Skip to main content

Advertisement

SpringerLink
Log in

Treating Disease Mechanisms in Patients With Heart Failure and Diabetes Mellitus

  • Comorbidities of Heart Failure (C Angermann and F Edelmann, Section Editors)
  • Published:
Current Heart Failure Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Diabetes and heart failure commonly coexist and portend worsened prognosis than either disease alone. We explore mechanisms that may serve as potential treatment targets and review the effects of various contemporary glucose-lowering agents on heart failure outcomes.

Recent Findings

Promising data has emerged on sodium-glucose cotransporter 2 (SLGT2) inhibitors as the first class of agents to improve cardiovascular mortality and heart failure outcomes in diabetic individuals both with and without established heart failure.

Summary

Poor glycemic control is linked to worse heart failure outcomes; however, targeting glycemic control alone has not been sufficient. Furthermore, multiple commonly used antihyperglycemic agents may lead to adverse heart failure effects. SGLT2 inhibitors target multiple mechanisms implicated in diabetes and heart failure and may play a promising role in primary prevention of heart failure and in treatment of individuals with diabetes and established heart failure.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Disease GBD, Injury I, Prevalence C. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the global burden of disease study 2015. Lancet (London, England). 2016;388(10053):1545–602. https://doi.org/10.1016/S0140-6736(16)31678-6.

    Article  Google Scholar 

  2. Rawshani A, Rawshani A, Franzen S, Eliasson B, Svensson AM, Miftaraj M, et al. Mortality and cardiovascular disease in type 1 and type 2 diabetes. N Engl J Med. 2017;376(15):1407–18. https://doi.org/10.1056/NEJMoa1608664.

    Article  PubMed  Google Scholar 

  3. Emerging Risk Factors C, Seshasai SR, Kaptoge S, Thompson A, Di Angelantonio E, Gao P, et al. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med. 2011;364(9):829–41. https://doi.org/10.1056/NEJMoa1008862.

    Article  Google Scholar 

  4. Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: the Framingham study. Am J Cardiol. 1974;34(1):29–34.

    Article  CAS  PubMed  Google Scholar 

  5. Shah AD, Langenberg C, Rapsomaniki E, Denaxas S, Pujades-Rodriguez M, Gale CP, et al. Type 2 diabetes and incidence of cardiovascular diseases: a cohort study in 1.9 million people. Lancet Diabetes Endocrinol. 2015;3(2):105–13. https://doi.org/10.1016/S2213-8587(14)70219-0.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Martinez-Selles M, Doughty RN, Poppe K, Whalley GA, Earle N, Tribouilloy C, et al. Gender and survival in patients with heart failure: interactions with diabetes and aetiology. Results from the MAGGIC individual patient meta-analysis. Eur J Heart Fail. 2012;14(5):473–9. https://doi.org/10.1093/eurjhf/hfs026.

    Article  PubMed  Google Scholar 

  7. Greenberg BH, Abraham WT, Albert NM, Chiswell K, Clare R, Stough WG, et al. Influence of diabetes on characteristics and outcomes in patients hospitalized with heart failure: a report from the organized program to initiate lifesaving treatment in hospitalized patients with heart failure (OPTIMIZE-HF). Am Heart J. 2007;154(2):277.e1–8. https://doi.org/10.1016/j.ahj.2007.05.001.

    Article  Google Scholar 

  8. MacDonald MR, Petrie MC, Varyani F, Ostergren J, Michelson EL, Young JB, et al. Impact of diabetes on outcomes in patients with low and preserved ejection fraction heart failure: an analysis of the candesartan in heart failure: assessment of reduction in mortality and morbidity (CHARM) programme. Eur Heart J. 2008;29(11):1377–85. https://doi.org/10.1093/eurheartj/ehn153.

    Article  PubMed  Google Scholar 

  9. Aguilar D, Solomon SD, Kober L, Rouleau JL, Skali H, McMurray JJ, et al. Newly diagnosed and previously known diabetes mellitus and 1-year outcomes of acute myocardial infarction: the VALsartan in acute myocardial iNfarcTion (VALIANT) trial. Circulation. 2004;110(12):1572–8. https://doi.org/10.1161/01.cir.0000142047.28024.f2.

    Article  PubMed  Google Scholar 

  10. Boudina S, Abel ED. Diabetic cardiomyopathy revisited. Circulation. 2007;115(25):3213–23. https://doi.org/10.1161/circulationaha.106.679597.

