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Published in: Cardiovascular Diabetology 1/2017

Open Access 01-12-2017 | Original investigation

The effects of vildagliptin compared with metformin on vascular endothelial function and metabolic parameters: a randomized, controlled trial (Sapporo Athero-Incretin Study 3)

Authors: Naoyuki Kitao, Hideaki Miyoshi, Tomoo Furumoto, Kota Ono, Hiroshi Nomoto, Aika Miya, Chiho Yamamoto, Atsushi Inoue, Kenichi Tsuchida, Naoki Manda, Yoshio Kurihara, Shin Aoki, Akinobu Nakamura, Tatsuya Atsumi, SAIS Study Group

Published in: Cardiovascular Diabetology | Issue 1/2017

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Abstract

Background

Dipeptidyl peptidase-4 (DPP-4) inhibitors may have protective effects in the early stage of atherosclerosis in patients with type 2 diabetes, although similar effects in advanced atherosclerosis were not shown in recent randomized placebo-controlled studies. Therefore, we investigated the efficacy of DPP-4 inhibitor on endothelial function and glycemic metabolism compared with high-dose metformin.

Methods

In this multicenter, open-labeled, prospective, randomized, parallel-group comparison study, patients with type 2 diabetes treated with low-dose metformin (500–750 mg/day) were enrolled and randomly assigned to a vildagliptin, a DPP-4 inhibitor, add-on group (Vilda) or a double dose of metformin group (high Met) for 12 weeks. Flow-mediated dilation (FMD) and serum metabolic markers were assessed before and after treatment. In addition, glycemic control and metabolic parameters were also assessed.

Results

Ninety-seven subjects (aged 58.7 ± 11.0 years; body mass index, 25.9 ± 4.4 kg/m2; HbA1c, 7.3 ± 0.5%; FMD, 5.8 ± 2.6%) were enrolled. Eight subjects dropped out by the end of the study. There were no significant differences between the two groups in baseline characteristics. After 12 weeks, HbA1c was significantly improved in the Vilda group compared with the high Met group (− 0.80 ± 0.38% vs. − 0.40 ± 0.47%, respectively; p < 0.01). However, there were no significant differences in FMD (− 0.51 [− 1.08–0.06]% vs. − 0.58 [− 1.20–0.04]%). Although the apolipoprotein B/apolipoprotein A1 ratio was significantly reduced in the Vilda group compared with baseline (0.66–0.62; p < 0.01), the change did not differ significantly between the two groups (− 0.04 vs. 0.00; p = 0.27). Adiponectin levels were significantly increased in the Vilda group compared with the high Met group (0.75 μg/mL vs. 0.01 μg/mL; p < 0.01).

Conclusions

Regardless of glycemic improvement, combination therapy of vildagliptin and metformin did not affect endothelial function but may exert favorable effects on adipokine levels and lipid profile in patients with type 2 diabetes without advanced atherosclerosis.
Appendix
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Literature
1.
go back to reference Ahren B, Landin-Olsson M, Jansson PA, Svensson M, Holmes D, Schweizer A. Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes. J Clin Endocrinol Metab. 2004;89(5):2078–84.CrossRefPubMed Ahren B, Landin-Olsson M, Jansson PA, Svensson M, Holmes D, Schweizer A. Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes. J Clin Endocrinol Metab. 2004;89(5):2078–84.CrossRefPubMed
2.
3.
go back to reference Barnett A. DPP-4 inhibitors and their potential role in the management of type 2 diabetes. Int J Clin Pract. 2006;60(11):1454–70.CrossRefPubMed Barnett A. DPP-4 inhibitors and their potential role in the management of type 2 diabetes. Int J Clin Pract. 2006;60(11):1454–70.CrossRefPubMed
4.
go back to reference Foley JE, Jordan J. Weight neutrality with the DPP-4 inhibitor, vildagliptin: mechanistic basis and clinical experience. Vasc Health Risk Manag. 2010;6:541–8.CrossRefPubMedPubMedCentral Foley JE, Jordan J. Weight neutrality with the DPP-4 inhibitor, vildagliptin: mechanistic basis and clinical experience. Vasc Health Risk Manag. 2010;6:541–8.CrossRefPubMedPubMedCentral
5.
go back to reference Anagnostis P, Athyros VG, Adamidou F, Panagiotou A, Kita M, Karagiannis A, Mikhailidis DP. Glucagon-like peptide-1-based therapies and cardiovascular disease: looking beyond glycaemic control. Diabetes Obes Metab. 2011;13(4):302–12.CrossRefPubMed Anagnostis P, Athyros VG, Adamidou F, Panagiotou A, Kita M, Karagiannis A, Mikhailidis DP. Glucagon-like peptide-1-based therapies and cardiovascular disease: looking beyond glycaemic control. Diabetes Obes Metab. 2011;13(4):302–12.CrossRefPubMed
6.
go back to reference Nystrom T, Gutniak MK, Zhang Q, Zhang F, Holst JJ, Ahren B, Sjoholm A. Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease. Am J Physiol Endocrinol Metab. 2004;287(6):E1209–15.CrossRefPubMed Nystrom T, Gutniak MK, Zhang Q, Zhang F, Holst JJ, Ahren B, Sjoholm A. Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease. Am J Physiol Endocrinol Metab. 2004;287(6):E1209–15.CrossRefPubMed
7.
