Research Article

SGLT2 Inhibitors and nephroprotection in diabetic kidney disease: From mechanisms of action to the latest evidence in the literature

Jorge Rico-Fontalvo, Rodrigo Daza-Arnedo, Maria Ximena Cardona-Blanco, Victor Leal-Martínez, Emilio Abuabara-Franco, Nehomar Pajaro-Galvis, Jose Cabrales, José Correa, Manuel Cueto, Amable Duran, Alejandro Castellanos, Javier Enamorado, José Bohórquez, Isabella Uparella, Julio Zuñiga, Abraham Chagui, Alfonso Ramos and Luis Lara

Published: 08/21/2020 | Volume 4 - Issue 2 | Pages: 044-055

Summary

Type 2 Diabetes Mellitus constitutes a major problem in public health worldwide. The disease poses a high risk of severe microvascular and macrovascular complications. Diabetic kidney disease is the most common cause of end-stage chronic kidney disease and contributes to the increasing morbidity and mortality associated to diabetes. Sodium-glucose contransporter-2 inhibitors (SGLT2 inhibitors) are the latest oral diabetic medications, which exhibit a great nephroprotective potential, not only by improving glycemic control, but also by glucose-independent mechanisms, such as decreasing blood pressure and other direct renal effects. We conduct a literature review based on the most recent scientific evidence with the goal to elucidate the postulated mechanisms of action of SGLT2 inhibitors in diabetic kidney disease, which are the base of the beneficial clinical effects that are seen in the condition.