    Article  PubMed  Google Scholar 

  11. • Low Wang CC, Hess CN, Hiatt WR, Goldfine AB. Clinical update: cardiovascular disease in diabetes mellitus: atherosclerotic cardiovascular disease and heart failure in type 2 diabetes mellitus - mechanisms, management, and clinical considerations. Circulation. 2016;133(24):2459–502. https://doi.org/10.1161/CIRCULATIONAHA.116.022194. This article reviews the disease mechanisms and currently recommended clinical management of cardiovascular disease and heart failure in diabetic patients.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Abel ED, O'Shea KM, Ramasamy R. Insulin resistance: metabolic mechanisms and consequences in the heart. Arterioscler Thromb Vasc Biol. 2012;32(9):2068–76. https://doi.org/10.1161/ATVBAHA.111.241984.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Berg TJ, Snorgaard O, Faber J, Torjesen PA, Hildebrandt P, Mehlsen J, et al. Serum levels of advanced glycation end products are associated with left ventricular diastolic function in patients with type 1 diabetes. Diabetes Care. 1999;22(7):1186–90.

    Article  CAS  PubMed  Google Scholar 

  14. Young ME, McNulty P, Taegtmeyer H. Adaptation and maladaptation of the heart in diabetes: part II: potential mechanisms. Circulation. 2002;105(15):1861–70.

    Article  CAS  PubMed  Google Scholar 

  15. Kosmala W, Sanders P, Marwick TH. Subclinical myocardial impairment in metabolic diseases. JACC Cardiovasc Imaging. 2017;10(6):692–703. https://doi.org/10.1016/j.jcmg.2017.04.001.

    Article  PubMed  Google Scholar 

  16. Iribarren C, Karter AJ, Go AS, Ferrara A, Liu JY, Sidney S, et al. Glycemic control and heart failure among adult patients with diabetes. Circulation. 2001;103(22):2668–73.

    Article  CAS  PubMed  Google Scholar 

  17. Lind M, Bounias I, Olsson M, Gudbjornsdottir S, Svensson AM, Rosengren A. Glycaemic control and incidence of heart failure in 20,985 patients with type 1 diabetes: an observational study. Lancet. 2011;378(9786):140–6. https://doi.org/10.1016/s0140-6736(11)60471-6.

    Article  PubMed  Google Scholar 

  18. Held C, Gerstein HC, Yusuf S, Zhao F, Hilbrich L, Anderson C, et al. Glucose levels predict hospitalization for congestive heart failure in patients at high cardiovascular risk. Circulation. 2007;115(11):1371–5. https://doi.org/10.1161/circulationaha.106.661405.

    Article  CAS  PubMed  Google Scholar 

  19. Barzilay JI, Kronmal RA, Gottdiener JS, Smith NL, Burke GL, Tracy R, et al. The association of fasting glucose levels with congestive heart failure in diabetic adults > or =65 years: the Cardiovascular Health Study. J Am Coll Cardiol. 2004;43(12):2236–41. https://doi.org/10.1016/j.jacc.2003.10.074.

    Article  CAS  PubMed  Google Scholar 

  20. Pazin-Filho A, Kottgen A, Bertoni AG, Russell SD, Selvin E, Rosamond WD, et al. HbA 1c as a risk factor for heart failure in persons with diabetes: the atherosclerosis risk in communities (ARIC) study. Diabetologia. 2008;51(12):2197–204. https://doi.org/10.1007/s00125-008-1164-z.

    Article  CAS  PubMed  Google Scholar 

  21. Erqou S, Lee CT, Adler A. Intensive glycemic control and the risk of heart failure in patients with type 2 diabetes. Am Heart J. 2012;163(5):e35; author reply e7. https://doi.org/10.1016/j.ahj.2012.02.021.

    Article  PubMed  Google Scholar 

  22. Matsushita K, Blecker S, Pazin-Filho A, Bertoni A, Chang PP, Coresh J, et al. The association of hemoglobin a1c with incident heart failure among people without diabetes: the atherosclerosis risk in communities study. Diabetes. 2010;59(8):2020–6. https://doi.org/10.2337/db10-0165.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, Byington RP, Goff DC, Bigger JT Jr, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24):2545–59. https://doi.org/10.1056/NEJMoa0802743.

