Protective Potential of Sodium-Glucose Cotransporter 2 Inhibitors in Internal Medicine (Part 2)

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are now uncovering new possibilities in the field of internal medicine owing to their diverse protective effects. In the second part of the literature review, we explore potential applications of SGLT2i in hepatology, neurology, ophthalmology, and oncology, mechanisms of action of such drugs as dapagliflozin, empagliflozin, canagliflozin, etc, and their effect on different organs and systems.

1. Vafa RG, Sabahizadeh A, Mofarrah R. Guarding the heart: how SGLT-2 inhibitors protect against chemotherapy-induced cardiotoxicity: SGLT-2 inhibitors and chemotherapy-induced cardiotoxicity. Curr Probl Cardiol. 2024;49(3):102350. PMID: 38128634. https://doi.org/10.1016/j.cpcardiol.2023.102350

2. Lin L, Zhong S, Zhou Y, et al. Dapagliflozin improves the dysfunction of human umbilical vein endothelial cells (HUVECs) by downregulating high glucose/high fat-induced autophagy through inhibiting SGLT-2. J Diabetes Complications. 2025;39(1):108907. PMID: 39580877. https://doi.org/10.1016/j.jdiacomp.2024.108907

3. AvagimyanAA, Sheibani M, TrofimenkoAI, et al. Protective potential of sodium-glucose cotransporter 2 inhibitors in internal medicine (part 1). Innovative Medicine of Kuban. 2024;9(4):126– 135. https://doi.org/10.35401/2541-9897-2024-9-4-126-135

4. Bhanushali KB, Asnani HK, Nair A, Ganatra S, Dani SS. Pharmacovigilance study for SGLT 2 inhibitors- safety review of real-world data & randomized clinical trials. Curr Probl Cardiol. 2024;49(9):102664. https://doi.org/10.1016/j.cpcardiol.2024.102664

5. Pouwels S, Sakran N, Graham Y, 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. PMID: 35287643. PMCID: PMC8919523. https://doi.org/10.1186/s12902-022-00980-1

6. Nassir F. NAFLD: mechanisms, treatments, and biomarkers. Biomolecules. 2022;12(6):824. PMID: 35740949. PMCID: PMC9221336. https://doi.org/10.3390/biom12060824

7. Nakano D, Akiba J, Tsutsumi T, et al. Hepatic expression of sodium-glucose cotransporter 2 (SGLT2) in patients with chronic liver disease. Med Mol Morphol. 2022;55(4):304–315. PMID: 36131166. PMCID: PMC9606064. https://doi.org/10.1007/s00795-022-00334-9

8. Cusi K, Bril F, Barb D, et al. Effect of canagliflozin treatment on hepatic triglyceride content and glucose metabolism in patients with type 2 diabetes. Diabetes Obes Metab. 2019;21(4):812– 821. PMID: 30447037. https://doi.org/10.1111/dom.13584

9. Calapkulu M, Cander S, Gul OO, Ersoy C. Lipid profile in type 2 diabetic patients with new dapagliflozin treatment; actual clinical experience data of six months retrospective lipid profile from single center. Diabetes Metab Syndr. 2019;13(2):1031–1034. PMID: 31336439. https://doi.org/10.1016/j.dsx.2019.01.016

10. Akuta N, Watanabe C, Kawamura Y, et al. Effects of a sodium-glucose cotransporter 2 inhibitor in nonalcoholic fatty liver disease complicated by diabetes mellitus: preliminary prospective study based on serial liver biopsies. Hepatol Commun. 2017;1(1):46–52. PMID: 29404432. PMCID: PMC5747031. https://doi.org/10.1002/hep4.1019

11. 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):623–631. PMID: 30684076. https://doi.org/10.1007/s10620-019-5477-1

