McGuire, D. K. et al. Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: a meta-analysis. JAMA Cardiol. 6, 148–158 (2021).

Article  PubMed  Google Scholar 

US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04564742 (2023).

US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04509674 (2023).

McDonagh, T. A. et al. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur. Heart J. 42, 3599–3726 (2021).

Article  CAS  PubMed  Google Scholar 

Heidenreich, P. A. et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J. Am. Coll. Cardiol. 79, 1757–1780 (2022).

Article  PubMed  Google Scholar 

UK Kidney Association. UK Kidney Association clinical practice guideline: sodium-glucose co-transporter-2 (SGLT-2) inhibition in adults with kidney disease.https://ukkidney.org/sites/renal.org/files/UKKA%20guideline_SGLT2i%20in%20adults%20with%20kidney%20disease%20v1%2020.10.21.pdf (2021).

Cowie, M. R. & Fisher, M. SGLT2 inhibitors: mechanisms of cardiovascular benefit beyond glycaemic control. Nat. Rev. Cardiol. 17, 761–772 (2020).

Article  CAS  PubMed  Google Scholar 

Youssef, M. E. et al. Unlocking the full potential of SGLT2 inhibitors: expanding applications beyond glycemic control. Int. J. Mol. Sci. 24, 6039 (2023).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Curthoys, N. P. & Moe, O. W. Proximal tubule function and response to acidosis. Clin. J. Am. Soc. Nephrol. 9, 1627–1638 (2014).

Article  CAS  PubMed  Google Scholar 

Hou, Y. C., Zheng, C. M., Yen, T. H. & Lu, K. C. Molecular mechanisms of SGLT2 inhibitor on cardiorenal protection. Int. J. Mol. Sci. 21, 7833 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Heerspink, H. J., Perkins, B. A., Fitchett, D. H., Husain, M. & Cherney, D. Z. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications. Circulation 134, 752–772 (2016).

Article  CAS  PubMed  Google Scholar 

Cherney, D. Z., Kanbay, M. & Lovshin, J. A. Renal physiology of glucose handling and therapeutic implications. Nephrol. Dial. Transpl. 35, i3–i12 (2020).

Article  CAS  Google Scholar 

Zaccardi, F. et al. Efficacy and safety of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes mellitus: systematic review and network meta-analysis. Diabetes Obes. Metab. 18, 783–794 (2016).

Article  CAS  PubMed  Google Scholar 

DeFronzo, R. A. et al. Characterization of renal glucose reabsorption in response to dapagliflozin in healthy subjects and subjects with type 2 diabetes. Diabetes Care 36, 3169–3176 (2013).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Ojima, A., Matsui, T., Nishino, Y., Nakamura, N. & Yamagishi, S. Empagliflozin, an inhibitor of sodium-glucose cotransporter 2 exerts anti-inflammatory and antifibrotic effects on experimental diabetic nephropathy partly by suppressing AGEs-receptor axis. Horm. Metab. Res. 47, 686–692 (2015).

Article  CAS  PubMed  Google Scholar 

Yang, L. et al. Dapagliflozin alleviates advanced glycation end product induced podocyte injury through AMPK/mTOR mediated autophagy pathway. Cell Signal. 90, 110206 (2022).

Article  CAS  PubMed  Google Scholar 

Thomas, M. C. & Cherney, D. Z. I. The actions of SGLT2 inhibitors on metabolism, renal function and blood pressure. Diabetologia 61, 2098–2107 (2018).

Article  CAS  PubMed  Google Scholar 

Cravedi, P. & Remuzzi, G. Pathophysiology of proteinuria and its value as an outcome measure in chronic kidney disease. Br. J. Clin. Pharmacol. 76, 516–523 (2013).

Article  PubMed  PubMed Central  Google Scholar 

Karg, M. V. et al. SGLT-2-inhibition with dapagliflozin reduces tissue sodium content: a randomised controlled trial. Cardiovasc. Diabetol. 17, 5 (2018).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Hallow, K. M., Helmlinger, G., Greasley, P. J., McMurray, J. J. V. & Boulton, D. W. Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis. Diabetes Obes. Metab. 20, 479–487 (2018).

