International Journal of Endocrinology and Metabolism

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Cardiovascular and Renal Benefits of SGLT2 Inhibitors: A Narrative Review

Soghra Rabizadeh 1 , Manouchehr Nakhjavani 1 and Alireza Esteghamati 1 , *
Authors Information
1 Endocrinology and Metabolism Research Center (EMRC), Vali-Asr Hospital, Tehran University of Medical Sciences, Tehran, Iran
Article information
  • International Journal of Endocrinology and Metabolism: April 30, 2019, 17 (2); e84353
  • Published Online: April 22, 2019
  • Article Type: Review Article
  • Received: September 16, 2018
  • Revised: February 27, 2019
  • Accepted: March 3, 2019
  • DOI: 10.5812/ijem.84353

To Cite: Rabizadeh S, Nakhjavani M, Esteghamati A. Cardiovascular and Renal Benefits of SGLT2 Inhibitors: A Narrative Review, Int J Endocrinol Metab. 2019 ; 17(2):e84353. doi: 10.5812/ijem.84353.

Abstract
Copyright © 2019, International Journal of Endocrinology and Metabolism. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.
1. Context
2. Evidence Acquisition
3. Results
4. Conclusions
Footnotes
References
  • 1. Farkouh ME, Boden WE, Bittner V, Muratov V, Hartigan P, Ogdie M, et al. Risk factor control for coronary artery disease secondary prevention in large randomized trials. J Am Coll Cardiol. 2013;61(15):1607-15. doi: 10.1016/j.jacc.2013.01.044. [PubMed: 23500281].
  • 2. Saydah SH, Fradkin J, Cowie CC. Poor control of risk factors for vascular disease among adults with previously diagnosed diabetes. JAMA. 2004;291(3):335-42. doi: 10.1001/jama.291.3.335. [PubMed: 14734596].
  • 3. Emerging Risk Factors Collaboration , Sarwar N, Gao P, Seshasai SR, Gobin R, Kaptoge S, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: A collaborative meta-analysis of 102 prospective studies. Lancet. 2010;375(9733):2215-22. doi: 10.1016/s0140-6736(10)60484-9. [PubMed: 20609967]. [PubMed Central: PMC2904878].
  • 4. Mukamal KJ, Nesto RW, Cohen MC, Muller JE, Maclure M, Sherwood JB, et al. Impact of diabetes on long-term survival after acute myocardial infarction: Comparability of risk with prior myocardial infarction. Diabetes Care. 2001;24(8):1422-7. doi: 10.2337/diacare.24.8.1422. [PubMed: 11473080].
  • 5. Alemi H, Khaloo P, Mansournia MA, Rabizadeh S, Salehi SS, Mirmiranpour H, et al. Pulse pressure and diabetes treatments: Blood pressure and pulse pressure difference among glucose lowering modality groups in type 2 diabetes. Medicine (Baltimore). 2018;97(6). e9791. doi: 10.1097/MD.0000000000009791. [PubMed: 29419672]. [PubMed Central: PMC5944681].
  • 6. Raee MR, Nargesi AA, Heidari B, Mansournia MA, Larry M, Rabizadeh S, et al. All-cause and cardiovascular mortality following treatment with metformin or glyburide in patients with type 2 diabetes mellitus. Arch Iran Med. 2017;20(3):141-6. [PubMed: 28287807].
  • 7. Rabizadeh S, Dehghani Firouzabadi F, Noshad S, Esteghamati S, Afarideh M, Ghajar A, et al. Beneficial effects of pentoxifylline plus losartan dual therapy in type 2 diabetes with nephropathy. Am J Med Sci. 2018;355(5):442-8. doi: 10.1016/j.amjms.2017.12.015. [PubMed: 29753374].
  • 8. Esteghamati A, Larijani B, Aghajani MH, Ghaemi F, Kermanchi J, Shahrami A, et al. Diabetes in Iran: Prospective analysis from first nationwide diabetes report of national program for prevention and control of diabetes (NPPCD-2016). Sci Rep. 2017;7(1):13461. doi: 10.1038/s41598-017-13379-z. [PubMed: 29044139]. [PubMed Central: PMC5647418].
  • 9. Wang Y, Katzmarzyk PT, Horswell R, Zhao W, Johnson J, Hu G. Kidney function and the risk of cardiovascular disease in patients with type 2 diabetes. Kidney Int. 2014;85(5):1192-9. doi: 10.1038/ki.2013.396. [PubMed: 24107845]. [PubMed Central: PMC4141539].
  • 10. Link JT, Sorensen BK. A method for preparing C-glycosides related to phlorizin. Tetrahedron Letters. 2000;41(48):9213-7. doi: 10.1016/s0040-4039(00)01709-3.