go back to reference Henderson A. Endothelial dysfunction: a reversible clinical measure of atherogenic susceptibility and cardiovascular inefficiency. Int J Cardiol. 1997;62(Suppl 1):S43–8.CrossRefPubMed Henderson A. Endothelial dysfunction: a reversible clinical measure of atherogenic susceptibility and cardiovascular inefficiency. Int J Cardiol. 1997;62(Suppl 1):S43–8.CrossRefPubMed
8.
go back to reference Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. New Engl J Med. 1998;339(4):229–34.CrossRefPubMed Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. New Engl J Med. 1998;339(4):229–34.CrossRefPubMed
9.
go back to reference Iso H, Imano H, Kitamura A, Sato S, Naito Y, Tanigawa T, Ohira T, Yamagishi K, Iida M, Shimamoto T. Type 2 diabetes and risk of non-embolic ischaemic stroke in Japanese men and women. Diabetologia. 2004;47(12):2137–44.CrossRefPubMed Iso H, Imano H, Kitamura A, Sato S, Naito Y, Tanigawa T, Ohira T, Yamagishi K, Iida M, Shimamoto T. Type 2 diabetes and risk of non-embolic ischaemic stroke in Japanese men and women. Diabetologia. 2004;47(12):2137–44.CrossRefPubMed
10.
go back to reference UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352(9131):854–65.CrossRef UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352(9131):854–65.CrossRef
11.
go back to reference Selvin E, Bolen S, Yeh HC, Wiley C, Wilson LM, Marinopoulos SS, Feldman L, Vassy J, Wilson R, Bass EB, et al. Cardiovascular outcomes in trials of oral diabetes medications: a systematic review. Arch Intern Med. 2008;168(19):2070–80.CrossRefPubMedPubMedCentral Selvin E, Bolen S, Yeh HC, Wiley C, Wilson LM, Marinopoulos SS, Feldman L, Vassy J, Wilson R, Bass EB, et al. Cardiovascular outcomes in trials of oral diabetes medications: a systematic review. Arch Intern Med. 2008;168(19):2070–80.CrossRefPubMedPubMedCentral
12.
go back to reference Saenz A, Fernandez-Esteban I, Mataix A, Ausejo M, Roque M, Moher D. Metformin monotherapy for type 2 diabetes mellitus. Cochrane database Syst Rev. 2005;3:cd002966. Saenz A, Fernandez-Esteban I, Mataix A, Ausejo M, Roque M, Moher D. Metformin monotherapy for type 2 diabetes mellitus. Cochrane database Syst Rev. 2005;3:cd002966.
13.
go back to reference Kim YG, Hahn S, Oh TJ, Kwak SH, Park KS, Cho YM. Differences in the glucose-lowering efficacy of dipeptidyl peptidase-4 inhibitors between Asians and non-Asians: a systematic review and meta-analysis. Diabetologia. 2013;56(4):696–708.CrossRefPubMed Kim YG, Hahn S, Oh TJ, Kwak SH, Park KS, Cho YM. Differences in the glucose-lowering efficacy of dipeptidyl peptidase-4 inhibitors between Asians and non-Asians: a systematic review and meta-analysis. Diabetologia. 2013;56(4):696–708.CrossRefPubMed
14.
go back to reference Nomoto H, Miyoshi H, Furumoto T, Oba K, Tsutsui H, Inoue A, Atsumi T, Manda N, Kurihara Y, Aoki S. A Randomized controlled trial comparing the effects of sitagliptin and glimepiride on endothelial function and metabolic parameters: Sapporo Athero-Incretin Study 1 (SAIS1). PLoS ONE. 2016;11(10):e0164255.CrossRefPubMedPubMedCentral Nomoto H, Miyoshi H, Furumoto T, Oba K, Tsutsui H, Inoue A, Atsumi T, Manda N, Kurihara Y, Aoki S. A Randomized controlled trial comparing the effects of sitagliptin and glimepiride on endothelial function and metabolic parameters: Sapporo Athero-Incretin Study 1 (SAIS1). PLoS ONE. 2016;11(10):e0164255.CrossRefPubMedPubMedCentral
15.
go back to reference Nomoto H, Miyoshi H, Furumoto T, Oba K, Tsutsui H, Miyoshi A, Kondo T, Tsuchida K, Atsumi T, Manda N, et al. A comparison of the effects of the GLP-1 analogue liraglutide and insulin glargine on endothelial function and metabolic parameters: a randomized, controlled trial Sapporo Athero-Incretin Study 2 (SAIS2). PLoS ONE. 2015;10(8):e0135854.CrossRefPubMedPubMedCentral Nomoto H, Miyoshi H, Furumoto T, Oba K, Tsutsui H, Miyoshi A, Kondo T, Tsuchida K, Atsumi T, Manda N, et al. A comparison of the effects of the GLP-1 analogue liraglutide and insulin glargine on endothelial function and metabolic parameters: a randomized, controlled trial Sapporo Athero-Incretin Study 2 (SAIS2). PLoS ONE. 2015;10(8):e0135854.CrossRefPubMedPubMedCentral
16.
go back to reference Rizzo MR, Barbieri M, Marfella R, Paolisso G, et al. Reduction of oxidative stress and inflammation by blunting daily acute glucose fluctuations in patients with type 2 diabetes: role of dipeptidyl peptidase-IV inhibition. Diabetes Care. 2012;35(10):2076–82.CrossRefPubMedPubMedCentral Rizzo MR, Barbieri M, Marfella R, Paolisso G, et al. Reduction of oxidative stress and inflammation by blunting daily acute glucose fluctuations in patients with type 2 diabetes: role of dipeptidyl peptidase-IV inhibition. Diabetes Care. 2012;35(10):2076–82.CrossRefPubMedPubMedCentral
17.