12. Bellanti F, Lo Buglio A, Dobrakowski M, et al. Impact of sodium glucose cotransporter-2 inhibitors on liver steatosis/fibrosis/inflammation and redox balance in non-alcoholic fatty liver disease. World J Gastroenterol. 2022;28(26):3243–3257. PMID: 36051336. PMCID: PMC9331534. https://doi.org/10.3748/wjg.v28.i26.3243

13. Arai T, Atsukawa M, Tsubota A, et al. Antifibrotic effect and long-term outcome of SGLT2 inhibitors in patients with NAFLD complicated by diabetes mellitus. Hepatol Commun. 2022;6(11):3073–3082. PMID: 36039537. PMCID: PMC9592771. https://doi.org/10.1002/hep4.2069

14. Sakurai S, Jojima T, Iijima T, Tomaru T, Usui I, Aso Y. Empagliflozin decreases the plasma concentration of plasminogen activator inhibitor-1 (PAI-1) in patients with type 2 diabetes: association with improvement of fibrinolysis. J Diabetes Complications. 2020;34(11):107703. PMID: 32883567. https://doi.org/10.1016/j.jdiacomp.2020.107703

15. Arai T, Atsukawa M, Tsubota A, et al. Effect of sodiumglucose cotransporter 2 inhibitor in patients with non-alcoholic fatty liver disease and type 2 diabetes mellitus: a propensity score-matched analysis of real-world data. Ther Adv Endocrinol Metab. 2021;12:20420188211000243. PMID: 33815743. PMCID: PMC7989116. https://doi.org/10.1177/20420188211000243

16. Xing B, Zhao Y, Dong B, Lv W, Zhao W. Effects of sodium-glucose cotransporter 2 inhibitors on non-alcoholic fatty liver disease in patients with type 2 diabetes: a meta-analysis of randomized controlled trials. J Diabetes Investig. 2020;11(5):1238– 1247. PMID: 32083798. PMCID: PMC7477503. https://doi.org/10.1111/jdi.13237

17. Simental-Mendía M, Sánchez-García A, RodríguezRamírez M, Simental-Mendía LE. Effect of sodium-glucose co-transporter 2 inhibitors on hepatic parameters: a systematic review and meta-analysis of randomized controlled trials. Pharmacol Res. 2021;163:105319. PMID: 33246172. https://doi.org/10.1016/j.phrs.2020.105319

18. Zhou P, Tan Y, Hao Z, et al. Effects of SGLT2 inhibitors on hepatic fibrosis and steatosis: a systematic review and metaanalysis. Front Endocrinol (Lausanne). 2023;14:1144838. PMID: 36936142. PMCID: PMC10014961. https://doi.org/10.3389/fendo.2023.1144838

19. Kalantari E, Zolbanin NM, Ghasemnejad-Berenji M. Protective effects of empagliflozin on methotrexate induced hepatotoxicity in rats. Biomed Pharmacother. 2024;170:115953. PMID: 38064971. https://doi.org/10.1016/j.biopha.2023.115953

20. Satyam SM, Bairy LK, Rehman A, et al. Dapagliflozin: a promising strategy to combat cisplatin-induced hepatotoxicity in Wistar rats. Biology (Basel). 2024;13(9):672. PMID: 39336099. PMCID: PMC11428795. https://doi.org/10.3390/biology13090672

21. Teshev AF, Malyshev AV, Golovin AS. Proliferative diabetic retinopathy in severe stages: modern approaches to diagnosis and treatment (systematic review). Russian Medicine. 2024;30(1):77– 85. (In Russ.). https://doi.org/10.17816/medjrf624868

22. Wong TY, Sabanayagam C. Strategies to tackle the global burden of diabetic retinopathy: from epidemiology to artificial intelligence. Ophthalmologica. 2020;243(1):9–20. PMID: 31408872. https://doi.org/10.1159/000502387

