SGLT2 inhibitors: suggestions from the amphibian world

Authors

  • Stefano Michelassi SOC Nefrologia e Dialisi Firenze 2, USL Toscana Centro, Firenze - Italy

DOI:

https://doi.org/10.33393/gcnd.2022.2423

Keywords:

Chronic kidney disease, Diabetes, Estivation, Ketonic bodies, SGLT2 inhibitors

Abstract

Sodium-glucose cotransporter 2 inhibitors are a class of antidiabetic drugs that inhibit glucose reabsorption in the proximal renal tubules. In many trials these drugs have shown unpredictable major cardio- and nephroprotective properties. Multiple hypotheses have been raised to elucidate the mechanisms underlying the last effects. Some authors suggest they may be due to the contemporary urinary loss of energy (as glucose) and water (by osmotic diuresis). This particular condition could induce metabolic changes resulting in more efficient energetics at cardiac and renal levels and in less oxidative stress. These changes might really be part of a series of evolutionarily conserved metabolic switches that allow organisms to survive in arid habitats with restricted nutrients and water availability, well studied in amphibians and collectively named “estivation”.

References

  1. Zinman B, Wanner C, Lachin JM, et al; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128. https://doi.org/10.1056/NEJMoa1504720 PMID:26378978 DOI: https://doi.org/10.1056/NEJMoa1504720
  2. Wanner Ch, Inzucchi SE, Zinman B. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375(18):1801-1802. https://doi.org/10.1056/NEJMoa1515920PMID:27806236 DOI: https://doi.org/10.1056/NEJMc1611290
  3. Neal B, Perkovic V, Mahaffey KW, et al; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-657. https://doi.org/10.1056/NEJMoa1611925 PMID:28605608 DOI: https://doi.org/10.1056/NEJMoa1611925
  4. Wiviott SD, Raz I, Bonaca MP, et al; DECLARE–TIMI 58 Investigators. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347-357. https://doi.org/10.1056/NEJMoa1812389 PMID:30415602 DOI: https://doi.org/10.1056/NEJMoa1812389
  5. Packer M, Anker SD, Butler J, et al; EMPEROR-Reduced Trial Investigators. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med. 2020;383(15):1413-1424. https://doi.org/10.1056/NEJMoa2022190 PMID:32865377 DOI: https://doi.org/10.1056/NEJMoa2022190
  6. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al; DAPA-CKD Trial Committees and Investigators. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020;383(15):1436-1446. https://doi.org/10.1056/NEJMoa2024816 PMID:32970396 DOI: https://doi.org/10.1056/NEJMoa2024816
  7. Filippatos TD, Liontos A, Papakitsou I, Elisaf MS. SGLT2 inhibitors and cardioprotection: a matter of debate and multiple hypotheses. Postgrad Med. 2019;131(2):82-88. https://doi.org/10.1080/00325481.2019.1581971 PMID:30757937 DOI: https://doi.org/10.1080/00325481.2019.1581971
  8. Miyata KN, Zhang S-L, Chan JSD. The rationale and evidence for SGLT2 inhibitors as a treatment for nondiabetic glomerular diseases. Glomerular Dis. 2021;1(1):21-33. https://doi.org/10.1159/000513659 DOI: https://doi.org/10.1159/000513659
  9. Patel A, MacMahon S, Chalmers J, et al; ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet. 2007;370(9590):829-840. https://doi.org/10.1016/S0140-6736(07)61303-8 PMID:17765963 DOI: https://doi.org/10.1016/S0140-6736(07)61303-8
  10. Wing RR, Bolin P, Brancati FL, et al; Look AHEAD Research Group. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med. 2013;369(2):145-154. https://doi.org/10.1056/NEJMoa1212914 PMID:23796131 DOI: https://doi.org/10.1056/NEJMoa1212914
  11. Fitchett DH, Udell JA, Inzucchi SE. Heart failure outcomes in clinical trials of glucose-lowering agents in patients with diabetes. Eur J Heart Fail. 2017;19(1):43-53. https://doi.org/10.1002/ejhf.633 PMID:27653447 DOI: https://doi.org/10.1002/ejhf.633
