Skip to main navigation menu Skip to main content Skip to site footer
##common.pageHeaderLogo.altText##

Review article: Biomedical intelligence

Vol. 150 No. 3536 (2020)

Use of SGLT2 inhibitors in cardiovascular diseases: why, when and how? A narrative literature review

DOI
https://doi.org/10.4414/smw.2020.20341
Cite this as:
Swiss Med Wkly. 2020;150:w20341
Published
01.09.2020

Summary

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of drugs that reduce blood glucose levels by increasing urinary glucose excretion. On top of the glucose-lowering effect, they offer cardiovascular and renal benefits, the mechanisms of which are probably pleiotropic and include blood pressure reduction, volume depletion, weight loss and several metabolic effects (such as lipolysis and synthesis of ketone bodies). SGLT2 inhibitors are currently indicated in Europe and the USA, as first- or second-line treatments of type 2 diabetes mellitus (T2DM) in patients with established cardiovascular disease, high/very high cardiovascular risk, renal disease or heart failure. The use of dapagliflozin has recently been extended to patients with heart failure without T2DM, as new emerging data show benefits in this population. Despite an overall favourable safety profile, attention has to be paid to the increased risk of euglycaemic diabetic ketoacidosis and genital mycotic infections, as well as lower limb amputations and fractures, which have been inconsistently associated with SGLT2 inhibition. For the moment, cost related data for the Swiss setting is lacking but corresponding analyses from abroad suggest cost-effectiveness. Despite their numerous favourable cardiorenal implications, many physicians remain hesitant to use SGLT2 inhibitors. In this article, we present an up-to-date narrative literature review of the physiological mechanisms of action, current indications, therapeutic utility and side effects of SGLT2 inhibitors.

