455
Views
4
CrossRef citations to date
0
Altmetric
Review

Effects of anti-diabetic treatments in type 2 diabetes and fatty liver disease

, , &
Pages 837-852 | Received 31 Jan 2021, Accepted 12 Apr 2021, Published online: 22 Apr 2021

References

  • Lonardo A, Leoni S, Alswat KA, et al. History of nonalcoholic fatty liver disease. Int J Mol Sci. 2020;21(16):5888. .
  • Haas JT, Francque S, Staels B. Pathophysiology and mechanisms of nonalcoholic fatty liver disease. Annu Rev Physiol. 2016;78(1):181–205.
  • Kawano Y, Cohen DE. Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease. J Gastroenterol. 2013;48(4):434–441.
  • Cohen DE, Fisher EA. Lipoprotein metabolism, dyslipidemia, and nonalcoholic fatty liver disease. Semin Liver Dis. 2013;33(4):380–388.
  • Alves-Bezerra M, Cohen DE. Triglyceride metabolism in the liver. Compr Physiol. 2017;8(1):1–8.
  • Gastaldelli A, Cusi K. From NASH to diabetes and from diabetes to NASH: mechanisms and treatment options. JHEP reports Innov Hepatol. 2019;1(4):312–328.
  • Birkenfeld AL, Shulman GI. Nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 diabetes. Hepatology. 2014;59(2):713–723.
  • Machado MV, Diehl AM. Pathogenesis of Nonalcoholic Steatohepatitis. Gastroenterology. 2016;150(8):1769–1777.
  • Rufinatscha K, Ress C, Folie S, et al. Metabolic effects of reduced growth hormone action in fatty liver disease. Hepatol Int. 2018;12(5):474–481. .
  • Tilg H, Adolph TE, Moschen AR. Multiple parallel hits hypothesis in nonalcoholic fatty liver disease: revisited after a decade. Hepatology. 2021;73(2):833–842.
  • Ballestri S, Nascimbeni F, Romagnoli D, et al. The role of nuclear receptors in the pathophysiology, natural course, and drug treatment of NAFLD in humans. Adv Ther. 2016;33:291–319.
  • Cariello M, Piccinin E, Moschetta A. Transcriptional regulation of metabolic pathways via Lipid-Sensing nuclear receptors: PPARs, FXR, and LXR in NASH. Cell Mol Gastroenterol Hepatol. 2021;11(5):1519–1539.
  • Wall CE, Yu RT, Atkins AR, et al. Nuclear receptors and AMPK: can exercise mimetics cure diabetes? J Mol Endocrinol. 2016;57(1):R49–58. .
  • Diehl AM, Day C. Cause, pathogenesis, and treatment of nonalcoholic steatohepatitis. N Engl J Med. 2017;377(21):2063–2072.
  • Adams LA, Angulo P, Lindor KD. Nonalcoholic fatty liver disease. CMAJ. 2005;173(7):735.
  • Younossi ZM, Stepanova M, Afendy M, et al. Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clin Gastroenterol Hepatol. 2011;9(6):524–530.e1. quiz e60. .
  • Lonardo A, Bellentani S, Argo CK, et al. Epidemiological modifiers of non-alcoholic fatty liver disease: focus on high-risk groups. Dig Liver Dis off J Ital Soc Gastroenterol Ital Assoc Study Liver. 2015;47:997–1006.
  • Lonardo A, Nascimbeni F, Mantovani A, et al. Hypertension, diabetes, atherosclerosis and NASH: cause or consequence? J Hepatol. 2018;68(2):335–352. .
  • Lonardo A, Lugari S, Ballestri S, et al. A round trip from nonalcoholic fatty liver disease to diabetes: molecular targets to the rescue? Acta Diabetol. 2019;56(4):385–396. .
  • Xia M-F, Bian H, Gao X. NAFLD and diabetes: two sides of the same coin? Rationale for Gene-Based personalized NAFLD treatment. Front Pharmacol. 2019;10:877.
  • Mantovani A, Petracca G, Beatrice G, et al. Non-alcoholic fatty liver disease and risk of incident diabetes mellitus: an updated meta-analysis of 501 022 adult individuals. Gut. 2020. doi: 10.1136/gutjnl-2020-323082.
  • Tilg H, Moschen AR, Roden M. NAFLD and diabetes mellitus. Nat Rev Gastroenterol Hepatol. 2017;14(1):32–42.
  • Targher G, Bertolini L, Padovani R, et al. Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care. 2007;30(5):1212–1218.
  • European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO). EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64(6):1388–1402.
