The SGLT2 pathway is also involved in the association between hyperglycemia and DN, and hyperglycemia has been linked to tubular senescence mediated in part via the SGLT2 pathway.11 The US Food and Drug Administration (FDA) has approved three SGLT2i agents for glucose-lowering in conjunction with diet and exercise for adults with type 2 diabetes: canagliflozin, dapagliflozin, and empagliflozin.12
Lytvyn and colleagues note that synergisms between SGLT2 inhibition and RAAS blockade might block two different pathways central to hyperfiltration and DN, and call for clinical studies of such dual-blockade strategies.1
“Current ongoing dedicated renal outcome trials have the potential to change clinical practice,” Lytvyn said.
1. Lytvyn Y, Bjornstad P, Pun N, Cherney DZI. New and old agents in the management of diabetic nephropathy. Current Opinion in Nephrology and Hypertension. 2016. (In press.) DOI: 10.1097/MNH.0000000000000214.
2. Satirapoj B, Adler SG. Comprehensive approach to diabetic nephropathy. Kidney Research and Clinical Practice. 2014;33:121-131.
3. Ahmad J. Management of diabetic nephropathy: recent progress and future perspectives. Diabetes & Metabolic Syndrome: Clinical Research & Reviews. 2015;9:343-358. DOI: 10.1016/j.dsx.2015.02.008.
4. Lv M, Chen Z, Hu G, Li Q. Therapeutic strategies of diabetic nephropathy: recent progress and future perspectives. Drug Discovery Today. 2015;20(3):332-346.
5. Usuelli V, La Rocca E. Novel therapeutic approaches for diabetic nephropathy and retinopathy. Pharmacological Research. 2015;98:39-44. DOI: 10.1016/j.phrs.2014.10.003.
6. National Institutes of Health. National Library of Medicine. Glomerular filtration rate: MedlinePlus Medical Encyclopedia. https://www.nlm.nih.gov/medlineplus/ency/article/007305.htm. Accessed March 19, 2016.
7. De Nicola L, Gabbai FB, Liberti ME, et al. Sodium/glucose cotransporter 2 inhibitors and prevention of diabetic nephropathy: targeting the renal tubule in diabetes. American Journal of Kidney Disease. 2014;64(1):16-24. http://www.ajkd.org/article/S0272-6386(14)00587-3/abstract.
8. Panchapakesan U, Pegg K, Gross S, et al. Effects of SGLT2 inhibition in human kidney proximal tubular cells—renoprotection in diabetic nephropathy? PLoS One. 2013;8(2):e54442. DOI: 10.1371/journal.pone.0054442.
9. Ishibashi Y, Matsui T, Yamagishi S. Tofogliflozin, a highly selective inhibitor of SGLT2 blocks proinflammatory and proapoptotic effects of glucose overload on proximal tubular cells partly by suppressing oxidative stress generation. Hormones and Metabolic Research. 2016;48(3):191-195. DOI: 10.1055/s-0035-1555791.
10. 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. Hormones and Metabolic Research. 2015;47(9):686-692. DOI: 10.1055/s-0034-1395609.
11. Kitada K, Nakano D, Ohsaki H, et al. Hyperglycemia causes cellular senescence via a SGLT2- and p21-dependent pathway in proximal tubules in the early stage of diabetic nephropathy. Journal of Diabetes and Its Complications. 2014;28:604-611. DOI: 10.1016/j.jdiacomp.2014.05.010.
12. US Food and Drug Administration (FDA). Sodium-glucose Cotransporter-2 (SGLT2) Inhibitors. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm446852.htm. Accessed March 22, 2016.