References

  1. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al.; EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22):2117–28. doi:.https://doi.org/10.1056/NEJMoa1504720
  2. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al.; CANVAS Program Collaborative Group. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017;377(7):644–57. doi:.https://doi.org/10.1056/NEJMoa1611925
  3. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al.; DECLARE–TIMI 58 Investigators. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2019;380(4):347–57. doi:.https://doi.org/10.1056/NEJMoa1812389
  4. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, et al.; CREDENCE Trial Investigators. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019;380(24):2295–306. doi:.https://doi.org/10.1056/NEJMoa1811744
  5. McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, et al.; DAPA-HF Trial Committees and Investigators. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019;381(21):1995–2008. doi:.https://doi.org/10.1056/NEJMoa1911303
  6. U.S. Food and Drug Administration. FDA approves new treatment for a type of heart failure [article online]. 2020. Available from https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-type-heart-failure [Accessed 2020 May 13].
  7. World Health Organization. Diabetes country profiles, Switzerland [article online]. 2016. Available from https://www.who.int/diabetes/country-profiles/che_en.pdf?ua=1 [Accessed 2020 May 11].
  8. Störk S, Handrock R, Jacob J, Walker J, Calado F, Lahoz R, et al. Treatment of chronic heart failure in Germany: a retrospective database study. Clin Res Cardiol. 2017;106(11):923–32. doi:.https://doi.org/10.1007/s00392-017-1138-6
  9. Vardeny O, Vaduganathan M. Practical Guide to Prescribing Sodium-Glucose Cotransporter 2 Inhibitors for Cardiologists. JACC Heart Fail. 2019;7(2):169–72. doi:.https://doi.org/10.1016/j.jchf.2018.11.013
  10. DeFronzo RA, Norton L, Abdul-Ghani M. Renal, metabolic and cardiovascular considerations of SGLT2 inhibition. Nat Rev Nephrol. 2017;13(1):11–26. doi:.https://doi.org/10.1038/nrneph.2016.170
  11. Vallon V, Thomson SC. Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition. Diabetologia. 2017;60(2):215–25. doi:.https://doi.org/10.1007/s00125-016-4157-3
  12. Gomez-Peralta F, Abreu C, Lecube A, Bellido D, Soto A, Morales C, et al. Practical Approach to Initiating SGLT2 Inhibitors in Type 2 Diabetes. Diabetes Ther. 2017;8(5):953–62. doi:.https://doi.org/10.1007/s13300-017-0277-0
  13. Custodio JS, Jr, Duraes AR, Abreu M, Albuquerque Rocha N, Roever L. SGLT2 inhibition and heart failure-current concepts. Heart Fail Rev. 2018;23(3):409–18. doi:.https://doi.org/10.1007/s10741-018-9703-2
  14. Vasilakou D, Karagiannis T, Athanasiadou E, Mainou M, Liakos A, Bekiari E, et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med. 2013;159(4):262–74. doi:.https://doi.org/10.7326/0003-4819-159-4-201308200-00007
  15. Hardy E, Salsali A, Hruba V, Mansfield T, Rohwedder K, Wessman C, et al. Efficacy increases with increasing baseline HbA1c category with dapagliflozin therapy. Diabetes. 2012;61(Suppl.1):23.
  16. Filippatos TD, Liontos A, Papakitsou I, Elisaf MS. SGLT2 inhibitors and cardioprotection: a matter of debate and multiple hypotheses. Postgrad Med. 2019;131(2):82–8. doi:.https://doi.org/10.1080/00325481.2019.1581971
  17. Scheen AJ. Effect of SGLT2 Inhibitors on the Sympathetic Nervous System and Blood Pressure. Curr Cardiol Rep. 2019;21(8):70. doi:.https://doi.org/10.1007/s11886-019-1165-1
  18. Pham SV, Chilton R. EMPA-REG OUTCOME: the cardiologist’s point of view. Am J Med. 2017;130(6S):S57–62. doi:.https://doi.org/10.1016/j.amjmed.2017.04.006
  19. Rahman A, Hitomi H, Nishiyama A. Cardioprotective effects of SGLT2 inhibitors are possibly associated with normalization of the circadian rhythm of blood pressure. Hypertens Res. 2017;40(6):535–40. doi:.https://doi.org/10.1038/hr.2016.193
  20. Packer M. Leptin-Aldosterone-Neprilysin Axis: Identification of Its Distinctive Role in the Pathogenesis of the Three Phenotypes of Heart Failure in People With Obesity. Circulation. 2018;137(15):1614–31. doi:.https://doi.org/10.1161/CIRCULATIONAHA.117.032474