  • American Diabetes Association. 8. Obesity management for the treatment of type 2 diabetes: standards of medical care in diabetesd2019. Diabetes Care. 2019.
  • Unick JL, Beavers D, Jakicic JM, et al. Effectiveness of lifestyle interventions for individuals with severe obesity and type 2 diabetes: results from the Look AHEAD trial. Diabetes Care. 2011;34(10):2152–2157.
  • Musso G, Cassader M, Rosina F, et al. Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials. Diabetologia. 2012;55(4):885–904.
  • Wadden TA. Eight-year weight losses with an intensive lifestyle intervention: the look AHEAD study. Obesity. 201422(1):5-13.
  • Kirk E, Reeds DN, Finck BN, et al. Dietary fat and carbohydrates differentially alter insulin sensitivity during caloric restriction. Gastroenterology. 2009;136(5):1552–1560.
  • Haufe S, Engeli S, Kast P, et al. Randomized comparison of reduced fat and reduced carbohydrate hypocaloric diets on intrahepatic fat in overweight and obese human subjects. Hepatology. 2011;53(5):1504–1514.
  • Lazo M, Solga SF, Horska A, et al. Effect of a 12-month intensive lifestyle intervention on hepatic steatosis in adults with type 2 diabetes. Diabetes Care. 2010;33(10):2156–2163.
  • Nishimori E, Ogata S, Naka M Comparison of effects of Low-carbohydrate diet and Calorie-Restricted diet on nonalcoholic fatty liver disease in Japanese patients with Type 2 diabetes. Diabetes [Internet]. 2018;67:761–P. [cited 2021 Jan 31]. Available from: http://diabetes.diabetesjournals.org/content/67/Supplement_1/761-P.abstract.
  • Markova M, Pivovarova O, Hornemann S, et al. Isocaloric diets high in animal or plant protein reduce liver fat and inflammation in individuals with type 2 diabetes. Gastroenterology. 2017;152:571–585.e8.
  • Andersen T, Gluud C, Franzmann MBB, et al. Hepatic effects of dietary weight loss in morbidly obese subjects. J Hepatol. 1991;12(2):224–229. .
  • Gerber L, Otgonsuren M, Mishra A, et al. Non-alcoholic fatty liver disease (NAFLD) is associated with low level of physical activity: a population-based study. Aliment Pharmacol Ther. 2012;36(8):772–781.
  • Lonardo A, Suzuki A. Sexual Dimorphism of NAFLD in adults. focus on clinical aspects and implications for practice and translational research. J Clin Med. 2020;9(5):1278.
  • Kautzky-Willer A, Harreiter J, Pacini G. Sex and gender differences in risk, pathophysiology and complications of type 2 diabetes mellitus. Endocr Rev. 2016;37:278–316.
  • Umpierre D, Ribeiro PAB, Kramer CK, et al. Physical activity advice only or structured exercise training and association with HbA1c levels in type 2 diabetes. J Am Med Assoc. 2011;305(17):1790.
  • St George A, Bauman A, Johnston A, et al. Independent effects of physical activity in patients with nonalcoholic fatty liver disease. Hepatology. 2009;50(1):68–76.
  • Schauer PRR, Bhatt DLL, Kirwan JPP, et al. Bariatric surgery versus intensive medical therapy for diabetes - 5-Year outcomes. N Engl J Med. 2017;376(7):641–651.
  • Caiazzo R, Lassailly G, Leteurtre E, et al. Roux-en-Y gastric bypass versus adjustable gastric banding to reduce nonalcoholic fatty liver disease: a 5-year controlled longitudinal study. Ann Surg. 2014;260(5):893–899.
  • Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41(6):1313–1321.
  • Lassailly G, Caiazzo R, Buob D, et al. Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients. Gastroenterology. 2015;149(2):376–379.
  • Froylich D, Corcelles R, Daigle C, et al. Effect of Roux-en-Y gastric bypass and sleeve gastrectomy on nonalcoholic fatty liver disease: a comparative study. Surg Obes Relat Dis. 2016;12(1):127–131.
  • Lassailly G, Caiazzo R, Ntandja-Wandji L-C, et al., Bariatric surgery provides long-term resolution of nonalcoholic steatohepatitis and regression of fibrosis. Gastroenterology. 159(4): 1290–1301.e5. 2020.
  • 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(6):2005–2023.
  • Wu R, Ortiz J, Dallal R. Is bariatric surgery safe in cirrhotics? Hepat Mon. 2013;13(2):e8536.