  • 11. Ehrenkranz JR, Lewis NG, Kahn CR, Roth J. Phlorizin: A review. Diabetes Metab Res Rev. 2005;21(1):31-8. doi: 10.1002/dmrr.532. [PubMed: 15624123].
  • 12. Larson GL. The synthesis of gliflozins. Chem Today. 2015;33:37-40.
  • 13. Brito-Arias M. Synthesis and characterization of glycosides. Springer; 2007.
  • 14. Satirapoj B. Sodium-glucose cotransporter 2 inhibitors with renoprotective effects. Kidney Dis (Basel). 2017;3(1):24-32. doi: 10.1159/000471765. [PubMed: 28785561]. [PubMed Central: PMC5527177].
  • 15. Meng W, Ellsworth BA, Nirschl AA, McCann PJ, Patel M, Girotra RN, 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(5):1145-9. doi: 10.1021/jm701272q. [PubMed: 18260618].
  • 16. Nomura S, Sakamaki S, Hongu M, Kawanishi E, Koga Y, Sakamoto T, 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(17):6355-60. doi: 10.1021/jm100332n. [PubMed: 20690635].
  • 17. Grempler R, Thomas L, Eckhardt M, Himmelsbach F, Sauer A, Sharp DE, et al. Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: Characterisation and comparison with other SGLT-2 inhibitors. Diabetes Obes Metab. 2012;14(1):83-90. doi: 10.1111/j.1463-1326.2011.01517.x. [PubMed: 21985634].
  • 18. Anderson KS, LaBaer J. The sentinel within: Exploiting the immune system for cancer biomarkers. J Proteome Res. 2005;4(4):1123-33. doi: 10.1021/pr0500814. [PubMed: 16083262]. [PubMed Central: PMC2522321].
  • 19. Zhang XL, Zhu QQ, Chen YH, Li XL, Chen F, Huang JA, et al. Cardiovascular safety, long-term noncardiovascular safety, and efficacy of sodium-glucose cotransporter 2 inhibitors in patients with type 2 diabetes mellitus: A systemic review and meta-analysis with trial sequential analysis. J Am Heart Assoc. 2018;7(2). doi: 10.1161/JAHA.117.007165. [PubMed: 29353233]. [PubMed Central: PMC5850151].
  • 20. Marsenic O. Glucose control by the kidney: An emerging target in diabetes. Am J Kidney Dis. 2009;53(5):875-83. doi: 10.1053/j.ajkd.2008.12.031. [PubMed: 19324482].
  • 21. Zhao Y, Gao P, Sun F, Li Q, Chen J, Yu H, et al. Sodium intake regulates glucose Homeostasis through the PPARdelta/adiponectin-mediated SGLT2 Pathway. Cell Metab. 2016;23(4):699-711. doi: 10.1016/j.cmet.2016.02.019. [PubMed: 27053360].
  • 22. Tanaka A, Node K. Emerging roles of sodium-glucose cotransporter 2 inhibitors in cardiology. J Cardiol. 2017;69(3):501-7. doi: 10.1016/j.jjcc.2016.10.019. [PubMed: 28043708].
  • 23. van Bommel EJ, Muskiet MH, Tonneijck L, Kramer MH, Nieuwdorp M, van Raalte DH. SGLT2 inhibition in the diabetic kidney-from mechanisms to clinical outcome. Clin J Am Soc Nephrol. 2017;12(4):700-10. doi: 10.2215/CJN.06080616. [PubMed: 28254770]. [PubMed Central: PMC5383382].
  • 24. Inzucchi SE, Zinman B, Wanner C, Ferrari R, Fitchett D, Hantel S, et al. SGLT-2 inhibitors and cardiovascular risk: Proposed pathways and review of ongoing outcome trials. Diab Vasc Dis Res. 2015;12(2):90-100. doi: 10.1177/1479164114559852. [PubMed: 25589482]. [PubMed Central: PMC4361459].
  • 25. Powell DR, DaCosta CM, Gay J, Ding ZM, Smith M, Greer J, et al. Improved glycemic control in mice lacking Sglt1 and Sglt2. Am J Physiol Endocrinol Metab. 2013;304(2):E117-30. doi: 10.1152/ajpendo.00439.2012. [PubMed: 23149623].
  • 26. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-28. doi: 10.1056/NEJMoa1504720. [PubMed: 26378978].
  • 27. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-57. doi: 10.1056/NEJMoa1611925. [PubMed: 28605608].
  • 28. Birkeland KI, Jorgensen ME, Carstensen B, Persson F, Gulseth HL, Thuresson M, et al. Cardiovascular mortality and morbidity in patients with type 2 diabetes following initiation of sodium-glucose co-transporter-2 inhibitors versus other glucose-lowering drugs (CVD-REAL Nordic): A multinational observational analysis. Lancet Diabetes Endocrinol. 2017;5(9):709-17. doi: 10.1016/S2213-8587(17)30258-9. [PubMed: 28781064].
