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Cardiovascular Diabetology
Published in: Cardiovascular Diabetology 1/2018

Open Access 01-12-2018 | Original investigation

Effect of sitagliptin on tissue characteristics of the carotid wall in patients with type 2 diabetes: a post hoc sub-analysis of the sitagliptin preventive study of intima-media thickness evaluation (SPIKE)

Authors: Naoto Katakami, Tomoya Mita, Yoko Irie, Mitsuyoshi Takahara, Taka-aki Matsuoka, Masahiko Gosho, Hirotaka Watada, Iichiro Shimomura, on behalf of the Sitagliptin Preventive study of Intima-media thickness Evaluation (SPIKE) Collaborators

Published in: Cardiovascular Diabetology | Issue 1/2018

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Abstract

Background

Ultrasonic gray-scale median (GSM) of the carotid wall reflects its composition and low-GSM carotid plaque is considered to be vulnerable. This study aimed to evaluate the effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on the longitudinal change in GSM, an index of the tissue characteristics of the carotid wall, in patients with type 2 diabetes mellitus (T2DM).

Methods

This is a post hoc sub-analysis using data obtained from the SPIKE trial, a randomized controlled trial that demonstrated the beneficial effect of sitagliptin on the progression of carotid intima-media thickness in patients with T2DM. A total of 274 T2DM patients with no past history of apparent cardiovascular disease (137 in the sitagliptin treatment group and 137 in the conventional treatment group) were enrolled. The primary outcome was the change from baseline in mean GSM-CCA during the 104-week treatment period.

Results

The mean GSM-CCA significantly increased in the sitagliptin treatment group (adjusted ΔGSM = 2.40 ± 1.19 [mean ± SE], p = 0.044) but not in the conventional treatment group (adjusted ΔGSM = 1.32 ± 1.19, p = 0.27). However, there was no significant difference in changes in mean GSM-CCA between the treatment groups.

