Skip to main content
SpringerLink
Log in

Effects of sitagliptin on exercise capacity and hemodynamics in patients with type 2 diabetes mellitus and coronary artery disease

  • Original Article
  • Published:
Heart and Vessels Aims and scope Submit manuscript

Abstract

Sitagliptin attenuates left ventricular (LV) dysfunction and may improve oxygen uptake in animals. The effects of sitagliptin on oxygen uptake (VO2) and exercise hemodynamics have been unclear in patients with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD). Thirty patients with T2DM and CAD were randomized into a sitagliptin (50 mg/day) or voglibose (0.6 mg/day) group. Patients underwent maximal cardiopulmonary exercise testing. VO2 and hemodynamics were evaluated at rest, anaerobic threshold and peak exercise. Resting LV diastolic function (E’, peak early diastolic mitral annular velocity) and geometry were evaluated by echocardiography, and endothelial function by reactive hyperemia peripheral arterial tonometry. A total of 24 patients (69 ± 9 years) completed 6 months of intervention. Peak VO2 in the sitagliptin and voglibose groups (25.3 ± 7.3 vs. 24.0 ± 7.4, 22.7 ± 4.8 vs. 22.1 ± 5.2 ml/kg/min) was slightly decreased after 6 months (time effect p = 0.051; group × time effect p = 0.49). No effects were observed on LV ejection fraction, E’, or reactive hyperemia index in either group. Heart rate during exercise was unaffected in both groups. Systolic blood pressure was unchanged by sitagliptin at rest and during exercise, but slightly lowered by voglibose at anaerobic threshold and peak exercise. In patients with T2DM and CAD, sitagliptin had little effect on resting LV and arterial function, exercise capacity, or exercise hemodynamics. Further studies need to be conducted with more patients as the number of the patients in this study was limited.

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

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Palmieri V, Bella JN, Arnett DK, Liu JE, Oberman A, Schuck MY, Kitzman DW, Hopkins PN, Morgan D, Rao DC, Devereux RB (2001) Effect of type 2 diabetes mellitus on left ventricular geometry and systolic function in hypertensive subjects: Hypertension Genetic Epidemiology Network (HyperGEN) study. Circulation 103:102–107

    Article  CAS  Google Scholar 

  2. Lakatta EG, Wang M, Najjar SS (2009) Arterial aging and subclinical arterial disease are fundamentally intertwined at macroscopic and molecular levels. Med Clin North Am 93:583–604

    Article  CAS  Google Scholar 

  3. Thanassoulis G, Lyass A, Benjamin EJ, Larson MG, Vita JA, Levy D, Hamburg NM, Widlansky ME, O'Donnell CJ, Mitchell GF, Vasan RS (2012) Relations of exercise blood pressure response to cardiovascular risk factors and vascular function in the Framingham Heart Study. Circulation 125:2836–2843

    Article  Google Scholar 

  4. Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, Josse R, Kaufman KD, Koglin J, Korn S, Lachin JM, McGuire DK, Pencina MJ, Standl E, Stein PP, Suryawanshi S, Van de Werf F, Peterson ED, Holman RR, TECOS Study Group (2015) Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 373:232–242

    Article  CAS  Google Scholar 

  5. Shigeta T, Aoyama M, Bando YK, Monji A, Mitsui T, Takatsu M, Cheng XW, Okumura T, Hirashiki A, Nagata K, Murohara T (2012) Dipeptidyl peptidase-4 modulates left ventricular dysfunction in chronic heart failure via angiogenesis-dependent and -independent actions. Circulation 126:1838–1851

    Article  CAS  Google Scholar 

  6. Read PA, Khan FZ, Heck PM, Hoole SP, Dutka DP (2010) DPP-4 inhibition by sitagliptin improves the myocardial response to dobutamine stress and mitigates stunning in a pilot study of patients with coronary artery disease. Circ Cardiovasc Imaging 3:195–201

    Article  Google Scholar 

  7. Moriwaki K, Takeuchi T, Fujimoto N, Sawai T, Sato Y, Kumagai N, Masuda J, Nakamori S, Ishida M, Yamada N, Nakamura M, Sakuma H, Ito M, Dohi K (2018) The effect of sitagliptin on coronary flow reserve assessed by magnetic resonance imaging in type 2 diabetic patients with coronary artery disease. Circ J 82:2119–2127

    Article  CAS  Google Scholar 

  8. Sohn DW, Chai IH, Lee DJ, Kim HC, Kim HS, Oh BH, Lee MM, Park YB, Choi YS, Seo JD, Lee YW (1997) Assessment of mitral annulus velocity by Doppler tissue imaging in the evaluation of left ventricular diastolic function. J Am Coll Cardiol 30:474–480

    Article  CAS  Google Scholar 

  9. Kim YJ, Sohn DW (2000) Mitral annulus velocity in the estimation of left ventricular filling pressure: prospective study in 200 patients. J Am Soc Echocardiogr 13:980–985

