Advertisement

Cardiovascular Drugs and Therapy

, Volume 33, Issue 4, pp 435–442 | Cite as

Effect of Tofogliflozin on Systolic and Diastolic Cardiac Function in Type 2 Diabetic Patients

  • Munemitsu Otagaki
  • Koichiro MatsumuraEmail author
  • Hiromi Kin
  • Kenichi Fujii
  • Hiroki Shibutani
  • Hiroshi Matsumoto
  • Hiroki Takahashi
  • Haengnam Park
  • Yoshihiro Yamamoto
  • Tetsuro Sugiura
  • Ichiro Shiojima
ORIGINAL ARTICLE

Abstract

Purpose

Recent studies have shown that sodium glucose cotransporter 2 (SGLT2) inhibitors have a favorable effect on cardiovascular events in diabetic patients. However, the underlying mechanism associated with a favorable outcome has not been clearly identified. The purpose of this study was to investigate the effect of tofogliflozin, SGLT2 inhibitor, on systolic and diastolic cardiac function in patients with type 2 diabetes mellitus (T2DM).

Methods

We enrolled 26 consecutive T2DM out-patients on glucose-lowering drugs who initiated tofogliflozin and underwent echocardiography before and ≥ 6 months after tofogliflozin administration. During this period, we also enrolled 162 T2DM out-patients taking other glucose-lowering drugs as a control group. Propensity score analysis was performed to match the patient characteristics. As a result, 42 patients (tofogliflozin group 21 patients and control group 21 patients) were finally used for analysis. Left ventricular systolic function was assessed by measuring 2D-echocardiographic left ventricular ejection fraction (LVEF) and diastolic cardiac function by pulsed wave Doppler-derived early diastolic velocity (E/e′).

Results

There were no significant differences in patient characteristics and echocardiographic parameters at baseline. The change in LVEF from baseline to follow-up was 5.0 ± 6.9% in the tofogliflozin group and − 0.6 ± 5.5% in the control group; difference significant, p = 0.006. The change in E/e′ was − 1.7 ± 3.4 in the tofogliflozin group and 0.7 ± 4.1 in the control group; difference significant, p = 0.024.

Conclusions

In addition to conventional oral glucose-lowering drugs, additional tofogliflozin administration had a favorable effect on left ventricular systolic and diastolic function in patients with T2DM.

Keywords

Diabetes mellitus Cardiac function SGLT2 inhibitor Tofogliflozin 

Notes

Compliance with Ethical Standards

Conflict of Interest

The authors declare that there is no conflict of interest.

Ethical Approval

The study was approved by the ethical committee of the Kansai Medical University Medical Center and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed Consent

Informed consent was obtained from all individual participants included in the study using opt-out procedure.