23. Lahoti S, Nashawi M, Sheikh O, Massop D, Mir M, ChiltonR. Sodium-glucose co-transporter 2 inhibitors and diabetic retinopathy: insights into preservation of sight and looking beyond. Cardiovasc Endocrinol Metab. 2020;10(1):3–13. PMID: 33634250. PMCID: PMC7901818. https://doi.org/10.1097/XCE.0000000000000209

24. Nadelmann JB, Miller CG, McGeehan B, Yu Y, VanderBeek BL. SGLT2 inhibitors and diabetic retinopathy progression. Graefes Arch Clin Exp Ophthalmol. 2024;262(3):753–758. PMID: 37847267. PMCID: PMC11196159. https://doi.org/10.1007/s00417-023-06273-0

25. Yen FS, Wei JC, Yu TS, Hung YT, Hsu CC, Hwu CM. Sodium-glucose cotransporter 2 inhibitors and risk of retinopathy in patients with type 2 diabetes. JAMA Netw Open. 2023;6(12):e2348431. PMID: 38117497. PMCID: PMC10733799. https://doi.org/10.1001/jamanetworkopen.2023.48431

26. Benlarbi-Ben Khedher M, Hajri K, Dellaa A, et al. Astaxanthin inhibits aldose reductase activity in Psammomys obesus, a model of type 2 diabetes and diabetic retinopathy. Food Sci Nutr. 2019;7(12):3979–3985. PMID: 31890176. PMCID: PMC6924305. https://doi.org/10.1002/fsn3.1259

27. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321(7258):405–412. PMID: 10938048. PMCID: PMC27454. https://doi.org/10.1136/bmj.321.7258.405

28. American Diabetes Association. 1. Improving Care and Promoting Health in Populations: Standards of Medical Care in Diabetes-2020. Diabetes Care. 2020;43(Suppl 1):S7–S13. PMID: 31862744. https://doi.org/10.2337/dc20-S001

29. Ott C, Jumar A, Striepe K, et al. A randomised study of the impact of the SGLT2 inhibitor dapagliflozin on microvascular and macrovascular circulation. Cardiovasc Diabetol. 2017;16(1):26. PMID: 28231831. PMCID: PMC5324272. https://doi.org/10.1186/s12933-017-0510-1

30. Yoshizumi H, Ejima T, Nagao T, Wakisaka M. Recovery from diabetic macular edema in a diabetic patient after minimal dose of a sodium glucose co-transporter 2 inhibitor. Am J Case Rep. 2018;19:462–466. PMID: 29670074. PMCID: PMC5928754. https://doi.org/10.12659/ajcr.909708

31. Straznicky NE, Grima MT, Eikelis N, et al. The effects of weight loss versus weight loss maintenance on sympathetic nervous system activity and metabolic syndrome components. J Clin Endocrinol Metab. 2011;96(3):E503–E508. PMID: 21177786. https://doi.org/10.1210/jc.2010-2204

32. Thorp AA, Schlaich MP. Relevance of sympathetic nervous system activation in obesity and metabolic syndrome. J Diabetes Res. 2015;2015:341583. PMID: 26064978. PMCID: PMC4430650. https://doi.org/10.1155/2015/341583

33. Matthews VB, Elliot RH, Rudnicka C, Hricova J, Herat L, Schlaich MP. Role of the sympathetic nervous system in regulation of the sodium glucose cotransporter 2. J Hypertens. 2017;35(10):2059–2068. PMID: 28598954. https://doi.org/10.1097/HJH.0000000000001434

34. Cunningham C, Jabri A, Alhuneafat L, Aneja A. A comprehensive guide to sodium glucose cotransport inhibitors. Curr Probl Cardiol. 2023;48(10):101817. PMID: 37211299. https://doi.org/10.1016/j.cpcardiol.2023.101817

35. WangS, XuL, JonasJB, etal. Major eye diseases and risk factors associated with systemic hypertension in an adult Chinese population: the Beijing Eye Study. Ophthalmology. 2009;116(12):2373–2380. PMID: 19815279. https://doi.org/10.1016/j.ophtha.2009.05.041