  21. Sano M. A new class of drugs for heart failure: SGLT2 inhibitors reduce sympathetic overactivity. J Cardiol. 2018;71(5):471–6. doi:.https://doi.org/10.1016/j.jjcc.2017.12.004
  22. Bertero E, Prates Roma L, Ameri P, Maack C. Cardiac effects of SGLT2 inhibitors: the sodium hypothesis. Cardiovasc Res. 2018;114(1):12–8. doi:.https://doi.org/10.1093/cvr/cvx149
  23. Lambers Heerspink HJ, de Zeeuw D, Wie L, Leslie B, List J. Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes Metab. 2013;15(9):853–62. doi:.https://doi.org/10.1111/dom.12127
  24. Sano M, Goto S. Possible Mechanism of Hematocrit Elevation by Sodium Glucose Cotransporter 2 Inhibitors and Associated Beneficial Renal and Cardiovascular Effects. Circulation. 2019;139(17):1985–7. doi:.https://doi.org/10.1161/CIRCULATIONAHA.118.038881
  25. Tsimihodimos V, Karanatsis N, Tzavela E, Elisaf M. Antidiabetic drugs and the kidney. Curr Pharm Des. 2017;23(41):6310–20. doi:.https://doi.org/10.2174/1381612823666170307103222
  26. Ndrepepa G, Braun S, King L, Hadamitzky M, Haase HU, Birkmeier KA, et al. Association of uric acid with mortality in patients with stable coronary artery disease. Metabolism. 2012;61(12):1780–6. doi:.https://doi.org/10.1016/j.metabol.2012.05.014
  27. Kaplan A, Abidi E, El-Yazbi A, Eid A, Booz GW, Zouein FA. Direct cardiovascular impact of SGLT2 inhibitors: mechanisms and effects. Heart Fail Rev. 2018;23(3):419–37. doi:.https://doi.org/10.1007/s10741-017-9665-9
  28. Scheen AJ. Beneficial effects of SGLT2 inhibitors on fatty liver in type 2 diabetes: A common comorbidity associated with severe complications. Diabetes Metab. 2019;45(3):213–23. doi:.https://doi.org/10.1016/j.diabet.2019.01.008
  29. Sato T, Aizawa Y, Yuasa S, Kishi S, Fuse K, Fujita S, et al. The effect of dapagliflozin treatment on epicardial adipose tissue volume. Cardiovasc Diabetol. 2018;17(1):6. doi:.https://doi.org/10.1186/s12933-017-0658-8
  30. Al Jobori H, Daniele G, Adams J, Cersosimo E, Triplitt C, DeFronzo RA, et al. Determinants of the increase in ketone concentration during SGLT2 inhibition in NGT, IFG and T2DM patients. Diabetes Obes Metab. 2017;19(6):809–13. doi:.https://doi.org/10.1111/dom.12881
  31. Gormsen LC, Svart M, Thomsen HH, Søndergaard E, Vendelbo MH, Christensen N, et al. Ketone body infusion with 3-hydroxybutyrate reduces myocardial glucose uptake and increases blood flow in humans: a positron emission tomography study. J Am Heart Assoc. 2017;6(3):e005066. doi:.https://doi.org/10.1161/JAHA.116.005066
  32. Polidori D, Iijima H, Goda M, Maruyama N, Inagaki N, Crawford PA. Intra- and inter-subject variability for increases in serum ketone bodies in patients with type 2 diabetes treated with the sodium glucose co-transporter 2 inhibitor canagliflozin. Diabetes Obes Metab. 2018;20(5):1321–6. doi:.https://doi.org/10.1111/dom.13224
  33. Kaneto H, Obata A, Kimura T, Shimoda M, Okauchi S, Shimo N, et al. Beneficial effects of sodium-glucose cotransporter 2 inhibitors for preservation of pancreatic β-cell function and reduction of insulin resistance. J Diabetes. 2017;9(3):219–25. doi:.https://doi.org/10.1111/1753-0407.12494
  34. Packer M, Anker SD, Butler J, Filippatos G, Zannad F. Effects of sodium-glucose cotransporter 2 inhibitors for the treatment of patients with heart failure: proposal of a novel mechanism of action. JAMA Cardiol. 2017;2(9):1025–9. doi:.https://doi.org/10.1001/jamacardio.2017.2275
  35. Uthman L, Baartscheer A, Bleijlevens B, Schumacher CA, Fiolet JWT, Koeman A, et al. Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: inhibition of Na+/H+ exchanger, lowering of cytosolic Na+ and vasodilation. Diabetologia. 2018;61(3):722–6. doi:.https://doi.org/10.1007/s00125-017-4509-7
  36. Despa S, Islam MA, Weber CR, Pogwizd SM, Bers DM. Intracellular Na(+) concentration is elevated in heart failure but Na/K pump function is unchanged. Circulation. 2002;105(21):2543–8. doi:.https://doi.org/10.1161/01.CIR.0000016701.85760.97
  37. Solini A, Giannini L, Seghieri M, Vitolo E, Taddei S, Ghiadoni L, et al. Dapagliflozin acutely improves endothelial dysfunction, reduces aortic stiffness and renal resistive index in type 2 diabetic patients: a pilot study. Cardiovasc Diabetol. 2017;16(1):138. doi:.https://doi.org/10.1186/s12933-017-0621-8
