Heart Failure Reviews

, Volume 23, Issue 3, pp 439–444 | Cite as

Potential impact of SGLT2 inhibitors on left ventricular diastolic function in patients with diabetes mellitus

  • Hidekazu TanakaEmail author
  • Ken-ichi Hirata


The pathogenesis of diabetes mellitus (DM)-related cardiac dysfunction is thought to be multifactorial, and possibly a key factor for the development of heart failure with preserved ejection fraction (HFpEF) in patients with DM and preserved left ventricular (LV) ejection fraction. Currently, there is no effective treatment for HFpEF, which is presented as LV diastolic dysfunction. Furthermore, it is well known that, in addition to DM, hypertension and overweight/obesity are also important factors associated with HFpEF. Sodium glucose cotransporter 2 (SGLT2) inhibitors are a new class of diabetic medications indicated only for the treatment of type 2 DM, and a recent clinical trial showed that patients with this disease and at high risk for cardiovascular events attained cardiovascular benefits from SGLT2 inhibitor in comparison with placebo efficacy. In addition to reduction of glycated hemoglobin levels in patients with type 2 DM, SGLT2 inhibitors are associated with weight loss and reductions in blood pressure. However, despite such intriguing results, it remains uncertain whether SGLT2 inhibitors are beneficial for LV diastolic function in patients with DM. This review deals with the impact of SGLT2 inhibitors on LV diastolic function in patients with DM and their current potential for prevention of the future development of HFpEF in such patients.


SGLT2 inhibitors Left ventricular diastolic function Diabetes mellitus Hypertension Overweight/obesity HFpEF Global longitudinal strain 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standards

The manuscript does not contain clinical studies or patient data.


  1. 1.
    Marsenic O (2009) Glucose control by the kidney: an emerging target in diabetes. Am J Kidney Dis 53(5):875–883. CrossRefPubMedGoogle Scholar
  2. 2.
    Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE, Investigators E-RO (2015) Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 373(22):2117–2128. CrossRefPubMedGoogle Scholar
  3. 3.
    Haring HU, Merker L, Seewaldt-Becker E, Weimer M, Meinicke T, Woerle HJ, Broedl UC, Investigators E-RMT (2013) Empagliflozin as add-on to metformin plus sulfonylurea in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care 36(11):3396–3404. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Rosenstock J, Jelaska A, Frappin G, Salsali A, Kim G, Woerle HJ, Broedl UC, Investigators E-RMT (2014) Improved glucose control with weight loss, lower insulin doses, and no increased hypoglycemia with empagliflozin added to titrated multiple daily injections of insulin in obese inadequately controlled type 2 diabetes. Diabetes Care 37(7):1815–1823. CrossRefPubMedGoogle Scholar
  5. 5.
    Paulus WJ, van Ballegoij JJ (2010) Treatment of heart failure with normal ejection fraction: an inconvenient truth. J Am Coll Cardiol 55(6):526–537. CrossRefPubMedGoogle Scholar
  6. 6.
    Holland DJ, Kumbhani DJ, Ahmed SH, Marwick TH (2011) Effects of treatment on exercise tolerance, cardiac function, and mortality in heart failure with preserved ejection fraction. A meta-analysis. J Am Coll Cardiol 57(16):1676–1686. CrossRefPubMedGoogle Scholar
  7. 7.
    Anand IS, Rector TS, Cleland JG, Kuskowski M, McKelvie RS, Persson H, McMurray JJ, Zile MR, Komajda M, Massie BM, Carson PE (2011) Prognostic value of baseline plasma amino-terminal pro-brain natriuretic peptide and its interactions with irbesartan treatment effects in patients with heart failure and preserved ejection fraction: findings from the I-PRESERVE trial. Circ Heart Fail 4(5):569–577. CrossRefPubMedGoogle Scholar
  8. 8.
