Heart and Vessels

, Volume 31, Issue 8, pp 1303–1310 | Cite as

Teneligliptin improves left ventricular diastolic function and endothelial function in patients with diabetes

  • Takehiro Hashikata
  • Minako Yamaoka-Tojo
  • Ryota Kakizaki
  • Teruyoshi Nemoto
  • Kazuhiro Fujiyoshi
  • Sayaka Namba
  • Lisa Kitasato
  • Takuya Hashimoto
  • Ryo Kameda
  • Emi Maekawa
  • Takao Shimohama
  • Taiki Tojo
  • Junya Ako
Original Article

Abstract

Incretin hormones have been reported to have cytoprotective actions in addition to their glucose-lowering effects. We evaluated whether teneligliptin, a novel dipeptidyl peptidase-4 (DPP-4) inhibitor, affects left ventricular (LV) function in patients with type 2 diabetes mellitus (T2DM). Twenty-nine T2DM patients not receiving any incretin-based drugs were enrolled and prescribed with teneligliptin for 3 months. Compared to baseline levels, hemoglobin A1c levels decreased (7.6 ± 1.0 % to 6.9 ± 0.7 %, p < 0.01) and 1,5-anhydro-d-glucitol levels increased (9.6 ± 7.2 μg/mL to 13.5 ± 8.7 μg/mL, p < 0.01) after treatment. Clinical parameters, including body mass index and blood pressure, did not show any difference before and after treatment. Three months after treatment, there were improvements in LV systolic and diastolic function [LV ejection fraction, 62.0 ± 6.5 % to 64.5 ± 5.0 %, p = 0.01; peak early diastolic velocity/basal septal diastolic velocity (E/e′) ratio, 13.3 ± 4.1 to 11.9 ± 3.3, p = 0.01]. Moreover, there was an improvement in endothelial function (reactive hyperemia peripheral arterial tonometry [RH-PAT] index; 1.58 ± 0.47 to 2.01 ± 0.72, p < 0.01). There was a significant negative correlation between changes in the E/e’ ratio and RH-PAT values. Furthermore, circulating adiponectin levels increased (27.0 ± 38.5 pg/mL to 42.7 ± 33.2 pg/mL, p < 0.01) without changes in patient body weight. Teneligliptin treatment was associated with improvements in LV function and endothelial functions, and an increase in serum adiponectin levels. These results support the cardio-protective effects of teneligliptin in T2DM patients and increase in serum adiponectin levels.

Keywords

Dipeptidyl peptidase-4 inhibitor Teneligliptin Left ventricular function Endothelial function Adiponectin 

Notes

Acknowledgments

We appreciate the assistance from Ms. Kazumi Nakazato, the technical assistant in the Department of Cardiovascular Medicine, Kitasato University School of Medicine.

Compliance with ethical standards

Conflict of interest

This study was partly supported by International Grants-in-Aid for Research from the Kitasato University School of Allied Health Sciences, Daiichi-Sankyo, MSD K.K., Bayer Pharma, Tanabe Mitsubishi, and Boehringer Ingelheim (M. Y–T.). Dr. Junya Ako received speaking honorarium from Tanabe Mitsubishi, Daiichi-Sankyo, MSD K.K., Boehringer Ingelheim, Kowa, and Kyowa Hakko Kirin. The other authors have nothing to disclose regarding this study.