References

  1. 1.
    Vazquez-Benitez G, Desai JR, Xu S, Goodrich GK, Schroeder EB, Nichols GA, et al. Preventable major cardiovascular events associated with uncontrolled glucose, blood pressure, and lipids and active smoking in adults with diabetes with and without cardiovascular disease: a contemporary analysis. Diabetes Care. 2015;38:905–12.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Chen G, McAlister FA, Walker RL, Hemmelgarn BR, Campbell NR. Cardiovascular outcomes in Framingham participants with diabetes: the importance of blood pressure. Hypertension. 2011;57:891–7.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    From AM, Scott CG, Chen HH. Changes in diastolic dysfunction in diabetes mellitus over time. Am J Cardiol. 2009;103:1463–6.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    van den Hurk K, Alssema M, Kamp O, Henry RM, Stehouwer CD, Smulders YM, et al. Independent associations of glucose status and arterial stiffness with left ventricular diastolic dysfunction: an 8-year follow-up of the Hoorn Study. Diabetes Care. 2012;35:1258–64.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Ernande L, Derumeaux G. Diabetic cardiomyopathy: myth or reality? Arch Cardiovasc. 2012;105:218–25.CrossRefGoogle Scholar
  6. 6.
    Zhang X, Chen C. A new insight of mechanisms, diagnosis and treatment of diabetic cardiomyopathy. Endocrine. 2012;41:398–409.CrossRefGoogle Scholar
  7. 7.
    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;369:1317–26.CrossRefPubMedGoogle Scholar
  8. 8.
    Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366:1279–89.CrossRefPubMedGoogle Scholar
  9. 9.
    Fischer M, Baessler A, Hense HW, et al. Prevalence of left ventricular diastolic dysfunction in the community. Results from a Doppler echocardiographic-based survey of a population sample. Eur Heart J. 2003;24:320–8.CrossRefPubMedGoogle Scholar
  10. 10.
    Klapholz M, Maurer M, Lowe AM, Messineo F, Meisner JS, Mitchell J, et al. Hospitalization for heart failure in the presence of a normal left ventricular ejection fraction: results of the New York Heart Failure Registry. J Am Coll Cardiol. 2004;43:1432–8.CrossRefPubMedGoogle Scholar
  11. 11.
    Nauck MA, Del Prato S, Meier JJ, et al. Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes Care. 2011;34:2015–22.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Bolinder J, Ljunggren Ö, Kullberg J, Johansson L, Wilding J, Langkilde AM, et al. Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin. J Clin Endocrinol Metab. 2012;97:1020–31.CrossRefPubMedGoogle Scholar
  13. 13.
    Chilton R, Tikkanen I, Hehnke U, Woerle HJ, Johansen OE. Impact of empagliflozin on blood pressure in dipper and non-dipper patients with type 2 diabetes mellitus and hypertension. Diabetes Obes Metab. 2017;19:1620–4.CrossRefPubMedGoogle Scholar
  14. 14.
    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;373:2117–28.CrossRefGoogle Scholar
  15. 15.
    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;377:644–57.CrossRefGoogle Scholar
  16. 16.
    Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging. 2015;16:233–70.CrossRefPubMedGoogle Scholar
  17. 17.
    Ommen SR, Nishimura RA, Appleton CP, Miller FA, Oh JK, Redfield MM, et al. Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures: a comparative simultaneous Doppler-catheterization study. Circulation. 2000;102:1788–94.CrossRefPubMedGoogle Scholar
  18. 18.
    Oh JK, Park SJ, Nagueh SF. Established and novel clinical applications of diastolic function assessment by echocardiography. Circ Cardiovasc Imaging. 2011;4:444–55.CrossRefPubMedGoogle Scholar
  19. 19.
    Jessup M, Brozena S. Heart failure. N Engl J Med. 2003;348:2007–18.CrossRefPubMedGoogle Scholar
  20. 20.
    Verma S, Garg A, Yan AT, Gupta AK, al-Omran M, Sabongui A, et al. 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. 2016;39:e212–3.CrossRefPubMedGoogle Scholar
  21. 21.
    Matsutani D, Sakamoto M, Kayama Y, Takeda N, Horiuchi R, Utsunomiya K. Effect of canagliflozin on left ventricular diastolic function in patients with type 2 diabetes. Cardiovasc Diabetol. 2018;17:73.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Soga F, Tanaka H, Tatsumi K, Mochizuki Y, Sano H, Toki H, et al. Impact of dapagliflozin on left ventricular diastolic function of patients with type 2 diabetic mellitus with chronic heart failure. Cardiovasc Diabetol. 2018;17:132.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Pham SV, Chilton RJ. EMPA-REG OUTCOME: The Cardiologist’s point of view. Am J Cardiol. 2017;120:S53–8.CrossRefPubMedGoogle Scholar
  24. 24.
