Sitagliptin improves vascular endothelial function in Japanese type 2 diabetes patients without cardiovascular disease


We evaluated the effect of sitagliptin on vascular endothelial function in Japanese type 2 diabetes patients without cardiovascular disease. Subjects included 24 Japanese type 2 diabetes patients without cardiovascular disease. This study was a prospective, open-label, randomized clinical trial. We divided the study subjects into 2 groups: subjects who received sitagliptin 50 mg daily (sitagliptin group, n = 12) and subjects who did not receive sitagliptin (control group, n = 12). Brachial artery flow-mediated dilation (FMD) was measured after overnight fasting. Sitagliptin administration was initiated at 1 month after enrollment in study (baseline). FMD and level of biochemical variables in the sitagliptin and control groups were measured at baseline and 3 months from baseline (3 months). We evaluated the effect of sitagliptin on vascular endothelial function by measuring FMD. FMD at 3 months was significantly higher in the sitagliptin group than in the control group (5.36% ± 2.18% vs 3.41% ± 2.29%, P = 0.040), while FMD at baseline was not significantly different between the 2 groups. In addition, FMD of the sitagliptin group at 3 months was significantly higher than that at baseline (5.36% ± 2.18% vs 3.67% ± 2.30%, P = 0.004), while no significant differences were observed in the FMD of the control group during the study period. The change in the adiponectin from baseline to 3 months was significantly higher in the sitagliptin group than that in the control group (0.82 ± 2.18 μg/mL vs 0.01 ± 0.55 μg/mL, P = 0.039). Sitagliptin improves vascular endothelial function of the brachial artery in Japanese type 2 diabetes patients without cardiovascular disease. Furthermore, elevation of adiponectin may induce reduction of endothelial dysfunction in type 2 diabetes patients treated with sitagliptin.

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Suzuki, K. , Watanabe, K. , Suzuki, T. , Ouchi, M. , Futami-Suda, S. , Igari, Y. , Nakano, H. and Oba, K. (2012) Sitagliptin improves vascular endothelial function in Japanese type 2 diabetes patients without cardiovascular disease. Journal of Diabetes Mellitus, 2, 338-345. doi: 10.4236/jdm.2012.23053.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Haffner, S.M., Agostino, R.D., Jr., Saad, M.F., O’Leary, D.H., Savage, P.J., Rewers, M., Selby, J., Bergman, R.N. and Mykkanen, L. (2000) Carotid artery atherosclerosis in type-2 diabetic and nondiabetic subjects with and without symptomatic coronary artery disease (The insulin resistance atherosclerosis study). American Journal of Cardiology, 85, 1395-1400. doi:10.1016/S0002-9149(00)00784-0
[2] Li, J., Luo, Y., Xu, Y., Yang, J., Zheng, L., Hasimu, B., Yu, J. and Hu, D. (2007) Risk factors of peripheral arterial disease and relationship between low ankle-brachial index and mortality from all-cause and cardiovascular disease in Chinese patients with type 2 diabetes. Circulation Journal, 71, 377-381. doi:10.1253/circj.71.377
[3] Ter Avest, E., Stalenhoef, A.F. and de Graaf, J. (2007) What is the role of non-invasive measurements of atherosclerosis in individual cardiovascular risk prediction? Clinical Science, 112, 507-516. doi:10.1042/CS20060266
[4] J Yeboah, J.R. Crouse, F.C. Hsu, G.L. and Burke, D.M. (2007) Herrington, brachial flow-mediated dilation predicts incident cardiovascular events in older adults: The Cardiovascular Health Study. Circulation, 115, 2390-2397. doi:10.1161/CIRCULATIONAHA.106.678276
[5] Yeboah, J., Folsom, A.R., Burke, G.L., Johnson, C., Polak, J.F., Post, W., Lima, J.A., Crouse, J.R. and Herrington, D.M. (2009) Predictive value of brachial flow-mediated dilation for incident cardiovascular events in a population-based study: The multi-ethnic study of atherosclerosis. Circulation, 120, 502-509. doi:10.1161/CIRCULATIONAHA.109.864801