References

  1. 1.
    Xu L, Man CD, Charbonnel B, Meninger G, Davies MJ, Williams-Herman D, Cobelli C, Stein PP (2008) Effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on beta-cell function in patients with type 2 diabetes: a model-based approach. Diabetes Obes Metab 10:1212–1220PubMedGoogle Scholar
  2. 2.
    Deacon CF (2011) Dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes: a comparative review. Diabetes Obes Metab 13:7–18CrossRefPubMedGoogle Scholar
  3. 3.
    Ban K, Noyan-Ashraf MH, Hoefer J, Bolz SS, Drucker DJ, Husain M (2008) Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways. Circulation 117:2340–2350CrossRefPubMedGoogle Scholar
  4. 4.
    Monji A, Mitsui T, Bando YK, Aoyama M, Shigeta T, Murohara T (2013) Glucagon-like peptide-1 receptor activation reverses cardiac remodeling via normalizing cardiac steatosis and oxidative stress in type 2 diabetes. Am J Physiol Heart Circ Physiol 305:H295–H304CrossRefPubMedGoogle Scholar
  5. 5.
    Best JH, Hoogwerf BJ, Herman WH, Pelletier EM, Smith DB, Wenten M, Hussein MA (2011) Risk of cardiovascular disease events in patients with type 2 diabetes prescribed the glucagon-like peptide 1 (GLP-1) receptor agonist exenatide twice daily or other glucose-lowering therapies: a retrospective analysis of the lifelink database. Diabetes Care 34:90–95CrossRefPubMedGoogle Scholar
  6. 6.
    Brandt I, Lambeir AM, Ketelslegers JM, Vanderheyden M, Scharpe S, De Meester I (2006) Dipeptidyl-peptidase IV converts intact B-type natriuretic peptide into its des-SerPro form. Clin Chem 52:82–87CrossRefPubMedGoogle Scholar
  7. 7.
    Gomez N, Matheeussen V, Damoiseaux C, Tamborini A, Merveille AC, Jespers P, Michaux C, Clercx C, De Meester I, Mc Entee K (2012) Effect of heart failure on dipeptidyl peptidase IV activity in plasma of dogs. J Vet Intern Med 26:929–934CrossRefPubMedGoogle Scholar
  8. 8.
    Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P, Frederich R, Wiviott SD, Hoffman EB, Cavender MA, Udell JA, Desai NR, Mosenzon O, McGuire DK, Ray KK, Leiter LA, Raz I, SAVOR-TIMI 53 Steering Committee and Investigators (2013) Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 369:1317–1326CrossRefPubMedGoogle Scholar
  9. 9.
    Ussher JR, Drucker DJ (2012) Cardiovascular biology of the incretin system. Endocr Rev 33:187–215CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Matsubara J, Sugiyama S, Akiyama E, Iwashita S, Kurokawa H, Ohba K, Maeda H, Fujisue K, Yamamoto E, Kaikita K, Hokimoto S, Jinnouchi H, Ogawa H (2013) Dipeptidyl peptidase-4 inhibitor, sitagliptin, improves endothelial dysfunction in association with its anti-inflammatory effects in patients with coronary artery disease and uncontrolled diabetes. Circ J 77:1337–1344CrossRefPubMedGoogle Scholar
  11. 11.
    Chinda K, Palee S, Surinkaew S, Phornphutkul M, Chattipakorn S, Chattipakorn N (2013) Cardioprotective effect of dipeptidyl peptidase-4 inhibitor during ischemia-reperfusion injury. Int J Cardiol 167:451–457CrossRefPubMedGoogle Scholar
  12. 12.
    Nogueira KC, Furtado M, Fukui RT, Correia MR, Dos Santos RF, Andrade JL, Rossi da Silva ME (2014) Left ventricular diastolic function in patients with type 2 diabetes treated with a dipeptidyl peptidase-4 inhibitor- a pilot study. Diabetol Metab Syndr 6:103CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Fujiwara T, Yoshida M, Nakamura T, Sakakura K, Wada H, Arao K, Katayama T, Funayama H, Sugawara Y, Mitsuhashi T, Kakei M, Momomura SI, Ako J (2014) Dipeptidyl peptidase-4 inhibitors are associated with improved left ventricular diastolic function after acute myocardial infarction in diabetic patients. Heart Vessels. doi:10.1007/s00380-014-0509-4 Google Scholar
  14. 14.