go back to reference Koyanagawa N, Miyoshi H, Ono K, Nakamura A, Cho KY, Yamamoto K, Takano Y, Dan-Noura M, Atsumi T. Comparative effects of vildagliptin and sitagliptin determined by continuous glucose monitoring in patients with type 2 diabetes mellitus. Endocr J. 2016;63(8):747–53.CrossRefPubMed Koyanagawa N, Miyoshi H, Ono K, Nakamura A, Cho KY, Yamamoto K, Takano Y, Dan-Noura M, Atsumi T. Comparative effects of vildagliptin and sitagliptin determined by continuous glucose monitoring in patients with type 2 diabetes mellitus. Endocr J. 2016;63(8):747–53.CrossRefPubMed
18.
go back to reference Nomoto H, Kimachi K, Miyoshi H, Kameda H, Cho KY, Nakamura A, Nagai S, Kondo T, Atsumi T. Effects of 50 mg vildagliptin twice daily vs. 50 mg sitagliptin once daily on blood glucose fluctuations evaluated by long-term self-monitoring of blood glucose. Endocr J. 2017;64(4):417–24.CrossRefPubMed Nomoto H, Kimachi K, Miyoshi H, Kameda H, Cho KY, Nakamura A, Nagai S, Kondo T, Atsumi T. Effects of 50 mg vildagliptin twice daily vs. 50 mg sitagliptin once daily on blood glucose fluctuations evaluated by long-term self-monitoring of blood glucose. Endocr J. 2017;64(4):417–24.CrossRefPubMed
19.
go back to reference Suzuki K, Watanabe K, Suzuki T, Ouchi M, Futami-Suda S, Igari Y, Nakano H, Oba K. Sitagliptin improves vascular endothelial function in Japanese type 2 diabetes patients without cardiovascular disease. J Diabetes Mellit. 2012;02(03):338–45.CrossRef Suzuki K, Watanabe K, Suzuki T, Ouchi M, Futami-Suda S, Igari Y, Nakano H, Oba K. Sitagliptin improves vascular endothelial function in Japanese type 2 diabetes patients without cardiovascular disease. J Diabetes Mellit. 2012;02(03):338–45.CrossRef
20.
go back to reference Kubota Y, Miyamoto M, Takagi G, Ikeda T, Kirinoki-Ichikawa S, Tanaka K, Mizuno K. The dipeptidyl peptidase-4 inhibitor sitagliptin improves vascular endothelial function in type 2 diabetes. J Korean Med Sci. 2012;27(11):1364–70.CrossRefPubMedPubMedCentral Kubota Y, Miyamoto M, Takagi G, Ikeda T, Kirinoki-Ichikawa S, Tanaka K, Mizuno K. The dipeptidyl peptidase-4 inhibitor sitagliptin improves vascular endothelial function in type 2 diabetes. J Korean Med Sci. 2012;27(11):1364–70.CrossRefPubMedPubMedCentral
21.
go back to reference Mather KJ, Verma S, Anderson TJ. Improved endothelial function with metformin in type 2 diabetes mellitus. J Am Coll Cardiol. 2001;37(5):1344–50.CrossRefPubMed Mather KJ, Verma S, Anderson TJ. Improved endothelial function with metformin in type 2 diabetes mellitus. J Am Coll Cardiol. 2001;37(5):1344–50.CrossRefPubMed
22.
go back to reference Naka KK, Papathanassiou K, Bechlioulis A, Pappas K, Kazakos N, Kanioglou C, Kostoula A, Vezyraki P, Makriyiannis D, Tsatsoulis A, et al. Effects of pioglitazone and metformin on vascular endothelial function in patients with type 2 diabetes treated with sulfonylureas. Diabetes Vasc Dis Res. 2012;9(1):52–8.CrossRef Naka KK, Papathanassiou K, Bechlioulis A, Pappas K, Kazakos N, Kanioglou C, Kostoula A, Vezyraki P, Makriyiannis D, Tsatsoulis A, et al. Effects of pioglitazone and metformin on vascular endothelial function in patients with type 2 diabetes treated with sulfonylureas. Diabetes Vasc Dis Res. 2012;9(1):52–8.CrossRef
23.
24.
go back to reference Manrique C, Habibi J, Aroor AR, Sowers JR, Jia G, Hayden MR, Garro M, Martinez-Lemus LA, Ramirez-Perez FI, Klein T, et al. Dipeptidyl peptidase-4 inhibition with linagliptin prevents western diet-induced vascular abnormalities in female mice. Cardiovasc Diabetol. 2016;15:94.CrossRefPubMedPubMedCentral Manrique C, Habibi J, Aroor AR, Sowers JR, Jia G, Hayden MR, Garro M, Martinez-Lemus LA, Ramirez-Perez FI, Klein T, et al. Dipeptidyl peptidase-4 inhibition with linagliptin prevents western diet-induced vascular abnormalities in female mice. Cardiovasc Diabetol. 2016;15:94.CrossRefPubMedPubMedCentral
25.
go back to reference Murase H, Kuno A, Miki T, Tanno M, Yano T, Kouzu H, Ishikawa S, Tobisawa T, Ogasawara M, Nishizawa K, et al. Inhibition of DPP-4 reduces acute mortality after myocardial infarction with restoration of autophagic response in type 2 diabetic rats. Cardiovasc Diabetol. 2015;14:103.CrossRefPubMedPubMedCentral Murase H, Kuno A, Miki T, Tanno M, Yano T, Kouzu H, Ishikawa S, Tobisawa T, Ogasawara M, Nishizawa K, et al. Inhibition of DPP-4 reduces acute mortality after myocardial infarction with restoration of autophagic response in type 2 diabetic rats. Cardiovasc Diabetol. 2015;14:103.CrossRefPubMedPubMedCentral
26.