36. Zhang HY, Wang JY, Ying GS, Shen LP, Zhang Z. Serum lipids and other risk factors for diabetic retinopathy in Chinese type 2 diabetic patients. J Zhejiang Univ Sci B. 2013;14(5):392–399. PMID: 23645176. PMCID: PMC3650453. https://doi.org/10.1631/jzus.B1200237

37. Filippas-Ntekouan S, Tsimihodimos V, Filippatos T, Dimitriou T, Elisaf M. SGLT-2 inhibitors: pharmacokinetics characteristics and effects on lipids. Expert Opin Drug Metab Toxicol. 2018;14(11):1113–1121. PMID: 30360662. https://doi.org/10.1080/17425255.2018.1541348

38. LiJX, HungYT, Bair H, Hsu SB, Hsu CY, Lin CJ. Sodiumglucose co-transporter 2 inhibitor add-on therapy for metformin delays diabetic retinopathy progression in diabetes patients: a population-based cohort study. Sci Rep. 2023;13(1):17049. PMID: 37816862. PMCID: PMC10564914. https://doi.org/10.1038/s41598-023-43893-2

39. Pascale RM, Calvisi DF, Simile MM, Feo CF, Feo F. The Warburg effect 97 years after its discovery. Cancers (Basel). 2020;12(10):2819. PMID: 33008042. PMCID: PMC7599761. https://doi.org/10.3390/cancers12102819

40. Wang Y, Patti GJ. The Warburg effect: a signature of mitochondrial overload. Trends Cell Biol. 2023;33(12):1014– 1020. PMID: 37117116. PMCID: PMC10600323. https://doi.org/10.1016/j.tcb.2023.03.013

41. Naeimzadeh Y, Tajbakhsh A, Nemati M, Fallahi J. Exploring the anti-cancer potential of SGLT2 inhibitors in breast cancer treatment in pre-clinical and clinical studies. Eur J Pharmacol. 2024;978:176803. PMID: 38950839. https://doi.org/10.1016/j.ejphar.2024.176803

42. Basak D, Gamez D, Deb S. SGLT2 inhibitors as potential anticancer agents. Biomedicines. 2023;11(7):1867. PMID: 37509506. PMCID: PMC10376602. https://doi.org/10.3390/biomedicines11071867

43. Dhas Y, Biswas N, M R D, Jones LD, Ashili S. Repurposing metabolic regulators: antidiabetic drugs as anticancer agents. Mol Biomed. 2024;5(1):40. PMID: 39333445. PMCID: PMC11436690. https://doi.org/10.1186/s43556-024-00204-z

44. Masoudkabir F, Mohammadifard N, Mani A, et al. Shared lifestyle-related risk factors of cardiovascular disease and cancer: evidence for joint prevention. ScientificWorldJournal. 2023;2023:2404806. PMID: 37520844. PMCID: PMC10386903. https://doi.org/10.1155/2023/2404806

45. Phoomak C, Vaeteewoottacharn K, Silsirivanit A, et al. High glucose levels boost the aggressiveness of highly metastatic cholangiocarcinoma cells via O-GlcNAcylation. Sci Rep. 2017;7:43842. PMID: 28262738. PMCID: PMC5338328. https://doi.org/10.1038/srep43842

46. Zhou J, Zhu J, Yu SJ, et al. Sodium-glucose co-transporter-2 (SGLT-2) inhibition reduces glucose uptake to induce breast cancer cell growth arrest through AMPK/mTOR pathway. Biomed Pharmacother. 2020;132:110821. PMID: 33068934. https://doi.org/10.1016/j.biopha.2020.110821

47. Villani LA, Smith BK, Marcinko K, et al. The diabetes medication Canagliflozin reduces cancer cell proliferation by inhibiting mitochondrial complex-I supported respiration. Mol Metab. 2016;5(10):1048–1056. PMID: 27689018. PMCID: PMC5034684. https://doi.org/10.1016/j.molmet.2016.08.014

