Systemic and Organ-specific Anti-inflammatory Effects of Sodium-glucose Cotransporter-2 Inhibitors

Overview

Journal Trends Endocrinol Metab

Specialty Endocrinology

Date 2024 Feb 29

PMID 38423898

Authors

Mona Mashayekhi

Bilgunay Ilkin Safa

Matthew S C Gonzalez

Sangwon F Kim

Justin B Echouffo-Tcheugui

Affiliations

Soon will be listed here.

Abstract

Inflammation plays an essential role and is a common feature in the pathogenesis of many chronic diseases. The exact mechanisms through which sodium-glucose cotransporter-2 (SGLT2) inhibitors achieve their much-acclaimed clinical benefits largely remain unknown. In this review, we detail the systemic and tissue- or organ-specific anti-inflammatory effects of SGLT2 inhibitors using evidence from animal and human studies. We discuss the potential pathways through which SGLT2 inhibitors exert their anti-inflammatory effects, including oxidative stress, mitochondrial, and inflammasome pathways. Finally, we highlight the need for further investigation of the extent of the contribution of the anti-inflammatory effects of SGLT2 inhibition to improvements in cardiometabolic and renal outcomes in clinical studies.

Citing Articles

The Impact of Sodium-Glucose Co-Transporter-2 Inhibition on Insulin Resistance and Inflammation in Patients with Type 2 Diabetes: A Retrospective Study.

Iordan L, Lazar S, Timar R, Popescu S, Sorescu T, Albai O Medicina (Kaunas). 2025; 61(2).

PMID: 40005325 PMC: 11857714. DOI: 10.3390/medicina61020209.

Anti-Inflammatory Effects of SGLT2 Inhibitors: Focus on Macrophages.

Rykova E, Klimontov V, Shmakova E, Korbut A, Merkulova T, Kzhyshkowska J Int J Mol Sci. 2025; 26(4).

PMID: 40004134 PMC: 11854991. DOI: 10.3390/ijms26041670.

Inflammatory Trajectory of Type 2 Diabetes: Novel Opportunities for Early and Late Treatment.

Pellegrini V, La Grotta R, Carreras F, Giuliani A, Sabbatinelli J, Olivieri F Cells. 2024; 13(19.

PMID: 39404426 PMC: 11476093. DOI: 10.3390/cells13191662.

Relative efficacy of five SGLT2 inhibitors: a network meta-analysis of 20 cardiovascular and respiratory outcomes.

Huang L, Hu R, Zou H Front Pharmacol. 2024; 15:1419729.

PMID: 38933668 PMC: 11199404. DOI: 10.3389/fphar.2024.1419729.

References

Zaibi N, Li P, Xu S . Protective effects of dapagliflozin against oxidative stress-induced cell injury in human proximal tubular cells. PLoS One. 2021; 16(2):e0247234. PMC: 7894948. DOI: 10.1371/journal.pone.0247234. View

Youssef M, Abd El-Fattah E, Abdelhamid A, Eissa H, El-Ahwany E, Amin N . Interference With the AMPKα/mTOR/NLRP3 Signaling and the IL-23/IL-17 Axis Effectively Protects Against the Dextran Sulfate Sodium Intoxication in Rats: A New Paradigm in Empagliflozin and Metformin Reprofiling for the Management of Ulcerative.... Front Pharmacol. 2021; 12:719984. PMC: 8417441. DOI: 10.3389/fphar.2021.719984. View

Bica I, Stoica R, Salmen T, Janez A, Volcansek S, Popovic D . The Effects of Sodium-Glucose Cotransporter 2-Inhibitors on Steatosis and Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease or Steatohepatitis and Type 2 Diabetes: A Systematic Review of Randomized Controlled Trials. Medicina (Kaunas). 2023; 59(6). PMC: 10301940. DOI: 10.3390/medicina59061136. View

Sato T, Aizawa Y, Yuasa S, Fujita S, Ikeda Y, Okabe M . The Effect of Dapagliflozin Treatment on Epicardial Adipose Tissue Volume and P-Wave Indices: An Ad-hoc Analysis of The Previous Randomized Clinical Trial. J Atheroscler Thromb. 2020; 27(12):1348-1358. PMC: 7840164. DOI: 10.5551/jat.48009. View

Theofilis P, Sagris M, Oikonomou E, Antonopoulos A, Siasos G, Tsioufis K . The impact of SGLT2 inhibitors on inflammation: A systematic review and meta-analysis of studies in rodents. Int Immunopharmacol. 2022; 111:109080. DOI: 10.1016/j.intimp.2022.109080. View