    Article  Google Scholar 

  24. ADVANCE Collaboration Group, Patel A, MacMahon S, Chalmers J, Neal B, Billot L, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560–72. https://doi.org/10.1056/NEJMoa0802987.

    Article  Google Scholar 

  25. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360(2):129–39. https://doi.org/10.1056/NEJMoa0808431.

    Article  CAS  PubMed  Google Scholar 

  26. Turnbull FM, Abraira C, Anderson RJ, Byington RP, Chalmers JP, Duckworth WC, et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia. 2009;52(11):2288–98. https://doi.org/10.1007/s00125-009-1470-0.

    Article  CAS  PubMed  Google Scholar 

  27. Bozkurt B, Aguilar D, Deswal A, Dunbar SB, Francis GS, Horwich T, et al. Contributory risk and Management of Comorbidities of hypertension, obesity, diabetes mellitus, hyperlipidemia, and metabolic syndrome in chronic heart failure: a scientific statement from the American Heart Association. Circulation. 2016;134(23):e535–e78. https://doi.org/10.1161/CIR.0000000000000450.

    Article  PubMed  Google Scholar 

  28. Aguilar D, Bozkurt B, Ramasubbu K, Deswal A. Relationship of hemoglobin A1C and mortality in heart failure patients with diabetes. J Am Coll Cardiol. 2009;54(5):422–8. https://doi.org/10.1016/j.jacc.2009.04.049.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Elder DH, Singh JS, Levin D, Donnelly LA, Choy AM, George J, et al. Mean HbA1c and mortality in diabetic individuals with heart failure: a population cohort study. Eur J Heart Fail. 2016;18(1):94–102. https://doi.org/10.1002/ejhf.455.

    Article  CAS  PubMed  Google Scholar 

  30. Eshaghian S, Horwich TB, Fonarow GC. An unexpected inverse relationship between HbA1c levels and mortality in patients with diabetes and advanced systolic heart failure. Am Heart J. 2006;151(1):91. https://doi.org/10.1016/j.ahj.2005.10.008.

    Article  PubMed  Google Scholar 

  31. Tomova GS, Nimbal V, Horwich TB. Relation between hemoglobin a(1c) and outcomes in heart failure patients with and without diabetes mellitus. Am J Cardiol. 2012;109(12):1767–73. https://doi.org/10.1016/j.amjcard.2012.02.022.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. American Diabetes Association. 6. Glycemic targets. Diabetes Care. 2017;40(Suppl 1):S48–56. https://doi.org/10.2337/dc17-S009.

    Article  Google Scholar 

  33. American Diabetes Association. 8. Pharmacologic approaches to glycemic treatment. Diabetes Care. 2017;40(Suppl 1):S64–74. https://doi.org/10.2337/dc17-S011.

    Article  Google Scholar 

  34. Misbin RI, Green L, Stadel BV, Gueriguian JL, Gubbi A, Fleming GA. Lactic acidosis in patients with diabetes treated with metformin. N Engl J Med. 1998;338(4):265–6. https://doi.org/10.1056/NEJM199801223380415.

    Article  CAS  PubMed  Google Scholar 

  35. Aguilar D, Chan W, Bozkurt B, Ramasubbu K, Deswal A. Metformin use and mortality in ambulatory patients with diabetes and heart failure. Circ Heart Fail. 2011;4(1):53–8. https://doi.org/10.1161/CIRCHEARTFAILURE.110.952556.

    Article  CAS  PubMed  Google Scholar 

  36. Andersson C, Olesen JB, Hansen PR, Weeke P, Norgaard ML, Jorgensen CH, et al. Metformin treatment is associated with a low risk of mortality in diabetic patients with heart failure: a retrospective nationwide cohort study. Diabetologia. 2010;53(12):2546–53. https://doi.org/10.1007/s00125-010-1906-6.

    Article  CAS  PubMed  Google Scholar 

  37. Eurich DT, Majumdar SR, McAlister FA, Tsuyuki RT, Johnson JA. Improved clinical outcomes associated with metformin in patients with diabetes and heart failure. Diabetes Care. 2005;28(10):2345–51.