Read Full Article HTML DOI: 10.29328/journal.jcn.1001058 Cite this Article

References

  1. De Nicola L, Gabbai FB, Liberti ME, Sagliocca A, Conte G, et al. Sodium/glucose cotransporter 2 inhibitors and prevention of diabetic nephropathy: Targeting the renal tubule in diabetes. Am J Kidney Dis. 2014; 64: 16–24. PubMed: https://pubmed.ncbi.nlm.nih.gov/24673844
  2. Kattyuska V, Daniela M, Manuel TR, Gema R, Rafel C, et al. Complicaciones microvasculares de la diabetes. Rev Venez Endocrinol Metab. 2012; 10(Suppl 1): 111-137. http://ve.scielo.org/scielo.php?script=sci_arttext&pid=S1690-31102012000400014&lng=es.
  3. Alicic RZ, Neumiller JJ, Johnson EJ, Dieter B, Tuttle KR. Sodium–glucose cotransporter 2 inhibition and diabetic kidney disease. Diabetes. 2019; 68: 248–257. PubMed: https://pubmed.ncbi.nlm.nih.gov/30665953/
  4. Rosas Guzmán J, García Rubí E, Gómez Pérez F, Calles J. Prevención, diagnóstico y tratamiento temprano de la Nefropatía Diabética. Revista ALAD (Revista On-line) 2009. 2016; 26. Consesos ALAD. 2011; 16: 106–114.
  5. Barutta F, Bernardi S, Gargiulo G, Gruden G. SGLT2 inhibition to address the unmet needs in diabetic nephropathy. Diabetes Metab Res Rev. 2019; 35: e3171. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849789/
  6. Torres A, Zacarías R. Nefropatía diabética. Rev Hosp Gral Dr. M Gea González. 2002; 5: 24-32.
  7. Espa G. Tema monográfico Fisiopatología de la nefropatía diabética. 2008. https://www.revistanefrologia.com/es-fisiopatologia-nefropatia-diabetica-articulo-X1888970008000118
  8. Kawanami D, Matoba K, Takeda Y, Nagai Y, Akamine T, et al. SGLT2 Inhibitors as a Therapeutic Option for Diabetic Nephropathy. Int J Mol Sci. 2017; 18: 1083. PubMed: https://pubmed.ncbi.nlm.nih.gov/28524098
  9. Maltese G, Abou-saleh A, Gnudi L, Karalliedde J. Preventing diabetic renal disease: the potential reno-protective effects of SGLT2 inhibitors. Br J Diabetes Vasc Dis. 2015; 15: 114-118.
  10. Gonzalez DE, Foresto RD, Ribeiro AB. SGLT-2 inhibitors in diabetes: a focus on renoprotection. Rev Assoc Med Bras. 2020; 66(Suppl 1): 17–24. PubMed: https://pubmed.ncbi.nlm.nih.gov/31939531/
  11. Washburn W. Case History: ForxigaTM (Dapagliflozin), a Potent Selective SGLT2 Inhibitor for Treatment of Diabetes. Annual Reports in Medicinal Chemistry. 2014; 49.
  12. Meng W, Ellsworth B, Nirschl A, McCann P, Patel M, et al. Discovery of Dapagliflozin: A Potent, Selective Renal Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 Diabetes. J Med Chem. 2008; 51: 1145–1149. PubMed: https://pubmed.ncbi.nlm.nih.gov/18260618/
  13. Choi C. Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors from Natural Products: Discovery of Next-Generation Antihyperglycemic Agents. Molecules. 2016; 21: 1136. PubMed: https://pubmed.ncbi.nlm.nih.gov/27618891/
  14. Cai W, Jiang L, Xie Y, Liu Y, Liu W, et al. Design of SGLT2 Inhibitors for the Treatment of Type 2 Diabetes: A History Driven by Biology to Chemistry. Medicinal Chemistry. 2015; 11: 317-328. PubMed: https://pubmed.ncbi.nlm.nih.gov/25557661/
  15. White J. Apple Trees to Sodium Glucose Co-Transporter Inhibitors: A Review of SGLT2 Inhibition. Clinical Diabetes. 2010; 28.
  16. Nomura S, Sakamaki S, Hongu M, Kawanishi E, Koga Y, et al. Discovery of Canagliflozin, a Novel C-Glucoside with Thiophene Ring, as Sodium-Dependent Glucose Cotransporter 2 Inhibitor for the Treatment of Type 2 Diabetes Mellitus. J Med Chem. 2010; 53: 6355–6360. PubMed: https://pubmed.ncbi.nlm.nih.gov/20690635/
  17. Rieg T, Vallon V. Development of SGLT1 and SGLT2 inhibitors. Diabetologia. 2018; 61: 2079–2086. PubMed: https://pubmed.ncbi.nlm.nih.gov/30132033/
  18. Nomura S, Sakamaki S, Hongu M, Kawanishi E, Koga Y, et al. Discovery of Canagliflozin, a Novel C-Glucoside with Thiophene Ring, as Sodium-Dependent Glucose Cotransporter 2 Inhibitor for the Treatment of Type 2 Diabetes Mellitus. J Med Chem 2010; 53: 6355–6360. PubMed: https://pubmed.ncbi.nlm.nih.gov/20690635/
  19. Grempler R, Thomas L, Eckhardt M, Himmelsbach F, Sauer A, et al. Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors. Diabetes, Obesity and Metabolism. 2012; 14: 83–90. PubMed: https://pubmed.ncbi.nlm.nih.gov/21985634
  20. Rossato M, Busetto L. SGLT2 Inhibitors and the Diabetic Kidney. Diabetes Care 2016; 39(Suppl 2): S165-S171. PubMed: https://pubmed.ncbi.nlm.nih.gov/27440829/
  21. Dekkers CCJ. Sodium-glucose cotransporter 2 inhibitors: extending the indication to non-diabetic kidney disease? Nephrol Dial Transplant. 2020; 35: i33–i42. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993196/
  22. Rola N, Elias K, Farid N, Inbal D, Farber E, et al. Sodium-Glucose Transporter Inhibitors and ŝĂbĞtic Nephropathy in Humans and Animal Model. J Clin Exp Nephrol. 2018; 3: 10.
  23. Cowie MR. Fisher M. SGLT2 inhibitors: Mechanisms of cardiovascular benefit beyond glycaemic control. Nat Rev Cardiol. 2020. PubMed: https://pubmed.ncbi.nlm.nih.gov/32665641/
  24. Górriz JL, Navarro-González JF, Ortiz A, Vergara A, Nuñez J, et al. Sodium-glucose cotransporter 2 inhibition: towards an indication to treat diabetic kidney disease, Nephrology Dialysis Transplantation. 2020. 35 (Suppl 1): i13–i23. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993197/