Zhang X, Wang N, Fu P, An Y, Sun F, Wang C . Dapagliflozin Attenuates Heart Failure With Preserved Ejection Fraction Remodeling and Dysfunction by Elevating β-Hydroxybutyrate-activated Citrate Synthase. J Cardiovasc Pharmacol. 2023; 82(5):375-388. PMC: 10635406. DOI: 10.1097/FJC.0000000000001474. View

Sato T, Aizawa Y, Yuasa S, Kishi S, Fuse K, Fujita S . The effect of dapagliflozin treatment on epicardial adipose tissue volume. Cardiovasc Diabetol. 2018; 17(1):6. PMC: 5753537. DOI: 10.1186/s12933-017-0658-8. View

Takano M, Kondo H, Harada T, Takahashi M, Ishii Y, Yamasaki H . Empagliflozin Suppresses the Differentiation/Maturation of Human Epicardial Preadipocytes and Improves Paracrine Secretome Profile. JACC Basic Transl Sci. 2023; 8(9):1081-1097. PMC: 10544075. DOI: 10.1016/j.jacbts.2023.05.007. View

. Impact of diabetes on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes: collaborative meta-analysis of large placebo-controlled trials. Lancet. 2022; 400(10365):1788-1801. PMC: 7613836. DOI: 10.1016/S0140-6736(22)02074-8. View

10.

Bouchi R, Terashima M, Sasahara Y, Asakawa M, Fukuda T, Takeuchi T . Luseogliflozin reduces epicardial fat accumulation in patients with type 2 diabetes: a pilot study. Cardiovasc Diabetol. 2017; 16(1):32. PMC: 5335851. DOI: 10.1186/s12933-017-0516-8. View

11.

Zaghloul M, Elshal M, Abdelmageed M . Preventive empagliflozin activity on acute acetic acid-induced ulcerative colitis in rats via modulation of SIRT-1/PI3K/AKT pathway and improving colon barrier. Environ Toxicol Pharmacol. 2022; 91:103833. DOI: 10.1016/j.etap.2022.103833. View

12.

Takahashi H, Kessoku T, Kawanaka M, Nonaka M, Hyogo H, Fujii H . Ipragliflozin Improves the Hepatic Outcomes of Patients With Diabetes with NAFLD. Hepatol Commun. 2021; 6(1):120-132. PMC: 8710792. DOI: 10.1002/hep4.1696. View

13.

Pennig J, Scherrer P, Gissler M, Anto-Michel N, Hoppe N, Funer L . Glucose lowering by SGLT2-inhibitor empagliflozin accelerates atherosclerosis regression in hyperglycemic STZ-diabetic mice. Sci Rep. 2019; 9(1):17937. PMC: 6884628. DOI: 10.1038/s41598-019-54224-9. View

14.

Wiviott S, Raz I, Bonaca M, Mosenzon O, Kato E, Cahn A . Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2018; 380(4):347-357. DOI: 10.1056/NEJMoa1812389. View

15.

Zhao Y, Xu L, Tian D, Xia P, Zheng H, Wang L . Effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on serum uric acid level: A meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2017; 20(2):458-462. DOI: 10.1111/dom.13101. View

16.

Juni R, Kuster D, Goebel M, Helmes M, Musters R, van der Velden J . Cardiac Microvascular Endothelial Enhancement of Cardiomyocyte Function Is Impaired by Inflammation and Restored by Empagliflozin. JACC Basic Transl Sci. 2019; 4(5):575-591. PMC: 6872802. DOI: 10.1016/j.jacbts.2019.04.003. View

17.

Ke Q, Shi C, Lv Y, Wang L, Luo J, Jiang L . SGLT2 inhibitor counteracts NLRP3 inflammasome via tubular metabolite itaconate in fibrosis kidney. FASEB J. 2021; 36(1):e22078. DOI: 10.1096/fj.202100909RR. View

18.

Leng W, Wu M, Pan H, Lei X, Chen L, Wu Q . The SGLT2 inhibitor dapagliflozin attenuates the activity of ROS-NLRP3 inflammasome axis in steatohepatitis with diabetes mellitus. Ann Transl Med. 2019; 7(18):429. PMC: 6803170. DOI: 10.21037/atm.2019.09.03. View

19.

Abdelmageed M, Abdelrahman R . Canagliflozin attenuates thioacetamide-induced liver injury through modulation of HMGB1/RAGE/TLR4 signaling pathways. Life Sci. 2023; 322:121654. DOI: 10.1016/j.lfs.2023.121654. View

20.

Requena-Ibanez J, Santos-Gallego C, Rodriguez-Cordero A, Vargas-Delgado A, Mancini D, Sartori S . Mechanistic Insights of Empagliflozin in Nondiabetic Patients With HFrEF: From the EMPA-TROPISM Study. JACC Heart Fail. 2021; 9(8):578-589. DOI: 10.1016/j.jchf.2021.04.014. View