Iberoamerican Journal of Medicine
Iberoamerican Journal of Medicine

Sodium-Glucose Co-Transporter Type 2 Inhibitors and Heart Failure: A Review of the State of the Art

Inhibidores del Cotransportador de Sodio-Glucosa Tipo 2 e Insuficiencia Cardíaca: Una Revisión del Estado del Arte

Yilmar Alexader Meza-González, Natalia Alfonso-Arrieta, Stephany Salas-Solorzano, Victor Florez-Garcia

Downloads: 12
Views: 836


Heart Failure (HF) is a cardiovascular condition with high morbidity and mortality that conditions one of the most critical problems in public health. Despite advances in recent decades, patients continue to have major cardiovascular events and marked reduction in their quality of life. Sodium-Glucose Cotransporter Type 2 Inhibitors (SGLT2 Inhibitors) initially entered the market to treat hyperglycemia in patients with type 2 diabetes mellitus (T2DM), however the discovery of the cardiovascular benefits in patients with HF, regardless of the presence or absence of T2DM positioned it as a new pillar in clinical management.
In this state-of-the-art review resulting from a comprehensive literature search (Medline, Cochrane and EMBASE), we describe the impact of SGLT2 Inhibitors on mortality and rehospitalizations in patients with HF and we propose a therapeutic plan for patients with HF to maximizes the benefits.


Heart failure; SGLT2 inhibitors; Nephtoprotection; Type 2 diabetes mellitus


La Insuficiencia Cardíaca (IC) es una condición cardiovascular con alta morbilidad y mortalidad que condiciona uno de los problemas más críticos en salud pública. A pesar de los avances en las últimas décadas, los pacientes continúan presentando eventos cardiovasculares importantes y una marcada reducción de su calidad de vida. Los inhibidores del cotransportador de sodio-glucosa tipo 2 (SGLT2) ingresaron inicialmente al mercado para tratar la hiperglucemia en pacientes con diabetes mellitus tipo 2 (DMT2), sin embargo, el descubrimiento de los beneficios cardiovasculares en pacientes con IC, independientemente de la presencia o ausencia de DMT2, lo posicionó como un nuevo pilar en manejo clínico.
Esta revisión de la literatura es resultante de una búsqueda bibliográfica exhaustiva (Medline, Cochrane y EMBASE), y describimos el impacto de los iSGLT2 en la mortalidad y rehospitalizaciones en pacientes con IC y proponemos un plan terapéutico para pacientes con IC para maximizar los beneficios.

Palabras clave

Insuficiencia cardiaca; Inhibidores SGLT2; Nefroprotección; Diabetes mellitus tipo 2


