Empagliflozin for liver and lipid profile in metabolic dysfunction-associated fatty liver disease: a meta-analysis
DOI:
https://doi.org/10.13181/mji.oa.257855Keywords:
meta-analysis, non-alcoholic fatty liver disease, sodium-glucose transporter 2 inhibitors, systematic reviewAbstract
BACKGROUND Metabolic dysfunction-associated fatty liver disease (MAFLD) is a common chronic liver condition often associated with obesity and diabetes. Empagliflozin, a sodium-glucose cotransporter 2 inhibitor, is an antidiabetic medication that improves glycemic control, insulin resistance, and body weight. This study aimed to examine the efficacy of empagliflozin in adults with MAFLD.
METHODS A comprehensive literature search was performed using the PubMed, ScienceDirect, Cochrane Library, Scopus, and Wiley Online Library databases. Randomized controlled trials assessing liver function, lipid profile, metabolic profile, and body composition were included. Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated using random-effects models, and study quality was assessed using the Cochrane Risk of Bias Tool for Randomized Trials.
RESULTS 6 RCTs with a total of 636 participants were analyzed. Empagliflozin significantly reduced alanine aminotransferase levels (WMD: –6.65 IU/l, 95% CI: –13.02 to –0.28; p = 0.04) and gamma-glutamyl transferase levels (WMD: −10.60 IU/l, 95% CI: −29.05 to −7.68; p<0.00001). A non-significant reduction in aspartate aminotransferase was observed (WMD: –4.69 IU/l, 95% CI: –9.89 to 0.51; p = 0.08). Empagliflozin significantly improved low-density lipoprotein cholesterol (p = 0.02) and total cholesterol (p = 0.05) levels but did not significantly affect triglycerides, high-density lipoprotein cholesterol, metabolic profiles, or body composition.
CONCLUSIONS This meta-analysis highlights the beneficial effects of empagliflozin on liver function and indicates the need for further research on its metabolic effects and long-term outcomes in managing MAFLD.
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References
Rinella ME, Lazarus JV, Ratziu V, Francque SM, Sanyal AJ, Kanwal F, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. J Hepatol. 2023;78(6):1542-56. https://doi.org/10.1016/j.jhep.2023.06.003
Riazi K, Azhari H, Charette JH, Underwood FE, King JA, Afshar EE, et al. The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2022;7(9):851-61. https://doi.org/10.1016/S2468-1253(22)00165-0
Le MH, Yeo YH, Li X, Li J, Zhou B, Wu Y, et al. 2019 Global NAFLD Prevalence: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2022;20(12):2809-17.e28. https://doi.org/10.1016/j.cgh.2021.12.002
Targher G, Byrne CD, Tilg H. NAFLD and increased risk of cardiovascular disease: clinical associations, pathophysiological mechanisms and pharmacological implications. Gut. 2020;69(9):1691-705. https://doi.org/10.1136/gutjnl-2020-320622
Carr RM, Oranu A, Khungar V. Nonalcoholic fatty liver disease: pathophysiology and management. Gastroenterol Clin North Am. 2016;45(4):639-52. https://doi.org/10.1016/j.gtc.2016.07.003
Chávez-Tapia NN, Uribe M, Ponciano-Rodríguez G, Medina-Santillán R, Méndez-Sánchez N. New insights into the pathophysiology of nonalcoholic fatty liver disease. Ann Hepatol. 2009;8 Suppl 1:S9-17. https://doi.org/10.1016/S1665-2681(19)31821-6
Pouwels S, Sakran N, Graham Y, Leal A, Pintar T, Yang W, et al. Non-alcoholic fatty liver disease (NAFLD): a review of pathophysiology, clinical management and effects of weight loss. BMC Endocr Disord. 2022;22(1):63. https://doi.org/10.1186/s12902-022-00980-1