  12. Storey KB, Storey JM. Aestivation: signaling and hypometabolism. J Exp Biol. 2012;215(Pt 9):1425-1433. https://doi.org/10.1242/jeb.054403 PMID:22496277 DOI: https://doi.org/10.1242/jeb.054403
  13. Marton A, Kaneko T, Kovalik JP, et al. Organ protection by SGLT2 inhibitors: role of metabolic energy and water conservation. Nat Rev Nephrol. 2021;17(1):65-77. https://doi.org/10.1038/s41581-020-00350-x PMID:33005037 DOI: https://doi.org/10.1038/s41581-020-00350-x
  14. Hyodo S, Kakumura K, Takagi W, Hasegawa K, Yamaguchi Y. Morphological and functional characteristics of the kidney of cartilaginous fishes: with special reference to urea reabsorption. Am J Physiol Regul Integr Comp Physiol. 2014;307(12):R1381-R1395. https://doi.org/10.1152/ajpregu.00033.2014 PMID:25339681 DOI: https://doi.org/10.1152/ajpregu.00033.2014
  15. McBean RL, Goldstein L. Renal function during osmotic stress in the aquatic toad Xenopus laevis. Am J Physiol. 1970;219(4):1115-1123. https://doi.org/10.1152/ajplegacy.1970.219.4.1115PMID:5466608 DOI: https://doi.org/10.1152/ajplegacy.1970.219.4.1115
  16. Kitada K, Daub S, Zhang Y, et al. High salt intake reprioritizes osmolyte and energy metabolism for body fluid conservation. J Clin Invest. 2017;127(5):1944-1959. https://doi.org/10.1172/JCI88532 PMID:28414295 DOI: https://doi.org/10.1172/JCI88532
  17. Yasui A, Lee G, Hirase T, et al. Empagliflozin induces transient diuresis without changing long-term overall fluid balance in Japanese patients with type 2 diabetes. Diabetes Ther. 2018;9(2):863-871. https://doi.org/10.1007/s13300-018-0385-5 PMID:29488164 DOI: https://doi.org/10.1007/s13300-018-0385-5
  18. Chen L, LaRocque LM, Efe O, Wang J, Sands JM, Klein JD. Effect of dapagliflozin treatment on fluid and electrolyte balance in diabetic rats. Am J Med Sci. 2016;352(5):517-523. https://doi.org/10.1016/j.amjms.2016.08.015 PMID:27865300 DOI: https://doi.org/10.1016/j.amjms.2016.08.015
  19. Masuda T, Muto S, Fukuda K, et al. Osmotic diuresis by SGLT2 inhibition stimulates vasopressin-induced water reabsorption to maintain body fluid volume. Physiol Rep. 2020;8(2):e14360. https://doi.org/10.14814/phy2.14360 PMID:31994353 DOI: https://doi.org/10.14814/phy2.14360
  20. Bankir LT, Trinh-Trang-Tan MM. Renal urea transporters. Direct and indirect regulation by vasopressin. Exp Physiol. 2000;85(Spec No):243S-252S. https://doi.org/10.1111/j.1469-445X.2000.tb00029.x PMID:10795928 DOI: https://doi.org/10.1111/j.1469-445X.2000.tb00029.x
  21. Felig P, Owen OE, Wahren J, Cahill GF Jr. Amino acid metabolism during prolonged starvation. J Clin Invest. 1969;48(3):584-594. https://doi.org/10.1172/JCI106017 PMID:5773094 DOI: https://doi.org/10.1172/JCI106017
  22. Felig P. The glucose-alanine cycle. Metabolism. 1973;22(2):179-207. https://doi.org/10.1016/0026-0495(73)90269-2 PMID:4567003 DOI: https://doi.org/10.1016/0026-0495(73)90269-2
  23. Esterline RL, Vaag A, Oscarsson J, Vora J. MECHANISMS IN ENDOCRINOLOGY: SGLT2 inhibitors: clinical benefits by restoration of normal diurnal metabolism? Eur J Endocrinol. 2018;178(4):R113-R125. https://doi.org/10.1530/EJE-17-0832 PMID:29371333 DOI: https://doi.org/10.1530/EJE-17-0832
  24. Santos-Gallego CG, Requena-Ibanez JA, San Antonio R, et al. Empagliflozin ameliorates adverse left ventricular remodeling in nondiabetic heart failure by enhancing myocardial energetics. J Am Coll Cardiol. 2019;73(15):1931-1944. https://doi.org/10.1016/j.jacc.2019.01.056PMID:30999996 DOI: https://doi.org/10.1016/j.jacc.2019.01.056