  • Dallal RM, Mattar SG, Lord JL, et al. Results of laparoscopic gastric bypass in patients with cirrhosis. Obes Surg. 2004;14(1):47–53.
  • Ali MR, Moustarah F, Kim JJ. American society for metabolic and bariatric surgery position statement on intragastric balloon therapy endorsed by the society of American Gastrointestinal and endoscopic surgeons. Surg Obes Relat Dis. 2016;12(3):462–467.
  • Lee Y-M, 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(4):756–760.
  • Forlano R, Ippolito AM, Iacobellis A, et al. Effect of the bioEnterics intragastric balloon on weight, insulin resistance, and liver steatosis in obese patients. Gastrointest Endosc. 2010;71(6):927–933.
  • Folini L, Veronelli A, Benetti A, et al. Liver steatosis (LS) evaluated through chemical-shift magnetic resonance imaging liver enzymes in morbid obesity; effect of weight loss obtained with intragastric balloon gastric banding. Acta Diabetol. 2014;51(3):361–368.
  • Nguyen V, Li J, Gan J, et al. Outcomes following serial intragastric balloon therapy for obesity and nonalcoholic fatty liver disease in a single centre. Can J Gastroenterol Hepatol. 2017;2017:4697194.
  • Bazerbachi F, Vargas EJ, Rizk M, et al. Intragastric balloon placement induces significant metabolic and histologic improvement in patients with nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. 2021;19:146–154.e4.
  • Chandan S, Mohan BP, Khan SR, et al. Efficacy and Safety of Intragastric Balloon (IGB) in Non-alcoholic Fatty Liver Disease (NAFLD): a comprehensive review and Meta-analysis. Obes Surg. 2021;31(3):1271–1279.
  • Maisel W. The FDA alerts health care providers about potential risks with liquid-filled intragastric balloons [Internet]. 2020 [ cited 2020 Sep 11]. Available from: https://www.fda.gov/medical-devices/letters-health-care-providers/fda-alerts-health-care-providers-about-potential-risks-liquid-filled-intragastric-balloons.
  • Rajagopalan H, Cherrington ADD, Thompson CCC, et al. Endoscopic duodenal mucosal resurfacing for the treatment of type 2 diabetes: 6-Month interim analysis from the first-in-Human Proof-of-Concept study. Diabetes Care. 2016;39(12):2254–2261.
  • Thompson CCC, Abu Dayyeh BKK, Kushner R, et al. Percutaneous gastrostomy device for the treatment of class II and class III obesity: results of a randomized controlled trial. Am J Gastroenterol. 2017;112(3):447–457.
  • American Diabetes Association. 9. Cardiovascular disease and risk management: standards of medical care in diabetesd2018. Diabetes Care. 2018 Jan;41(Suppl 1):S86-S104.
  • Athyros VG, Boutari C, Stavropoulos K, et al. Statins: an Under-Appreciated asset for the prevention and the treatment of NAFLD or NASH and the related cardiovascular risk. Curr Vasc Pharmacol. 2018;16(3):246–253.
  • Athyros VGG, Tziomalos K, Gossios TDD, 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(9756):1916–1922.
  • German MN, Lutz MK, Pickhardt PJ, et al. Statin use is protective against hepatocellular carcinoma in patients with nonalcoholic fatty liver disease: a case-control study. J Clin Gastroenterol. 2020;54(8):733–740.
  • Wong Y-J, Qiu T-Y, Ng G-K, et al. Efficacy and safety of statin for hepatocellular carcinoma prevention among chronic liver disease patients: a systematic review and meta-analysis. J Clin Gastroenterol. 2021. 10.1097/MCG.0000000000001478.
  • Nelson A, Torres DM, Morgan AE, et al. A pilot study using simvastatin in the treatment of nonalcoholic steatohepatitis: a randomized placebo-controlled trial. J Clin Gastroenterol. 2009;43(10):990–994.
  • Athyros VG, Mikhailidis DP, Didangelos TP, et al. Effect of multifactorial treatment on non-alcoholic fatty liver disease in metabolic syndrome: a randomised study. Curr Med Res Opin. 2006;22(5):873–883.
  • Tomizawa M, Kawanabe Y, Shinozaki F, et al. Triglyceride is strongly associated with nonalcoholic fatty liver disease among markers of hyperlipidemia and diabetes. Biomed Reports. 2014;2(5):633–636.
  • ASCEND Study Collaborative Group, Bowman L, Mafham M, Wallendszus K, et al. Effects of n−3 fatty acid supplements in diabetes mellitus. N Engl J Med. 2018 Oct 18;379(16):1540-1550.