go back to reference White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, Perez AT, Fleck PR, Mehta CR, Kupfer S, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. New Engl J Med. 2013;369(14):1327–35.CrossRefPubMed White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, Perez AT, Fleck PR, Mehta CR, Kupfer S, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. New Engl J Med. 2013;369(14):1327–35.CrossRefPubMed
27.
go back to reference Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P, Frederich R, Wiviott SD, Hoffman EB, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. New Engl J Med. 2013;369(14):1317–26.CrossRefPubMed Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P, Frederich R, Wiviott SD, Hoffman EB, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. New Engl J Med. 2013;369(14):1317–26.CrossRefPubMed
28.
go back to reference Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, Josse R, Kaufman KD, Koglin J, Korn S, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. New Engl J Med. 2015;373(3):232–42.CrossRefPubMed Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, Josse R, Kaufman KD, Koglin J, Korn S, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. New Engl J Med. 2015;373(3):232–42.CrossRefPubMed
29.
go back to reference Giaccari A, Giorda CB, Riccardi G, De Micheli A, Bruno G, Monge L, Frontoni S. Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35:1364–79.CrossRef Giaccari A, Giorda CB, Riccardi G, De Micheli A, Bruno G, Monge L, Frontoni S. Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35:1364–79.CrossRef
30.
go back to reference Kao J, Tobis J, McClelland RL, Heaton MR, Davis BR, Holmes DR Jr, Currier JW. Relation of metformin treatment to clinical events in diabetic patients undergoing percutaneous intervention. Am J Cardiol. 2004;93(11):1347–50.CrossRefPubMed Kao J, Tobis J, McClelland RL, Heaton MR, Davis BR, Holmes DR Jr, Currier JW. Relation of metformin treatment to clinical events in diabetic patients undergoing percutaneous intervention. Am J Cardiol. 2004;93(11):1347–50.CrossRefPubMed
31.
go back to reference Mannucci E, Ognibene A, Cremasco F, Bardini G, Mencucci A, Pierazzuoli E, Ciani S, Messeri G, Rotella CM. Effect of metformin on glucagon-like peptide 1 (GLP-1) and leptin levels in obese nondiabetic subjects. Diabetes Care. 2001;24(3):489–94.CrossRefPubMed Mannucci E, Ognibene A, Cremasco F, Bardini G, Mencucci A, Pierazzuoli E, Ciani S, Messeri G, Rotella CM. Effect of metformin on glucagon-like peptide 1 (GLP-1) and leptin levels in obese nondiabetic subjects. Diabetes Care. 2001;24(3):489–94.CrossRefPubMed
32.
go back to reference Maida A, Lamont BJ, Cao X, Drucker DJ. Metformin regulates the incretin receptor axis via a pathway dependent on peroxisome proliferator-activated receptor-alpha in mice. Diabetologia. 2011;54(2):339–49.CrossRefPubMed Maida A, Lamont BJ, Cao X, Drucker DJ. Metformin regulates the incretin receptor axis via a pathway dependent on peroxisome proliferator-activated receptor-alpha in mice. Diabetologia. 2011;54(2):339–49.CrossRefPubMed
33.
go back to reference Noguchi K, Hirota M, Miyoshi T, Tani Y, Noda Y, Ito H, Nanba S. Single administration of vildagliptin attenuates postprandial hypertriglyceridemia and endothelial dysfunction in normoglycemic individuals. Exp Ther Med. 2015;9(1):84–8.CrossRefPubMed Noguchi K, Hirota M, Miyoshi T, Tani Y, Noda Y, Ito H, Nanba S. Single administration of vildagliptin attenuates postprandial hypertriglyceridemia and endothelial dysfunction in normoglycemic individuals. Exp Ther Med. 2015;9(1):84–8.CrossRefPubMed
34.
go back to reference Ayaori M, Iwakami N, Uto-Kondo H, Sato H, Sasaki M, Komatsu T, Iizuka M, Takiguchi S, Yakushiji E, Nakaya K, et al. Dipeptidyl peptidase-4 inhibitors attenuate endothelial function as evaluated by flow-mediated vasodilatation in type 2 diabetic patients. J Am Heart Assoc. 2013;2(1):e003277.CrossRefPubMedPubMedCentral Ayaori M, Iwakami N, Uto-Kondo H, Sato H, Sasaki M, Komatsu T, Iizuka M, Takiguchi S, Yakushiji E, Nakaya K, et al. Dipeptidyl peptidase-4 inhibitors attenuate endothelial function as evaluated by flow-mediated vasodilatation in type 2 diabetic patients. J Am Heart Assoc. 2013;2(1):e003277.CrossRefPubMedPubMedCentral
35.
go back to reference Nakamura K, Oe H, Kihara H, Shimada K, Fukuda S, Watanabe K, Takagi T, Yunoki K, Miyoshi T, Hirata K, et al. DPP-4 inhibitor and alpha-glucosidase inhibitor equally improve endothelial function in patients with type 2 diabetes: EDGE study. Cardiovasc Diabetol. 2014;13:110.CrossRefPubMedPubMedCentral Nakamura K, Oe H, Kihara H, Shimada K, Fukuda S, Watanabe K, Takagi T, Yunoki K, Miyoshi T, Hirata K, et al. DPP-4 inhibitor and alpha-glucosidase inhibitor equally improve endothelial function in patients with type 2 diabetes: EDGE study. Cardiovasc Diabetol. 2014;13:110.CrossRefPubMedPubMedCentral
36.