1. Ho KK, Pinsky JL, Kannel WB, Levy D. The epidemiology of heart failure: the Framingham Study. J Am Coll Cardiol. 1993;22(4 Suppl A):6A-13A. doi: 10.1016/0735-1097(93)90455-a.
2. Cowie MR, Mosterd A, Wood DA, Deckers JW, Poole-Wilson PA, Sutton GC, et al. The epidemiology of heart failure. Eur Heart J. 1997;18(2):208-25. doi: 10.1093/oxfordjournals.eurheartj.a015223.
3. Savarese G, Lund LH. Global Public Health Burden of Heart Failure. Card Fail Rev. 2017;3(1):7-11. doi: 10.15420/cfr.2016:25:2.
4. Tsao CW, Aday AW, Almarzooq ZI, Alonso A, Beaton AZ, Bittencourt MS, et al. Heart Disease and Stroke Statistics-2022 Update: A Report From the American Heart Association. Circulation. 2022;145(8):e153-e639. doi: 10.1161/CIR.0000000000001052.
5. GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1789-858. doi: 10.1016/S0140-6736(18)32279-7.
6. McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42(36):3599-726. doi: 10.1093/eurheartj/ehab368.
7. Chioncel O, Lainscak M, Seferovic PM, Anker SD, Crespo-Leiro MG, Harjola VP, et al. Epidemiology and one-year outcomes in patients with chronic heart failure and preserved, mid-range and reduced ejection fraction: an analysis of the ESC Heart Failure Long-Term Registry. Eur J Heart Fail. 2017;19(12):1574-85. doi: 10.1002/ejhf.813.
8. Coelho R, Ramos S, Prata J, Bettencourt P, Ferreira A, Cerqueira-Gomes M. Heart failure and health related quality of life. Clin Pract Epidemiol Ment Health. 2005;1:19. doi: 10.1186/1745-0179-1-19.
9. van Riet EE, Hoes AW, Wagenaar KP, Limburg A, Landman MA, Rutten FH. Epidemiology of heart failure: the prevalence of heart failure and ventricular dysfunction in older adults over time. A systematic review. Eur J Heart Fail. 2016;18(3):242-52. doi: 10.1002/ejhf.483.
10. Gerber Y, Weston SA, Redfield MM, Chamberlain AM, Manemann SM, Jiang R, et al. A contemporary appraisal of the heart failure epidemic in Olmsted County, Minnesota, 2000 to 2010. JAMA Intern Med. 2015;175(6):996-1004. doi: 10.1001/jamainternmed.2015.0924.
11. Tsao CW, Lyass A, Enserro D, Larson MG, Ho JE, Kizer JR, et al. Temporal Trends in the Incidence of and Mortality Associated With Heart Failure With Preserved and Reduced Ejection Fraction. JACC Heart Fail. 2018;6(8):678-85. doi: 10.1016/j.jchf.2018.03.006.
12. Motiejūnaitė J, Akiyama E, Cohen-Solal A, Maggioni AP, Mueller C, Choi DJ, et al. The association of long-term outcome and biological sex in patients with acute heart failure from different geographic regions. Eur Heart J. 2020;41(13):1357-64. doi: 10.1093/eurheartj/ehaa071.
13. Barasa A, Schaufelberger M, Lappas G, Swedberg K, Dellborg M, Rosengren A. Heart failure in young adults: 20-year trends in hospitalization, aetiology, and case fatality in Sweden. Eur Heart J. 2014;35(1):25-32. doi: 10.1093/eurheartj/eht278.
14. Mosterd A, Hoes AW. Clinical epidemiology of heart failure. Heart. 2007;93(9):1137-46. doi: 10.1136/hrt.2003.025270.
15. Writing Committee; Maddox TM, Januzzi JL Jr, Allen LA, Breathett K, Butler J, et al. 2021 Update to the 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment: Answers to 10 Pivotal Issues About Heart Failure With Reduced Ejection Fraction: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2021;77(6):772-810. doi: 10.1016/j.jacc.2020.11.022.
16. Rajasekeran H, Lytvyn Y, Cherney DZ. Sodium-glucose cotransporter 2 inhibition and cardiovascular risk reduction in patients with type 2 diabetes: the emerging role of natriuresis. Kidney Int. 2016;89(3):524-6. doi: 10.1016/j.kint.2015.12.038.
17. 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: 10.1001/jamacardio.2017.2275.
18. 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: 10.1007/s00125-017-4509-7.
19. Wojcik C, Warden BA. Mechanisms and Evidence for Heart Failure Benefits from SGLT2 Inhibitors. Curr Cardiol Rep. 2019;21(10):130. doi: 10.1007/s11886-019-1219-4.
20. U.S. Food and Drug Administration. Guidance for industry: diabetes mellitus - evaluating cardiovascular risk in new antidiabetic therapies to treat
type 2 diabetes. Available from https://www.fda.gov/media/135936/download (accessed March 2022).
21. 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.
22. Neal B, Perkovic V, Matthews DR. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017;377(21):2099. doi: 10.1056/NEJMc1712572.
23. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019;380(24):2295-306. doi: 10.1056/NEJMoa1811744.
24. 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.
25. 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.
26. McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019;381(21):1995-2008. doi: 10.1056/NEJMoa1911303.
27. Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, et al. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med. 2020;383(15):1413-24. doi: 10.1056/NEJMoa2022190.
28. Zannad F, Ferreira JP, Pocock SJ, Anker SD, Butler J, Filippatos G, et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet. 2020;396(10254):819-29. doi: 10.1016/S0140-6736(20)31824-9.