  • Hartweg J, Perera R, Montori V, et al. Omega-3 polyunsaturated fatty acids (PUFA) for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2008; (1):CD003205. 10.1002/14651858.CD003205.pub2.
  • Scorletti E, Bhatia L, Mccormick KGG, et al. Effects of purified eicosapentaenoic and docosahexaenoic acids in nonalcoholic fatty liver disease: results from the welcome* study. Hepatology. 2014;60(4):1211–1221.
  • 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(2):377–84.e1.
  • Lu W, Li S, Li J, et al. Effects of Omega-3 fatty acid in nonalcoholic fatty liver disease: a Meta-Analysis. Gastroenterol Res Pract. 2016;2016:1459790.
  • American Diabetes Association. 5.Lifestyle management: standards of medical care in diabetes 2019. Diabetes Care. 2019 Jan;42(Suppl 1):S46-S60.
  • American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes 2019. Diabetes Care. 2019 Jan;42(Suppl 1):S90-S102.
  • Tiikkainen M, Häkkinen AM, Korsheninnikova E, et al. Effects of rosiglitazone and metformin on liver fat content, hepatic insulin resistance, insulin clearance, and gene expression in adipose tissue in patients with type 2 diabetes. Diabetes. 2004;53(8):2169–2176.
  • Loomba R, Lutchman G, Kleiner DE, et al. Clinical trial: pilot study of metformin for the treatment of non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2009;29(2):172–182.
  • Nar A, Gedik O. The effect of metformin on leptin in obese patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease. Acta Diabetol. 2009;46(2):113–118.
  • Haukeland JW, Konopski Z, Eggesbo HB, et al. Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial. Scand J Gastroenterol. 2009;44(7):853–860.
  • Lingvay I, Raskin P, Szczepaniak LS. Effect of insulin-metformin combination on hepatic steatosis in patients with type 2 diabetes. J Diabetes Complications. 2007;21(3):137–142.
  • Li Y, Liu L, Wang B, et al., Metformin in non-alcoholic fatty liver disease: a systematic review and meta-analysis. Biomed Reports. 1(1): 57–64. 2013.
  • Rakoski MO, Singal AG, Rogers MAM, et al. Meta-analysis: insulin sensitizers for the treatment of non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2010;32(10):1211–1221. .
  • Brackett CC. Clarifying metformin’s role and risks in liver dysfunction. J Am Pharm Assoc. 2010;50(3):407–410.
  • Zhang X, Harmsen WS, Mettler TA, et al. Continuation of metformin use after a diagnosis of cirrhosis significantly improves survival of patients with diabetes. Hepatology. 2014;60(6):2008–2016.
  • Pettinelli P, Videla LA. Up-regulation of PPAR-γ mRNA expression in the liver of obese patients: an additional reinforcing lipogenic mechanism to SREBP-1c induction. J Clin Endocrinol Metab. 2011;96(5):1424–1430.
  • 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(4):1008–1017.
  • Ratziu V, Giral P, Jacqueminet S, et al. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial. Gastroenterology. 2008;135(1):100–110.
  • Ratziu V, Charlotte F, Bernhardt C, et al. Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial. Hepatology. 2010;51(2):445–453.
  • Belfort R, Harrison SA, Brown K, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006;355(22):2297–2307.
  • 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(4):558–566.e2.
  • Bril F, Biernacki DM, Kalavalapalli S, et al. Role of vitamin E for nonalcoholic steatohepatitis in patients with type 2 diabetes: a randomized controlled trial. Diabetes Care. 2019;42(8):1481–1488.
  • Mahady SE, Webster AC, Walker S, et al., The role of thiazolidinediones in non-alcoholic steatohepatitis - a systematic review and meta analysis. J Hepatol. 55(6): 1383–1390. 2011. .
  • Yki-Järvinen H. Thiazolidinediones. N Engl J Med. 2004;351(11):1106–1118.
  • Varas-Lorenzo C, Margulis AV, Pladevall M, et al. The risk of heart failure associated with the use of noninsulin blood glucose-lowering drugs: systematic review and meta-analysis of published observational studies. BMC Cardiovasc Disord. 2014;14(1):129.
  • Aubert RE, Herrera V, Chen W, et al. Rosiglitazone and pioglitazone increase fracture risk inwomen andmen with type 2 diabetes. Diabetes Obes Metab. 2010;12(8):716–721. .