    McCormick LM, Kydd AC, Read PA, Ring LS, Bond SJ, Hoole SP, Dutka DP (2014) Chronic dipeptidyl peptidase-4 inhibition with sitagliptin is associated with sustained protection against ischemic left ventricular dysfunction in a pilot study of patients with type 2 diabetes mellitus and coronary artery disease. Circ Cardiovasc Imaging 7:274–281CrossRefPubMedGoogle Scholar
  15. 15.
    Mori Y, Taniguchi Y, Matsuura K, Sezaki K, Yokoyama J, Utsunomiya K (2011) Effects of sitagliptin on 24-h glycemic changes in Japanese patients with type 2 diabetes assessed using continuous glucose monitoring. Diabetes Technol Ther 13:699–703CrossRefPubMedGoogle Scholar
  16. 16.
    Goda M, Kadowaki T (2013) Teneligliptin for the treatment of type 2 diabetes. Drugs Today (Barc) 49:615–629Google Scholar
  17. 17.
    Kadowaki T, Kondo K (2014) Efficacy and safety of teneligliptin added to glimepiride in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled study with an open-label, long-term extension. Diabetes Obes Metab 16:418–425CrossRefPubMedGoogle Scholar
  18. 18.
    Kadowaki T, Kondo K (2013) Efficacy and safety of teneligliptin in combination with pioglitazone in Japanese patients with type 2 diabetes mellitus. J Diabetes Investig 4:576–584CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Otsuki H, Kosaka T, Nakamura K, Shimomura F, Kuwahara Y, Tsukamoto T (2014) Safety and efficacy of teneligliptin: a novel DPP-4 inhibitor for hemodialysis patients with type 2 diabetes. Int Urol Nephrol 46:427–432CrossRefPubMedGoogle Scholar
  20. 20.
    Tanaka S, Suzuki K, Aoki C, Niitani M, Kato K, Tomotsune T, Aso Y (2014) Add-on treatment with teneligliptin ameliorates glucose fluctuations and improves glycemic control index in Japanese patients with type 2 diabetes on insulin therapy. Diabetes Technol Ther 16(12):840–845CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Matsuzawa Y, Sugiyama S, Sugamura K, Nozaki T, Ohba K, Konishi M, Matsubara J, Sumida H, Kaikita K, Kojima S, Nagayoshi Y, Yamamuro M, Izumiya Y, Iwashita S, Matsui K, Jinnouchi H, Kimura K, Umemura S, Ogawa H (2010) Digital assessment of endothelial function and ischemic heart disease in women. J Am Coll Cardiol 55:1688–1696CrossRefPubMedGoogle Scholar
  22. 22.
    Bonetti PO, Barsness GW, Keelan PC, Schnell TI, Pumper GM, Kuvin JT, Schnall RP, Holmes DR, Higano ST, Lerman A (2003) Enhanced external counterpulsation improves endothelial function in patients with symptomatic coronary artery disease. J Am Coll Cardiol 41(10):1761–1768CrossRefPubMedGoogle Scholar
  23. 23.
    Kume T, Akasaka T, Kawamoto T, Ogasawara Y, Watanabe N, Toyota E, Neishi Y, Sukmawan R, Sadahira Y, Yoshida K (2006) Assessment of coronary arterial thrombus by optical coherence tomography. Am J Cardiol 97:1713–1717CrossRefPubMedGoogle Scholar
  24. 24.
    Mor-Avi V, Lang RM, Badano LP, Belohlavek M, Cardim NM, Derumeaux G, Galderisi M, Marwick T, Nagueh SF, Sengupta PP, Sicari R, Smiseth OA, Smulevitz B, Takeuchi M, Thomas JD, Vannan M, Voigt JU, Zamorano JL (2011) Current and evolving echocardiographic techniques for the quantitative evaluation of cardiac mechanics: ASE/EAE consensus statement on methodology and indications endorsed by the Japanese Society of Echocardiography. J Am Soc Echocardiogr 24:277–313CrossRefPubMedGoogle Scholar
  25. 25.
    Ommen SR, Nishimura RA, Appleton CP, Miller FA, Oh JK, Redfield MM, Tajik AJ (2000) Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures: A comparative simultaneous Doppler-catheterization study. Circulation 102:1788–1794CrossRefPubMedGoogle Scholar
  26. 26.
    Cosson S, Kevorkian JP (2003) Left ventricular diastolic dysfunction: an early sign of diabetic cardiomyopathy? Diabetes Metab 29:455–466CrossRefPubMedGoogle Scholar
  27. 27.
    Cohn JN, Johnson G (1990) Heart failure with normal ejection fraction. The V-HeFT Study. Veterans Administration Cooperative Study Group. Circulation 81:Iii48–Iii53CrossRefPubMedGoogle Scholar