Conclusions

A post hoc sub-analysis suggests that the tissue characteristics of the carotid arterial wall were improved in the sitagliptin treatment group during the 104-week treatment period, but not in the conventional treatment group. However, there was no between-group difference in the changes of GSM values between the two treatment groups. Prespecified studies with large sample sizes would be necessary to confirm our findings.
Trial registration UMIN000028664, Registered 15 August 2017 (“retrospectively registered”)
Literature
1.
Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med. 1992;326:242–50.CrossRefPubMed
2.
Lee RT, Grodzinsky AJ, Frank EH, Kamm RD, Schoen FJ. Structure-dependent dynamic mechanical behavior of fibrous caps from human atherosclerotic plaques. Circulation. 1991;83:1764–70.CrossRefPubMed
3.
Davies MJ, Richardson PD, Woolf N, Katz DR, Mann J. Risk of thrombosis in human atherosclerotic plaques: role of extracellular lipid, macrophage, and smooth muscle cell content. Br Heart J. 1993;69:377–81.CrossRefPubMedPubMedCentral
4.
5.
Creager MA, Lüscher TF, Cosentino F, Beckman JA. Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I. Circulation. 2003;108:1527–32.CrossRefPubMed
6.
Fadini GP, Avogaro A. Cardiovascular effects of DPP-4 inhibition: beyond GLP-1. Vascul Pharmacol. 2011;55:10–6.CrossRefPubMed
7.
Song X, Jia H, Jiang Y, Wang L, Zhang Y, Mu Y, Liu Y. Anti-atherosclerotic effects of the glucagon-like peptide-1 (GLP-1) based therapies in patients with type 2 Diabetes Mellitus: a meta-analysis. Sci Rep. 2015;26(5):10202.CrossRef
8.
Terasaki M, Nagashima M, Nohtomi K, Kohashi K, Tomoyasu M, Sinmura K, Nogi Y, Katayama Y, Sato K, Itoh F, Watanabe T, Hirano T. Preventive effect of dipeptidyl peptidase-4 inhibitor on atherosclerosis is mainly attributable to incretin’s actions in nondiabetic and diabetic apolipoprotein E-null mice. PLoS ONE. 2013;8:e70933.CrossRefPubMedPubMedCentral
9.
Terasaki Y, Nomiyama T, Kawanami T, Hamaguchi Y, Takahashi H, Tanaka T, Murase K, Nagaishi R, Tanabe M, Yanase T. Dipeptidyl peptidase-4 inhibitor linagliptin attenuates neointima formation after vascular injury. Cardiovasc Diabetol. 2014;13:154.CrossRef
10.
Nader MA. Sitagliptin ameliorates lipid profile changes and endothelium dysfunction induced by atherogenic diet in rabbits. Naunyn Schmiedebergs Arch Pharmacol. 2014;387:433–44.CrossRefPubMed
11.
Hirano T, Mori Y. Anti-atherogenic and anti-inflammatory properties of glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, and dipeptidyl peptidase-4 inhibitors in experimental animals. J Diabetes Investig. 2016;7:80–6.CrossRefPubMedPubMedCentral
12.
Matsubara J, Sugiyama S, Sugamura K, Nakamura T, Fujiwara Y, Akiyama E, Kurokawa H, Nozaki T, Ohba K, Konishi M, Maeda H, Izumiya Y, Kaikita K, Sumida H, Jinnouchi H, Matsui K, Kim-Mitsuyama S, Takeya M, Ogawa H. A dipeptidyl peptidase-4 inhibitor, des-fluoro-sitagliptin, improves endothelial function and reduces atherosclerotic lesion formation in apolipoprotein E-deficient mice. J Am Coll Cardiol. 2012;59:265–76.CrossRefPubMed
13.
Vittone F, Liberman A, Vasic D, Ostertag R, Esser M, Walcher D, Ludwig A, Marx N, Burgmaier M. Sitagliptin reduces plaque macrophage content and stabilises arteriosclerotic lesions in Apoe (-/-) mice. Diabetologia. 2012;55:2267–75.CrossRefPubMed
14.
Satoh-Asahara N, Sasaki Y, Wada H, Tochiya M, Iguchi A, Nakagawachi R, Odori S, Kono S, Hasegawa K, Shimatsu A. A dipeptidyl peptidase-4 inhibitor, sitagliptin, exerts anti-inflammatory effects in type 2 diabetic patients. Metabolism. 2013;62:347–51.CrossRefPubMed
15.
Tremblay AJ, Lamarche B, Deacon CF, Weisnagel SJ, Couture P. Effects of sitagliptin therapy on markers of low-grade inflammation and cell adhesion molecules in patients with type 2 diabetes. Metabolism. 2014;63:1141–8.CrossRefPubMed
16.
O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK Jr, Cardiovascular Health Study Collaborative Research Group. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. N Engl J Med. 1999;340:14–22.CrossRefPubMed