  • Scheen AJ. Thiazolidinediones and liver toxicity. Diabetes Metab. 2001;27(3):305–313
  • Matsuyama T, Komatsu R, Namba M, et al. Glucagon-like peptide-1 (7-36 amide): a potent glucagonostatic and insulinotropic hormone. Diabetes Res Clin Pract. 1988;5(4):281–284.
  • Wettergren A, Schjoldager B, Mortensen PE, et al. Truncated GLP-1 (proglucagon 78-107-amide) inhibits gastric and pancreatic functions in man. Dig Dis Sci. 1993;38(4):665–673. .
  • Tourrel C, Bailbé D, Meile MJ, et al. Glucagon-Like Peptide-1 and Exendin-4 Stimulate β-Cell Neogenesis in Streptozotocin-Treated newborn rats resulting in persistently improved glucose homeostasis at adult age. Diabetes. 2001;50(7):1562–1570.
  • Perfetti R, Zhou JIE, Doyle ME, et al. Glucagon-like peptide-1 induces cell proliferation and pancreatic-duodenum homeobox-1 expression and increases endocrine cell mass in the pancreas of old, glucose-intolerant rats. Endocrinology. 2000;141(12):4600–4605.
  • Holz IV GG, Kiihtreiber WM, Habener JF, Pancreatic beta-cells are rendered glucose-competent by the insulinotropic hormone glucagon-like peptide-1(7-37). Nature. 1993Jan 28;361(6410):362-365.
  • Balaban YH, Korkusuz P, Simsek H, et al. Dipeptidyl peptidase IV (DDP IV) in NASH patients. Ann Hepatol. 2007;6(4):242–250.
  • Arase Y, Kawamura Y, Seko Y, et al. Efficacy and safety in sitagliptin therapy for diabetes complicated by non-alcoholic fatty liver disease. Hepatol Res. 2013;43(11):1163–1168.
  • Deng X-LX-L, Ma R, Zhu H-XH-X, et al., Short article: a randomized-controlled study of sitagliptin for treating diabetes mellitus complicated by nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol. 2017;29(3): 297–301.
  • Fukuhara T, Hyogo H, Ochi H, et al. Efficacy and safety of sitagliptin for the treatment of nonalcoholic fatty liver disease with type 2 diabetes mellitus. Hepatogastroenterology. 2014;61(130):323–328.
  • Iwasaki T, Yoneda M, Inamori M, et al. Sitagliptin as a novel treatment agent for non-alcoholic fatty liver disease patients with type 2 diabetes mellitus. Hepatogastroenterology. 2011;58(112):2103–2105. .
  • Macauley M, Hollingsworth KG, Smith FE, et al. Effect of vildagliptin on hepatic steatosis. J Clin Endocrinol Metab. 2015;100(4):1578–1585.
  • Kanazawa I, Tanaka K, Sugimoto T. DPP-4 inhibitors improve liver dysfunction in type 2 diabetes mellitus. Med Sci Monit. 2014;20:1662–1667.
  • Migoya EMM, Stevens CHH, Bergman AJJ, et al. Effect of moderate hepatic insufficiency on the pharmacokinetics of sitagliptin. Can J Clin Pharmacol. 2009;16(1):e165–70.
  • Boulton DWW, Li L, Frevert EUU, et al. Influence of renal or hepatic impairment on the pharmacokinetics of saxagliptin. Clin Pharmacokinet. 2011;50(4):253–265.
  • Graefe-Mody U, Retlich S, Friedrich C. Clinical pharmacokinetics and pharmacodynamics of linagliptin. Clin Pharmacokinet. 2012;51(7):411–427.
  • National Library of Medicine US, U.S. National Library of Medicine. ClinicalTrials.gov. [Internet]. 2020 cited 2019 Aug 2. Available from: https://www.clinicaltrials.gov.
  • Astrup A, Rössner S, Van Gaal L, et al. Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet. 2009;374(9701):1606–1616. .
  • Tran S, Retnakaran R, Zinman B, et al. Efficacy of glucagon-like peptide-1 receptor agonists compared to dipeptidyl peptidase-4 inhibitors for the management of type 2 diabetes: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2018;20(Suppl 1):68–76.
  • Ding X, Saxena NK, Lin S, et al. Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice. Hepatology. 2006;43(1):173–181. .
  • Trevaskis JL, Griffin PS, Wittmer C, 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(8):G762–72.
  • Somm E, Montandon SA, Loizides-Mangold U, et al. The GLP-1R agonist liraglutide limits hepatic lipotoxicity and inflammatory response in mice fed a methionine-choline deficient diet. Transl Res. 2021;227:75–88.
  • Armstrong MJ, Houlihan DD, Rowe IA, 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. 2013;37(2):234–242.