    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;89:524–6.CrossRefGoogle Scholar
  25. 25.
    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. Diabetes Vasc Dis Res. 2015;12:90–100.CrossRefGoogle Scholar
  26. 26.
    Bouchi R, Terashima M, Sasahara Y, Asakawa M, Fukuda T, Takeuchi T, et al. Luseogliflozin reduces epicardial fat accumulation in patients with type 2 diabetes: a pilot study. Cardiovasc Diabetol. 2017;16:32.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Lioudaki E, Androulakis ES, Whyte M, Stylianou KG, Daphnis EK, Ganotakis ES. The effect of sodium-glucose co-transporter-2 (SGLT-2) inhibitors on cardiometabolic profile; beyond the hypoglycaemic action. Cardiovasc Drugs Ther. 2017;31:215–25.CrossRefPubMedGoogle Scholar
  28. 28.
    Cherney DZ, Perkins BA, Soleymanlou N, et al. Sodium glucose cotransport-2 inhibition and intrarenal RAS activity in people with type 1 diabetes. Kidney Int. 2014;86:1057–8.CrossRefGoogle Scholar
  29. 29.
    Heise T, Jordan J, Wanner C, Heer M, Macha S, Mattheus M, et al. Pharmacodynamic effects of single and multiple doses of empagliflozin in patients with type 2 diabetes. Clin Ther. 2016;38:2265–76.CrossRefPubMedGoogle Scholar
  30. 30.
    Cohen ND, Gutman SJ, Briganti EM, Taylor AJ. The effects of empagliflozin treatment on cardiac function and structure in patients with type 2 diabetes – a cardiac MR study. Intern Med J 2019 (In press).Google Scholar
  31. 31.
    Wright EM, Loo DD, Hirayama BA. Biology of human sodium glucose transporters. Physiol Rev. 2011;91:733–94.CrossRefPubMedGoogle Scholar
  32. 32.
    Kashiwagi Y, Nagoshi T, Yoshino T, Tanaka TD, Ito K, Harada T, et al. Expression of SGLT1 in human hearts and impairment of cardiac glucose uptake by phlorizin during ischemia-reperfusion injury in mice. PLoS One. 2015;10:e0130605.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Banerjee SK, McGaffin KR, Pastor-Soler NM, Ahmad F. SGLT1 is a novel cardiac glucose transporter that is perturbed in disease states. Cardiovasc Res. 2009;84:111–8.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Connelly KA, Zhang Y, Desjardins JF, Thai K, Gilbert RE. Dual inhibition of sodium–glucose linked cotransporters 1 and 2 exacerbates cardiac dysfunction following experimental myocardial infarction. Cardiovasc Diabetol. 2018;17:99.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Suzuki M, Honda K, Fukazawa M, Ozawa K, Hagita H, Kawai T, et al. Tofogliflozin, a potent and highly specific sodium/glucose cotransporter 2 inhibitor, improves glycemic control in diabetic rats and mice. J Phamacol Exp Ther. 2012;341:692–701.CrossRefGoogle Scholar
  36. 36.
    Hammoudi N, Jeong D, Singh R, Farhat A, Komajda M, Mayoux E, et al. Empagliflozin improves left ventricular diastolic dysfunction in a genetic model of type 2 diabetes. Cardiovasc Drugs Ther. 2017;31:233–46.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Habibi J, Aroor AR, Sowers JR, Jia G, Hayden MR, Garro M, et al. Sodium glucose transporter 2 (SGLT2) inhibition with empagliflozin improves cardiac diastolic function in a female rodent model of diabetes. Cardiovasc Diabetol. 2017;16:9.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Gupte M, Umbarkar P, Lal H. Mechanistic insights of empagliflozin-mediated cardiac benefits: nearing the starting line: editorial to: “Empagliflozin improves left ventricular diastolic dysfunction in a genetic model of type 2 diabetes” by N. Hammoudi et al. Cardiovasc Drugs Ther. 2017;31:229–32.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Ryden L, Grant PJ, Anker SD, et al. 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. 2013;34(39):3035–87.CrossRefPubMedGoogle Scholar
  40. 40.
    Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, et al. 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. 2013;62(16):e147–239.CrossRefPubMedGoogle Scholar
  41. 41.
    González-Vilchez F, Ayuela J, Ares M, Pi J, Castillo L, Martin-Durán R. Oxidative stress and fibrosis in incipient myocardial dysfunction in type 2 diabetic patients. Int J Cardiol. 2005;101(1):53–8.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Munemitsu Otagaki
    • 1
  • Koichiro Matsumura
    • 1
    Email author
  • Hiromi Kin
    • 1
  • Kenichi Fujii
    • 2
  • Hiroki Shibutani
    • 2
  • Hiroshi Matsumoto
    • 1
  • Hiroki Takahashi
    • 1
  • Haengnam Park
    • 1
  • Yoshihiro Yamamoto
    • 1
  • Tetsuro Sugiura
    • 1
  • Ichiro Shiojima
    • 2
  1. 1.Department of CardiologyKansai Medical University Medical CenterMoriguchiJapan
  2. 2.Division of Cardiology, Department of Medicine IIKansai Medical UniversityHirakataJapan

Personalised recommendations