go back to reference Ida S, Murata K, Betou K, Kobayashi C, Ishihara Y, Imataka K, Uchida A, Monguchi K, Kaneko R, Fujiwara R, et al. Effect of trelagliptin on vascular endothelial functions and serum adiponectin level in patients with type 2 diabetes: a preliminary single-arm prospective pilot study. Cardiovasc Diabetol. 2016;15(1):153.CrossRefPubMedPubMedCentral Ida S, Murata K, Betou K, Kobayashi C, Ishihara Y, Imataka K, Uchida A, Monguchi K, Kaneko R, Fujiwara R, et al. Effect of trelagliptin on vascular endothelial functions and serum adiponectin level in patients with type 2 diabetes: a preliminary single-arm prospective pilot study. Cardiovasc Diabetol. 2016;15(1):153.CrossRefPubMedPubMedCentral
37.
go back to reference Li F, Chen J, Leng F, Lu Z, Ling Y. Effect of saxagliptin on circulating endothelial progenitor cells and endothelial function in newly diagnosed type 2 diabetic patients. Exp Clin Endocrinol Diabetes. 2017;125(6):400–7.CrossRefPubMed Li F, Chen J, Leng F, Lu Z, Ling Y. Effect of saxagliptin on circulating endothelial progenitor cells and endothelial function in newly diagnosed type 2 diabetic patients. Exp Clin Endocrinol Diabetes. 2017;125(6):400–7.CrossRefPubMed
38.
go back to reference Baltzis D, Dushay JR, Loader J, Wu J, Greenman RL, Roustit M, Veves A. Effect of linagliptin on vascular function: a randomized, placebo-controlled study. J Clin Endocrinol Metab. 2016;101(11):4205–13.CrossRefPubMed Baltzis D, Dushay JR, Loader J, Wu J, Greenman RL, Roustit M, Veves A. Effect of linagliptin on vascular function: a randomized, placebo-controlled study. J Clin Endocrinol Metab. 2016;101(11):4205–13.CrossRefPubMed
39.
go back to reference Mita T, Katakami N, Shiraiwa T, Yoshii H, Onuma T, Kuribayashi N, Osonoi T, Kaneto H, Kosugi K, Umayahara Y, et al. Sitagliptin attenuates the progression of carotid intima-media thickening in insulin-treated patients with type 2 diabetes: the Sitagliptin Preventive Study of Intima-Media Thickness Evaluation (SPIKE): a randomized controlled trial. Diabetes Care. 2016;39(3):455–64.CrossRefPubMed Mita T, Katakami N, Shiraiwa T, Yoshii H, Onuma T, Kuribayashi N, Osonoi T, Kaneto H, Kosugi K, Umayahara Y, et al. Sitagliptin attenuates the progression of carotid intima-media thickening in insulin-treated patients with type 2 diabetes: the Sitagliptin Preventive Study of Intima-Media Thickness Evaluation (SPIKE): a randomized controlled trial. Diabetes Care. 2016;39(3):455–64.CrossRefPubMed
40.
go back to reference Mita T, Katakami N, Yoshii H, Onuma T, Kaneto H, Osonoi T, Shiraiwa T, Kosugi K, Umayahara Y, Yamamoto T, et al. Alogliptin, a dipeptidyl peptidase 4 inhibitor, prevents the progression of carotid atherosclerosis in patients with type 2 diabetes: the study of preventive effects of alogliptin on diabetic atherosclerosis (SPEAD-A). Diabetes Care. 2016;39(1):139–48.CrossRefPubMed Mita T, Katakami N, Yoshii H, Onuma T, Kaneto H, Osonoi T, Shiraiwa T, Kosugi K, Umayahara Y, Yamamoto T, et al. Alogliptin, a dipeptidyl peptidase 4 inhibitor, prevents the progression of carotid atherosclerosis in patients with type 2 diabetes: the study of preventive effects of alogliptin on diabetic atherosclerosis (SPEAD-A). Diabetes Care. 2016;39(1):139–48.CrossRefPubMed
41.
go back to reference Dell’Oro R, Maloberti A, Nicoli F, Villa P, Gamba P, Bombelli M, Mancia G, Grassi G. Long-term Saxagliptin Treatment improves endothelial function but not pulse wave velocity and intima-media thickness in type 2 diabetic patients. High blood Press Cardiovas Prev. 2017. Dell’Oro R, Maloberti A, Nicoli F, Villa P, Gamba P, Bombelli M, Mancia G, Grassi G. Long-term Saxagliptin Treatment improves endothelial function but not pulse wave velocity and intima-media thickness in type 2 diabetic patients. High blood Press Cardiovas Prev. 2017.