    Solomon SD, Claggett B, Lewis EF, Desai A, Anand I, Sweitzer NK, O'Meara E, Shah SJ, McKinlay S, Fleg JL, Sopko G, Pitt B, Pfeffer MA, Investigators T (2016) Influence of ejection fraction on outcomes and efficacy of spironolactone in patients with heart failure with preserved ejection fraction. Eur Heart J 37(5):455–462. CrossRefPubMedGoogle Scholar
  9. 9.
    Sanderson JE (2007) Heart failure with a normal ejection fraction. Heart 93(2):155–158. CrossRefPubMedGoogle Scholar
  10. 10.
    Packer M (2011) Can brain natriuretic peptide be used to guide the management of patients with heart failure and a preserved ejection fraction? The wrong way to identify new treatments for a nonexistent disease. Circ Heart Fail 4(5):538–540. CrossRefPubMedGoogle Scholar
  11. 11.
    Shah AM, Solomon SD (2012) Phenotypic and pathophysiological heterogeneity in heart failure with preserved ejection fraction. Eur Heart J 33(14):1716–1717. CrossRefPubMedGoogle Scholar
  12. 12.
    Shah AM, Pfeffer MA (2012) The many faces of heart failure with preserved ejection fraction. Nat Rev Cardiol 9(10):555–556. CrossRefPubMedGoogle Scholar
  13. 13.
    Ferrari R, Bohm M, Cleland JG, Paulus WJ, Pieske B, Rapezzi C, Tavazzi L (2015) Heart failure with preserved ejection fraction: uncertainties and dilemmas. Eur J Heart Fail 17(7):665–671. CrossRefPubMedGoogle Scholar
  14. 14.
    Givertz MM, Slawsky MT, Moraes DL, McIntyre KM, Colucci WS (2001) Noninvasive determination of pulmonary artery wedge pressure in patients with chronic heart failure. Am J Cardiol 87(10):1213–1215; A1217. CrossRefPubMedGoogle Scholar
  15. 15.
    Lucas C, Johnson W, Hamilton MA, Fonarow GC, Woo MA, Flavell CM, Creaser JA, Stevenson LW (2000) Freedom from congestion predicts good survival despite previous class IV symptoms of heart failure. Am Heart J 140(6):840–847. CrossRefPubMedGoogle Scholar
  16. 16.
    Dhingra A, Garg A, Kaur S, Chopra S, Batra JS, Pandey A, Chaanine AH, Agarwal SK (2014) Epidemiology of heart failure with preserved ejection fraction. Curr Heart Fail Rep 11(4):354–365. CrossRefPubMedGoogle Scholar
  17. 17.
    Sharma GV, Woods PA, Lambrew CT, Berg CM, Pietro DA, Rocco TP, Welt FW, Sacchetti P, McIntyre KM (2002) Evaluation of a noninvasive system for determining left ventricular filling pressure. Arch Intern Med 162(18):2084–2088. CrossRefPubMedGoogle Scholar
  18. 18.
    Bando YK, Murohara T (2014) Diabetes-related heart failure. Circ J 78(3):576–583. CrossRefPubMedGoogle Scholar
  19. 19.
    Ryden L, Grant PJ, Anker SD, Berne C, Cosentino F, Danchin N, Deaton C, Escaned J, Hammes HP, Huikuri H, Marre M, Marx N, Mellbin L, Ostergren J, Patrono C, Seferovic P, Uva MS, Taskinen MR, Tendera M, Tuomilehto J, Valensi P, Zamorano JL, Zamorano JL, Achenbach S, Baumgartner H, Bax JJ, Bueno H, Dean V, Deaton C, Erol C, Fagard R, Ferrari R, Hasdai D, Hoes AW, Kirchhof P, Knuuti J, Kolh P, Lancellotti P, Linhart A, Nihoyannopoulos P, Piepoli MF, Ponikowski P, Sirnes PA, Tamargo JL, Tendera M, Torbicki A, Wijns W, Windecker S, De Backer G, Sirnes PA, Ezquerra EA, Avogaro A, Badimon L, Baranova E, Baumgartner H, Betteridge J, Ceriello A, Fagard R, Funck-Brentano C, Gulba DC, Hasdai D, Hoes AW, Kjekshus JK, Knuuti J, Kolh P, Lev E, Mueller C, Neyses L, Nilsson PM, Perk J, Ponikowski P, Reiner Z, Sattar N, Schachinger V, Scheen A, Schirmer H, Stromberg A, Sudzhaeva S, Tamargo JL, Viigimaa M, Vlachopoulos C, Xuereb RG (2013) ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the task force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD). Eur Heart J 34(39):3035–3087. CrossRefPubMedGoogle Scholar
  20. 20.
    Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, Wilkoff BL (2013) 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines. J Am Coll Cardiol 62(16):e147–e239. CrossRefPubMedGoogle Scholar
  21. 21.
    Sacre JW, Franjic B, Jellis CL, Jenkins C, Coombes JS, Marwick TH (2010) Association of cardiac autonomic neuropathy with subclinical myocardial dysfunction in type 2 diabetes. JACC Cardiovasc Imaging 3(12):1207–1215. CrossRefPubMedGoogle Scholar
  22. 22.
    Galderisi M (2006) Diastolic dysfunction and diabetic cardiomyopathy: evaluation by Doppler echocardiography. J Am Coll Cardiol 48(8):1548–1551. CrossRefPubMedGoogle Scholar
  23. 23.
    From AM, Scott CG, Chen HH (2010) The development of heart failure in patients with diabetes mellitus and pre-clinical diastolic dysfunction a population-based study. J Am Coll Cardiol 55(4):300–305. CrossRefPubMedGoogle Scholar
  24. 24.
    Poirier P, Bogaty P, Garneau C, Marois L, Dumesnil JG (2001) Diastolic dysfunction in normotensive men with well-controlled type 2 diabetes: importance of maneuvers in echocardiographic screening for preclinical diabetic cardiomyopathy. Diabetes Care 24(1):5–10. CrossRefPubMedGoogle Scholar
  25. 25.
    Di Bonito P, Moio N, Cavuto L, Covino G, Murena E, Scilla C, Turco S, Capaldo B, Sibilio G (2005) Early detection of diabetic cardiomyopathy: usefulness of tissue Doppler imaging. Diabet Med 22(12):1720–1725. CrossRefPubMedGoogle Scholar
  26. 26.
    Ravassa S, Barba J, Coma-Canella I, Huerta A, Lopez B, Gonzalez A, Diez J (2013) The activity of circulating dipeptidyl peptidase-4 is associated with subclinical left ventricular dysfunction in patients with type 2 diabetes mellitus. Cardiovasc Diabetol 12(1):143. CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Boyer JK, Thanigaraj S, Schechtman KB, Perez JE (2004) Prevalence of ventricular diastolic dysfunction in asymptomatic, normotensive patients with diabetes mellitus. Am J Cardiol 93(7):870–875. CrossRefPubMedGoogle Scholar
  28. 28.
    Kiencke S, Handschin R, von Dahlen R, Muser J, Brunner-Larocca HP, Schumann J, Felix B, Berneis K, Rickenbacher P (2010) Pre-clinical diabetic cardiomyopathy: prevalence, screening, and outcome. Eur J Heart Fail 12(9):951–957. CrossRefPubMedGoogle Scholar
  29. 29.
    Ernande L, Bergerot C, Rietzschel ER, De Buyzere ML, Thibault H, Pignonblanc PG, Croisille P, Ovize M, Groisne L, Moulin P, Gillebert TC, Derumeaux G (2011) Diastolic dysfunction in patients with type 2 diabetes mellitus: is it really the first marker of diabetic cardiomyopathy? J Am Soc Echocardiogr 24(11):1268–1275 e1261. CrossRefPubMedGoogle Scholar
  30. 30.
    Nakai H, Takeuchi M, Nishikage T, Lang RM, Otsuji Y (2009) Subclinical left ventricular dysfunction in asymptomatic diabetic patients assessed by two-dimensional speckle tracking echocardiography: correlation with diabetic duration. Eur J Echocardiogr 10(8):926–932. CrossRefPubMedGoogle Scholar
  31. 31.