    Article  CAS  Google Scholar 

  10. Nakanishi M, Takaki H, Kumasaka R, Arakawa T, Noguchi T, Sugimachi M, Goto Y (2014) Targeting of high peak respiratory exchange ratio is safe and enhances the prognostic power of peak oxygen uptake for heart failure patients. Circ J 78:2268–2275

    Article  Google Scholar 

  11. Beaver WL, Wasserman K (1985) Whipp BJ (1986) A new method for detecting anaerobic threshold by gas exchange. J Appl Physiol 60:2020–2027

    Article  Google Scholar 

  12. Murata M, Adachi H, Oshima S, Kurabayashi M (2017) Influence of stroke volume and exercise tolerance on peak oxygen pulse in patients with and without beta-adrenergic receptor blockers in patients with heart disease. J Cardiol 69:176–181

    Article  Google Scholar 

  13. Kelly RP, Ting CT, Yang TM, Liu CP, Maughan WL, Chang MS, Kass DA (1992) Effective arterial elastance as index of arterial vascular load in humans. Circulation 86:513–521

    Article  CAS  Google Scholar 

  14. Hamburg NM, Keyes MJ, Larson MG, Vasan RS, Schnabel R, Pryde MM, Mitchell GF, Sheffy J, Vita JA, Benjamin EJ (2008) Cross-sectional relations of digital vascular function to cardiovascular risk factors in the Framingham heart study. Circulation 117:2467–2474

    Article  Google Scholar 

  15. Balakumar P, Dhanaraj SA (2013) Cardiovascular pleiotropic actions of DPP-4 inhibitors: a step at the cutting edge in understanding their additional therapeutic potentials. Cell Signal 25:1799–1803

    Article  CAS  Google Scholar 

  16. dos Santos L, Salles TA, Arruda-Junior DF, Campos LC, Pereira AC, Barreto AL, Antonio EL, Mansur AJ, Tucci PJ, Krieger JE, Girardi AC (2013) Circulating dipeptidyl peptidase IV activity correlates with cardiac dysfunction in human and experimental heart failure. Circ Heart Fail 6:1029–1038

    Article  CAS  Google Scholar 

  17. Gomez N, Touihri K, Matheeussen V, Mendes Da Costa A, Mahmoudabady M, Mathieu M, Baerts L, Peace A, Lybaert P, Scharpé S, De Meester I, Bartunek J, Vanderheyden M, Mc Entee K (2012) Dipeptidyl peptidase IV inhibition improves cardiorenal function in overpacing-induced heart failure. Eur J Heart Fail 14:14–21

    Article  CAS  Google Scholar 

  18. Hamdani N, Hervent AS, Vandekerckhove L, Matheeussen V, Demolder M, Baerts L, De Meester I, Linke WA, Paulus WJ, De Keulenaer GW (2014) Left ventricular diastolic dysfunction and myocardial stiffness in diabetic mice is attenuated by inhibition of dipeptidyl peptidase 4. Cardiovasc Res 104:423–431

    Article  CAS  Google Scholar 

  19. Oe H, Nakamura K, Kihara H, Shimada K, Fukuda S, Takagi T, Miyoshi T, Hirata K, Yoshikawa J, Ito H, FESC, for Effect of a DPP-4 inhibitor on left ventricular diastolic dysfunction in patients with type 2 diabetes, and diabetic cardiomyopathy (3D) study investigators (2015) Comparison of effects of sitagliptin and voglibose on left ventricular diastolic dysfunction in patients with type 2 diabetes: results of the 3D trial. Cardiovasc Diabetol 14:83

    Article  CAS  Google Scholar 

  20. Lamers D, Famulla S, Wronkowitz N, Hartwig S, Lehr S, Ouwens DM, Lamers D, Famulla S, Wronkowitz N, Hartwig S, Lehr S, Ouwens DM, Eckardt K, Kaufman JM, Ryden M, Müller S, Hanisch FG, Ruige J, Arner P, Sell H, Eckel J et al (2011) Dipeptidyl peptidase 4 is a novel adipokine potentially linking obesity to the metabolic syndrome. Diabetes 60:1917–1925

    Article  CAS  Google Scholar 

  21. Romacho T, Vallejo S, Villalobos LA, Wronkowitz N, Indrakusuma I, Sell H, Eckel J, Sánchez-Ferrer CF, Peiró C (2016) Soluble dipeptidyl peptidase-4 induces microvascular endothelial dysfunction through proteinase-activated receptor-2 and thromboxane A2 release. J Hypertens 34:869–876

    Article  CAS  Google Scholar 

  22. Leung M, Leung DY, Wong VW (2016) Effects of dipeptidyl peptidase-4 inhibitors on cardiac and endothelial function in type 2 diabetes mellitus: A pilot study. Diabetes Vasc Dis Res 13:236–243