    Article  CAS  PubMed  Google Scholar 

  38. MacDonald MR, Eurich DT, Majumdar SR, Lewsey JD, Bhagra S, Jhund PS, et al. Treatment of type 2 diabetes and outcomes in patients with heart failure: a nested case-control study from the U.K. general practice research database. Diabetes Care. 2010;33(6):1213–8. https://doi.org/10.2337/dc09-2227.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Masoudi FA, Inzucchi SE, Wang Y, Havranek EP, Foody JM, Krumholz HM. Thiazolidinediones, metformin, and outcomes in older patients with diabetes and heart failure: an observational study. Circulation. 2005;111(5):583–90. https://doi.org/10.1161/01.CIR.0000154542.13412.B1.

    Article  CAS  PubMed  Google Scholar 

  40. Roumie CL, Min JY, Agostino-Mcgowan L, Presley C, Grijalva CG, Hackstadt AJ et al. Comparative safety of sulfonylurea and metformin monotherapy on the risk of heart failure: a cohort study. J Am Heart Assoc. 2017;6(4):e005379. https://doi.org/10.1161/JAHA.116.005379.

  41. Eurich DT, Weir DL, Majumdar SR, Tsuyuki RT, Johnson JA, Tjosvold L et al. Comparative safety and effectiveness of metformin in patients with diabetes and heart failure: systematic review of observational studies involving 34000 patients. Circ Heart Fail. 2013;6(3):395-402. https://doi.org/10.1161/CIRCHEARTFAILURE.112.000162.

  42. Inzucchi SE, Masoudi FA, McGuire DK. Metformin in heart failure. Diabetes Care. 2007;30(12):e129. https://doi.org/10.2337/dc07-1686.

    Article  PubMed  Google Scholar 

  43. Tzoulaki I, Molokhia M, Curcin V, Little MP, Millett CJ, Ng A, et al. Risk of cardiovascular disease and all cause mortality among patients with type 2 diabetes prescribed oral antidiabetes drugs: retrospective cohort study using UK general practice research database. BMJ. 2009;339:b4731. https://doi.org/10.1136/bmj.b4731.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Erdmann E, Charbonnel B, Wilcox RG, Skene AM, Massi-Benedetti M, Yates J, et al. Pioglitazone use and heart failure in patients with type 2 diabetes and preexisting cardiovascular disease: data from the PROactive study (PROactive 08). Diabetes Care. 2007;30(11):2773–8. https://doi.org/10.2337/dc07-0717.

    Article  CAS  PubMed  Google Scholar 

  45. Kaul S, Bolger AF, Herrington D, Giugliano RP, Eckel RH, American Heart Association, et al. Thiazolidinedione drugs and cardiovascular risks: a science advisory from the American Heart Association and American college of cardiology foundation. J Am Coll Cardiol. 2010;55(17):1885–94. https://doi.org/10.1016/j.jacc.2010.02.014.

    Article  PubMed  Google Scholar 

  46. Komajda M, McMurray JJ, Beck-Nielsen H, Gomis R, Hanefeld M, Pocock SJ, et al. Heart failure events with rosiglitazone in type 2 diabetes: data from the RECORD clinical trial. Eur Heart J. 2010;31(7):824–31. https://doi.org/10.1093/eurheartj/ehp604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Lago RM, Singh PP, Nesto RW. Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials. Lancet. 2007;370(9593):1129–36. https://doi.org/10.1016/s0140-6736(07)61514-1.

    Article  CAS  PubMed  Google Scholar 

  48. Home PD, Pocock SJ, Beck-Nielsen H, Curtis PS, Gomis R, Hanefeld M, et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet. 2009;373(9681):2125–35. https://doi.org/10.1016/s0140-6736(09)60953-3.

    Article  CAS  PubMed  Google Scholar 

  49. Guan Y, Hao C, Cha DR, Rao R, Lu W, Kohan DE, et al. Thiazolidinediones expand body fluid volume through PPARgamma stimulation of ENaC-mediated renal salt absorption. Nat Med. 2005;11(8):861–6. https://doi.org/10.1038/nm1278.

    Article  CAS  PubMed  Google Scholar 

  50. Dargie HJ, Hildebrandt PR, Riegger GA, McMurray JJ, McMorn SO, Roberts JN, et al. A randomized, placebo-controlled trial assessing the effects of rosiglitazone on echocardiographic function and cardiac status in type 2 diabetic patients with New York Heart Association Functional Class I or II heart failure. J Am Coll Cardiol. 2007;49(16):1696–704. https://doi.org/10.1016/j.jacc.2006.10.077.