[6] Watanabe, K., Suzuki, T., Nakano, H. and Oba K. (2007) Relationship between diabetic retinopathy and vascular endothelial function in elderly type 2 diabetic Japanese patients without cardiovascular disease. Geriatrics and Gerontology International, 7, 348-351. doi:10.1111/j.1447-0594.2007.00423.x
[7] Suetsugu, M., Takebayashi, K. and Aso, Y. (2007) Association between diabetic microangiopathy and vascular endothelial function evaluated by flow-mediated vasodilatation in patients with type 2 diabetes. International Journal of Clinical Practice, 61, 920-926. doi:10.1111/j.1742-1241.2006.01223.x
[8] Chen, L.L., Yu, F., Zeng, T.S., Liao, Y.F., Li, Y.M. and Ding, H.C. (2011) Effects of gliclazide on endothelial function in patients with newly diagnosed type 2 diabetes. European Journal of Pharmacology, 659, 296-301. doi:10.1016/j.ejphar.2011.02.044
[9] Shimabukuro, M., Higa, N., Chinen, I., Yamakawa, K. and Takasu, N. (2006) Effects of a single administration of acarbose on postprandial glucose excursion and endothelial dysfunction in type 2 diabetic patients: A randomized crossover study. Journal of Clinical Endocrinology and Metabolism, 91, 837-842. doi:10.1210/jc.2005-1566
[10] Mather, K.J., Verma, S. and Anderson, T.J. (2001) Improved endothelial function with metformin in type 2 diabetes mellitus. Journal of the American College of Cardiology, 37, 1344 -1350. doi:10.1016/S0735-1097(01)01129-9
[11] Papathanassiou, K., Naka, K.K., Kazakos, N., Kanioglou, C., Makriyiannis, D., Pappas, K., Katsouras, C.S., Liveris, K., Kolettis, T., Tsatsoulis, A. and Michalis, L.K. (2009) Pioglitazone vs glimepiride: Differential effects on vascular endothelial function in patients with type 2 diabetes. Atherosclerosis, 205, 221-226. doi:10.1016/j.atherosclerosis.2008.11.027
[12] Athen, B., Landin-Olsson, M., Jansson, P.A., Svensson, D. Holmes, M. and Schweizer, A. (2004) Inhibition of dipeptidyl peptidase-4 reduces glycemia, susutains levels in type 2 diabetes. Journal of Clinical Endocrinology and Metabolism, 89, 2078-2084. doi:10.1210/jc.2003-031907
[13] Seino, Y., Fukushima, M. and Yabe, D. (2010) GIP and GLP-1, the two incretin hormines: Similarities and differences. Journal of Diabetes Investigation, 1, 8-23. doi:10.1111/j.2040-1124.2010.00022.x
[14] Nystrom, T., Gutniak, M.K., Zhang, Q., Zhang, F., Holst, J.J., Ahren, B. and Sjoholm A. (2004) Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease. American Journal of Physiology—Endocrinology and Metabolism, 287, E1209-E1215. doi:10.1152/ajpendo.00237.2004
[15] The Committee of the Japan Diabetes Society on the Diagnostic Criteria of Diabetes Mellitus (2010) Report of the Committee on the classification and diagnostic criteria of diabetes mellitus. Diabetology International, 1, 2-20. doi:10.1007/s13340-010- 0006-7
[16] Nishimura, A. and Sawai, A. (2006) Determination of adiponectin in selum using a latex particle-enhanced turbidimetric immunoassay with an automated analyzer. Clinica Chimica Acta, 371, 163-168. doi:10.1016/j.cca.2006.03.008
[17] Watanabe, K., Oba, K., Suzuki, T., Ouchi, M., Suzuki, K., Futami-Suda, S., Sekimizu, K., Yamamoto, N. and Nakano, H. (2011) Oral glucose loading attenuates endothelial function in normal individual. European Journal of Clinical Investigation, 41, 465-473. doi:10.1111/j.1365-2362.2010.02424.x
[18] Corretti, M.C., Anderson, T.J., Benjamin, E.J., Celermajer, D., Charbonneau, F., Creager, M.A., Deanfield, J., Drexler, H., Gerhard-Herman, M., Herrington, D., Vallance, P., Vita, J., Vogel, R.; International Brachial Artery Reactivity Task Force (2005) Guideline for the Ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: A report of International Brachial Artery Reactivity Task Force. Journal of the American College of Cardiology, 39, 257-265. doi:10.1016/S07
[19] Potenza, M.A., Gagliardi, S., Nacci, C., Carratu’, M.R. and Montagnani, M. (2009) Endothelial dysfunction in diabetes: From mechanism to therapeutic targets. Current Medicinal Chemistry, 16, 94-112. doi:10.2174/092986709787002853