  • Gluud LL, Knop FK, Vilsboll T. Effects of lixisenatide on elevated liver transaminases: systematic review with individual patient data meta-analysis of randomised controlled trials on patients with type 2 diabetes. BMJ Open. 2014;4(12):e005325.
  • Cusi K, Sattar N, García-Pérez LE, et al. Dulaglutide decreases plasma aminotransferases in people with Type 2 diabetes in a pattern consistent with liver fat reduction: a post hoc analysis of the AWARD programme. Diabet Med. 2018;35(10):1434–1439.
  • Petit JM, Cercueil JP, Loffroy R, et al. Effect of liraglutide therapy on liver fat content in patients with inadequately controlled type 2 diabetes: the Lira-NAFLD study. J Clin Endocrinol Metab. 2017;102(2):407–415.
  • Armstrong MJJ, Gaunt P, Aithal GPP, 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(10019): 679–690.
  • Guo W, Tian W, Lin L, et al. Liraglutide or insulin glargine treatments improves hepatic fat in obese patients with type 2 diabetes and nonalcoholic fatty liver disease in twenty-six weeks: a randomized placebo-controlled trial. Diabetes Res Clin Pract. 2020;170:108487.
  • Seko Y, Sumida Y, Tanaka S, et al. Effect of 12-week dulaglutide therapy in Japanese patients with biopsy-proven non-alcoholic fatty liver disease and type 2 diabetes mellitus. Hepatol Res. 2017;47(11):1206–1211. .
  • Newsome PN, Buchholtz K, Cusi K, et al., A Placebo-Controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis. N Engl J Med. 2020;384(12): 1113–1124. .
  • Mantovani A, Petracca G, Beatrice G, et al. Glucagon-Like Peptide-1 receptor agonists for treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: an Updated Meta-Analysis of randomized controlled trials. Metabolites. 2021;11(2). doi: 10.3390/metabo11020073.
  • Ohki T, Isogawa A, Iwamoto M, et al. The effectiveness of liraglutide in nonalcoholic fatty liver disease patients with type 2 diabetes mellitus compared to sitagliptin and pioglitazone. ScientificWorldJournal. 2012;2012:496453.
  • Feng W, Gao C, Bi Y, et al. Randomized trial comparing the effects of gliclazide, liraglutide, and metformin on diabetes with non-alcoholic fatty liver disease. J Diabetes. 2017;9(8):800–809.
  • Feng W-HW-H, Bi Y, Li P, et al. Effects of liraglutide, metformin and gliclazide on body composition in patients with both type 2 diabetes and non-alcoholic fatty liver disease: a randomized trial. J Diabetes Investig. 2019;10(2):399–407.
  • Tian F, Zheng Z, Zhang D, et al. Efficacy of liraglutide in treating type 2 diabetes mellitus complicated with non-alcoholic fatty liver disease. Biosci Rep. 2018;38(6). doi: 10.1042/BSR20181304.
  • Fan H, Pan Q, Xu Y, et al. Exenatide improves type 2 diabetes concomitant with non-alcoholic fatty liver disease. Arq Bras Endocrinol Metabol. 2013;57(9):702–708.
  • Yan J, Yao B, Kuang H, et al. Liraglutide, sitagliptin, and insulin glargine added to metformin: the effect on body weight and intrahepatic lipid in patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease. Hepatology. 2019;69(6):2414–2426.
  • Shao N, Kuang HYY, Hao M, et al. Benefits of exenatide on obesity and non-alcoholic fatty liver disease with elevated liver enzymes in patients with type 2 diabetes. Diabetes Metab Res Rev. 2014;30(6):521–529.
  • Bethel MA, Patel RA, Merrill P, et al. Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis. Lancet Diabetes Endocrinol. 2018;6(2):105–113.
  • Lupsa BC, Inzucchi SE. Use of SGLT2 inhibitors in type 2 diabetes: weighing the risks and benefits. Diabetologia. 2018;61(10):2118–2125.
  • Hayashizaki-Someya Y, Kurosaki E, Takasu T, et al. 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.
  • Tahara A, Kurosaki E, Yokono M, et al. Effects of SGLT2 selective inhibitor ipragliflozin on hyperglycemia, hyperlipidemia, hepatic steatosis, oxidative stress, inflammation, and obesity in type 2 diabetic mice. Eur J Pharmacol. 2013;715(1–3):246–255.