  38. Lee TM, Chang NC, Lin SZ. Dapagliflozin, a selective SGLT2 Inhibitor, attenuated cardiac fibrosis by regulating the macrophage polarization via STAT3 signaling in infarcted rat hearts. Free Radic Biol Med. 2017;104:298–310. doi:.https://doi.org/10.1016/j.freeradbiomed.2017.01.035
  39. Lam CSP, Chandramouli C, Ahooja V, Verma S. SGLT-2 Inhibitors in Heart Failure: Current Management, Unmet Needs, and Therapeutic Prospects. J Am Heart Assoc. 2019;8(20):e013389. doi:.https://doi.org/10.1161/JAHA.119.013389
  40. Fitchett D, Inzucchi SE, Cannon CP, McGuire DK, Scirica BM, Johansen OE, et al. Empagliflozin Reduced Mortality and Hospitalization for Heart Failure Across the Spectrum of Cardiovascular Risk in the EMPA-REG OUTCOME Trial. Circulation. 2019;139(11):1384–95. doi:.https://doi.org/10.1161/CIRCULATIONAHA.118.037778
  41. Seferović PM, Coats AJS, Ponikowski P, Filippatos G, Huelsmann M, Jhund PS, et al. European Society of Cardiology/Heart Failure Association position paper on the role and safety of new glucose-lowering drugs in patients with heart failure. Eur J Heart Fail. 2020;22(2):196–213. doi:.https://doi.org/10.1002/ejhf.1673
  42. 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:.https://doi.org/10.1016/S0140-6736(18)32590-X
  43. Rådholm K, Figtree G, Perkovic V, Solomon SD, Mahaffey KW, de Zeeuw D, et al. Canagliflozin and heart failure in type 2 diabetes mellitus. Circulation. 2018;138(5):458–68. doi:.https://doi.org/10.1161/CIRCULATIONAHA.118.034222
  44. Kato ET, Silverman MG, Mosenzon O, Zelniker TA, Cahn A, Furtado RHM, et al. Effect of dapagliflozin on heart failure and mortality in type 2 diabetes mellitus. Circulation. 2019;139(22):2528–36. doi:.https://doi.org/10.1161/CIRCULATIONAHA.119.040130
  45. Verma S, McMurray JJV. The Serendipitous Story of SGLT2 Inhibitors in Heart Failure: New Insights From DECLARE-TIMI 58. Circulation. 2019;139(22):2537–41. doi:.https://doi.org/10.1161/CIRCULATIONAHA.119.040514
  46. Greene SJ, Fonarow GC, Vaduganathan M, Khan SS, Butler J, Gheorghiade M. The vulnerable phase after hospitalization for heart failure. Nat Rev Cardiol. 2015;12(4):220–9. doi:.https://doi.org/10.1038/nrcardio.2015.14
  47. Shah KS, Xu H, Matsouaka RA, Bhatt DL, Heidenreich PA, Hernandez AF, et al. Heart Failure With Preserved, Borderline, and Reduced Ejection Fraction: 5-Year Outcomes. J Am Coll Cardiol. 2017;70(20):2476–86. doi:.https://doi.org/10.1016/j.jacc.2017.08.074
  48. Opingari E, Partridge ACR, Verma S, Bajaj HS. SGLT2 inhibitors: practical considerations and recommendations for cardiologists. Curr Opin Cardiol. 2018;33(6):676–82. doi:.https://doi.org/10.1097/HCO.0000000000000561
  49. Li D, Wang T, Shen S, Fang Z, Dong Y, Tang H. Urinary tract and genital infections in patients with type 2 diabetes treated with sodium-glucose co-transporter 2 inhibitors: A meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2017;19(3):348–55. doi:.https://doi.org/10.1111/dom.12825
  50. Donnan JR, Grandy CA, Chibrikov E, Marra CA, Aubrey-Bassler K, Johnston K, et al. Comparative safety of the sodium glucose co-transporter 2 (SGLT2) inhibitors: a systematic review and meta-analysis. BMJ Open. 2019;9(1):e022577. doi:.https://doi.org/10.1136/bmjopen-2018-022577
  51. Bersoff-Matcha SJ, Chamberlain C, Cao C, Kortepeter C, Chong WH. Fournier Gangrene Associated With Sodium-Glucose Cotransporter-2 Inhibitors: A Review of Spontaneous Postmarketing Cases. Ann Intern Med. 2019;170(11):764–9. doi:.https://doi.org/10.7326/M19-0085
  52. Dave CV, Schneeweiss S, Kim D, Fralick M, Tong A, Patorno E. Sodium-Glucose Cotransporter-2 Inhibitors and the Risk for Severe Urinary Tract Infections: A Population-Based Cohort Study. Ann Intern Med. 2019;171(4):248–56. doi:.https://doi.org/10.7326/M18-3136
  53. Rawla P, Vellipuram AR, Bandaru SS, Pradeep Raj J. Euglycemic diabetic ketoacidosis: a diagnostic and therapeutic dilemma. Endocrinol Diabetes Metab Case Rep. 2017;2017:17–0081. doi:.https://doi.org/10.1530/EDM-17-0081
  54. Rosenstock J, Ferrannini E. Euglycemic Diabetic Ketoacidosis: A Predictable, Detectable, and Preventable Safety Concern With SGLT2 Inhibitors. Diabetes Care. 2015;38(9):1638–42. doi:.https://doi.org/10.2337/dc15-1380