Forycka J, Hajdys J, Krzemińska J, Wilczopolski P, Wronka M, Młynarska E, et al. New insights into the use of empagliflozin-a comprehensive review. Biomedicines. 2022;10(12):3294. https://doi.org/10.3390/biomedicines10123294
Raj H, Durgia H, Palui R, Kamalanathan S, Selvarajan S, Kar SS, et al. SGLT-2 inhibitors in non-alcoholic fatty liver disease patients with type 2 diabetes mellitus: a systematic review. World J Diabetes. 2019;10(2):114-32. https://doi.org/10.4239/wjd.v10.i2.114
Lee KW, Devaraj NK, Ching SM, Veettil SK, Hoo FK, Deuraseh I, et al. Effect of SGLT-2 inhibitors on non-alcoholic fatty liver disease among patients with type 2 diabetes mellitus: systematic review with meta-analysis and trial sequential analysis of randomized clinical trials. Oman Med J. 2021;36(3):e273. https://doi.org/10.5001/omj.2021.62
Takahashi H, Kessoku T, Kawanaka M, Nonaka M, Hyogo H, Fujii H, et al. Ipragliflozin improves the hepatic outcomes of patients with diabetes with NAFLD. Hepatol Commun. 2022;6(1):120-32. https://doi.org/10.1002/hep4.1696
Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097. https://doi.org/10.1371/journal.pmed.1000097
Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. J Clin Epidemiol. 2009;62(10):e1-34. https://doi.org/10.1016/j.jclinepi.2009.06.006
Cusi K, Orsak B, Bril F, Lomonaco R, Hecht J, Ortiz-Lopez C, et al. Long-term pioglitazone treatment for patients with on-alcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial. Ann Intern Med. 2016;165(5):305-15. https://doi.org/10.7326/M15-1774
Sterne JA, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898. https://doi.org/10.1136/bmj.l4898
Fletcher J. What is heterogeneity and is it important? BMJ. 2007;334(7584):94-6. https://doi.org/10.1136/bmj.39057.406644.68
Elhini SH, Wahsh EA, Elberry AA, El Ameen NF, Abdelfadil Saedii A, Refaie SM, et al. The impact of an SGLT2 inhibitor versus ursodeoxycholic acid on liver steatosis in diabetic patients. Pharmaceuticals. 2022;15(12):1516. https://doi.org/10.3390/ph15121516
Chehrehgosha H, Sohrabi MR, Ismail-Beigi F, Malek M, Reza Babaei M, Zamani F, et al. Empagliflozin improves liver steatosis and fibrosis in patients with non-alcoholic fatty liver disease and type 2 diabetes: a randomized, double-blind, placebo-controlled clinical trial. Diabetes Ther. 2021;12(3):843-61. https://doi.org/10.1007/s13300-021-01011-3
Gaborit B, Ancel P, Abdullah AE, Maurice F, Abdesselam I, Calen A, et al. Effect of empagliflozin on ectopic fat stores and myocardial energetics in type 2 diabetes: the EMPACEF study. Cardiovasc Diabetol. 2021;20(1):57. https://doi.org/10.1186/s12933-021-01237-2
Taheri H, Malek M, Ismail-Beigi F, Zamani F, Sohrabi M, Reza Babaei M, et al. Effect of empagliflozin on liver steatosis and fibrosis in patients with non-alcoholic fatty liver disease without diabetes: a randomized, double-blind, placebo-controlled trial. Adv Ther. 2020;37(11):4697-708. https://doi.org/10.1007/s12325-020-01498-5
Kuchay MS, Krishan S, Mishra SK, Farooqui KJ, Singh MK, Wasir JS, 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(8):1801-8. https://doi.org/10.2337/dc18-0165
Kahl S, Gancheva S, Straßburger K, Herder C, Machann J, Katsuyama H, 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. 2020;43(2):298-305. https://doi.org/10.2337/dc19-0641
Zhang Y, Liu X, Zhang H, Wang X. Efficacy and safety of empagliflozin on nonalcoholic fatty liver disease: a systematic review and meta-analysis. Front Endocrinol. 2022;13:836455. https://doi.org/10.3389/fendo.2022.836455