  25. Ferrannini E, Muscelli E, Frascerra S, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014;124(2):499-508. https://doi.org/10.1172/JCI72227 PMID:24463454 DOI: https://doi.org/10.1172/JCI72227
  26. Merovci A, Solis-Herrera C, Daniele G, et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest. 2014;124(2):509-514. https://doi.org/10.1172/JCI70704 PMID:24463448 DOI: https://doi.org/10.1172/JCI70704
  27. Kappel BA, Lehrke M, Schütt K, et al. Effect of empagliflozin on the metabolic signature of patients with type 2 diabetes mellitus and cardiovascular disease. Circulation. 2017;136(10):969-972. https://doi.org/10.1161/CIRCULATIONAHA.117.029166 PMID:28874423 DOI: https://doi.org/10.1161/CIRCULATIONAHA.117.029166
  28. Cahill GF Jr. Fuel metabolism in starvation. Annu Rev Nutr. 2006;26(1):1-22. https://doi.org/10.1146/annurev.nutr.26.061505.111258 PMID:16848698 DOI: https://doi.org/10.1146/annurev.nutr.26.061505.111258
  29. Stanley WC, Recchia FA, Lopaschuk GD. Myocardial substrate metabolism in the normal and failing heart. Physiol Rev. 2005;85(3):1093-1129. https://doi.org/10.1152/physrev.00006.2004PMID:15987803 DOI: https://doi.org/10.1152/physrev.00006.2004
  30. Bedi KC Jr, Snyder NW, Brandimarto J, et al. Evidence for intramyocardial disruption of lipid metabolism and increased myocardial ketone utilization in advanced human heart failure. Circulation. 2016;133(8):706-716. https://doi.org/10.1161/CIRCULATIONAHA.115.017545PMID:26819374 DOI: https://doi.org/10.1161/CIRCULATIONAHA.115.017545
  31. Boudina S, Abel ED. Diabetic cardiomyopathy revisited. Circulation. 2007;115(25):3213-3223. https://doi.org/10.1161/CIRCULATIONAHA.106.679597 PMID:17592090 DOI: https://doi.org/10.1161/CIRCULATIONAHA.106.679597
  32. Veech RL. The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism. Prostaglandins Leukot Essent Fatty Acids. 2004;70(3):309-319. https://doi.org/10.1016/j.plefa.2003.09.007 PMID:14769489 DOI: https://doi.org/10.1016/j.plefa.2003.09.007
  33. Stanley WC, Lopaschuk GD, McCormack JG. Regulation of energy substrate metabolism in the diabetic heart. Cardiovasc Res. 1997;34(1):25-33. https://doi.org/10.1016/S0008-6363(97)00047-3 PMID:9217869 DOI: https://doi.org/10.1016/S0008-6363(97)00047-3
  34. Mudaliar S, Alloju S, Henry RR. Can a shift in suel energetics explain the beneficial cardiorenal outcomes in the EMPA-REG OUTCOME Study? A Unifying Hypothesis. Diabetes Care. 2016;39(7):1115-1122. PMID: 27289124 https://doi.org/10.2337/dc16-0542 PMID:27289124 DOI: https://doi.org/10.2337/dc16-0542
  35. Sato K, Kashiwaya Y, Keon CA, et al. Insulin, ketone bodies, and mitochondrial energy transduction. FASEB J. 1995;9(8):651-658. https://doi.org/10.1096/fasebj.9.8.7768357PMID:7768357 DOI: https://doi.org/10.1096/fasebj.9.8.7768357
  36. Kalra S, Jain A, Ved J, Unnikrishnan AG. Sodium-glucose cotransporter 2 inhibition and health benefits: The Robin Hood effect. Indian J Endocrinol Metab. 2016;20(5):725-729. https://doi.org/10.4103/2230-8210.183826 PMID:27730088 DOI: https://doi.org/10.4103/2230-8210.183826
  37. Youm YH, Nguyen KY, Grant RW, et al. The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med. 2015;21(3):263-269. https://doi.org/10.1038/nm.3804 PMID:25686106 DOI: https://doi.org/10.1038/nm.3804
  38. Rahman M, Muhammad S, Khan MA, et al. The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages. Nat Commun. 2014;5(1):3944. https://doi.org/10.1038/ncomms4944 PMID:24845831 DOI: https://doi.org/10.1038/ncomms4944
  39. Shimazu T, Hirschey MD, Newman J, et al. Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science. 2013;339(6116):211-214. https://doi.org/10.1126/science.1227166 PMID:23223453 DOI: https://doi.org/10.1126/science.1227166
