- Email: [email protected]
Impact of Sitagliptin on Carotid Intima-Media Thickness in Patients With Coronary Artery Disease and Impaired Glucose Tolerance or Mild Diabetes Mellitus
Impact of Sitagliptin on Carotid Intima-Media Thickness in Patients With Coronary Artery Disease and Impaired Glucose Tolerance or Mild Diabetes Mellitus Shinji Ishikawa, MDa,b, Masayuki Shimano, MD, PhDa,c,*, Masato Watarai, MD, PhDb, Masayoshi Koyasu, MD, PhDb, Tomohiro Uchikawa, MDb, Hideki Ishii, MD, PhDa, Yasuya Inden, MD, PhDa, Kenji Takemoto, MD, PhDb, and Toyoaki Murohara, MD, PhDa Sitagliptin has been widely used for the treatment of diabetes and shown recently to have beneficial pleiotropic outcomes on cardiovascular systems in experimental studies. However, little is known about the influence of sitagliptin on atherosclerosis-related cardiovascular diseases in a clinical setting. This study examined the effect of sitagliptin on carotid intima-media thickness (IMT). A total of 76 patients with clinically stable and documented coronary artery disease, who were newly diagnosed with impaired glucose tolerance or mild type 2 diabetes mellitus, were allocated, randomly, to receive either sitagliptin 100 mg/day or the placebo control. Common carotid IMT, glucose profiles, glycosylated hemoglobin (HbA1c), and lipid profiles were measured at baseline and repeated at 12 months. Sitagliptin-treated patients showed less IMT progression than the control group (p [ 0.02). In addition, the sitagliptin group showed greater reductions in body weight (2.2%), 2-hour glucose levels on the 75-g oral glucose tolerance test (17.3%), HbA1c (4.7%), and low-density lipoprotein cholesterol levels (7.9%) from that at baseline. In conclusion, treatment with sitagliptin for 12 months was associated with a beneficial effect in the prevention of carotid IMT progression, compared with the diet control. Ó 2014 Elsevier Inc. All rights reserved. (Am J Cardiol 2014;-:-e-) Sitagliptin, which has been used widely to treat type 2 diabetes mellitus (T2DM), binds to dipeptidyl peptidase 4 (DPP-4), preventing the breakdown of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide.1 Incretin hormones, including glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide depend on blood glucose levels to stimulate insulin secretion2; thus, DPP-4 inhibitors are superior to conventional hypoglycemic drugs, as there is a decreased incidence of hypoglycemia. Moreover, it has been demonstrated recently that sitagliptin has effects, in addition to those on glycemia, on the cardiovascular systems.3,4 However, little is known about its effect on atherosclerosis-related cardiovascular diseases.5,6 Carotid intima-media thickness (IMT) is a marker for atherosclerosis.7,8 Absolute IMT values and an increase in IMT have been reported to be highly associated with the risk of future cardiovascular events.9 However, no a Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan; bDepartment of Cardiology, Cardiovascular Center, Anjyo Kosei Hospital, Anjyo, Japan; and cDepartment of Cardiology, Japanese Red Cross Nagoya Daiichi Hospital, Nagoya, Japan. Manuscript received March 4, 2014; revised manuscript received and accepted April 29, 2014. This work was supported by grant YRY1311 from Yokoyama Foundation for Clinical Pharmacology, Nagoya, Japan to Dr. Shimano. This trial is registered at http://center.umin.ac.jp; unique identifier: UMIN (University Hospital Medical Information Network) 000006432. See page 4 for disclosure information. *Corresponding author: Tel: (þ81) 52-744-2147; fax: (þ81) 52-7442138. E-mail address: [email protected] (M. Shimano).
0002-9149/14/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2014.04.050
studies have examined the effects of sitagliptin on the progression of IMT in patients with coronary artery disease and impaired glucose tolerance (IGT) or mild T2DM. Thus, we examined the effect of sitagliptin on common carotid IMT progression in patients with established coronary artery disease, who had been newly diagnosed with IGT or mild T2DM. Methods This study was a prospective, randomized, open-label, single-center, parallel-group, comparative trial. The trial is known as the “early treatment of glucose toxicity with Sitagliptin Prevent progression of ARteriosclerosis in Cardiovascular disease patients” study, was registered at https:// center.umin.ac.jp as UMIN 000006432, and was approved by the hospital ethics committee. Participants were recruited from patients admitted to the Department of Cardiology at Anjyo Kosei Hospital (Anjyo, Japan) for elective coronary angiography from January 2009 to December 2010. For inclusion, it was essential that patients had stable angina pectoris (50% stenosis by quantitative coronary angiography), were newly diagnosed with IGT or mild T2DM, and received statins to decrease low-density lipoprotein cholesterol (LDL-C) to <100 mg/dl. IGT was defined as a fasting plasma glucose level of <126 mg/dl and a 2-hour plasma glucose level of 140 to 199 mg/dl on the 75-g oral glucose tolerance test (OGTT). Mild T2DM was defined as a fasting plasma glucose level of <126 mg/dl, a 2-hour plasma glucose level of >200 mg/dl on OGTT, and glycosylated hemoglobin (HbA1c) of <6.5%. Patients were excluded www.ajconline.org
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Table 1 Baseline clinical characteristics Variables Age (years) Male Weight (kg) Body mass index (kg/m2) Systolic blood pressure (mm Hg) Angiotensin converting enzyme inhibitors/sartans The duration of statin use (months) Fasting blood sugar (mg/dL) Immunoreactive insulin 75-g oral glucose tolerance test (120 minutes) Homeostasis model assessment ratio Homeostatic model assessment of beta cell function Glycosylated hemoglobin (%) Lipid profile Total cholesterol (mg/dL) Triglycerides (mg/dL) High-density lipoprotein cholesterol (mg/dL) Low-density lipoprotein cholesterol (mg/dL) Intima-media thickness (mm)
Sitagliptin (N ¼ 37)
Control (N ¼ 39)
73.7 32 65.8 25.3 130.2 30
(7.3) (86.4%) (12.5) (3.9) (7.0) (81.1%)
69.0 33 61.5 23.8 128.9 31
(8.0) (84.0%) (11.6) (3.8) (9.8) (79.5%)
53.9 106.4 11.2 181.7
(27.1) (8.8) (8.6) (38.0)
52.8 108.2 10.2 177.4
(33.8) (11.5) (12.1) (39.7)
2.99 (4.9) 89.5 (134.2)
2.73 (2.9) 86.4 (125.3)
5.77 (0.31)
5.49 (0.29)
161.6 (27.3) 110.3 (46.9) 51.9 (13.3)
165.7 (31.1) 107.3 (60.4) 53.3 (15.2)
94.6 (17.0)
93.0 (19.1)
1.11 (0.42)
1.07 (0.42)
Values are the mean (standard deviations) or frequency (%).
from the study if they were aged >70 years, had previously been treated with antidiabetic drugs, had previously been diagnosed with diabetes mellitus, and had an HbA1c of >6.5%. In addition, patients were excluded if they were previously diagnosed with cerebrovascular disease, liver dysfunction, renal dysfunction, severe anemia, or systemic inflammatory diseases. All patients provided written informed consent. If coronary stenosis was confirmed by angiography, informed consent was obtained the following day and patients randomly allocated to either the sitagliptin 100 mg/day group or the diet control (no treatment) group. Randomization was performed by a stratification method. A total of 80 Japanese patients (aged 48 to 83 years) were enrolled in the study. At baseline, fasting blood samples were obtained from all patients between 7:00 and 8:00 A.M. on the day of the 75-g OGTT. After resting for 10 minutes in a supine position, 20 ml of blood was collected from the antecubital vein for the determination of plasma glucose, HbA1c, serum insulin, and serum lipids (total cholesterol, LDL-C, high-density lipoprotein cholesterol, and triglycerides). In addition, homeostasis model assessment was performed. On the day of the 12-month follow-up, carotid IMT ultrasonography was performed, the 75-g OGTT was repeated, and fasting blood samples were obtained for repeat laboratory testing. Plasma glucose levels, HbA1c, and serum lipids were analyzed by the hospital laboratory immediately after blood sampling. The homeostasis model assessment index was calculated as follows: (fasting immunoreactive insulin level [mU/ml] fasting glucose level [mg/dl])/405.10 Serum insulin levels were measured using a radioimmunoassay (Insulin-RIA bead II;
Abbott, Tokyo, Japan) at a commercial clinical testing laboratory, SRL Inc. (Tokyo, Japan). Carotid IMT was measured by ultrasonography at baseline and at the 12-month followup.11,12 In brief, the IMT was defined as the distance from the edge of the lumen-intima interface to the edge of the collagen containing upper layer of the adventitia and was measured using high-resolution ultrasonography (LOGIQ 7; GE Healthcare, Bedford, United Kingdom). Baseline measurement of IMT was performed immediately after the OGTT. At the 12-month follow-up, ultrasonography was performed and evaluated by the same operators as at baseline. All patients underwent regular follow-up (generally every 2 months) at outpatient clinics for assessment of adverse events, drug adherence, and changes in medications. Adverse events were recorded on the basis of spontaneous reports and questioning by the investigator. The primary end point was the relative change from baseline to 12 months in the largest measured IMT value in the right or left common carotid arteries. Secondary end points included the change from baseline to 12 months in glucose profiles (OGTT), HbA1c, and lipid profiles. All data are expressed as mean (SD) or frequency (%). Differences between the 2 groups at baseline were evaluated by the t test for continuous variables and the chi-square test for categorical variables. The change from baseline to 12-month follow-up in the 2 groups was evaluated using the paired t test for continuous variables. A p value of <0.05 was considered to be statistically significant. All analyses were performed using SPSS (version 22.0; SAS Institute Inc., Cary, North Carolina).
Results A total of 80 patients were enrolled in the study, with 40 patients in each group. One patient in the sitagliptin group discontinued antidiabetic therapy owing to drug-related nausea, and 1 patient in each group was withdrawn because of newly identified cardiovascular events. An additional 2 patients in the sitagliptin group were lost to follow-up. Thus, complete baseline and follow-up data were available for 37 patients in the sitagliptin group and 39 in the control group. The baseline characteristics of the study subjects are listed in Table 1, which were comparable between the groups. In the sitagliptin group, IMT decreased from a mean of 1.11 (0.43) mm at baseline to 1.09 (0.42) mm at 12-month follow-up (p ¼ NS), whereas in the control group, IMT increased from a mean of 1.02 (0.44) mm to 1.07 (0.41) mm (p <0.05; Table 2). The representative pictures in both groups are shown in Figure 1. The difference in the change in IMT from baseline to 12-month follow-up between groups was statistically significant (p ¼ 0.02, Figure 2). In addition, the sitagliptin group had greater reductions in body weight (2.2%, p ¼ 0.03), 2-hour glucose levels on the 75-g OGTT (17.3%, p <0.001), HbA1c (4.7%, p <0.001), and LDL-C levels (7.9%, p ¼ 0.04) than the control group did (0.3%, 0.3%, 1.3%, and 0.5% decrease, respectively). However, there were no differences between the 2 groups in the occurrence of cardiovascular events; in both groups, only a single patient had a cardiovascular event.
Coronary Artery Disease/Sitagliptin Attenuates Progression of IMT
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Table 2 Comparison of clinical and biochemical parameters at baseline and 12 months Variables
Sitagliptin Group Baseline
Systolic blood pressure (mm Hg) Weight (kg) Body mass index (kg/m2) Fasting blood sugar (mg/dL) 75-g oral glucose tolerance test (120) Immunoreactive insulin (mU/ml) Homeostasis model assessment ratio Homeostatic model assessment of beta cell function Glycosylated hemoglobin (%) Total cholesterol Triglycerides High-density lipoprotein cholesterol Low-density lipoprotein cholesterol Intima-media thickness (mm)
130.2 65.8 25.4 106.4 181.7 11.2 2.99 89.5 5.77 161.4 110.3 51.9 94.6 1.11
(7.2) (12.5) (3.9) (8.8) (38.0) (8.6) (4.9) (134.2) (0.31) (30.2) (46.9) (13.3) (17.0) (0.43)
12 Months 128.5 64.3 23.2 104.2 156.3 8.63 2.73 69.7 5.49 155.8 108.9 51.5 85.9 1.09
(9.8) (12.4) (7.5) (21.0) (44.5) (5.5) (2.01) (34.6) (0.31) (28.8) (51.3) (10.4) (20.89) (0.42)
Control Group p 0.32 0.02 0.05 0.52 <0.01 0.39 0.49 0.38 <0.01 0.12 0.84 0.82 <0.01 0.43
Baseline 128.9 61.6 23.8 108.2 177 10.2 2.73 86.4 5.76 168.0 110.3 53.6 94.4 1.02
(9.8) (11.6) (3.1) (11.5) (39.3) (12.1) (2.9) (125.3) (0.40) (33.8) (62.5) (15.1) (20.8) (0.44)
12 Months 133.3 61.4 24.3 107.4 182 7.7 2.08 62.8 5.68 164.2 107.3 55.9 93.9 1.07
(10.1) (11.3) (3.1) (11.8) (45.9) (6.0) (1.8) (54.7) (0.42) (34.3) (52.3) (13.7) (23.4) (0.41)
p 0.08 0.69 0.14 0.80 0.48 0.05 0.03 0.10 0.02 0.55 0.62 0.02 0.88 0.04
Values are the mean (standard deviations).
Figure 1. Representative ultrasonography of IMT. Example showing assessment of (A) sitagliptin group and (B) diet control group (before treatment: left panel, after treatment: right panel). The numbers and symbols mean measurement of IMT of CCA. R-CCA ¼ right common carotid artery; L-CCA ¼ left common carotid artery.
Discussion This small, prospective, open-label, randomized study demonstrated, for the first time, that 12 months of treatment with sitagliptin was associated with a beneficial effect in terms of preventing the progression of carotid IMT. However, the use of sitagliptin was not associated with a significant decrease in IMT from baseline. The treatment options for T2DM have expanded since the development of several DPP-4 inhibitors. There is a
growing body of evidence that these agents may have protective effects on cardiovascular systems in the presence and absence of hyperglycemia.13e15 However, clinical evidence is limited regarding the beneficial effects of DPP-4 inhibitors on atherosclerosis. The measurement of IMT has been used to monitor the effectiveness of oral antidiabetic agents in the prevention of atherosclerosis.16,17 Therefore, we measured IMT progression to show that sitagliptin attenuated progression. Experimental studies using LDL
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LDL reduction, HbA1c decrease, or body weight loss in this small study. We showed the reduction in 2-hour glucose levels on the 75-g OGTT, HbA1c, and body weight, which was already known about DPP-4 inhibitors before, while new findings are the slowing IMT progression and the decrease in LDL-C in patients who already received statins. This study had several limitations. First, the small sample size and short duration of follow-up have low statistical power to monitor data on major adverse events including cardiovascular events. Second, there is a possibility that there was selection bias because the study was performed at a single center and had an open-label design. Third, although all subjects were receiving statin therapy, the reduction in LDL-C levels by sitagliptin may have effects on IMT progression. Therefore, there is a need for further studies, with larger sample sizes and longer durations, to detect differences in the occurrence of major adverse events. Acknowledgment: The authors gratefully acknowledge the technical assistance of Akihiro Suzuki, BSc. Disclosures
Figure 2. Change in mean IMT from baseline to 12-month follow-up between the sitagliptin and control groups.
receptor13 or apolipoprotein E knockout mice18 have recently demonstrated that DPP-4 inhibitors reduced atherosclerotic plaque area. A possible mechanism of the pleiotropic effects of DPP-4 inhibitors involves the suppression of inflammatory cytokines and oxidative stress, resulting in the suppression of atherogenesis.15,19 Thus, in our patients, sitagliptin may have had a beneficial effect on the progression of carotid IMT through similar mechanisms. Recently, it has been shown that prevention of postprandial hyperglycemia has several beneficial effects on vessel walls, including the reduction of oxidative stress, increased flow-mediated vasodilatation, and increased endothelial nitric oxide release.20,21 We and other groups have also reported that metformin, pioglitazone, and a-glucosidase inhibitors significantly attenuate the progression of carotid IMT compared with placebo or glimepiride.11,17,22,23 Thus, the showed IMT regression may result from a decrease in HbA1c. In addition, sitagliptin has a greater effect on weight loss and LDL-C controlled by statin therapy, which might influence IMT progression.24 Consequently, sitagliptin could potentially slow the progression of atherosclerosis for patients with coronary artery disease with IGT through these effects rather than pleiotropic effects, although IMT variation was not significantly correlated with
Dr. Ishii has received lecture fees from Astellas (Tokyo, Japan) and Otsuka (Tokyo, Japan). Dr. Murohara has received lecture fees from Bayer, Daiichi Sankyo, Dainippon Sumitomo, Kowa, MSD, Mitsubishi Tanabe, Nippon Boehringer Ingelheim, Novartis, Pfizer Japan, Sanofi-Aventis, and Takeda. Dr. Murohara has received unrestricted research grant for Department of Cardiology, Nagoya University Graduate School of Medicine, from Astellas (Tokyo, Japan), Daiichi Sankyo (Tokyo, Japan), Dainippon Sumitomo (Tokyo, Japan), Kowa (Nagoya, Japan), MSD (Tokyo, Japan), Mitsubishi Tanabe (Osaka, Japan), Nippon Boehringer Ingelheim (Tokyo, Japan), Novartis (Tokyo, Japan), Otsuka (Tokyo, Japan), Pfizer Japan (Tokyo, Japan), SanofiAventis (Tokyo, Japan), Takeda (Tokyo, Japan), and Teijin (Tokyo, Japan). 1. Gallwitz B. Review of sitagliptin phosphate: a novel treatment for type 2 diabetes. Vasc Health Risk Manag 2007;3:203e210. 2. Schmidt WE, Siegel EG, Creutzfeldt W. Glucagon-like peptide-1 but not glucagon-like peptide-2 stimulates insulin release from isolated rat pancreatic islets. Diabetologia 1985;28:704e707. 3. 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, KimMitsuyama 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;59:265e276. 4. Liu L, Liu J, Wong WT, Tian XY, Lau CW, Wang YX, Xu G, Pu Y, Zhu Z, Xu A, Lam KS, Chen ZY, Ng CF, Yao X, Huang Y. Dipeptidyl peptidase 4 inhibitor sitagliptin protects endothelial function in hypertension through a glucagon-like peptide 1-dependent mechanism. Hypertension 2012;60:833e841. 5. 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;62:347e351. 6. 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. Dipeptidyl peptidase-4 inhibitor, sitagliptin,
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improves endothelial dysfunction in association with its antiinflammatory effects in patients with coronary artery disease and uncontrolled diabetes. Circ J 2013;77:1337e1344. Bots ML, Mulder PG, Hofman A, van Es GA, Grobbee DE. Reproducibility of carotid vessel wall thickness measurements. The Rotterdam Study. J Clin Epidemiol 1994;47:921e930. Smilde TJ, Wollersheim H, Van Langen H, Stalenhoef AF. Reproducibility of ultrasonographic measurements of different carotid and femoral artery segments in healthy subjects and in patients with increased intima-media thickness. Clin Sci (Lond) 1997;93: 317e324. O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK Jr. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med 1999;340:14e22. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and betacell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412e419. Koyasu M, Ishii H, Watarai M, Takemoto K, Inden Y, Takeshita K, Amano T, Yoshikawa D, Matsubara T, Murohara T. Impact of acarbose on carotid intima-media thickness in patients with newly diagnosed impaired glucose tolerance or mild type 2 diabetes mellitus: a one-year, prospective, randomized, open-label, parallel-group study in Japanese adults with established coronary artery disease. Clin Ther 2010;32:1610e1617. Uemura Y, Watarai M, Ishii H, Koyasu M, Takemoto K, Yoshikawa D, Shibata R, Matsubara T, Murohara T. Atorvastatin 10 mg plus ezetimibe 10mg compared with atorvastatin 20 mg: impact on the lipid profile in Japanese patients with abnormal glucose tolerance and coronary artery disease. J Cardiol 2012;59:50e56. Shah Z, Kampfrath T, Deiuliis JA, Zhong J, Pineda C, Ying Z, Xu X, Lu B, Moffatt-Bruce S, Durairaj R, Sun Q, Mihai G, Maiseyeu A, Rajagopalan S. Long-term dipeptidyl-peptidase 4 inhibition reduces atherosclerosis and inflammation via effects on monocyte recruitment and chemotaxis. Circulation 2011;124:2338e2349. Shigeta T, Aoyama M, Bando YK, Monji A, Mitsui T, Takatsu M, Cheng XW, Okumura T, Hirashiki A, Nagata K, Murohara T. Dipeptidyl peptidase-4 modulates left ventricular dysfunction in
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chronic heart failure via angiogenesis-dependent and -independent actions. Circulation 2012;126:1838e1851. Jialal I, Bajaj M. DPP-4 inhibitors and atherosclerosis: the promise. Atherosclerosis 2013;227:224e225. Hanefeld M, Chiasson JL, Koehler C, Henkel E, Schaper F, TemelkovaKurktschiev T. Acarbose slows progression of intima-media thickness of the carotid arteries in subjects with impaired glucose tolerance. Stroke 2004;35:1073e1078. Mazzone T, Meyer PM, Feinstein SB, Davidson MH, Kondos GT, D’Agostino RB Sr, Perez A, Provost JC, Haffner SM. Effect of pioglitazone compared with glimepiride on carotid intima-media thickness in type 2 diabetes: a randomized trial. JAMA 2006;296:2572e2581. Ervinna N, Mita T, Yasunari E, Azuma K, Tanaka R, Fujimura S, Sukmawati D, Nomiyama T, Kanazawa A, Kawamori R, Fujitani Y, Watada H. Anagliptin, a DPP-4 inhibitor, suppresses proliferation of vascular smooth muscles and monocyte inflammatory reaction and attenuates atherosclerosis in male apo E-deficient mice. Endocrinology 2013;154:1260e1270. Murohara T. Dipeptidyl peptidase-4 inhibitor: another player for cardiovascular protection. J Am Coll Cardiol 2012;59:277e279. Ceriello A, Taboga C, Tonutti L, Giacomello R, Stel L, Motz E, Pirisi M. Post-meal coagulation activation in diabetes mellitus: the effect of acarbose. Diabetologia 1996;39:469e473. Kawano H, Motoyama T, Hirashima O, Hirai N, Miyao Y, Sakamoto T, Kugiyama K, Ogawa H, Yasue H. Hyperglycemia rapidly suppresses flow-mediated endothelium-dependent vasodilation of brachial artery. J Am Coll Cardiol 1999;34:146e154. Matsumoto K, Sera Y, Abe Y, Tominaga T, Yeki Y, Miyake S. Metformin attenuates progression of carotid arterial wall thickness in patients with type 2 diabetes. Diabetes Res Clin Pract 2004;64:225e228. Yamasaki Y, Katakami N, Hayaishi-Okano R, Matsuhisa M, Kajimoto Y, Kosugi K, Hatano M, Hori M. Alpha-glucosidase inhibitor reduces the progression of carotid intima-media thickness. Diabetes Res Clin Pract 2005;67:204e210. Fleg JL, Mete M, Howard BV, Umans JG, Roman MJ, Ratner RE, Silverman A, Galloway JM, Henderson JA, Weir MR, Wilson C, Stylianou M, Howard WJ. Effect of statins alone versus statins plus ezetimibe on carotid atherosclerosis in type 2 diabetes: the SANDS (Stop Atherosclerosis in Native Diabetics Study) trial. J Am Coll Cardiol 2008;52:2198e2205.
0002-9149/14/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2014.04.050
studies have examined the effects of sitagliptin on the progression of IMT in patients with coronary artery disease and impaired glucose tolerance (IGT) or mild T2DM. Thus, we examined the effect of sitagliptin on common carotid IMT progression in patients with established coronary artery disease, who had been newly diagnosed with IGT or mild T2DM. Methods This study was a prospective, randomized, open-label, single-center, parallel-group, comparative trial. The trial is known as the “early treatment of glucose toxicity with Sitagliptin Prevent progression of ARteriosclerosis in Cardiovascular disease patients” study, was registered at https:// center.umin.ac.jp as UMIN 000006432, and was approved by the hospital ethics committee. Participants were recruited from patients admitted to the Department of Cardiology at Anjyo Kosei Hospital (Anjyo, Japan) for elective coronary angiography from January 2009 to December 2010. For inclusion, it was essential that patients had stable angina pectoris (50% stenosis by quantitative coronary angiography), were newly diagnosed with IGT or mild T2DM, and received statins to decrease low-density lipoprotein cholesterol (LDL-C) to <100 mg/dl. IGT was defined as a fasting plasma glucose level of <126 mg/dl and a 2-hour plasma glucose level of 140 to 199 mg/dl on the 75-g oral glucose tolerance test (OGTT). Mild T2DM was defined as a fasting plasma glucose level of <126 mg/dl, a 2-hour plasma glucose level of >200 mg/dl on OGTT, and glycosylated hemoglobin (HbA1c) of <6.5%. Patients were excluded www.ajconline.org
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Table 1 Baseline clinical characteristics Variables Age (years) Male Weight (kg) Body mass index (kg/m2) Systolic blood pressure (mm Hg) Angiotensin converting enzyme inhibitors/sartans The duration of statin use (months) Fasting blood sugar (mg/dL) Immunoreactive insulin 75-g oral glucose tolerance test (120 minutes) Homeostasis model assessment ratio Homeostatic model assessment of beta cell function Glycosylated hemoglobin (%) Lipid profile Total cholesterol (mg/dL) Triglycerides (mg/dL) High-density lipoprotein cholesterol (mg/dL) Low-density lipoprotein cholesterol (mg/dL) Intima-media thickness (mm)
Sitagliptin (N ¼ 37)
Control (N ¼ 39)
73.7 32 65.8 25.3 130.2 30
(7.3) (86.4%) (12.5) (3.9) (7.0) (81.1%)
69.0 33 61.5 23.8 128.9 31
(8.0) (84.0%) (11.6) (3.8) (9.8) (79.5%)
53.9 106.4 11.2 181.7
(27.1) (8.8) (8.6) (38.0)
52.8 108.2 10.2 177.4
(33.8) (11.5) (12.1) (39.7)
2.99 (4.9) 89.5 (134.2)
2.73 (2.9) 86.4 (125.3)
5.77 (0.31)
5.49 (0.29)
161.6 (27.3) 110.3 (46.9) 51.9 (13.3)
165.7 (31.1) 107.3 (60.4) 53.3 (15.2)
94.6 (17.0)
93.0 (19.1)
1.11 (0.42)
1.07 (0.42)
Values are the mean (standard deviations) or frequency (%).
from the study if they were aged >70 years, had previously been treated with antidiabetic drugs, had previously been diagnosed with diabetes mellitus, and had an HbA1c of >6.5%. In addition, patients were excluded if they were previously diagnosed with cerebrovascular disease, liver dysfunction, renal dysfunction, severe anemia, or systemic inflammatory diseases. All patients provided written informed consent. If coronary stenosis was confirmed by angiography, informed consent was obtained the following day and patients randomly allocated to either the sitagliptin 100 mg/day group or the diet control (no treatment) group. Randomization was performed by a stratification method. A total of 80 Japanese patients (aged 48 to 83 years) were enrolled in the study. At baseline, fasting blood samples were obtained from all patients between 7:00 and 8:00 A.M. on the day of the 75-g OGTT. After resting for 10 minutes in a supine position, 20 ml of blood was collected from the antecubital vein for the determination of plasma glucose, HbA1c, serum insulin, and serum lipids (total cholesterol, LDL-C, high-density lipoprotein cholesterol, and triglycerides). In addition, homeostasis model assessment was performed. On the day of the 12-month follow-up, carotid IMT ultrasonography was performed, the 75-g OGTT was repeated, and fasting blood samples were obtained for repeat laboratory testing. Plasma glucose levels, HbA1c, and serum lipids were analyzed by the hospital laboratory immediately after blood sampling. The homeostasis model assessment index was calculated as follows: (fasting immunoreactive insulin level [mU/ml] fasting glucose level [mg/dl])/405.10 Serum insulin levels were measured using a radioimmunoassay (Insulin-RIA bead II;
Abbott, Tokyo, Japan) at a commercial clinical testing laboratory, SRL Inc. (Tokyo, Japan). Carotid IMT was measured by ultrasonography at baseline and at the 12-month followup.11,12 In brief, the IMT was defined as the distance from the edge of the lumen-intima interface to the edge of the collagen containing upper layer of the adventitia and was measured using high-resolution ultrasonography (LOGIQ 7; GE Healthcare, Bedford, United Kingdom). Baseline measurement of IMT was performed immediately after the OGTT. At the 12-month follow-up, ultrasonography was performed and evaluated by the same operators as at baseline. All patients underwent regular follow-up (generally every 2 months) at outpatient clinics for assessment of adverse events, drug adherence, and changes in medications. Adverse events were recorded on the basis of spontaneous reports and questioning by the investigator. The primary end point was the relative change from baseline to 12 months in the largest measured IMT value in the right or left common carotid arteries. Secondary end points included the change from baseline to 12 months in glucose profiles (OGTT), HbA1c, and lipid profiles. All data are expressed as mean (SD) or frequency (%). Differences between the 2 groups at baseline were evaluated by the t test for continuous variables and the chi-square test for categorical variables. The change from baseline to 12-month follow-up in the 2 groups was evaluated using the paired t test for continuous variables. A p value of <0.05 was considered to be statistically significant. All analyses were performed using SPSS (version 22.0; SAS Institute Inc., Cary, North Carolina).
Results A total of 80 patients were enrolled in the study, with 40 patients in each group. One patient in the sitagliptin group discontinued antidiabetic therapy owing to drug-related nausea, and 1 patient in each group was withdrawn because of newly identified cardiovascular events. An additional 2 patients in the sitagliptin group were lost to follow-up. Thus, complete baseline and follow-up data were available for 37 patients in the sitagliptin group and 39 in the control group. The baseline characteristics of the study subjects are listed in Table 1, which were comparable between the groups. In the sitagliptin group, IMT decreased from a mean of 1.11 (0.43) mm at baseline to 1.09 (0.42) mm at 12-month follow-up (p ¼ NS), whereas in the control group, IMT increased from a mean of 1.02 (0.44) mm to 1.07 (0.41) mm (p <0.05; Table 2). The representative pictures in both groups are shown in Figure 1. The difference in the change in IMT from baseline to 12-month follow-up between groups was statistically significant (p ¼ 0.02, Figure 2). In addition, the sitagliptin group had greater reductions in body weight (2.2%, p ¼ 0.03), 2-hour glucose levels on the 75-g OGTT (17.3%, p <0.001), HbA1c (4.7%, p <0.001), and LDL-C levels (7.9%, p ¼ 0.04) than the control group did (0.3%, 0.3%, 1.3%, and 0.5% decrease, respectively). However, there were no differences between the 2 groups in the occurrence of cardiovascular events; in both groups, only a single patient had a cardiovascular event.
Coronary Artery Disease/Sitagliptin Attenuates Progression of IMT
3
Table 2 Comparison of clinical and biochemical parameters at baseline and 12 months Variables
Sitagliptin Group Baseline
Systolic blood pressure (mm Hg) Weight (kg) Body mass index (kg/m2) Fasting blood sugar (mg/dL) 75-g oral glucose tolerance test (120) Immunoreactive insulin (mU/ml) Homeostasis model assessment ratio Homeostatic model assessment of beta cell function Glycosylated hemoglobin (%) Total cholesterol Triglycerides High-density lipoprotein cholesterol Low-density lipoprotein cholesterol Intima-media thickness (mm)
130.2 65.8 25.4 106.4 181.7 11.2 2.99 89.5 5.77 161.4 110.3 51.9 94.6 1.11
(7.2) (12.5) (3.9) (8.8) (38.0) (8.6) (4.9) (134.2) (0.31) (30.2) (46.9) (13.3) (17.0) (0.43)
12 Months 128.5 64.3 23.2 104.2 156.3 8.63 2.73 69.7 5.49 155.8 108.9 51.5 85.9 1.09
(9.8) (12.4) (7.5) (21.0) (44.5) (5.5) (2.01) (34.6) (0.31) (28.8) (51.3) (10.4) (20.89) (0.42)
Control Group p 0.32 0.02 0.05 0.52 <0.01 0.39 0.49 0.38 <0.01 0.12 0.84 0.82 <0.01 0.43
Baseline 128.9 61.6 23.8 108.2 177 10.2 2.73 86.4 5.76 168.0 110.3 53.6 94.4 1.02
(9.8) (11.6) (3.1) (11.5) (39.3) (12.1) (2.9) (125.3) (0.40) (33.8) (62.5) (15.1) (20.8) (0.44)
12 Months 133.3 61.4 24.3 107.4 182 7.7 2.08 62.8 5.68 164.2 107.3 55.9 93.9 1.07
(10.1) (11.3) (3.1) (11.8) (45.9) (6.0) (1.8) (54.7) (0.42) (34.3) (52.3) (13.7) (23.4) (0.41)
p 0.08 0.69 0.14 0.80 0.48 0.05 0.03 0.10 0.02 0.55 0.62 0.02 0.88 0.04
Values are the mean (standard deviations).
Figure 1. Representative ultrasonography of IMT. Example showing assessment of (A) sitagliptin group and (B) diet control group (before treatment: left panel, after treatment: right panel). The numbers and symbols mean measurement of IMT of CCA. R-CCA ¼ right common carotid artery; L-CCA ¼ left common carotid artery.
Discussion This small, prospective, open-label, randomized study demonstrated, for the first time, that 12 months of treatment with sitagliptin was associated with a beneficial effect in terms of preventing the progression of carotid IMT. However, the use of sitagliptin was not associated with a significant decrease in IMT from baseline. The treatment options for T2DM have expanded since the development of several DPP-4 inhibitors. There is a
growing body of evidence that these agents may have protective effects on cardiovascular systems in the presence and absence of hyperglycemia.13e15 However, clinical evidence is limited regarding the beneficial effects of DPP-4 inhibitors on atherosclerosis. The measurement of IMT has been used to monitor the effectiveness of oral antidiabetic agents in the prevention of atherosclerosis.16,17 Therefore, we measured IMT progression to show that sitagliptin attenuated progression. Experimental studies using LDL
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The American Journal of Cardiology (www.ajconline.org)
LDL reduction, HbA1c decrease, or body weight loss in this small study. We showed the reduction in 2-hour glucose levels on the 75-g OGTT, HbA1c, and body weight, which was already known about DPP-4 inhibitors before, while new findings are the slowing IMT progression and the decrease in LDL-C in patients who already received statins. This study had several limitations. First, the small sample size and short duration of follow-up have low statistical power to monitor data on major adverse events including cardiovascular events. Second, there is a possibility that there was selection bias because the study was performed at a single center and had an open-label design. Third, although all subjects were receiving statin therapy, the reduction in LDL-C levels by sitagliptin may have effects on IMT progression. Therefore, there is a need for further studies, with larger sample sizes and longer durations, to detect differences in the occurrence of major adverse events. Acknowledgment: The authors gratefully acknowledge the technical assistance of Akihiro Suzuki, BSc. Disclosures
Figure 2. Change in mean IMT from baseline to 12-month follow-up between the sitagliptin and control groups.
receptor13 or apolipoprotein E knockout mice18 have recently demonstrated that DPP-4 inhibitors reduced atherosclerotic plaque area. A possible mechanism of the pleiotropic effects of DPP-4 inhibitors involves the suppression of inflammatory cytokines and oxidative stress, resulting in the suppression of atherogenesis.15,19 Thus, in our patients, sitagliptin may have had a beneficial effect on the progression of carotid IMT through similar mechanisms. Recently, it has been shown that prevention of postprandial hyperglycemia has several beneficial effects on vessel walls, including the reduction of oxidative stress, increased flow-mediated vasodilatation, and increased endothelial nitric oxide release.20,21 We and other groups have also reported that metformin, pioglitazone, and a-glucosidase inhibitors significantly attenuate the progression of carotid IMT compared with placebo or glimepiride.11,17,22,23 Thus, the showed IMT regression may result from a decrease in HbA1c. In addition, sitagliptin has a greater effect on weight loss and LDL-C controlled by statin therapy, which might influence IMT progression.24 Consequently, sitagliptin could potentially slow the progression of atherosclerosis for patients with coronary artery disease with IGT through these effects rather than pleiotropic effects, although IMT variation was not significantly correlated with
Dr. Ishii has received lecture fees from Astellas (Tokyo, Japan) and Otsuka (Tokyo, Japan). Dr. Murohara has received lecture fees from Bayer, Daiichi Sankyo, Dainippon Sumitomo, Kowa, MSD, Mitsubishi Tanabe, Nippon Boehringer Ingelheim, Novartis, Pfizer Japan, Sanofi-Aventis, and Takeda. Dr. Murohara has received unrestricted research grant for Department of Cardiology, Nagoya University Graduate School of Medicine, from Astellas (Tokyo, Japan), Daiichi Sankyo (Tokyo, Japan), Dainippon Sumitomo (Tokyo, Japan), Kowa (Nagoya, Japan), MSD (Tokyo, Japan), Mitsubishi Tanabe (Osaka, Japan), Nippon Boehringer Ingelheim (Tokyo, Japan), Novartis (Tokyo, Japan), Otsuka (Tokyo, Japan), Pfizer Japan (Tokyo, Japan), SanofiAventis (Tokyo, Japan), Takeda (Tokyo, Japan), and Teijin (Tokyo, Japan). 1. Gallwitz B. Review of sitagliptin phosphate: a novel treatment for type 2 diabetes. Vasc Health Risk Manag 2007;3:203e210. 2. Schmidt WE, Siegel EG, Creutzfeldt W. Glucagon-like peptide-1 but not glucagon-like peptide-2 stimulates insulin release from isolated rat pancreatic islets. Diabetologia 1985;28:704e707. 3. 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, KimMitsuyama 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;59:265e276. 4. Liu L, Liu J, Wong WT, Tian XY, Lau CW, Wang YX, Xu G, Pu Y, Zhu Z, Xu A, Lam KS, Chen ZY, Ng CF, Yao X, Huang Y. Dipeptidyl peptidase 4 inhibitor sitagliptin protects endothelial function in hypertension through a glucagon-like peptide 1-dependent mechanism. Hypertension 2012;60:833e841. 5. 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;62:347e351. 6. 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. Dipeptidyl peptidase-4 inhibitor, sitagliptin,
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