29. Kosiborod MN, Jhund PS, Docherty KF, Diez M, Petrie MC, Verma S, et al. Effects of Dapagliflozin on Symptoms, Function, and Quality of Life in Patients With Heart Failure and Reduced Ejection Fraction: Results From the DAPA-HF Trial. Circulation. 2020;141(2):90-9. doi: 10.1161/CIRCULATIONAHA.119.044138.
30. Butler J, Anker SD, Filippatos G, Khan MS, Ferreira JP, Pocock SJ, et al. Empagliflozin and health-related quality of life outcomes in patients with heart failure with reduced ejection fraction: the EMPEROR-Reduced trial. Eur Heart J. 2021;42(13):1203-12. doi: 10.1093/eurheartj/ehaa1007.
31. Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, Böhm M, et al. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N Engl J Med. 2021;385(16):1451-61. doi: 10.1056/NEJMoa2107038.
32. Solomon SD, McMurray JJV, Claggett B, de Boer RA, DeMets D, Hernandez AF, et al. Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N Engl J Med. 2022;387(12):1089-98. doi: 10.1056/NEJMoa2206286.
33. Nieminen MS, Brutsaert D, Dickstein K, Drexler H, Follath F, Harjola VP, et al. EuroHeart Failure Survey II (EHFS II): a survey on hospitalized acute heart failure patients: description of population. Eur Heart J. 2006;27(22):2725-36. doi: 10.1093/eurheartj/ehl193.
34. Bhatt DL, Szarek M, Steg PG, Cannon CP, Leiter LA, McGuire DK, et al. Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure. N Engl J Med. 2021;384(2):117-28. doi: 10.1056/NEJMoa2030183.
35. Damman K, Beusekamp JC, Boorsma EM, Swart HP, Smilde TDJ, Elvan A, et al. Randomized, double-blind, placebo-controlled, multicentre pilot study on the effects of empagliflozin on clinical outcomes in patients with acute decompensated heart failure (EMPA-RESPONSE-AHF). Eur J Heart Fail. 2020;22(4):713-22. doi: 10.1002/ejhf.1713.
36. Voors AA, Angermann CE, Teerlink JR, Collins SP, Kosiborod M, Biegus J, et al. The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial. Nat Med. 2022;28(3):568-74. doi: 10.1038/s41591-021-01659-1.
37. Heerspink HJL, Stefánsson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020;383(15):1436-46. doi: 10.1056/NEJMoa2024816.
38. Aguilar D. Heart Failure, Diabetes Mellitus, and Chronic Kidney Disease: A Clinical Conundrum. Circ Heart Fail. 2016;9(7):e003316. doi: 10.1161/CIRCHEARTFAILURE.116.003316.
39. 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: 10.1016/S2213-8587(19)30256-6.
40. McGovern AP, Hogg M, Shields BM, Sattar NA, Holman RR, Pearson ER, et al. Risk factors for genital infections in people initiating SGLT2 inhibitors and their impact on discontinuation. BMJ Open Diabetes Res Care. 2020;8(1):e001238. doi: 10.1136/bmjdrc-2020-001238.
41. 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):752-72. doi: 10.1161/CIRCULATIONAHA.116.021887.
42. Rangaswami J, Bhalla V, de Boer IH, Staruschenko A, Sharp JA, Singh RR,et al. Cardiorenal Protection With the Newer Antidiabetic Agents in Patients With Diabetes and Chronic Kidney Disease: A Scientific Statement From the American Heart Association. Circulation. 2020;142(17):e265-e286. doi: 10.1161/CIR.0000000000000920.
43. Vardeny O, Vaduganathan M. Practical Guide to Prescribing Sodium-Glucose Cotransporter 2 Inhibitors for Cardiologists. JACC Heart Fail. 2019;7(2):169-72. doi: 10.1016/j.jchf.2018.11.013.
44. U.S. Food and Drug Administration. FDA removes Boxed Warning about risk of leg and foot amputations for the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR). Available from https://www.fda.gov/drugs/drug-safety-and-availability/fda-removes-boxed-
warning-about-risk-leg-and-footamputations-diabetes-medicine-canagliflozin (accessed March 2022).
45. Das SR, Everett BM, Birtcher KK, Brown JM, Januzzi JL Jr, Kalyani RR, et al. 2020 Expert Consensus Decision Pathway on Novel Therapies for Cardiovascular Risk Reduction in Patients With Type 2 Diabetes: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2020;76(9):1117-45. doi: 10.1016/j.jacc.2020.05.037.
46. Boehringer Ingelheim Pharmaceuticals. Prescribing Information Jardiance (Empagliflozin). Available from https://content.boehringer-ingelheim.com/DAM/7d9c411c-ec33-4f82-886f-af1e011f35bb/jardiance-us-pi.pdf (accessed March 2022).
47. Janssen Pharmaceuticals. Prescribing Information Invokana (Canagliflozin). Avalibale from: https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/INVOKANA-pi.pdf (accessed March 2022).
48. AstraZeneca Pharmaceuticals. Prescribing Information Farxiga (Dapagliflozin). Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/202293s020lbl.pdf(accessed March 2022).
49. Butler J, Usman MS, Khan MS, Greene SJ, Friede T, Vaduganathan M, et al. Efficacy and safety of SGLT2 inhibitors in heart failure: systematic review and meta-analysis. ESC Heart Fail. 2020;7(6):3298-3309. doi: 10.1002/ehf2.13169.
50. Bauersachs J. Heart failure drug treatment: the fantastic four. Eur Heart J. 2021;42(6):681-3. doi: 10.1093/eurheartj/ehaa1012.
51. Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145(18):e876-e894. doi: 10.1161/CIR.0000000000001062.

Submitted date:

Reviewed date:

Accepted date:

Publication date:

63e63354a953954f6b054753 iberoamericanjm Articles
Links & Downloads

Iberoam J Med

Share this page
Page Sections