42.
go back to reference Maruhashi T, Higashi Y, Kihara Y, Yamada H, Sata M, Ueda S, Odawara M, Terauchi Y, Dai K, Ohno J, et al. Long-term effect of sitagliptin on endothelial function in type 2 diabetes: a sub-analysis of the PROLOGUE study. Cardiovasc Diabetol. 2016;15(1):134.CrossRefPubMedPubMedCentral Maruhashi T, Higashi Y, Kihara Y, Yamada H, Sata M, Ueda S, Odawara M, Terauchi Y, Dai K, Ohno J, et al. Long-term effect of sitagliptin on endothelial function in type 2 diabetes: a sub-analysis of the PROLOGUE study. Cardiovasc Diabetol. 2016;15(1):134.CrossRefPubMedPubMedCentral
43.
go back to reference Benjamin EJ, Larson MG, Keyes MJ, Mitchell GF, Vasan RS, Keaney JF Jr, Lehman BT, Fan S, Osypiuk E, Vita JA. Clinical correlates and heritability of flow-mediated dilation in the community: the Framingham Heart Study. Circulation. 2004;109(5):613–9.CrossRefPubMed Benjamin EJ, Larson MG, Keyes MJ, Mitchell GF, Vasan RS, Keaney JF Jr, Lehman BT, Fan S, Osypiuk E, Vita JA. Clinical correlates and heritability of flow-mediated dilation in the community: the Framingham Heart Study. Circulation. 2004;109(5):613–9.CrossRefPubMed
44.
go back to reference Iwata M, Miyashita Y, Kumagai H. Seasonal variation of endothelium-dependent flow-mediated vasodilation measured in the same subjects. Am J Cardiovasc Dis. 2012;2(2):111–5.PubMedPubMedCentral Iwata M, Miyashita Y, Kumagai H. Seasonal variation of endothelium-dependent flow-mediated vasodilation measured in the same subjects. Am J Cardiovasc Dis. 2012;2(2):111–5.PubMedPubMedCentral
45.
go back to reference Li S, Wu Y, Yu G, Xia Q, Xu Y. Angiotensin II receptor blockers improve peripheral endothelial function: a meta-analysis of randomized controlled trials. PLoS ONE. 2014;9(3):e90217.CrossRefPubMedPubMedCentral Li S, Wu Y, Yu G, Xia Q, Xu Y. Angiotensin II receptor blockers improve peripheral endothelial function: a meta-analysis of randomized controlled trials. PLoS ONE. 2014;9(3):e90217.CrossRefPubMedPubMedCentral
46.
go back to reference Takagi H, Yamamoto H, Iwata K, Goto SN, Umemoto T. Low-density lipoprotein-independent improvement of flow-mediated dilatation with atorvastatin: a meta-analysis and meta-regression of randomized controlled trials. Int J Cardiol. 2012;158(2):285–9.CrossRefPubMed Takagi H, Yamamoto H, Iwata K, Goto SN, Umemoto T. Low-density lipoprotein-independent improvement of flow-mediated dilatation with atorvastatin: a meta-analysis and meta-regression of randomized controlled trials. Int J Cardiol. 2012;158(2):285–9.CrossRefPubMed
47.
go back to reference Papathanassiou K, Naka KK, Kazakos N, Kanioglou C, Makriyiannis D, Pappas K, Katsouras CS, Liveris K, Kolettis T, Tsatsoulis A, et al. Pioglitazone vs glimepiride: differential effects on vascular endothelial function in patients with type 2 diabetes. Atherosclerosis. 2009;205(1):221–6.CrossRefPubMed Papathanassiou K, Naka KK, Kazakos N, Kanioglou C, Makriyiannis D, Pappas K, Katsouras CS, Liveris K, Kolettis T, Tsatsoulis A, et al. Pioglitazone vs glimepiride: differential effects on vascular endothelial function in patients with type 2 diabetes. Atherosclerosis. 2009;205(1):221–6.CrossRefPubMed
48.
go back to reference Wascher TC, Schmoelzer I, Wiegratz A, Stuehlinger M, Mueller-Wieland D, Kotzka J, Enderle M. Reduction of postchallenge hyperglycaemia prevents acute endothelial dysfunction in subjects with impaired glucose tolerance. Eur J Clin Invest. 2005;35(9):551–7.CrossRefPubMed Wascher TC, Schmoelzer I, Wiegratz A, Stuehlinger M, Mueller-Wieland D, Kotzka J, Enderle M. Reduction of postchallenge hyperglycaemia prevents acute endothelial dysfunction in subjects with impaired glucose tolerance. Eur J Clin Invest. 2005;35(9):551–7.CrossRefPubMed
49.
go back to reference Romualdi D, Costantini B, Selvaggi L, Giuliani M, Cristello F, Macri F, Bompiani A, Lanzone A, Guido M. Metformin improves endothelial function in normoinsulinemic PCOS patients: a new prospective. Hum Reprod. 2008;23(9):2127–33.CrossRefPubMed Romualdi D, Costantini B, Selvaggi L, Giuliani M, Cristello F, Macri F, Bompiani A, Lanzone A, Guido M. Metformin improves endothelial function in normoinsulinemic PCOS patients: a new prospective. Hum Reprod. 2008;23(9):2127–33.CrossRefPubMed
50.
go back to reference Bakhashab S, Ahmed FW, Schulten HJ, Bashir A, Karim S, Al-Malki AL, Gari MA, Abuzenadah AM, Chaudhary AG, Alqahtani MH, et al. Metformin improves the angiogenic potential of human CD34(+) cells co-incident with downregulating CXCL10 and TIMP1 gene expression and increasing VEGFA under hyperglycemia and hypoxia within a therapeutic window for myocardial infarction. Cardiovasc Diabetol. 2016;15:27.CrossRefPubMedPubMedCentral Bakhashab S, Ahmed FW, Schulten HJ, Bashir A, Karim S, Al-Malki AL, Gari MA, Abuzenadah AM, Chaudhary AG, Alqahtani MH, et al. Metformin improves the angiogenic potential of human CD34(+) cells co-incident with downregulating CXCL10 and TIMP1 gene expression and increasing VEGFA under hyperglycemia and hypoxia within a therapeutic window for myocardial infarction. Cardiovasc Diabetol. 2016;15:27.CrossRefPubMedPubMedCentral
51.