  28. 28.
    Neglia D, Michelassi C, Trivieri MG, Sambuceti G, Giorgetti A, Pratali L, Gallopin M, Salvadori P, Sorace O, Carpeggiani C, Poddighe R, L’Abbate A, Parodi O (2002) Prognostic role of myocardial blood flow impairment in idiopathic left ventricular dysfunction. Circulation 105:186–193CrossRefPubMedGoogle Scholar
  29. 29.
    Shida T, Nozawa T, Sobajima M, Ihori H, Matsuki A, Inoue H (2014) Fluvastatin-induced reduction of oxidative stress ameliorates diabetic cardiomyopathy in association with improving coronary microvasculature. Heart Vessels. doi:10.1007/s00380-013-0402-6 PubMedGoogle Scholar
  30. 30.
    Kishida K, Funahashi T, Shimomura I (2012) Molecular mechanisms of diabetes and atherosclerosis: role of adiponectin. Endocr Metab Immune Disord Drug Targets 12:118–131CrossRefPubMedGoogle Scholar
  31. 31.
    Pischon T, Girman CJ, Hotamisligil GS, Rifai N, Hu FB, Rimm EB (2004) Plasma adiponectin levels and risk of myocardial infarction in men. JAMA 291:1730–1737CrossRefPubMedGoogle Scholar
  32. 32.
    Kishida K, Funahashi T, Shimomura I (2014) Adiponectin as a routine clinical biomarker. Best Pract Res Clin Endocrinol Metab 28:119–130CrossRefPubMedGoogle Scholar
  33. 33.
    Derosa G, Maffioli P, Salvadeo SA, Ferrari I, Ragonesi PD, Querci F, Franzetti IG, Gadaleta G, Ciccarelli L, Piccinni MN, D’Angelo A, Cicero AF (2010) Effects of sitagliptin or metformin added to pioglitazone monotherapy in poorly controlled type 2 diabetes mellitus patients. Metabolism 59:887–895CrossRefPubMedGoogle Scholar
  34. 34.
    Hibuse T, Maeda N, Kishida K, Kimura T, Minami T, Takeshita E, Hirata A, Nakagawa Y, Kashine S, Oka A, Hayashi M, Nishizawa H, Funahashi T, Shimomura I (2014) A pilot three-month sitagliptin treatment increases serum adiponectin level in Japanese patients with type 2 diabetes mellitus–a randomized controlled trial START-J study. Cardiovasc Diabetol 13:96CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Shestakova MV, Suhareva OIu, Chernova TO, Shmushkovich IA, Aleksandrov AA, Il’in AV, Dedov II (2013) A combination of dipeptidyl peptidase-4 inhibitor and metformin in the treatment of patients with type 2 diabetes mellitus: effective control of glycemia, weight, and quantitative body composition. Ter Arkh 85:49–55PubMedGoogle Scholar
  36. 36.
    Li L, Yang G, Li Q, Tan X, Liu H, Tang Y, Boden G (2008) Exenatide prevents fat-induced insulin resistance and raises adiponectin expression and plasma levels. Diabetes Obes Metab 10(10):921–930CrossRefPubMedGoogle Scholar
  37. 37.
    Kim Chung le T, Hosaka T, Yoshida M, Harada N, Sakaue H, Sakai T, Nakaya Y (2009) Exendin-4, a GLP-1 receptor agonist, directly induces adiponectin expression through protein kinase A pathway and prevents inflammatory adipokine expression. Biochem Biophys Res Commun 390:613–618CrossRefPubMedGoogle Scholar
  38. 38.
    Diaz-Soto G, de Luis DA, Conde-Vicente R, Izaola-Jauregui O, Ramos C, Romero E (2014) Beneficial effects of liraglutide on adipocytokines, insulin sensitivity parameters and cardiovascular risk biomarkers in patients with Type 2 diabetes: a prospective study. Diabetes Res Clin Pract 104:92–96CrossRefPubMedGoogle Scholar

Copyright information

© Springer Japan 2015

Authors and Affiliations

  • Takehiro Hashikata
    • 1
  • Minako Yamaoka-Tojo
    • 2
  • Ryota Kakizaki
    • 1
  • Teruyoshi Nemoto
    • 1
  • Kazuhiro Fujiyoshi
    • 1
  • Sayaka Namba
    • 1
  • Lisa Kitasato
    • 1
  • Takuya Hashimoto
    • 1
  • Ryo Kameda
    • 1
  • Emi Maekawa
    • 1
  • Takao Shimohama
    • 1
  • Taiki Tojo
    • 1
  • Junya Ako
    • 1
  1. 1.Department of Cardiovascular MedicineKitasato University School of MedicineSagamiharaJapan
  2. 2.Department of RehabilitationKitasato University School of Allied Health SciencesSagamiharaJapan

Personalised recommendations