  40. Rojas-Morales P, Pedraza-Chaverri J, Tapia E. Ketone bodies, stress response, and redox homeostasis. Redox Biol. 2020;29:101395. https://doi.org/10.1016/j.redox.2019.101395PMID:31926621 DOI: https://doi.org/10.1016/j.redox.2019.101395
  41. Miller VJ, Villamena FA, Volek JS. Nutritional ketosis and mitohormesis: potential implications for mitochondrial function and human health. J Nutr Metab. 2018;2018:5157645. https://doi.org/10.1155/2018/5157645 PMID:29607218 DOI: https://doi.org/10.1155/2018/5157645
  42. Heerspink HJ, Perkins BA, Fitchett DH, Husain M, Cherney DZ. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications. Circulation. 2016;134(10):752-772. https://doi.org/10.1161/CIRCULATIONAHA.116.021887 PMID:27470878 DOI: https://doi.org/10.1161/CIRCULATIONAHA.116.021887
  43. Little JR Jr, Spitzer JJ. Uptake of ketone bodies by dog kidney in vivo. Am J Physiol. 1971;221(3):679-683. https://doi.org/10.1152/ajplegacy.1971.221.3.679 PMID:5570323 DOI: https://doi.org/10.1152/ajplegacy.1971.221.3.679
  44. Singh P, et al. Metabolic basis of solute transport. In: Skoreck K, Chertow GM, Marsden PA, Taal MW, Yu ASL, eds. Brenner & Rector’s the Kidney. 10th ed. Elsevier; 2016:122-143.
  45. Neugarten J, Golestaneh L. Blood oxygenation level-dependent MRI for assessment of renal oxygenation. Int J Nephrol Renovasc Dis. 2014;7:421-435. https://doi.org/10.2147/IJNRD.S42924PMID:25473304 DOI: https://doi.org/10.2147/IJNRD.S42924
  46. Vallon V, Thomson SC. Renal function in diabetic disease models: the tubular system in the pathophysiology of the diabetic kidney. Annu Rev Physiol. 2012;74(1):351-375. https://doi.org/10.1146/annurev-physiol-020911-153333 PMID:22335797 DOI: https://doi.org/10.1146/annurev-physiol-020911-153333
  47. Layton AT, Vallon V. SGLT2 inhibition in a kidney with reduced nephron number: modeling and analysis of solute transport and metabolism. Am J Physiol Renal Physiol. 2018;314(5):F969-F984. https://doi.org/10.1152/ajprenal.00551.2017 PMID:29361669 DOI: https://doi.org/10.1152/ajprenal.00551.2017
  48. Kaufman JM, Siegel NJ, Hayslett JP. Functional and hemodynamic adaptation to progressive renal ablation. Circ Res. 1975;36(2):286-293. https://doi.org/10.1161/01.RES.36.2.286PMID:1116239 DOI: https://doi.org/10.1161/01.RES.36.2.286
  49. Tanaka S, Sugiura Y, Saito H, et al. Sodium-glucose cotransporter 2 inhibition normalizes glucose metabolism and suppresses oxidative stress in the kidneys of diabetic mice. Kidney Int. 2018;94(5):912-925. https://doi.org/10.1016/j.kint.2018.04.025 PMID:30021702 DOI: https://doi.org/10.1016/j.kint.2018.04.025
  50. Morisawa N, Kitada K, Fujisawa Y, et al. Renal sympathetic nerve activity regulates cardiovascular energy expenditure in rats fed high salt. Hypertens Res. 2020;43(6):482-491. https://doi.org/10.1038/s41440-019-0389-1 PMID:31932643 DOI: https://doi.org/10.1038/s41440-019-0389-1
  51. Kaur J, Young BE, Fadel PJ. Sympathetic overactivity in chronic kidney disease: consequences and mechanisms. Int J Mol Sci. 2017;18(8):1682. https://doi.org/10.3390/ijms18081682 PMID:28767097 DOI: https://doi.org/10.3390/ijms18081682
  52. Herat LY, Magno AL, Rudnicka C, et al. SGLT2 inhibitor-induced sympathoinhibition: a novel mechanism for cardiorenal protection. JACC Basic Transl Sci. 2020;5(2):169-179. https://doi.org/10.1016/j.jacbts.2019.11.007 PMID:32140623 DOI: https://doi.org/10.1016/j.jacbts.2019.11.007
  53. Wan N, Fujisawa Y, Kobara H, et al. Effects of an SGLT2 inhibitor on the salt sensitivity of blood pressure and sympathetic nerve activity in a nondiabetic rat model of chronic kidney disease. Hypertens Res. 2020;43(6):492-499. https://doi.org/10.1038/s41440-020-0410-8PMID:32060381 DOI: https://doi.org/10.1038/s41440-020-0410-8

Most read articles by the same author(s)