go back to reference Triggle CR, Ding H. Metformin is not just an antihyperglycaemic drug but also has protective effects on the vascular endothelium. Acta Physiol. 2017;219(1):138–51.CrossRef Triggle CR, Ding H. Metformin is not just an antihyperglycaemic drug but also has protective effects on the vascular endothelium. Acta Physiol. 2017;219(1):138–51.CrossRef
52.
go back to reference Maruhashi T, Soga J, Fujimura N, Idei N, Mikami S, Iwamoto Y, Kajikawa M, Matsumoto T, Hidaka T, Kihara Y, et al. Relationship between flow-mediated vasodilation and cardiovascular risk factors in a large community-based study. Heart. 2013;99(24):1837–42.CrossRefPubMedPubMedCentral Maruhashi T, Soga J, Fujimura N, Idei N, Mikami S, Iwamoto Y, Kajikawa M, Matsumoto T, Hidaka T, Kihara Y, et al. Relationship between flow-mediated vasodilation and cardiovascular risk factors in a large community-based study. Heart. 2013;99(24):1837–42.CrossRefPubMedPubMedCentral
53.
go back to reference Roman MJ, Devereux RB, Kizer JR, Lee ET, Galloway JM, Ali T, Umans JG, Howard BV. Central pressure more strongly relates to vascular disease and outcome than does brachial pressure: the strong heart study. Hypertension. 2007;50(1):197–203.CrossRefPubMed Roman MJ, Devereux RB, Kizer JR, Lee ET, Galloway JM, Ali T, Umans JG, Howard BV. Central pressure more strongly relates to vascular disease and outcome than does brachial pressure: the strong heart study. Hypertension. 2007;50(1):197–203.CrossRefPubMed
54.
go back to reference Nissen SE, Tuzcu EM, Schoenhagen P, Crowe T, Sasiela WJ, Tsai J, Orazem J, Magorien RD, O’Shaughnessy C, Ganz P. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. New Engl J Med. 2005;352(1):29–38.CrossRefPubMed Nissen SE, Tuzcu EM, Schoenhagen P, Crowe T, Sasiela WJ, Tsai J, Orazem J, Magorien RD, O’Shaughnessy C, Ganz P. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. New Engl J Med. 2005;352(1):29–38.CrossRefPubMed
55.
go back to reference Sharma RK, Singh VN, Reddy HK. Thinking beyond low-density lipoprotein cholesterol: strategies to further reduce cardiovascular risk. Vasc Health Risk Manag. 2009;5:793–9.CrossRefPubMedPubMedCentral Sharma RK, Singh VN, Reddy HK. Thinking beyond low-density lipoprotein cholesterol: strategies to further reduce cardiovascular risk. Vasc Health Risk Manag. 2009;5:793–9.CrossRefPubMedPubMedCentral
56.
go back to reference Walldius G, Jungner I. Apolipoprotein B and apolipoprotein A–I: risk indicators of coronary heart disease and targets for lipid-modifying therapy. J Intern Med. 2004;255(2):188–205.CrossRefPubMed Walldius G, Jungner I. Apolipoprotein B and apolipoprotein A–I: risk indicators of coronary heart disease and targets for lipid-modifying therapy. J Intern Med. 2004;255(2):188–205.CrossRefPubMed
57.
go back to reference Cromwell WC, Barringer TA. Low-density lipoprotein and apolipoprotein B: clinical use in patients with coronary heart disease. Current Cardiol Rep. 2009;11(6):468–75.CrossRef Cromwell WC, Barringer TA. Low-density lipoprotein and apolipoprotein B: clinical use in patients with coronary heart disease. Current Cardiol Rep. 2009;11(6):468–75.CrossRef
58.
go back to reference Hoang A, Murphy AJ, Coughlan MT, Thomas MC, Forbes JM, O’Brien R, Cooper ME, Chin-Dusting JP, Sviridov D. Advanced glycation of apolipoprotein A–I impairs its anti-atherogenic properties. Diabetologia. 2007;50(8):1770–9.CrossRefPubMed Hoang A, Murphy AJ, Coughlan MT, Thomas MC, Forbes JM, O’Brien R, Cooper ME, Chin-Dusting JP, Sviridov D. Advanced glycation of apolipoprotein A–I impairs its anti-atherogenic properties. Diabetologia. 2007;50(8):1770–9.CrossRefPubMed
59.
go back to reference Sierra-Johnson J, Fisher RM, Romero-Corral A, Somers VK, Lopez-Jimenez F, Ohrvik J, Walldius G, Hellenius ML, Hamsten A. Concentration of apolipoprotein B is comparable with the apolipoprotein B/apolipoprotein A–I ratio and better than routine clinical lipid measurements in predicting coronary heart disease mortality: findings from a multi-ethnic US population. Eur Heart J. 2009;30(6):710–7.CrossRefPubMed Sierra-Johnson J, Fisher RM, Romero-Corral A, Somers VK, Lopez-Jimenez F, Ohrvik J, Walldius G, Hellenius ML, Hamsten A. Concentration of apolipoprotein B is comparable with the apolipoprotein B/apolipoprotein A–I ratio and better than routine clinical lipid measurements in predicting coronary heart disease mortality: findings from a multi-ethnic US population. Eur Heart J. 2009;30(6):710–7.CrossRefPubMed
60.
