Effect of empagliflozin on liver function in type 2 diabetes: A systematic review and meta-analysis of randomized trials

Zahra Rafat, Kourosh Delpasand, Davoud Roostaei

Abstract


Many reports are indicating the blood sugar-lowering potential of empagliflozin in type 2 diabetes mellitus and its anti-lipogenesis effects in the liver, as studied in mice models; while few clinical trials have evaluated its effect on liver fat content and liver function. This study aimed to evaluate the effect of empagliflozin on the treatment of non‐alcoholic fatty liver disease in type 2 diabetes mellitus patients. Scopus, Cochran Library, PubMed, and Web of Science databases were searched from 1990 to 2022 with reference checking and citation searching to identify additional studies. The inclusion criteria for studies included were the evaluation of patients with non‐alcoholic fatty liver disease and type 2 diabetes being treated with empagliflozin for 24 weeks. Our interest outcomes were Liver fat, Alanine transaminase (ALT), and Aspartate transaminase (AST). Data analysis random effect size model was used for pooling data to calculate mean differences in RevMan Version 5.3. I2 was used to evaluate heterogeneity. Three clinical trial studies were included with 2344 patients. In pooled ALT mean difference evaluation within 24 weeks of studies, there was a significant difference between subjects receiving empagliflozin versus controls (MD = -6.6 CI95% (-10.27 to -3.73; P = 0.06; I2 = 99%). In the case of AST (MD = -9.06 CI95% (-20.45 to 2.34; P = 0.12; I2 = 98%) and Liver fat (MD = -4.46 CI95% (-10.06 to 0.77; P = 0.09; I2 = 98%), there was not any significant difference between subjects receiving empagliflozin versus controls. While empagliflozin seems to be effective in lowering ALT levels; further studies are needed to confirm its efficacy in lowering liver fat.


Keywords


Non‐alcoholic fatty liver disease; Empagliflozin; Type 2 diabetes mellitus

Full Text:

Full-text PDF

References


Alkhouri N, Poordad F, Lawitz E. Management of nonalcoholic fatty liver disease: Lessons learned from type 2 diabetes. Hepatol Commun. 2018;2(7):778-85. DOI: 10.1002/hep4.1195 PMID: 30027137

Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R. Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. Clin Gastroenterol Hepatol. 2015;13(4):643-54 e1-9; quiz e39-40. DOI: 10.1016/j.cgh.2014.04.014 PMID: 24768810

Charlton MR, Burns JM, Pedersen RA, Watt KD, Heimbach JK, Dierkhising RA. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology. 2011;141(4):1249-53. DOI: 10.1053/j.gastro.2011.06.061 PMID: 21726509

Musso G, Cassader M, Rosina F, Gambino R. 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. DOI: 10.1007/s00125-011-2446-4 PMID: 22278337

Targher G, Bertolini L, Poli F, Rodella S, Scala L, Tessari R, et al. Nonalcoholic fatty liver disease and risk of future cardiovascular events among type 2 diabetic patients. Diabetes. 2005;54(12):3541-6. DOI: 10.2337/diabetes.54.12.3541 PMID: 16306373

Bertoccini L, Baroni MG. GLP-1 Receptor Agonists and SGLT2 Inhibitors for the Treatment of Type 2 Diabetes: New Insights and Opportunities for Cardiovascular Protection. Adv Exp Med Biol. 2021;1307:193-212. DOI: 10.1007/5584_2020_494 PMID: 32034729

Cherney DZI, Zinman B, Inzucchi SE, Koitka-Weber A, Mattheus M, von Eynatten M, et al. Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease: an exploratory analysis from the EMPA-REG OUTCOME randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2017;5(8):610-21. DOI: 10.1016/S2213-8587(17)30182-1 PMID: 28666775

Kaku K, Lee J, Mattheus M, Kaspers S, George J, Woerle HJ, et al. Empagliflozin and Cardiovascular Outcomes in Asian Patients With Type 2 Diabetes and Established Cardiovascular Disease - Results From EMPA-REG OUTCOME((R)). Circ J. 2017;81(2):227-34. DOI: 10.1253/circj.CJ-16-1148 PMID: 28025462

Trujillo JM, Nuffer WA. Impact of Sodium-Glucose Cotransporter 2 Inhibitors on Nonglycemic Outcomes in Patients with Type 2 Diabetes. Pharmacotherapy. 2017;37(4):481-91. DOI: 10.1002/phar.1903 PMID: 28102030

Petito-da-Silva TI, Souza-Mello V, Barbosa-da-Silva S. Empaglifozin mitigates NAFLD in high-fat-fed mice by alleviating insulin resistance, lipogenesis and ER stress. Mol Cell Endocrinol. 2019;498:110539. DOI: 10.1016/j.mce.2019.110539 PMID: 31419466

Jojima T, Tomotsune T, Iijima T, Akimoto K, Suzuki K, Aso Y. Empagliflozin (an SGLT2 inhibitor), alone or in combination with linagliptin (a DPP-4 inhibitor), prevents steatohepatitis in a novel mouse model of non-alcoholic steatohepatitis and diabetes. Diabetol Metab Syndr. 2016;8:45. DOI: 10.1186/s13098-016-0169-x PMID: 27462372

Sterne JAC, Savovic 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. DOI: 10.1136/bmj.l4898 PMID: 31462531

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. DOI: 10.2337/dc19-0641 PMID: 31540903

Sattar N, Fitchett D, Hantel S, George JT, Zinman B. 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):2155-63. DOI: 10.1007/s00125-018-4702-3 PMID: 30066148

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. DOI: 10.2337/dc18-0165 PMID: 29895557

Cherney DZI, Cooper ME, Tikkanen I, Pfarr E, Johansen OE, Woerle HJ, et al. Pooled analysis of Phase III trials indicate contrasting influences of renal function on blood pressure, body weight, and HbA1c reductions with empagliflozin. Kidney Int. 2018;93(1):231-44. DOI: 10.1016/j.kint.2017.06.017 PMID: 28860019

Goldman JD. Combination of Empagliflozin and Metformin Therapy: A Consideration of its Place in Type 2 Diabetes Therapy. Clin Med Insights Endocrinol Diabetes. 2018;11:1179551418786258. DOI: 10.1177/1179551418786258 PMID: 30013414

Bodis K, Jelenik T, Lundbom J, Markgraf DF, Strom A, Zaharia OP, et al. Expansion and Impaired Mitochondrial Efficiency of Deep Subcutaneous Adipose Tissue in Recent-Onset Type 2 Diabetes. J Clin Endocrinol Metab. 2020;105(4):e1331-43. DOI: 10.1210/clinem/dgz267 PMID: 31838512

Lee PCH, Gu Y, Yeung MY, Fong CHY, Woo YC, Chow WS, et al. Dapagliflozin and Empagliflozin Ameliorate Hepatic Dysfunction Among Chinese Subjects with Diabetes in Part Through Glycemic Improvement: A Single-Center, Retrospective, Observational Study. Diabetes Ther. 2018;9(1):285-95. DOI: 10.1007/s13300-017-0355-3 PMID: 29322486


Refbacks

  • There are currently no refbacks.


Copyright (c) 2023 © The Author(s)

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.