48. Kennedy SP, O’Neill M, Cunningham D, et al. Preclinical evaluation of a novel triple-acting PIM/PI3K/mTOR inhibitor, IBL-302, in breast cancer. Oncogene. 2020;39(14):3028–3040. PMID: 32042115. PMCID: PMC7118022. https://doi.org/10.1038/s41388-020-1202-y

49. Nakano D, Kawaguchi T, Iwamoto H, Hayakawa M, Koga H, Torimura T. Effects of canagliflozin on growth and metabolic reprograming in hepatocellular carcinoma cells: multi-omics analysis of metabolomics and absolute quantification proteomics (iMPAQT). PLoS One. 2020;15(4):e0232283. PMID: 32343721. PMCID: PMC7188283. https://doi.org/10.1371/journal.pone.0232283

50. Yu N, Kakunda M, Pham V, et al. HSP105 recruits protein phosphatase 2A to dephosphorylate β-catenin. Mol Cell Biol. 2015;35(8):1390–1400. PMID: 25645927. PMCID: PMC4372692. https://doi.org/10.1128/MCB.01307-14

51. Puglisi S, Rossini A, Poli R, et al. Effects of SGLT2 inhibitors and GLP-1 receptor agonists on renin-angiotensin-aldosterone system. Front Endocrinol (Lausanne). 2021;12:738848. PMID: 34745006. PMCID: PMC8567993. https://doi.org/10.3389/fendo.2021.738848

52. Cappetta D, De Angelis A, Bellocchio G, et al. Sodium-glucose cotransporter 2 inhibitors and heart failure: a bedside-to-bench journey. Front Cardiovasc Med. 2021;8:810791. PMID: 35004918. PMCID: PMC8733295. https://doi.org/10.3389/fcvm.2021.810791

53. Liu T, Wu J, Shi S, et al. Dapagliflozin attenuates cardiac remodeling and dysfunction in rats with β-adrenergic receptor overactivation through restoring calcium handling and suppressing cardiomyocyte apoptosis. Diab Vasc Dis Res. 2023;20(4):14791641231197106. PMID: 37589258. PMCID: PMC10437211. https://doi.org/10.1177/14791641231197106

54. Avagimyan A, Kakturskiy L, Heshmat-Ghahdarijani K, Pogosova N, Sarrafzadegan N. Anthracycline associated disturbances of cardiovascular homeostasis. Curr Probl Cardiol. 2022;47(5):100909. PMID: 34167841. https://doi.org/10.1016/j.cpcardiol.2021.100909

55. Avagimyan AA, Trofimenko AI, Sheibani M, et al. Comparison of cardioprotective effects of dapagliflozin and trimetazidine in the model of doxorubicin-cyclophosphamide cardiotoxicity. Innovative Medicine of Kuban. 2023;8(4):6–14. (In Russ.). https://doi.org/10.35401/2541-9897-2023-8-4-6-14

56. Avagimyan A, Kakturskiy L, Pogosova N, Ottaviani G, Rizzo M, Sarrafzadegan N. Doxorubicin and cyclophosphamide mode of chemotherapy-related cardiomyopathy: review of preclinical model. Curr Probl Cardiol. 2025;50(1):102882. PMID: 39427867. https://doi.org/10.1016/j.cpcardiol.2024.102882

57. Avagimyan A, Pogosova N, Kakturskiy L, et al. Doxorubicin-related cardiotoxicity: review of fundamental pathways of cardiovascular system injury. Cardiovasc Pathol. 2024;73:107683. PMID: 39111556. https://doi.org/10.1016/j.carpath.2024.107683

58. Avagimyan A, Sheibani M, Pogosova N, et al. Possibilities of dapagliflozin-induced cardioprotection on doxorubicin+cyclophosphamide mode of chemotherapy-induced cardiomyopathy. Int J Cardiol. 2023;391:131331. PMID: 37666280. https://doi.org/10.1016/j.ijcard.2023.131331