    Ng AC, Delgado V, Bertini M, van der Meer RW, Rijzewijk LJ, Shanks M, Nucifora G, Smit JW, Diamant M, Romijn JA, de Roos A, Leung DY, Lamb HJ, Bax JJ (2009) Findings from left ventricular strain and strain rate imaging in asymptomatic patients with type 2 diabetes mellitus. Am J Cardiol 104(10):1398–1401. CrossRefPubMedGoogle Scholar
  32. 32.
    Zoroufian A, Razmi T, Taghavi-Shavazi M, Lotfi-Tokaldany M, Jalali A (2014) Evaluation of subclinical left ventricular dysfunction in diabetic patients: longitudinal strain velocities and left ventricular dyssynchrony by two-dimensional speckle tracking echocardiography study. Echocardiography 31(4):456–463. CrossRefPubMedGoogle Scholar
  33. 33.
    Ernande L, Bergerot C, Girerd N, Thibault H, Davidsen ES, Gautier Pignon-Blanc P, Amaz C, Croisille P, De Buyzere ML, Rietzschel ER, Gillebert TC, Moulin P, Altman M, Derumeaux G (2014) Longitudinal myocardial strain alteration is associated with left ventricular remodeling in asymptomatic patients with type 2 diabetes mellitus. J Am Soc Echocardiogr 27(5):479–488. CrossRefPubMedGoogle Scholar
  34. 34.
    Ernande L, Rietzschel ER, Bergerot C, De Buyzere ML, Schnell F, Groisne L, Ovize M, Croisille P, Moulin P, Gillebert TC, Derumeaux G (2010) Impaired myocardial radial function in asymptomatic patients with type 2 diabetes mellitus: a speckle-tracking imaging study. J Am Soc Echocardiogr 23(12):1266–1272. CrossRefPubMedGoogle Scholar
  35. 35.
    Tadic M, Ilic S, Cuspidi C, Stojcevski B, Ivanovic B, Bukarica L, Jozika L, Celic V (2015) Left ventricular mechanics in untreated normotensive patients with type 2 diabetes mellitus: a two- and three-dimensional speckle tracking study. Echocardiography 6:947–955CrossRefGoogle Scholar
  36. 36.
    Mochizuki Y, Tanaka H, Matsumoto K, Sano H, Toki H, Shimoura H, Ooka J, Sawa T, Motoji Y, Ryo K, Hirota Y, Ogawa W, Hirata KI (2015) Clinical features of subclinical left ventricular systolic dysfunction in patients with diabetes mellitus. Cardiovasc Diabetol 14(1):37. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Mochizuki Y, Tanaka H, Matsumoto K, Sano H, Toki H, Shimoura H, Ooka J, Sawa T, Motoji Y, Ryo K, Hirota Y, Ogawa W, Hirata KI (2015) Association of peripheral nerve conduction in diabetic neuropathy with subclinical left ventricular systolic dysfunction. Cardiovasc Diabetol 14(1):47. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Mochizuki Y, Tanaka H, Tatsumi K, Matsumoto K, Imanishi J, Yoshida A, Yokoyama M, Kawai H, Hirata K (2014) Easy-to-use comprehensive speckle-tracking approach for cardiac resynchronization therapy. Circ J 78(9):2250–2258. CrossRefPubMedGoogle Scholar
  39. 39.
    Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, Flachskampf FA, Foster E, Goldstein SA, Kuznetsova T, Lancellotti P, Muraru D, Picard MH, Rietzschel ER, Rudski L, Spencer KT, Tsang W, Voigt JU (2015) Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 28(1):1–39 e14. CrossRefPubMedGoogle Scholar
  40. 40.