  • 29. Persson F, Nystrom T, Jorgensen ME, Carstensen B, Gulseth HL, Thuresson M, et al. Dapagliflozin is associated with lower risk of cardiovascular events and all-cause mortality in people with type 2 diabetes (CVD-REAL Nordic) when compared with dipeptidyl peptidase-4 inhibitor therapy: A multinational observational study. Diabetes Obes Metab. 2018;20(2):344-51. doi: 10.1111/dom.13077. [PubMed: 28771923]. [PubMed Central: PMC5811811].
  • 30. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347-57. doi: 10.1056/NEJMoa1812389. [PubMed: 30415602].
  • 31. Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: A systematic review and meta-analysis of cardiovascular outcome trials. Lancet. 2019;393(10166):31-9. doi: 10.1016/S0140-6736(18)32590-X. [PubMed: 30424892].
  • 32. Wu JH, Foote C, Blomster J, Toyama T, Perkovic V, Sundstrom J, et al. Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: A systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2016;4(5):411-9. doi: 10.1016/S2213-8587(16)00052-8. [PubMed: 27009625].
  • 33. Tang H, Fang Z, Wang T, Cui W, Zhai S, Song Y. Meta-analysis of effects of sodium-glucose cotransporter 2 inhibitors on cardiovascular outcomes and all-cause mortality among patients with type 2 diabetes mellitus. Am J Cardiol. 2016;118(11):1774-80. doi: 10.1016/j.amjcard.2016.08.061. [PubMed: 27666177].
  • 34. Kosiborod M, Birkeland KI, Cavender MA, Fu AZ, Wilding JP, Khunti K, et al. Rates of myocardial infarction and stroke in patients initiating treatment with SGLT2-inhibitors versus other glucose-lowering agents in real-world clinical practice: Results from the CVD-REAL study. Diabetes Obes Metab. 2018;20(8):1983-7. doi: 10.1111/dom.13299. [PubMed: 29569378]. [PubMed Central: PMC6055705].
  • 35. Kosiborod M, Lam CSP, Kohsaka S, Kim DJ, Karasik A, Shaw J, et al. Cardiovascular events associated with SGLT-2 inhibitors versus other glucose-lowering drugs. J Am Coll Cardiol. 2018;71(23):2628-39. doi: 10.1016/j.jacc.2018.03.009. [PubMed: 29540325].
  • 36. Saad M, Mahmoud AN, Elgendy IY, Abuzaid A, Barakat AF, Elgendy AY, et al. Cardiovascular outcomes with sodium-glucose cotransporter-2 inhibitors in patients with type II diabetes mellitus: A meta-analysis of placebo-controlled randomized trials. Int J Cardiol. 2017;228:352-8. doi: 10.1016/j.ijcard.2016.11.181. [PubMed: 27866027].
  • 37. Savarese G, D'Amore C, Federici M, De Martino F, Dellegrottaglie S, Marciano C, et al. Effects of dipeptidyl peptidase 4 inhibitors and sodium-glucose linked cotransporter-2 Inhibitors on cardiovascular events in patients with type 2 diabetes mellitus: A meta-analysis. Int J Cardiol. 2016;220:595-601. doi: 10.1016/j.ijcard.2016.06.208. [PubMed: 27390996].
  • 38. Monami M, Dicembrini I, Mannucci E. Effects of SGLT-2 inhibitors on mortality and cardiovascular events: A comprehensive meta-analysis of randomized controlled trials. Acta Diabetol. 2017;54(1):19-36. doi: 10.1007/s00592-016-0892-7. [PubMed: 27488726].
  • 39. Sonesson C, Johansson PA, Johnsson E, Gause-Nilsson I. Cardiovascular effects of dapagliflozin in patients with type 2 diabetes and different risk categories: A meta-analysis. Cardiovasc Diabetol. 2016;15:37. doi: 10.1186/s12933-016-0356-y. [PubMed: 26895767]. [PubMed Central: PMC4761166].
  • 40. Salsali A, Kim G, Woerle HJ, Broedl UC, Hantel S. Cardiovascular safety of empagliflozin in patients with type 2 diabetes: A meta-analysis of data from randomized placebo-controlled trials. Diabetes Obes Metab. 2016;18(10):1034-40. doi: 10.1111/dom.12734. [PubMed: 27376831]. [PubMed Central: PMC5096016].
  • 41. Bertoni AG, Hundley WG, Massing MW, Bonds DE, Burke GL, Goff DJ. Heart failure prevalence, incidence, and mortality in the elderly with diabetes. Diabetes Care. 2004;27(3):699-703. doi: 10.2337/diacare.27.3.699. [PubMed: 14988288].