go back to reference Yano W, Inoue N, Ito S, Itou T, Yasumura M, Yoshinaka Y, Hagita S, Goto M, Nakagawa T, Inoue K, et al. Mechanism of lipid-lowering action of the dipeptidyl peptidase-4 inhibitor, anagliptin, in low-density lipoprotein receptor-deficient mice. J diabetes Invest. 2017;8(2):155–60.CrossRef Yano W, Inoue N, Ito S, Itou T, Yasumura M, Yoshinaka Y, Hagita S, Goto M, Nakagawa T, Inoue K, et al. Mechanism of lipid-lowering action of the dipeptidyl peptidase-4 inhibitor, anagliptin, in low-density lipoprotein receptor-deficient mice. J diabetes Invest. 2017;8(2):155–60.CrossRef
61.
go back to reference Shigiyama F, Kumashiro N, Miyagi M, Iga R, Kobayashi Y, Kanda E, Uchino H, Hirose T. Linagliptin improves endothelial function in patients with type 2 diabetes: a randomized study of linagliptin effectiveness on endothelial function. J Diabetes Invest. 2017;8(3):330–40.CrossRef Shigiyama F, Kumashiro N, Miyagi M, Iga R, Kobayashi Y, Kanda E, Uchino H, Hirose T. Linagliptin improves endothelial function in patients with type 2 diabetes: a randomized study of linagliptin effectiveness on endothelial function. J Diabetes Invest. 2017;8(3):330–40.CrossRef
62.
go back to reference Kishida K, Funahashi T, Shimomura I. Molecular mechanisms of diabetes and atherosclerosis: role of adiponectin. Endocr Metab Immune Disord Drug Targets. 2012;12(2):118–31.CrossRefPubMed Kishida K, Funahashi T, Shimomura I. Molecular mechanisms of diabetes and atherosclerosis: role of adiponectin. Endocr Metab Immune Disord Drug Targets. 2012;12(2):118–31.CrossRefPubMed
63.
go back to reference Kishida K, Funahashi T, Shimomura I. Adiponectin as a routine clinical biomarker. Best Pract Res Clin Endocrinol Metab. 2014;28(1):119–30.CrossRefPubMed Kishida K, Funahashi T, Shimomura I. Adiponectin as a routine clinical biomarker. Best Pract Res Clin Endocrinol Metab. 2014;28(1):119–30.CrossRefPubMed
64.
go back to reference Miyagawa K, Kondo T, Goto R, Matsuyama R, Ono K, Kitano S, Kawasaki S, Igata M, Kawashima J, Matsumura T, et al. Effects of combination therapy with vildagliptin and valsartan in a mouse model of type 2 diabetes. Cardiovasc Diabetol. 2013;12:160.CrossRefPubMedPubMedCentral Miyagawa K, Kondo T, Goto R, Matsuyama R, Ono K, Kitano S, Kawasaki S, Igata M, Kawashima J, Matsumura T, et al. Effects of combination therapy with vildagliptin and valsartan in a mouse model of type 2 diabetes. Cardiovasc Diabetol. 2013;12:160.CrossRefPubMedPubMedCentral
65.
go back to reference Shestakova MV, Suhareva O, Chernova TO, Shmushkovich IA, Aleksandrov AA, Il’in AV, Dedov II. 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. 2013;85(8):49–55.PubMed Shestakova MV, Suhareva O, Chernova TO, Shmushkovich IA, Aleksandrov AA, Il’in AV, Dedov II. 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. 2013;85(8):49–55.PubMed
66.
go back to reference Hibuse T, Maeda N, Kishida K, Kimura T, Minami T, Takeshita E, Hirata A, Nakagawa Y, Kashine S, Oka A, et al. 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. 2014;13:96.CrossRefPubMedPubMedCentral Hibuse T, Maeda N, Kishida K, Kimura T, Minami T, Takeshita E, Hirata A, Nakagawa Y, Kashine S, Oka A, et al. 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. 2014;13:96.CrossRefPubMedPubMedCentral
67.
go back to reference Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med. 2001;7(8):941–6.CrossRefPubMed Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med. 2001;7(8):941–6.CrossRefPubMed
68.
go back to reference Hattori Y, Suzuki K, Hattori S, Kasai K. Metformin inhibits cytokine-induced nuclear factor kappaB activation via AMP-activated protein kinase activation in vascular endothelial cells. Hypertension. 2006;47(6):1183–8.CrossRefPubMed Hattori Y, Suzuki K, Hattori S, Kasai K. Metformin inhibits cytokine-induced nuclear factor kappaB activation via AMP-activated protein kinase activation in vascular endothelial cells. Hypertension. 2006;47(6):1183–8.CrossRefPubMed
Metadata
Title
The effects of vildagliptin compared with metformin on vascular endothelial function and metabolic parameters: a randomized, controlled trial (Sapporo Athero-Incretin Study 3)
Authors
Naoyuki Kitao
Hideaki Miyoshi
Tomoo Furumoto
Kota Ono
Hiroshi Nomoto
Aika Miya
Chiho Yamamoto
Atsushi Inoue
Kenichi Tsuchida
Naoki Manda
Yoshio Kurihara
Shin Aoki
Akinobu Nakamura
Tatsuya Atsumi
SAIS Study Group
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Cardiovascular Diabetology / Issue 1/2017
Electronic ISSN: 1475-2840
DOI
https://doi.org/10.1186/s12933-017-0607-6

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