Article  CAS  PubMed  Google Scholar 

Uthman, L. et al. Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: inhibition of Na+/H+ exchanger, lowering of cytosolic Na(+) and vasodilation. Diabetologia 61, 722–726 (2018).

Article  CAS  PubMed  Google Scholar 

Trum, M., Riechel, J. & Wagner, S. Cardioprotection by SGLT2 inhibitors-does it all come down to Na+? Int. J. Mol. Sci. 22, 7976 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Peyton, K. J., Behnammanesh, G., Durante, G. L. & Durante, W. Canagliflozin inhibits human endothelial cell inflammation through the induction of heme oxygenase-1. Int. J. Mol. Sci. 23, 8777 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Campbell, N. K., Fitzgerald, H. K. & Dunne, A. Regulation of inflammation by the antioxidant haem oxygenase 1. Nat. Rev. Immunol. 21, 411–425 (2021).

Article  CAS  PubMed  Google Scholar 

Consoli, V., Sorrenti, V., Grosso, S. & Vanella, L. Heme oxygenase-1 signaling and redox homeostasis in physiopathological conditions. Biomolecules 11, 589 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Gager, G. M. et al. Effects of SGLT2 inhibitors on ion homeostasis and oxidative stress associated mechanisms in heart failure. Biomed. Pharmacother. 143, 112169 (2021).

Article  CAS  PubMed  Google Scholar 

Oraby, M. A., El-Yamany, M. F., Safar, M. M., Assaf, N. & Ghoneim, H. A. Dapagliflozin attenuates early markers of diabetic nephropathy in fructose-streptozotocin-induced diabetes in rats. Biomed. Pharmacother. 109, 910–920 (2019).

Article  CAS  PubMed  Google Scholar 

Ye, Y., Bajaj, M., Yang, H. C., Perez-Polo, J. R. & Birnbaum, Y. SGLT-2 inhibition with dapagliflozin reduces the activation of the Nlrp3/ASC inflammasome and attenuates the development of diabetic cardiomyopathy in mice with type 2 diabetes. Further augmentation of the effects with saxagliptin, a DPP4 inhibitor. Cardiovasc. Drugs Ther. 31, 119–132 (2017).

Article  PubMed  Google Scholar 

Niu, Y. et al. Canagliflozin ameliorates NLRP3 inflammasome-mediated inflammation through inhibiting NF-kappaB signaling and upregulating Bif-1. Front. Pharmacol. 13, 820541 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Abdollahi, E. et al. Dapagliflozin exerts anti-inflammatory effects via inhibition of LPS-induced TLR-4 overexpression and NF-kappaB activation in human endothelial cells and differentiated macrophages. Eur. J. Pharmacol. 918, 174715 (2022).

Article  CAS  PubMed  Google Scholar 

Skrabic, R. et al. SGLT2 inhibitors in chronic kidney disease: from mechanisms to clinical practice. Biomedicines 10, 2458 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Androutsakos, T. et al. SGLT-2 inhibitors in NAFLD: expanding their role beyond diabetes and cardioprotection. Int. J. Mol. Sci. 23, 3107 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Lupsa, B. C., Kibbey, R. G. & Inzucchi, S. E. Ketones: the double-edged sword of SGLT2 inhibitors? Diabetologia 66, 23–32 (2023).

Article  CAS  PubMed  Google Scholar 

Ferrannini, E. et al. Shift to fatty substrate utilization in response to sodium-glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes. Diabetes 65, 1190–1195 (2016).

Article  CAS  PubMed  Google Scholar 

Youm, Y. H. et al. The ketone metabolite beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat. Med. 21, 263–269 (2015).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Swanson, K. V., Deng, M. & Ting, J. P. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat. Rev. Immunol. 19, 477–489 (2019).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Tomita, I. et al. SGLT2 inhibition mediates protection from diabetic kidney disease by promoting ketone body-induced mTORC1 inhibition. Cell Metab. 32, 404–419.e6 (2020).

Article  CAS  PubMed  Google Scholar 

Heerspink, H. J. L. et al. Canagliflozin reduces inflammation and fibrosis biomarkers: a potential mechanism of action for beneficial effects of SGLT2 inhibitors in diabetic kidney disease. Diabetologia 62, 1154–1166 (2019).