17.
Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M. Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation. 2007;115:459–67.CrossRefPubMed
18.
Li MF, Zhao CC, Li TT, Tu YF, Lu JX, Zhang R, Chen MY, Bao YQ, Li LX, Jia WP. The coexistence of carotid and lower extremity atherosclerosis further increases cardio-cerebrovascular risk in type 2 diabetes. Cardiovasc Diabetol. 2016;5(15):43.CrossRef
19.
Rassi CH, Churchill TW, Tavares CA, Fahel MG, Rassi FP, Uchida AH, Wajchenberg BL, Lerario AC, Hulten E, Nasir K, Bittencourt MS, Rochitte CE, Blankstein R. Use of imaging and clinical data to screen for cardiovascular disease in asymptomatic diabetics. Cardiovasc Diabetol. 2016;9(15):28.CrossRef
20.
Barbieri M, Rizzo MR, Marfella R, Boccardi V, Esposito A, Pansini A, Paolisso G. Decreased carotid atherosclerotic process by control of daily acute glucose fluctuations in diabetic patients treated by DPP-IV inhibitors. Atherosclerosis. 2013;227:349–54.CrossRefPubMed
21.
Mita T, Katakami N, Yoshii H, Onuma T, Kaneto H, Osonoi T, Shiraiwa T, Kosugi K, Umayahara Y, Yamamoto T, Yokoyama H, Kuribayashi N, Jinnouchi H, Gosho M, Shimomura I, Watada H, Collaborators on the Study of Preventive Effects of Alogliptin on Diabetic Atherosclerosis (SPEAD-A) Trial. 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;39:139–48.CrossRefPubMed
22.
Mita M, Katakami N, Shiraiwa T, Yoshii H, Onuma T, Kuribayashi N, Osonoi T, Kaneto H, Kosugi K, Umayahara U, Yamamoto T, Matsumoto K, Yokoyama H, Tsugawa M, Gosho M, Shimomura I, Watada H, Collaborators on Sitagliptin Preventive study of Intima media thickness Evaluation (SPIKE) Trial. Sitagliptin attenuates the progression of carotid intima-media thickening in insulin-treated patients with type 2 diabetes mellitus: the sitagliptin preventive study of intima-media thickness evaluation (SPIKE): a randomized controlled trial. Diabetes Care. 2016;39:455–64.CrossRefPubMed
23.
Grønholdt ML, Wiebe BM, Laursen H, Nielsen TG, Schroeder TV, Sillesen H. Lipid-rich carotid artery plaques appear echolucent on ultrasound B-mode images and may be associated with intraplaque haemorrhage. Eur J Vasc Endovasc Surg. 1997;14:439–45.CrossRefPubMed
24.
Nicolaides AN, Kakkos SK, Kyriacou E, Griffin M, Sabetai M, Thomas DJ, Tegos T, Geroulakos G, Labropoulos N, Doré CJ, Morris TP, Naylor R, Abbott AL, Asymptomatic Carotid Stenosis and Risk of Stroke (ACSRS) Study Group. Asymptomatic internal carotid artery stenosis and cerebrovascular risk stratification. J Vasc Surg. 2010;52:1486–96.CrossRefPubMed
25.
Irie Y, Katakami N, Kaneto H, Takahara M, Nishio M, Kasami R, Sakamoto K, Umayahara Y, Sumitsuji S, Ueda Y, Kosugi K, Shimomura I. The utility of ultrasonic tissue characterization of carotid plaque in the prediction of cardiovascular events in diabetic patients. Atherosclerosis. 2013;230:399–405.CrossRefPubMed
26.
Grønholdt ML, Nordestgaard BG, Schroeder TV, Vorstrup S, Sillesen H. Ultrasonic echolucent carotid plaques predict future strokes. Circulation. 2001;104:68–73.CrossRefPubMed
27.
Terminology and Diagnostic Criteria Committee. Japan society of ultrasonics in medicine. Subcommittee for preparing guidelines for ultrasound diagnosis of carotid artery. Standard method for ultrasound evaluation of carotid artery lesions. Jpn J Med Ultrason. 2009;36:501–18.
28.
Yanase T, Nasu S, Mukuta Y, Shimizu Y, Nishihara T, Okabe T, Nomura M, Inoguchi T, Nawata H. Evaluation of a new carotid intima-media thickness measurement by B-mode ultrasonography using an innovative measurement software, intimascope. Am J Hypertens. 2006;19:1206–12.CrossRefPubMed
29.
Sabetai MM, Tegos TJ, Nicolaides AN, Dhanjil S, Pare GJ, Stevens JM. Reproducibility of computer-quantified carotid plaque echogenicity: can we overcome the subjectivity? Stroke. 2000;31:2189–96.CrossRefPubMed
30.