    Ernande L, Thibault H, Bergerot C, Moulin P, Wen H, Derumeaux G, Croisille P (2012) Systolic myocardial dysfunction in patients with type 2 diabetes mellitus: identification at MR imaging with cine displacement encoding with stimulated echoes. Radiology 265(2):402–409. CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Holland DJ, Marwick TH, Haluska BA, Leano R, Hordern MD, Hare JL, Fang ZY, Prins JB, Stanton T (2015) Subclinical LV dysfunction and 10-year outcomes in type 2 diabetes mellitus. Heart 101(13):1061–1066. CrossRefPubMedGoogle Scholar
  42. 42.
    Cognet T, Vervueren PL, Dercle L, Bastie D, Richaud R, Berry M, Marchal P, Gautier M, Fouilloux A, Galinier M, Carrie D, Massabuau P, Berry I, Lairez O (2013) New concept of myocardial longitudinal strain reserve assessed by a dipyridamole infusion using 2D-strain echocardiography: the impact of diabetes and age, and the prognostic value. Cardiovasc Diabetol 12(1):84. CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Bhuiyan T, Maurer MS (2011) Heart failure with preserved ejection fraction: persistent diagnosis, therapeutic enigma. Curr Cardiovasc Risk Rep 5(5):440–449. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Solomon SD, Verma A, Desai A, Hassanein A, Izzo J, Oparil S, Lacourciere Y, Lee J, Seifu Y, Hilkert RJ, Rocha R, Pitt B, Exforge Intensive Control of Hypertension to Evaluate Efficacy in Diastolic Dysfunction I (2010) Effect of intensive versus standard blood pressure lowering on diastolic function in patients with uncontrolled hypertension and diastolic dysfunction. Hypertension 55(2):241–248. CrossRefPubMedGoogle Scholar
  45. 45.
    Haass M, Kitzman DW, Anand IS, Miller A, Zile MR, Massie BM, Carson PE (2011) Body mass index and adverse cardiovascular outcomes in heart failure patients with preserved ejection fraction: results from the Irbesartan in heart failure with preserved ejection fraction (I-PRESERVE) trial. Circ Heart Fail 4(3):324–331. CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Ichikawa R, Daimon M, Miyazaki T, Kawata T, Miyazaki S, Maruyama M, Chiang SJ, Suzuki H, Ito C, Sato F, Watada H, Daida H (2013) Influencing factors on cardiac structure and function beyond glycemic control in patients with type 2 diabetes mellitus. Cardiovasc Diabetol 12(1):38. CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Ruanpeng D, Ungprasert P, Sangtian J, Harindhanavudhi T (2017) Sodium glucose co-transporter 2 (SGLT2) inhibitors and fracture risk in patients with type 2 diabetes mellitus: a meta-analysis. Diabetes Metab Res Rev 33(6):347–356. Accepted 16 Jun 2017
  48. 48.
    Tikkanen I, Narko K, Zeller C, Green A, Salsali A, Broedl UC, Woerle HJ, Investigators E-RB (2015) Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care 38(3):420–428. CrossRefPubMedGoogle Scholar
  49. 49.
    Ridderstrale M, Andersen KR, Zeller C, Kim G, Woerle HJ, Broedl UC, investigators E-RHHSt (2014) Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week randomised, active-controlled, double-blind, phase 3 trial. Lancet Diabetes Endocrinol 2(9):691–700. CrossRefPubMedGoogle Scholar
  50. 50.
    Matthaei S, Bowering K, Rohwedder K, Grohl A, Parikh S, Study G (2015) Dapagliflozin improves glycemic control and reduces body weight as add-on therapy to metformin plus sulfonylurea: a 24-week randomized, double-blind clinical trial. Diabetes Care 38(3):365–372. CrossRefPubMedGoogle Scholar
  51. 51.
    Verma S, Garg A, Yan AT, Gupta AK, Al-Omran M, Sabongui A, Teoh H, Mazer CD, Connelly KA (2016) Effect of empagliflozin on left ventricular mass and diastolic function in individuals with diabetes: an important clue to the EMPA-REG OUTCOME trial? Diabetes Care 39(12):e212–e213. CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Internal Medicine, Division of Cardiovascular MedicineKobe University Graduate School of MedicineKobeJapan

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