  25. Yaribeygi H, Simental-mendía LE, Banach M, Bo S, Sahebkar A. Biomedicine & Pharmacotherapy The major molecular mechanisms mediating the renoprotective e ff ects of SGLT2 inhibitors : An update. 2019; 120: 109526.
  26. Neuen BL, Young T, Heerspink HJL, Neal B, Perkovic V, et al. Articles SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis. LANCET Diabetes Endocrinol. 2019; 7: 845-854. PubMed: https://pubmed.ncbi.nlm.nih.gov/31495651/
  27. Mikhail N. SGLT2 Inhibitors for Treatment of Diabetic Nephropathy. Curre Res Diabetes Obes J. 2019; 12: 555839.
  28. Gilbert RE. Sodium – glucose linked transporter-2 inhibitors: potential for renoprotection beyond blood glucose lowering? Kidney Int. 2013; 86: 693–700. PubMed: https://pubmed.ncbi.nlm.nih.gov/24257692/
  29. Davidson JA. SGLT2 inhibitors in patients with type 2 diabetes and renal disease: overview of current evidence. Postgrad Med. 2019. 131: 251-260. PubMed: https://pubmed.ncbi.nlm.nih.gov/30929540/
  30. Eren Z, Gunal MY, Ari E, Coban J, Cakalagaoglu F, et al. Pleiotropic and renoprotective effects of erythropoietin β on experimental diabetic nephropathy model. Nephron. 2016; 132: 292–300. PubMed: https://pubmed.ncbi.nlm.nih.gov/26938976/
  31. Tsuruya K, Yoshida H, Suehiro T, Fujisaki K, Masutani K, et al. Erythropoiesis-stimulating agent slows the progression of chronic kidney disease: A possibility of a direct action of erythropoietin. Ren Fail. 2016; 38: 390–396. PubMed: https://pubmed.ncbi.nlm.nih.gov/26822074/
  32. Zinman B, Wanner C, Lachin J, Fitchett D, Bluhmki E, Hantel S et al. Empaglifozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015; 373: 2117-2128. PubMed: https://pubmed.ncbi.nlm.nih.gov/26378978/
  33. Neal B, Perkovic V, Mahaffey K, Zeeuw D, Fulcher G, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017; 377: 644–657. PubMed: https://pubmed.ncbi.nlm.nih.gov/28605608/
  34. Perkovic V, Jardine M, Neal B, Bompoint S, Heerspink H, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019; 380: 2295–2306.                 PubMed: https://pubmed.ncbi.nlm.nih.gov/30990260/
  35. Wiviott S, Raz I, Bonaca M, Mosenzon O, Kato E, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019; 380: 347–357. PubMed: https://pubmed.ncbi.nlm.nih.gov/30415602/
  36. Taylor SI, Blau JE, Rother KI. SGLT2 Inhibitors May Predispose to Ketoacidosis. J Clin Endocrinol Metab. 2015; 100: 2849-2852. PubMed: https://pubmed.ncbi.nlm.nih.gov/26086329/
  37. Lytvyn Y, Bjornstad P, Udell JA, Lovshin JA, Cherney DZI. Sodium Glucose Cotransporter-2 Inhibition in Heart Failure: Potential Mechanisms, Clinical Applications, and Summary of Clinical Trials. Circulation. 2017; 136: 1643-1658. PubMed: https://pubmed.ncbi.nlm.nih.gov/29061576/
  38. Tsimihodimos V, Filippatos TD, Elisaf MS. SGLT2 INHIBITORS AND THE KIDNEY: EFFECTS AND MECHANISMS, Diabetes and Metabolic Syndrome: Clin Res Rev. 2018.
  39. Verma S. McMurray J. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia. 2018; 61: 2108-2117. PubMed: https://pubmed.ncbi.nlm.nih.gov/30132036/
  40. Shiba K, Tsuchiya K, Komiya C. Canagliflozin, an SGLT2 inhibitor, attenuates the development of hepatocellular carcinoma in a mouse model of human NASH. Sci Rep. 2018; 8: 2362. PubMed: https://pubmed.ncbi.nlm.nih.gov/29402900/
  41. Scheen AJ. An update on the safety of SGLT2 inhibitors, Expert Opin Drug Saf. 2019; 18: 295-311. PubMed: https://pubmed.ncbi.nlm.nih.gov/30933547/
  42. Hecking M, Jenssen T. Considerations for SGLT2 inhibitor use in post-transplantation diabetes. Nat Rev Nephrol. 2019; 15: 525-526. PubMed: https://pubmed.ncbi.nlm.nih.gov/31235880/
  43. Davies MJ, D’Alessio DA, Fradkin J, Kernan WN, Mathieu C, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018; 41: 2669–2701. PubMed: https://pubmed.ncbi.nlm.nih.gov/30291106/
  44. Rico J, Enfermedad Renal Diabética, Capitulo 15. Nefrología Básica. Asociación Colombiana de Nefrología e Hipertensión arterial. http://asocolnef.com/formacion-2/formacion/actualizacion-libro-nefrologia-basica-2/
  45. Lopera Vargas JM, Rico Fontalvo JE, Melgarejo E, Castillo Barrios GA, Ramírez Rincó A, et al. Efecto de terapias farmacológicas para el control glicémico en pacientes con diabetes mellitus tipo 2 en los desenlaces vasculares. Rev Colomb Nefrol. 2020; 7: 44-59.
  46. Nuffer W, Williams B, Trujillo J. A review of sotagliflozin for use in type 1 diabetes. Ther Adv Endocrinol Metab. 2019; 10: 2042018819890527. PubMed: https://pubmed.ncbi.nlm.nih.gov/31807264/
  47. Burns, K, Cherney, D. Renal Angiotensinogen and Sodium-Glucose Cotransporter-2 Inhibition: Insights from Experimental Diabetic Kidney Disease. Am J Nephrol. 2019; 49: 328–330. PubMed: https://www.karger.com/Article/Abstract/501081
  48. Bessho R, Takiyama Y, Takiyama T, Kitsunai H, Takeda Y, et al. Hypoxia-inducible factor-1α is the therapeutic target of the SGLT2 inhibitor for diabetic nephropathy. Scientific Reports. 2019; 9: 14754.
  49. Osataphan S, Macchi C, Singhal G, Chimene-Weiss J, et al. SGLT2 inhibition reprograms systemic metabolism via FGF21-dependent and -independent mechanisms. JCI Insight. 2019; 4: e123130.