Hossain MF, Khan NA, Rahman A, Chowdhury MF, Bari S, Khan MA, et al. Empagliflozin ameliorates progression from prediabetes to diabetes and improves hepatic lipid metabolism: a systematic review. Cureus. 2022;14(8):e28367. https://doi.org/10.7759/cureus.28367
Wei Q, Xu X, Guo L, Li J, Li L. Effect of SGLT2 inhibitors on type 2 diabetes mellitus with non-alcoholic fatty liver disease: a meta-analysis of randomized controlled trials. Front Endocrinol. 2021;12:635556. https://doi.org/10.3389/fendo.2021.635556
Pokharel A, Kc S, Thapa P, Karki N, Shrestha R, Jaishi B, et al. The effect of empagliflozin on liver fat in type 2 diabetes mellitus patients with non-alcoholic fatty liver disease. Cureus. 2021;13(7):e16687. https://doi.org/10.7759/cureus.16687
Shinozaki S, Tahara T, Lefor AK, Ogura M. Long-term empagliflozin therapy improves levels of hepatic fibrosis marker in patients with non-alcoholic fatty liver disease complicated by type 2 diabetes mellitus. J Med Invest. 2020;67(3.4):280-4. https://doi.org/10.2152/jmi.67.280
Lai LL, Vethakkan SR, Nik Mustapha NR, Mahadeva S, Chan WK. Empagliflozin for the treatment of nonalcoholic steatohepatitis in patients with type 2 diabetes mellitus. Dig Dis Sci. 2020;65(2):623-31. https://doi.org/10.1007/s10620-019-5477-1
Nasiri-Ansari N, Nikolopoulou C, Papoutsi K, Kyrou I, Mantzoros CS, Kyriakopoulos G, et al. Empagliflozin attenuates non-alcoholic fatty liver disease (NAFLD) in high fat diet fed apoe(-/-) mice by activating autophagy and reducing er stress and apoptosis. Int J Mol Sci. 2021;22(2):818. https://doi.org/10.3390/ijms22020818
Cheng L, Fu Q, Zhou L, Fan Y, Liu F, Fan Y, et al. Effect of SGLT-2 inhibitor, empagliflozin, on blood pressure reduction in Chinese elderly hypertension patients with type 2 diabetes and its possible mechanisms. Sci Rep. 2022;12(1):3525. https://doi.org/10.1038/s41598-022-07395-x
Mantovani A, Petracca G, Csermely A, Beatrice G, Targher G. Sodium-glucose cotransporter-2 inhibitors for treatment of nonalcoholic fatty liver disease: a meta-analysis of randomized controlled trials. Metabolites. 2020;11(1):22. https://doi.org/10.3390/metabo11010022
Kullmann S, Hummel J, Wagner R, Dannecker C, Vosseler A, Fritsche L, et al. Empagliflozin improves insulin sensitivity of the hypothalamus in humans with prediabetes: a randomized, double-blind, placebo-controlled, phase 2 trial. Diabetes Care. 2022;45(2):398-406. https://doi.org/10.2337/dc21-1136
Trnovska J, Svoboda P, Pelantova H, Kuzma M, Kratochvilova H, Kasperova BJ, et al. Complex positive effects of SGLT-2 inhibitor empagliflozin in the liver, kidney and adipose tissue of hereditary hypertriglyceridemic rats: possible contribution of attenuation of cell senescence and oxidative stress. Int J Mol Sci. 2021;22(19):10606. https://doi.org/10.3390/ijms221910606
Li T, Fang T, Xu L, Liu X, Li X, Xue M, et al. Empagliflozin alleviates hepatic steatosis by activating the AMPK-TET2-autophagy pathway in vivo and in vitro. Front Pharmacol. 2021;11:622153. Erratum in: Front Pharmacol. 2025;16:1478437. https://doi.org/10.3389/fphar.2020.622153
Xu L, Nagata N, Chen G, Nagashimada M, Zhuge F, Ni Y, et al. Empagliflozin reverses obesity and insulin resistance through fat browning and alternative macrophage activation in mice fed a high-fat diet. BMJ Open Diabetes Res Care. 2019;7(1):e000783. https://doi.org/10.1136/bmjdrc-2019-000783
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Copyright (c) 2025 Kevin Fernando Suhardi, Jonathan Christianto Sutadji, Agustina Rajendra Putri, Ghina Tsamara, Icha Farihah Deniyati Faratisha, Aqsha Tiara Viazelda, Soebagijo Adi Soeslistijo
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