59. Simanenkova AV, Fuks OS, Timkina NV, et al. Highly selective sodium-glucose co-transporter type 2 inhibitor empagliflozinas means of brain protection in conditions of chronic brain dyscirculation. Probl Endokrinol (Mosk). 2024;70(4):44–56. PMID: 39302864. PMCID: PMC11551795. (In Russ.). https://doi.org/10.14341/probl13336

60. Youssef ME, Yahya G, Popoviciu MS, Cavalu S, Abd-Eldayem MA, Saber S. Unlocking the full potential of SGLT2 inhibitors: expanding applications beyond glycemic control. Int J Mol Sci. 2023;24(7):6039. PMID: 37047011. PMCID: PMC10094124. https://doi.org/10.3390/ijms24076039

61. Mone P, Varzideh F, Jankauskas SS, et al. SGLT2 inhibition via empagliflozin improves endothelial function and reduces mitochondrial oxidative stress: insights from frail hypertensive and diabetic patients. Hypertension. 2022;79(8):1633–1643. PMID: 35703100. PMCID: PMC9642044. https://doi.org/10.1161/HYPERTENSIONAHA.122.19586

62. Zügner E, Yang HC, Kotzbeck P, et al. Differential in vitro effects of SGLT2 inhibitors on mitochondrial oxidative phosphorylation, glucose uptake and cell metabolism. Int J Mol Sci. 2022;23(14):7966. PMID: 35887308. PMCID: PMC9319636. https://doi.org/10.3390/ijms23147966

63. Pawlos A, Broncel M, Woźniak E, Gorzelak-Pabiś P. Neuroprotective effect of SGLT2 inhibitors. Molecules. 2021;26(23):7213. PMID: 34885795. PMCID: PMC8659196. https://doi.org/10.3390/molecules26237213

64. Shaikh S, Rizvi SM, Shakil S, Riyaz S, Biswas D, Jahan R. Forxiga (dapagliflozin): plausible role in the treatment of diabetes-associated neurological disorders. Biotechnol Appl Biochem. 2016;63(1):145–150. PMID: 25402624. https://doi.org/10.1002/ bab.1319

65. Miranda M, Morici JF, Zanoni MB, Bekinschtein P. Brain-derived neurotrophic factor: a key molecule for memory in the healthy and the pathological brain. Front Cell Neurosci. 2019;13:363. PMID: 31440144. PMCID: PMC6692714. https://doi.org/10.3389/fncel.2019.00363

66. Liu J, Shi X, Shao Y. Sodium-glucose cotransporter 1/2 inhibition and risk of neurodegenerative disorders: a Mendelian randomization study. Brain Behav. 2024;14(7):e3624. PMID: 39010704. PMCID: PMC11250420. https://doi.org/10.1002/brb3.3624

67. Lardaro A, Quarta L, Pagnotta S, et al. Impact of sodium glucose cotransporter 2 inhibitors (SGLT2i) therapy on dementia and cognitive decline. Biomedicines. 2024;12(8):1750. PMID: 39200215. PMCID: PMC11351143. https://doi.org/10.3390/biomedicines12081750

68. Shourav MMI, Anisetti B, Meschia J, Lin M. Effects of sodium-glucose co-transporter 2 inhibitors on cognition in patients with diabetes: a systematic review and meta-analysis (P11-9.002). Neurology. 2024;102(17_supplement_1). https://doi.org/10.1212/wnl.0000000000205318

69. YounYJ, Kim S, Jeong HJ, AhYM, YuYM. Sodium-glucose cotransporter-2 inhibitors and their potential role in dementia onset and cognitive function in patients with diabetes mellitus: a systematic review and meta-analysis. Front Neuroendocrinol. 2024;73:101131. PMID: 38367940. https://doi.org/10.1016/j.yfrne.2024.101131.