  • Sattar N, Fitchett D, Hantel S, et al. Empagliflozin is associated with improvements in liver enzymes potentially consistent with reductions in liver fat: results from randomised trials including the EMPA-REG OUTCOME(R) trial. Diabetologia. 2018;61(10):2155–2163.
  • 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. 41(8): 1801–1808. 2018.
  • Lai LL, Vethakkan SR, Nik Mustapha NR, et al. Empagliflozin for the treatment of nonalcoholic steatohepatitis in patients with type 2 diabetes mellitus. Dig Dis Sci. 2020;65(2):623–631.
  • Shimizu M, Suzuki K, Kato K, 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. 2019;21(2):285–292.
  • Aso Y, Kato K, Sakurai S, et al. Impact of dapagliflozin, an SGLT2 inhibitor, on serum levels of soluble dipeptidyl peptidase-4 in patients with type 2 diabetes and non-alcoholic fatty liver disease. Int J Clin Pract. 2019;73(5):e13335.
  • Eriksson JW, Lundkvist P, Jansson PA, 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(9):1923–1934.
  • Tobita H, Sato S, Miyake T, et al. Effects of Dapagliflozin on body composition and liver tests in patients with nonalcoholic steatohepatitis associated with type 2 diabetes mellitus: a Prospective, Open-label, Uncontrolled Study. Curr Ther Res Clin Exp. 2017;87:13–19.
  • Leiter LA, Forst T, Polidori D, et al. Effect of canagliflozin on liver function tests in patients with type 2 diabetes. Diabetes Metab. 2016;42(1):25–32.
  • 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.
  • 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(5):531–539. .
  • Itani T, Ishihara T. Efficacy of canagliflozin against nonalcoholic fatty liver disease: a prospective cohort study. Obes Sci Pract. 2018;4(5):477–482.
  • Inoue M, Hayashi A, Taguchi T, et al. Effects of canagliflozin on body composition and hepatic fat content in type 2 diabetes patients with non-alcoholic fatty liver disease. J Diabetes Investig. 2019 Jul;10(4):1004-1011.
  • Sumida Y, Murotani K, Saito M, et al. Effect of luseogliflozin on hepatic fat content in type 2 diabetes patients with non-alcoholic fatty liver disease: a prospective, single-arm trial (LEAD trial). Hepatol Res. 2019;49(1):64–71. .
  • Takase T, Nakamura A, Miyoshi H, et al. Amelioration of fatty liver index in patients with type 2 diabetes on ipragliflozin: an association with glucose-lowering effects. Endocr J. 2017;64(3):363–367. .
  • Ohta A, Kato H, Ishii S, et al. Ipragliflozin, a sodium glucose co-transporter 2 inhibitor, reduces intrahepatic lipid content and abdominal visceral fat volume in patients with type 2 diabetes. Expert Opin Pharmacother. 2017;18(14):1433–1438. .
  • Tabuchi H, Maegawa H, Tobe K, et al. Effect of ipragliflozin on liver function in Japanese type 2 diabetes mellitus patients: a subgroup analysis of the STELLA-LONG TERM study (3-month interim results). Endocr J. 2019;66(1):31–41. .
  • Miyake T, Yoshida S, Furukawa S, et al. Ipragliflozin ameliorates liver damage in non-alcoholic fatty liver disease. Open Med (Warsaw, Poland). 2018;13(1):402–409.
  • Ohki T, Isogawa A, Toda N, et al. Effectiveness of Ipragliflozin, a Sodium-Glucose Co-transporter 2 Inhibitor, as a Second-line treatment for Non-alcoholic fatty liver disease patients with type 2 diabetes mellitus who do not respond to Incretin-Based therapies including Glucagon-like Pep. Clin Drug Investig. 2016;36(4):313–319.
  • Mantovani A, Petracca G, Csermely A, et al. Sodium-Glucose Cotransporter-2 inhibitors for treatment of nonalcoholic fatty liver disease: a Meta-analysis of randomized controlled trials. Metabolites. 2020; 11(1). doi: 10.3390/metabo11010022.
  • Choi DH, Jung CH, Mok JO, et al. Effect of Dapagliflozin on Alanine Aminotransferase improvement in type 2 diabetes mellitus with Non-alcoholic fatty liver disease. Endocrinol Metab (Seoul, Korea). 2018;33(3):387–394.
  • Shibuya T, Fushimi N, Kawai M, et al. Luseogliflozin improves liver fat deposition compared to metformin in type 2 diabetes patients with non-alcoholic fatty liver disease: a prospective randomized controlled pilot study. Diabetes Obes Metab. 2018;20(2):438–442.