Ishikawa S, Shimano M, Watarai M, Koyasu M, Uchikawa T, Ishii H, Inden Y, Takemoto K, Murohara T. Impact of sitagliptin on carotid intima-media thickness in patients with coronary artery disease and impaired glucose tolerance or mild diabetes mellitus. Am J Cardiol. 2014;114:384–8.CrossRefPubMed
31.
Rizzo M, Rizvi AA, Patti AM, Nikolic D, Giglio RV, Castellino G, Li Volti G, Caprio M, Montalto G, Provenzano V, Genovese S, Ceriello A. Liraglutide improves metabolic parameters and carotid intima-media thickness in diabetic patients with the metabolic syndrome: an 18-month prospective study. Cardiovasc Diabetol. 2016;15(1):162.CrossRefPubMedPubMedCentral
32.
Oyama J, Murohara T, Kitakaze M, Ishizu T, Sato Y, Kitagawa K, Kamiya H, Ajioka M, Ishihara M, Dai K, Nanasato M, Sata M, Maemura K, Tomiyama H, Higashi Y, Kaku K, Yamada H, Matsuhisa M, Yamashita K, Bando YK, Kashihara N, Ueda S, Inoue T, Tanaka A, Node K, PROLOGUE Study Investigators. The Effect of sitagliptin on carotid artery atherosclerosis in type 2 diabetes: the PROLOGUE randomized controlled trial. PLoS Med. 2016;13(6):e1002051.CrossRefPubMedPubMedCentral
33.
Balestrieri ML, Rizzo MR, Barbieri M, Paolisso P, D’Onofrio N, Giovane A, Siniscalchi M, Minicucci F, Sardu C, D’Andrea D, Mauro C, Ferraraccio F, Servillo L, Chirico F, Caiazzo P, Paolisso G, Marfella R. Sirtuin 6 expression and inflammatory activity in diabetic atherosclerotic plaques: effects of incretin treatment. Diabetes. 2015;64:1395–406.CrossRefPubMed
34.
Libby P, Aikawa M. Stabilization of atherosclerotic plaques: new mechanisms and clinical targets. Nat Med. 2002;8:1257–62.CrossRefPubMed
35.
Irie Y, Katakami N, Kaneto H, Takahara M, Sakamoto K, Kosugi K, Shimomura I. The risk factors associated with ultrasonic tissue characterization of carotid plaque in type 2 diabetic patients. J Diabetes Complications. 2014;28:523–7.CrossRefPubMed
36.
Sawada T, Shite J, Shinke T, Otake H, Tanino Y, Ogasawara D, Kawamori H, Kato H, Miyoshi N, Yoshino N, Kozuki A, Hirata K. Low plasma adiponectin levels are associated with presence of thin-cap fibroatheroma in men with stable coronary artery disease. Int J Cardiol. 2010;142:250–6.CrossRefPubMed
37.
Barbieri M, Marfella R, Esposito A, Rizzo MR, Angellotti E, Mauro C, Siniscalchi M, Chirico F, Caiazzo P, Furbatto F, Bellis A, D’Onofrio N, Vitiello M, Ferraraccio F, Paolisso G, Balestrieri ML. Incretin treatment and atherosclerotic plaque stability: role of adiponectin/APPL1 signaling pathway. J Diabetes Complications. 2017;31:295–303.CrossRefPubMed
38.
Zheng TP, Yang F, Gao Y, Baskota A, Chen T, Tian HM, Ran XW. Increased plasma DPP4 activities predict new-onset atherosclerosis in association with its proinflammatory effects in Chinese over a 4 year period: a prospective study. Atherosclerosis. 2014;235:619–24.CrossRefPubMed
39.
Ikushima H, Munakata Y, Iwata S, Ohnuma K, Kobayashi S, Dang NH, Morimoto C. Soluble CD26/dipeptidyl peptidase IV enhances transendothelial migration via its interaction with mannose 6-phosphate/insulin-like growth factor II receptor. Cell Immunol. 2002;215:106–10.CrossRefPubMed
40.
Zhong J, Rao X, Rajagopalan S. An emerging role of dipeptidyl peptidase 4 (DPP4) beyond glucose control: potential implications in cardiovascular disease. Atherosclerosis. 2013;226:305–14.CrossRefPubMed
Metadata
Title
Effect of sitagliptin on tissue characteristics of the carotid wall in patients with type 2 diabetes: a post hoc sub-analysis of the sitagliptin preventive study of intima-media thickness evaluation (SPIKE)
Authors
Naoto Katakami
Tomoya Mita
Yoko Irie
Mitsuyoshi Takahara
Taka-aki Matsuoka
Masahiko Gosho
Hirotaka Watada
Iichiro Shimomura
on behalf of the Sitagliptin Preventive study of Intima-media thickness Evaluation (SPIKE) Collaborators
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Cardiovascular Diabetology / Issue 1/2018
Electronic ISSN: 1475-2840
DOI
https://doi.org/10.1186/s12933-018-0666-3

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