    Article  CAS  PubMed  Google Scholar 

  51. Waldrop G, Zhong J, Peters M, Rajagopalan S. Incretin-based therapy for diabetes: what a cardiologist needs to know. J Am Coll Cardiol. 2016;67(12):1488–96. https://doi.org/10.1016/j.jacc.2015.12.058.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, et al. Effect of Sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373(3):232–42. https://doi.org/10.1056/NEJMoa1501352.

    Article  CAS  PubMed  Google Scholar 

  53. Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317–26. https://doi.org/10.1056/NEJMoa1307684.

    Article  CAS  PubMed  Google Scholar 

  54. White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369(14):1327–35. https://doi.org/10.1056/NEJMoa1305889.

    Article  CAS  PubMed  Google Scholar 

  55. Scirica BM, Braunwald E, Raz I, Cavender MA, Morrow DA, Jarolim P, et al. Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial. Circulation. 2014;130(18):1579–88. https://doi.org/10.1161/CIRCULATIONAHA.114.010389.

    Article  CAS  PubMed  Google Scholar 

  56. Zannad F, Cannon CP, Cushman WC, Bakris GL, Menon V, Perez AT, et al. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet. 2015;385(9982):2067–76. https://doi.org/10.1016/s0140-6736(14)62225-x.

    Article  CAS  PubMed  Google Scholar 

  57. Verma S, Goldenberg RM, Bhatt DL, Farkouh ME, Quan A, Teoh H, et al. Dipeptidyl peptidase-4 inhibitors and the risk of heart failure: a systematic review and meta-analysis. CMAJ Open. 2017;5(1):E152–e77. https://doi.org/10.9778/cmajo.20160058.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Filion KB, Azoulay L, Platt RW, Dahl M, Dormuth CR, Clemens KK, et al. A multicenter observational study of Incretin-based drugs and heart failure. N Engl J Med. 2016;374(12):1145–54. https://doi.org/10.1056/NEJMoa1506115.

    Article  CAS  PubMed  Google Scholar 

  59. •• Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311–22. https://doi.org/10.1056/NEJMoa1603827. A randomized controlled trial in diabetic individuals with high cardiovascular risk that demonstrated liraglutide was associated with decreased advese cardiovascular events compared to placebo.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Pfeffer MA, Claggett B, Diaz R, Dickstein K, Gerstein HC, Køber LV, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373(23):2247–57. https://doi.org/10.1056/NEJMoa1509225.

    Article  CAS  PubMed  Google Scholar 

  61. Margulies KB, Hernandez AF, Redfield MM, et al. Effects of liraglutide on clinical stability among patients with advanced heart failure and reduced ejection fraction: a randomized clinical trial. JAMA. 2016;316(5):500–8. https://doi.org/10.1001/jama.2016.10260.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. • 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. https://doi.org/10.1161/CIRCULATIONAHA.116.021887. This article discusses potential pathophysiologic mechanisms through which SGLT-2 inhibitors work to affect cardiovascular and renal benefits.

    Article  CAS  PubMed  Google Scholar 

  63. Tahrani AA, Barnett AH, Bailey CJ. SGLT inhibitors in management of diabetes. Lancet Diabetes Endocrinol. 2013;1(2):140–51. https://doi.org/10.1016/S2213-8587(13)70050-0.

    Article  CAS  PubMed  Google Scholar 

  64. •• 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. https://doi.org/10.1056/NEJMoa1504720. A landmark clinical trial which demonstrated empagliflozin was associated with reduced adverse cardiovascular events and significant reductions in heart failure hospitalization in patients at high risk for cardiovascular events.

    Article  CAS  PubMed  Google Scholar 

  65. • Fitchett D, Zinman B, Wanner C, Lachin JM, Hantel S, Salsali A, et al. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME(R) trial. Eur Heart J. 2016;37(19):1526–34. https://doi.org/10.1093/eurheartj/ehv728. This follow-up study of the EMPA-REG OUTCOME trial highlighted the reduced rates of heart failure hospitalization and cardiovascular death with empagliflozin use in patients with diabetes and cardiovascular disease.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Fitchett D, Butler J, van de Borne P, Zinman B, Lachin JM, Wanner C et al. Effects of empagliflozin on risk for cardiovascular death and heart failure hospitalization across the spectrum of heart failure risk in the EMPA-REG OUTCOME trial. Eur Heart J. 2017. https://doi.org/10.1093/eurheartj/ehx511

  67. •• 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; https://doi.org/10.1056/NEJMoa1611925. A randomized clinical trial that demonstrated that canagliflozin was associated with reduced adverse cardiovascular events and heart failure hospitaliazation. This randomized trial provided further support for the potential of SGLT2 inhibitors to reduce heart failure.