  55. Dizon S, Keely EJ, Malcolm J, Arnaout A. Insights into the recognition and management of SGLT2-inhibitor-associated ketoacidosis: it’s not just euglycemic diabetic ketoacidosis. Can J Diabetes. 2017;41(5):499–503. doi:.https://doi.org/10.1016/j.jcjd.2017.05.004
  56. Taylor SI, Blau JE, Rother KI. SGLT2 Inhibitors May Predispose to Ketoacidosis. J Clin Endocrinol Metab. 2015;100(8):2849–52. doi:.https://doi.org/10.1210/jc.2015-1884
  57. Nadkarni GN, Ferrandino R, Chang A, Surapaneni A, Chauhan K, Poojary P, et al. Acute Kidney Injury in Patients on SGLT2 Inhibitors: A Propensity-Matched Analysis. Diabetes Care. 2017;40(11):1479–85. doi:.https://doi.org/10.2337/dc17-1011
  58. U.S. Food and Drug Administration. FDA drug safety communication: FDA strengthens kidney warnings for diabetes medicines canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR) [article online]. 2016. Available from https://www.fda.gov/Drugs/DrugSafety/ucm505860.htm. [Accessed 2020 July 2].
  59. Neuen BL, Young T, Heerspink HJL, Neal B, Perkovic V, Billot L, et al. 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(11):845–54. doi:.https://doi.org/10.1016/S2213-8587(19)30256-6
  60. Arnott C, Li Q, Kang A, Neuen BL, Bompoint S, Lam CSP, et al. Sodium-Glucose Cotransporter 2 Inhibition for the Prevention of Cardiovascular Events in Patients With Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis. J Am Heart Assoc. 2020;9(3):e014908. doi:.https://doi.org/10.1161/JAHA.119.014908
  61. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes-2020. Diabetes Care. 2020;43(Suppl 1):S98–110. doi:.https://doi.org/10.2337/dc20-S009
  62. Schweizerische Gesellschaft für Endokrinologie und Diabetologie (SGED). [article online]. 2020. Available from https://www.sgedssed.ch/fileadmin/user_upload/6_Diabetologie/61_Empfehlungen_Facharzt/2020_Swiss_Recomm_Medis_EN_def.pdf [Accessed 2020 2 July].
  63. Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, et al.; ESC Scientific Document Group. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J. 2020;41(2):255–323. doi:.https://doi.org/10.1093/eurheartj/ehz486
  64. Das SR, Everett BM, Birtcher KK, Brown JM, Cefalu WT, Januzzi JL, Jr, et al. 2018 ACC Expert Consensus Decision Pathway on Novel Therapies for Cardiovascular Risk Reduction in Patients With Type 2 Diabetes and Atherosclerotic Cardiovascular Disease: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2018;72(24):3200–23. doi:.https://doi.org/10.1016/j.jacc.2018.09.020
  65. Huber CA, Schwenkglenks M, Rapold R, Reich O. Epidemiology and costs of diabetes mellitus in Switzerland: an analysis of health care claims data, 2006 and 2011. BMC Endocr Disord. 2014;14(1):44. doi:.https://doi.org/10.1186/1472-6823-14-44
  66. Denis P, Aguadé A, Lesuffleur T, Pestel L, Nicolas M, Rachas A, et al. Economic burden of diabetes in France between 2012 and 2017 based on French national claim database. Eur J Public Health. 2019;29(Supplement_4): ckz187.068. doi:.https://doi.org/10.1093/eurpub/ckz187.068
  67. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al.; ESC Scientific Document Group. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37(27):2129–200. doi:.https://doi.org/10.1093/eurheartj/ehw128
  68. Stewart S, Ekman I, Ekman T, Odén A, Rosengren A. Population impact of heart failure and the most common forms of cancer: a study of 1 162 309 hospital cases in Sweden (1988 to 2004). Circ Cardiovasc Qual Outcomes. 2010;3(6):573–80. doi:.https://doi.org/10.1161/CIRCOUTCOMES.110.957571
  69. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al.; Writing Group Members; American Heart Association Statistics Committee; Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association. Circulation. 2016;133(4):e38–360. doi:.https://doi.org/10.1161/CIR.0000000000000350
  70. Hong D, Si L, Jiang M, Shao H, Ming WK, Zhao Y, et al. Cost Effectiveness of Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors, Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists, and Dipeptidyl Peptidase-4 (DPP-4) Inhibitors: A Systematic Review. Pharmacoeconomics. 2019;37(6):777–818.

Most read articles by the same author(s)