[20] Balas, B., Baig, M.R., Watson, C., Dunning, B.E., Ligueros-Saylan, M., Wang, Y., He, Y.L., Darland, C., Holst, J.J., Deacon, C.F., Cusi, K., Mari, A., Foley, J.E. and DeFronzo, R.A. (2007) The dipeptidyl peptidase 4 inhibitor vildagliptin suppresses endogenous glucose production and enhances islet function after single-dose administration in type 2 diabetic patients. Journal of Endocrinology and Metabolism, 92, 1249-1255. doi:10.1210/jc.2006-1882
[21] Nonaka, K., Kakikawa, T., Sato, A., Okuyama, K.,Fujimoto, G., Kato, N., Suzuki, H., Hirayama, Y., Ahmed, T., Davies, M.J. and Stein, P.P. (2008) Efficacy and safety of sitagliptin monotherapy in Japanese patients with type 2 diabetes. Diabetes Research and Clinical Practice, 79, 291-298. doi:10.1016/j.diabres.2007.08.021
[22] Scott, R., Loeys, T., Davies, M.J. and Engel, S.S. (2008) Efficacy and safety of sitagliptin when added to ongoing metformin therapy in patients with type 2 diabetes. Diabetes, Obesity and Metabolism, 10, 959-969. doi:10.1111/j.1463-1326.2007.00839.x
[23] Hermansen, K., Kipnes, M., Luo, E., Fanurik, D., Khatami, H., Stein, P.; Sitagliptin Study 035 Group (2007) Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes, Obesity and Metabolism, 9, 733-745. doi:10.1111/j.1463-1326.2007.00744.x
[24] Di Flaviani, A., Picconi, F., Di Stefano, P., Giordani, I., Malandrucco, I., Maggio, P.,Palazzo P., Sgreccia, F., Peraldo, C., Farina, F., Frajese, G. and Frontoni, S. (2011) Impact of glycemic and blood pressure variability on surrogate measures of cardiovascular outcomes in type 2 diabetic patients. Diabetes Care, 34, 1605-1609. doi:10.2337/dc11-0034
[25] Kato, T., Inoue, T. and Node, K. (2010) Postprandial endothelial dysfunction in subjects with new-onset type 2 diabetes: An acarbose and nateglinide comparative study. Cardiovascular Diabetology, 9, 12. doi:10.1186/1475-2840-9-12
[26] Lim, S., Choi, S.H., Shin, H., Cho, B.J., Park, H.S., Ahn, B.Y., Kang, S.M., Yoon, J.W., Jang, H.C., Kim, Y.B. and Park, K.S. (2012) Effect of a Dipeptidyl Peptidase-IV Inhibitor, des-fluoro-sitagliptin, on neointimal formation after balloon injury in rats. PLoS One, 7, e35007. doi:10.1371/journal.pone.0035007
[27] Schulze, M.B., Shai, I., Rimm, E.B., Li, T., Rifai, N. and Hu, F.B. (2005) Adiponectin and future coronary heart disease events among men with type 2 diabetes. Diabetes, 54, 534-539. doi:10.2337/diabetes.54.2.534
[28] Pischon, T., Girman, C.J., Hotamisligil, G.S., Rifai, N., Hu, F.B. and Rimm, E.B., (2004) Plasma adiponectin levels and risk of myocardial infarction in men. Journal of the American Medical Association, 291, 1730-1737. doi:10.1001/jama.291.14.1730
[29] Ouchi, N. and Walsh, K. (2007) Adiponectin as an anti-inflammatory factor. Clinica Chimica Acta, 380, 24-30. doi:10.1016/j.cca.2007.01.026
[30] Azuma, K., Kawamori, R., Toyofuku, Y., Kitahara, Y., Sato, F., Shimizu, T., Miura, K., Mine, T., Tanaka, Y., Mitsumata, M. and Watada, H. (2006) Repetitive fluctuations in blood glucose enhance monocyte adhesion to the endothelium of rat thoracic aorta. Arteriosclerosis, Thrombosis, and Vascular Biology, 26, 2275-2280. doi:10.1161/01.ATV.0000239488.05069.03
[31] Oeseburg, H., de Boer, R.A., Buikema, H., van der Harst, P., van Gilst, W.H. and Silljé, H.H. (2010) Glucagon-like peptide 1 prevents reactive oxygen species-induced endothelial cell senescence through the activation of protein kinase A. Arteriosclerosis, Thrombosis, and Vascular Biology, 30, 1407-1414. doi:10.1161/ATVBAHA.110.206425
[32] Liu, H, Dear, A.E., Knudsen, L.B. and Simpson, R.W. (2009) A long-acting glucagon-like peptide-1 analogue attenuates induction of plasminogen activator inhibitor type-1 and vascular ahhesion molecules. Journal of Endocrinology, 20, 59-66. doi:10.1677/JOE-08-0468
[33] Arakawa, M., Mita, T., Azuma, K., Ebato, C., Goto, H., Nomiyama, T., Fujitani, Y., Hirose, T., Kawamori, R. and Watada, H. (2010) Inhibition of monocyte adhesion to endothelial cells and attenuation of atherosclerotic lesion by a glucagon-like peptide-1 receptor agonist, exendin-4. Diabetes, 59, 1030-1037. doi:10.2337/db09-1694

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