  68. Kosiborod M, Cavender MA, AZ F, 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. https://doi.org/10.1161/CIRCULATIONAHA.117.029190.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Wanner C, Inzucchi SE, Zinman B. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375(18):1801–2. https://doi.org/10.1056/NEJMc1611290.

    PubMed  Google Scholar 

  70. Cherney DZ, Perkins BA, Soleymanlou N, Maione M, Lai V, Lee A, et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation. 2014;129(5):587–97. https://doi.org/10.1161/CIRCULATIONAHA.113.005081.

    Article  CAS  PubMed  Google Scholar 

  71. Scheen AJ. Reappraisal of the diuretic effect of empagliflozin in the EMPA-REG OUTCOME trial: comparison with classic diuretics. Diabetes Metab. 2016;42(4):224–33. https://doi.org/10.1016/j.diabet.2016.05.006.

    Article  CAS  PubMed  Google Scholar 

  72. 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. https://doi.org/10.1111/dom.12127.

    Article  CAS  PubMed  Google Scholar 

  73. Ferrannini E, Mark M, Mayoux E. CV protection in the EMPA-REG OUTCOME trial: a “thrifty substrate” hypothesis. Diabetes Care. 2016;39(7):1108–14. https://doi.org/10.2337/dc16-0330.

    Article  PubMed  Google Scholar 

  74. 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. https://doi.org/10.1186/1475-2840-13-28.

    Article  PubMed  PubMed Central  Google Scholar 

  75. 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. https://doi.org/10.1038/nm.3828.

    Article  CAS  PubMed  Google Scholar 

  76. Marx N, McGuire DK. Sodium-glucose cotransporter-2 inhibition for the reduction of cardiovascular events in high-risk patients with diabetes mellitus. Eur Heart J. 2016;37(42):3192–200. https://doi.org/10.1093/eurheartj/ehw110.

    Article  PubMed  Google Scholar 

  77. 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; https://doi.org/10.1001/jamacardio.2017.2275.

  78. Yokoyama H, Gunasegaram S, Harding SE, Avkiran M. Sarcolemmal Na+/H+ exchanger activity and expression in human ventricular myocardium. J Am Coll Cardiol. 2000;36(2):534–40.

    Article  CAS  PubMed  Google Scholar 

  79. Baartscheer A, Schumacher CA, Wust RC, Fiolet JW, Stienen GJ, Coronel R, et al. Empagliflozin decreases myocardial cytoplasmic Na+ through inhibition of the cardiac Na+/H+ exchanger in rats and rabbits. Diabetologia. 2017;60(3):568–73. https://doi.org/10.1007/s00125-016-4134-x.

    Article  CAS  PubMed  Google Scholar 

  80. Byrne NJ, Parajuli N, Levasseur JL, Boisvenue J, Beker D, Masson G et al. Empagliflozin prevents worsening of cardiac function in an experimental model of pressure overload-induced heart failure. J Am Coll Cardiol Basic Trans Sci. 2017;2(4):347-54; https://doi.org/10.1016/j.jacbts.2017.07.003.

Download references

Author information

Authors and Affiliations

  1. Cardiovascular Division, Baylor College of Medicine, 6620 Main Street, Houston, TX, 77030, USA

    Amanda Trang & David Aguilar

Authors
  1. Amanda Trang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David Aguilar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David Aguilar.

Ethics declarations

Conflict of Interest

Amanda Trang declares no potential conflicts of interest. David Aguilar reports a research grant from Astra-Zeneca.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Comorbidities of Heart Failure

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Trang, A., Aguilar, D. Treating Disease Mechanisms in Patients With Heart Failure and Diabetes Mellitus. Curr Heart Fail Rep 14, 445–453 (2017). https://doi.org/10.1007/s11897-017-0371-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11897-017-0371-7

Keywords

Search

Navigation