    Article  CAS  Google Scholar 

  23. Leung M, Wong VW, Hudson M, Leung DY (2016) Impact of improved glycemic control on cardiac function in type 2 diabetes mellitus. Circ Cardiovasc Imaging 9:e003643

    Article  Google Scholar 

  24. Fujimoto N, Hastings JL, Bhella PS, Shibata S, Gandhi NK, Carrick-Ranson G, Palmer D, Levine BD (2012) Effect of ageing on left ventricular compliance and distensibility in healthy sedentary humans. J Physiol 590:1871–1880

    Article  CAS  Google Scholar 

  25. Borlaug BA, Paulus WJ (2011) Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur Heart J 32:670–679

    Article  Google Scholar 

  26. Fujimoto N, Prasad A, Hastings JL, Arbab-Zadeh A, Bhella PS, Shibata S, Palmer D, Levine BD (2010) Cardiovascular effects of 1 year of progressive and vigorous exercise training in previously sedentary individuals older than 65 years of age. Circulation 122:1797–1805

    Article  Google Scholar 

  27. Stewart KJ (2002) Exercise training and the cardiovascular consequences of type 2 diabetes and hypertension: plausible mechanisms for improving cardiovascular health. JAMA 288:1622–1631

    Article  Google Scholar 

  28. Larson-Meyer DE, Redman L, Heilbronn LK, Martin CK, Ravussin E (2010) Caloric restriction with or without exercise: the fitness versus fatness debate. Med Sci Sports Exerc 42:152–159

    Article  Google Scholar 

  29. Chang G, Zhang P, Ye L, Lu K, Wang Y, Duan Q, Zheng A, Qin S, Zhang D (2013) Protective effects of sitagliptin on myocardial injury and cardiac function in an ischemia/reperfusion rat model. Eur J Pharmacol 718:105–113

    Article  CAS  Google Scholar 

  30. Hashikata T, Yamaoka-Tojo M, Kakizaki R, Nemoto T, Fujiyoshi K, Namba S, Kitasato L, Hashimoto T, Ishii S, Kameda R, Shimohama T, Tojo T, Ako J (2016) Teneligliptin improves left ventricular diastolic function and endothelial function in patients with diabetes. Heart Vessels 31:1303–1310

    Article  Google Scholar 

  31. Chandra A, Neeland IJ, Berry JD, Ayers CR, Rohatgi A, Das SR, Khera A, McGuire DK, de Lemos JA, Turer AT (2014) The relationship of body mass and fat distribution with incident hypertension: observations from the Dallas Heart Study. J Am Coll Cardiol 64:997–1002

    Article  Google Scholar 

  32. Fujitaka K, Otani H, Jo F, Jo H, Nomura E, Iwasaki M, Nishikawa M, Iwasaka T (2011) Comparison of metabolic profile and adiponectin level with pioglitazone versus voglibose in patients with type-2 diabetes mellitus associated with metabolic syndrome. Endocr J 58:425–432

    Article  CAS  Google Scholar 

  33. Wagner H, Degerblad M, Thorell A, Nygren J, Ståhle A, Kuhl J, Brismar TB, Ohrvik J, Efendic S, Båvenholm PN (2006) Combined treatment with exercise training and acarbose improves metabolic control and cardiovascular risk factor profile in subjects with mild type 2 diabetes. Diabetes Care 29:1471–1477

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by the Waksman Foundation of Japan.

Author information

Authors and Affiliations

  1. Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, 514-8507, Japan

    Naoki Fujimoto, Keishi Moriwaki, Tetsushiro Takeuchi, Toshiki Sawai, Yuichi Sato, Naoto Kumagai, Jun Masuda, Shiro Nakamori, Masaaki Ito & Kaoru Dohi

Authors
  1. Naoki Fujimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Keishi Moriwaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tetsushiro Takeuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Toshiki Sawai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yuichi Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Naoto Kumagai
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jun Masuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shiro Nakamori
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Masaaki Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Kaoru Dohi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Naoki Fujimoto.

Ethics declarations

Conflict of interest

Masaaki Ito received departmental research grant support ≥ 1,000,000 yen from Bristol-Myers Squibb K.K., MSD K.K., Shionogi & Co., Ltd., Otsuka Pharma Inc. and Takeda Pharmaceutical Company Limited in 2017. Masaaki Ito received lecture fees ≥ 500,000 yen from Daiichi Sankyo Company Limited, Bayer Holding Ltd. and Takeda Pharmaceutical Company Limited in 2017. Kaoru Dohi received lecture fees ≥ 500,000 yen from Otsuka Pharma Inc. in 2017. The other authors have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fujimoto, N., Moriwaki, K., Takeuchi, T. et al. Effects of sitagliptin on exercise capacity and hemodynamics in patients with type 2 diabetes mellitus and coronary artery disease. Heart Vessels 35, 605–613 (2020). https://doi.org/10.1007/s00380-019-01526-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00380-019-01526-7

Keywords

Search

Navigation