The cellular and molecular mechanisms mediating the protective effects of sodium–glucose linked transporter 2 inhibitors against metabolic dysfunction‐associated fatty liver disease

Na Ao; Jian Du; Shi Jin; Linna Suo; Jing Yang

doi:10.1111/dom.16043

journal article Nov 07, 2024

The cellular and molecular mechanisms mediating the protective effects of sodium–glucose linked transporter 2 inhibitors against metabolic dysfunction‐associated fatty liver disease

Na Ao Jian Du

Shi Jin

Linna Suo Jing Yang

Diabetes, Obesity and Metabolism Vol. 27 No. 2 pp. 457-467 · Wiley

View at Publisher Save 10.1111/dom.16043

Abstract

Abstract

Metabolic dysfunction‐associated fatty liver disease (MAFLD), formerly known as nonalcoholic fatty liver disease (NAFLD), is a common, highly heterogeneous condition that affects about a quarter of the world's population, with no approved drug therapy. Current evidence from preclinical research and a number of small clinical trials indicates that SGLT2 inhibitors could also be effective for MAFLD. MAFLD is associated with a higher risk of chronic liver disease and multiple extrahepatic events, especially cardiovascular disease (CVD) and chronic kidney disease (CKD). MAFLD is considered a more appropriate terminology than NAFLD because it captures the complex bidirectional interplay between fatty liver and metabolic dysfunctions associated with disease progression, such as obesity and type 2 diabetes mellitus (T2DM). SGLT2 inhibitors are antidiabetic drugs that block glucose reabsorption in the kidney proximal tubule. In this article, we reviewed current clinical evidence supporting the potential use of SGLT2 inhibitors as a drug therapy for MAFLD and discussed the possible cellular and molecular mechanisms involved. We also reviewed the clinical benefits of SGLT2 inhibitors against MAFLD‐related comorbidities, especially CVD, CKD and cardiovascular–kidney–metabolic syndrome (CKM). The broad beneficial effects of SGLT2 inhibitors support their use, likely in combination with other drugs, as a therapy for MAFLD.

Topics

No keywords indexed for this article. Browse by subject →

References

107

[1]

10.1210/endrev/bnz009

[2]

MAFLD: A Consensus-Driven Proposed Nomenclature for Metabolic Associated Fatty Liver Disease

Mohammed Eslam, Arun J. Sanyal, Jacob George et al.

Gastroenterology 10.1053/j.gastro.2019.11.312

[3]

10.1007/s12072-023-10568-z

[4]

10.1111/liv.15422

[5]

10.1007/s12072-022-10408-6

[6]

10.1016/j.hbpd.2022.05.007

[7]

A multisociety Delphi consensus statement on new fatty liver disease nomenclature

Mary E. Rinella, Jeffrey V. Lazarus, Vlad Ratziu et al.

Journal of Hepatology 10.1016/j.jhep.2023.06.003

[8]

10.1016/j.jhep.2023.07.021

[9]

10.1111/jgh.13856

[10]

A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis

Stephen A. Harrison, Pierre Bedossa, Cynthia D. Guy et al.

New England Journal of Medicine 10.1056/nejmoa2309000

[11]

10.1016/j.tips.2019.05.002

[12]

10.1111/hepr.13425

[13]

10.1007/s12072-024-10698-y

[14]

10.31083/j.fbl2805103

[15]

Biology of Human Sodium Glucose Transporters

Ernest M. Wright, Donald D. F. Loo, Bruce A. Hirayama

Physiological Reviews 10.1152/physrev.00055.2009

[16]

10.1016/j.bcp.2015.09.005

[17]

10.1517/14728222.2016.1168808

[18]

10.1186/s12933-019-0828-y

[19]

10.1016/j.molmet.2018.10.009

[20]

10.1007/s00125-018-4654-7

[21]

10.14797/mdcvj.1120

[22]

10.1016/j.curtheres.2017.07.002

[23]

10.2147/dmso.s184767

[24]

10.2337/dc18-0165

[25]

10.1097/hep.0000000000000855

[26]

10.1007/s00125-018-4675-2

[27]

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

Masanori Shimizu, Kunihiro Suzuki, Kanako Kato et al.

Diabetes, Obesity and Metabolism 10.1111/dom.13520

[28]

Chehrehgosha H "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)

[29]

10.1007/s10620-019-5477-1

[30]

10.1111/hepr.13304

[31]

10.1002/hep4.1696

[32]

10.3390/jcm9010259

[33]

10.2337/dc21-2049

[34]

10.1136/bmjdrc-2020-001990

[35]

10.1111/hepr.13236

[36]

10.1002/hep.23527

[37]

10.1038/s41598-018-19658-7

[38]

10.18632/oncotarget.16874

[39]

10.1002/ijc.31193

[40]

10.1210/endocr/bqab157

[41]

Xu L "Emerging roles of SGLT2 inhibitors in obesity and insulin resistance: focus on fat browning and macrophage polarization" Adipocyte (2018)

[42]

10.1371/journal.pone.0146337

[43]

10.1371/journal.pone.0151511

[44]

10.1016/j.ejphar.2018.03.043

[45]

10.1111/jphp.12223

[46]

10.1016/j.mce.2019.110539

[47]

10.3390/ijms22020818

[48]

10.1186/s13098-016-0169-x

[49]

Ferroptosis in Liver Diseases: An Overview

Martina Maria Capelletti, Hana Manceau, Hervé Puy et al.

International Journal of Molecular Sciences 10.3390/ijms21144908

[50]

Zhang H "Role of ferroptosis in non‐alcoholic fatty liver disease and its implications for therapeutic strategies" Biomedicine (2021)

Showing 50 of 107 references

Cited By

5

Metabolic dysfunction-associated steatotic liver disease and type 2 diabetes: Pathophysiology, diagnosis, and emerging therapeutic strategies

Mithil Gowda Suresh, Safia Mohamed · 2026

World Journal of Diabetes

Metrics

5

Citations

107

References

Details

Published: Nov 07, 2024
Vol/Issue: 27(2)
Pages: 457-467
License: View

Authors

N

Na Ao