  • Ito D, Shimizu S, Inoue K, et al. Comparison of Ipragliflozin and Pioglitazone effects on nonalcoholic fatty liver disease in patients with type 2 diabetes: a Randomized, 24-week, Open-Label, Active-Controlled trial. Diabetes Care. 2017;40(10):1364–1372.
  • Seko Y, Sumida Y, Tanaka S, et al. Effect of sodium glucose cotransporter 2 inhibitor on liver function tests in Japanese patients with non-alcoholic fatty liver disease and type 2 diabetes mellitus. Hepatol Res. 2017;47(10):1072–1078.
  • Arnott C, Li Q, Kang A, et al. Sodium-Glucose cotransporter 2 inhibition for the prevention of cardiovascular events in patients with type 2 diabetes mellitus: a systematic review and meta-Analysis. J Am Heart Assoc. 2020;9(3):e014908.
  • 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(9972):956–965. .
  • Westerouen Van Meeteren MJ, Drenth JPH, Tjwa ETTL. Elafibranor: a potential drug for the treatment of nonalcoholic steatohepatitis (NASH). Expert Opin Investig Drugs. 2020;29(2):117–123.
  • Zhang F, Yu L, Lin X, et al. Minireview: roles of fibroblast growth factors 19 and 21 in metabolic regulation and chronic diseases. Mol Endocrinol. 2015;29(10):1400–1413. .
  • Harrison SA, Rinella ME, Abdelmalek MF, et al. NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2018;391(10126):1174–1185. .
  • Sanyal A, Charles ED, Neuschwander-Tetri BA, 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. 2018;392(10165):2705–2717.
  • Beagley J, Guariguata L, Weil C, et al. Global estimates of undiagnosed diabetes in adults. Diabetes Res Clin Pract. 2014;103(2):150–160.
  • Mofrad P, Contos MJ, Haque M, et al. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Hepatology. 2003;37(6):1286–1292.
  • Ahlqvist E, Storm P, Käräjämäki A, et al. Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables. Lancet Diabetes Endocrinol. 2018;6(5):361–369.
  • Zaharia OP, Strassburger K, Strom A, et al. Risk of diabetes-associated diseases in subgroups of patients with recent-onset diabetes: a 5-year follow-up study. Lancet Diabetes Endocrinol. 2019;7(9):684–694.
  • Ahlqvist E, Prasad RB, Groop L. Subtypes of Type 2 Diabetes Determined From Clinical Parameters. Diabetes. 2020;69(10):2086–2093.
  • Wing RR, Bolin P, Brancati FL, et al. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med. 2013;369:145–154.
  • Petersen KF, Dufour S, Befroy D, et al. Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes. 2005;54(3):603–608.
  • Huang MA, Greenson JK, Chao C, et al. One-year intense nutritional counseling results in histological improvement in patients with nonalcoholic steatohepatitis: a pilot study. Am J Gastroenterol. 2005;100(5):1072–1081.
  • Ueno T, Sugawara H, Sujaku K, et al. Therapeutic effects of restricted diet and exercise in obese patients with fatty liver. J Hepatol. 1997;27(1):103–107.
  • Promrat K, Kleiner DE, Niemeier HM, et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology. 2010;51(1):121–129. .
  • Xourafas D, Ardestani A, Ashley SW, et al. Impact of weight-loss surgery and diabetes status on serum ALT levels. Obes Surg. 2012;22(10):1540–1547.
  • Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311–322.
  • Bajaj HS, Brown RE, Bhullar L, et al. SGLT2 inhibitors and incretin agents: associations with alanine aminotransferase activity in type 2 diabetes. Diabetes Metab. 2018;44(6):493–499.
  • Lonardo A, Nascimbeni F, Ballestri S, et al. Sex differences in nonalcoholic fatty liver disease: state of the art and identification of research gaps. Hepatology. 2019;70(4):1457–1469.
  • Balakrishnan M, Patel P, Dunn-Valadez S, et al. Women have a lower risk of nonalcoholic fatty liver disease but a higher risk of progression vs Men: a systematic review and Meta-analysis. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. 2021;19:61–71.e15.
  • Mauvais-Jarvis F, Bairey Merz N, Barnes PJ, et al. Sex and gender: modifiers of health, disease, and medicine. Lancet. 2020;396(10250):565–582.
  • Singh AK, Singh R. Gender difference in cardiovascular outcomes with SGLT-2 inhibitors and GLP-1 receptor agonist in type 2 diabetes: a systematic review and meta-analysis of cardio-vascular outcome trials. Diabetes Metab Syndr. 2020;14(3):181–187.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.