  • 42. Sattar N, McLaren J, Kristensen SL, Preiss D, McMurray JJ. SGLT2 Inhibition and cardiovascular events: Why did EMPA-REG outcomes surprise and what were the likely mechanisms? Diabetologia. 2016;59(7):1333-9. doi: 10.1007/s00125-016-3956-x. [PubMed: 27112340]. [PubMed Central: PMC4901113].
  • 43. Kosiborod M, Cavender MA, Fu AZ, Wilding JP, Khunti K, Holl RW, et al. Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: The CVD-REAL study (comparative effectiveness of cardiovascular outcomes in new users of sodium-glucose cotransporter-2 inhibitors). Circulation. 2017;136(3):249-59. doi: 10.1161/CIRCULATIONAHA.117.029190. [PubMed: 28522450]. [PubMed Central: PMC5515629].
  • 44. Cherney DZ, Perkins BA, Soleymanlou N, Har R, Fagan N, Johansen OE, et al. The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus. Cardiovasc Diabetol. 2014;13:28. doi: 10.1186/1475-2840-13-28. [PubMed: 24475922]. [PubMed Central: PMC3915232].
  • 45. Neeland IJ, McGuire DK, Chilton R, Crowe S, Lund SS, Woerle HJ, et al. Empagliflozin reduces body weight and indices of adipose distribution in patients with type 2 diabetes mellitus. Diab Vasc Dis Res. 2016;13(2):119-26. doi: 10.1177/1479164115616901. [PubMed: 26873905]. [PubMed Central: PMC4768401].
  • 46. Cheeseman C. Solute carrier family 2, member 9 and uric acid homeostasis. Curr Opin Nephrol Hypertens. 2009;18(5):428-32. doi: 10.1097/MNH.0b013e32832ee3de. [PubMed: 19593129].
  • 47. Jones BJ, Tan T, Bloom SR. Minireview: Glucagon in stress and energy homeostasis. Endocrinology. 2012;153(3):1049-54. doi: 10.1210/en.2011-1979. [PubMed: 22294753]. [PubMed Central: PMC3281544].
  • 48. Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014;124(2):499-508. doi: 10.1172/JCI72227. [PubMed: 24463454]. [PubMed Central: PMC3904627].
  • 49. Bonner C, Kerr-Conte J, Gmyr V, Queniat G, Moerman E, Thevenet J, et al. Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion. Nat Med. 2015;21(5):512-7. doi: 10.1038/nm.3828. [PubMed: 25894829].
  • 50. Ceriello A, Genovese S, Mannucci E, Gronda E. Glucagon and heart in type 2 diabetes: New perspectives. Cardiovasc Diabetol. 2016;15(1):123. doi: 10.1186/s12933-016-0440-3. [PubMed: 27568179]. [PubMed Central: PMC5002329].
  • 51. Cavaiola TS, Pettus J. Cardiovascular effects of sodium glucose cotransporter 2 inhibitors. Diabetes Metab Syndr Obes. 2018;11:133-48. doi: 10.2147/DMSO.S154602. [PubMed: 29695924]. [PubMed Central: PMC5905845].
  • 52. Luconi M, Raimondi L, Di Franco A, Mannucci E. Which is the main molecular target responsible for the cardiovascular benefits in the EMPA-REG OUTCOME trial? A journey through the kidney, the heart and other interesting places. Nutr Metab Cardiovasc Dis. 2016;26(12):1071-8. doi: 10.1016/j.numecd.2016.09.001. [PubMed: 27776917].
  • 53. Warner MR. Age incidence and site distribution of mammary dysplasias in young beagle bitches. J Natl Cancer Inst. 1976;57(1):57-61. doi: 10.1093/jnci/57.1.57. [PubMed: 1034018].
  • 54. Seidu S, Kunutsor SK, Cos X, Gillani S, Khunti K; For, et al. SGLT2 inhibitors and renal outcomes in type 2 diabetes with or without renal impairment: A systematic review and meta-analysis. Prim Care Diabetes. 2018;12(3):265-83. doi: 10.1016/j.pcd.2018.02.001. [PubMed: 29482993].
  • 55. Gross JL, de Azevedo MJ, Silveiro SP, Canani LH, Caramori ML, Zelmanovitz T. Diabetic nephropathy: Diagnosis, prevention, and treatment. Diabetes Care. 2005;28(1):164-76. doi: 10.2337/diacare.28.1.164. [PubMed: 15616252].
  • 56. Heerspink HJ, Desai M, Jardine M, Balis D, Meininger G, Perkovic V. Canagliflozin slows progression of renal function decline independently of glycemic effects. J Am Soc Nephrol. 2017;28(1):368-75. doi: 10.1681/ASN.2016030278. [PubMed: 27539604]. [PubMed Central: PMC5198289].

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