2781–2789 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Véniant, M. M. et al. Long-acting FGF21 has enhanced efficacy in diet-induced obese mice and in obese rhesus monkeys. Endocrinology 153, 4192–4203 (2012).

    Article  PubMed  Google Scholar 

  163. Xu, J. et al. Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. Diabetes 58, 250–259 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Charles, E. D. et al. Pegbelfermin (BMS-986036), PEGylated FGF21, in patients with obesity and type 2 diabetes: results from a randomized phase 2 study. Obesity 27, 41–49 (2019).

    Article  CAS  PubMed  Google Scholar 

  165. Sanyal, A. et al. Pegbelfermin (BMS-986036), a PEGylated fibroblast growth factor 21 analogue, in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 2a trial. Lancet 392, 2705–2717 (2019).

    Article  PubMed  Google Scholar 

  166. Armstrong, M. J. et al. Safety and efficacy of liraglutide in patients with type 2 diabetes and elevated liver enzymes: individual patient data meta-analysis of the LEAD program. Aliment. Pharmacol. Ther. 37, 234–242 (2013).

    Article  CAS  PubMed  Google Scholar 

  167. Fujita, K. et al. Dysfunctional very-low-density lipoprotein synthesis and release is a key factor in nonalcoholic steatohepatitis pathogenesis. Hepatology 50, 772–780 (2009).

    Article  CAS  PubMed  Google Scholar 

  168. Targher, G., Byrne, C. D. & Tilg, H. NAFLD and increased risk of cardiovascular disease: clinical associations, pathophysiological mechanisms and pharmacological implications. Gut 69, 1691–1705 (2020).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Work in the authors’ lab is supported by grants from the National Institutes of Health (R01 DK104735 and R01 DK117657). D.F. is supported by an NIH training grant, T32 DK007120.

Author information

Authors and Affiliations

  1. Division of Geriatrics and Nutritional Sciences, Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA

    Daniel Ferguson & Brian N. Finck

Authors
  1. Daniel Ferguson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Brian N. Finck
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Brian N. Finck.

Ethics declarations

Competing interests

B.N.F. is a stockholder and member of the scientific advisory board of Cirius Therapeutics Inc., which is developing MSDC-0602 for the treatment of NASH. D.F. declares no competing interests.

Additional information

Peer review information

Nature Reviews Endocrinology thanks A. Alisi and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ferguson, D., Finck, B.N. Emerging therapeutic approaches for the treatment of NAFLD and type 2 diabetes mellitus. Nat Rev Endocrinol 17, 484–495 (2021). https://doi.org/10.1038/s41574-021-00507-z

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41574-021-00507-z

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing