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 (HbA 1c ), 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%), HbA 1c (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.
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. Incretin hormones, including glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide depend on blood glucose levels to stimulate insulin secretion ; 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. However, little is known about its effect on atherosclerosis-related cardiovascular diseases. Carotid intima-media thickness (IMT) is a marker for atherosclerosis. Absolute IMT values and an increase in IMT have been reported to be highly associated with the risk of future cardiovascular events. However, no 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 (HbA 1c ) of <6.5%. Patients were excluded 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 HbA 1c 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, HbA 1c , 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, HbA 1c , 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 [μU/ml] × fasting glucose level [mg/dl])/405. 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 follow-up. 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), HbA 1c , 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.
| Variables | Sitagliptin (N = 37) | Control (N = 39) |
|---|---|---|
| Age (years) | 73.7 (7.3) | 69.0 (8.0) |
| Male | 32 (86.4%) | 33 (84.0%) |
| Weight (kg) | 65.8 (12.5) | 61.5 (11.6) |
| Body mass index (kg/m 2 ) | 25.3 (3.9) | 23.8 (3.8) |
| Systolic blood pressure (mm Hg) | 130.2 (7.0) | 128.9 (9.8) |
| Angiotensin converting enzyme inhibitors/sartans | 30 (81.1%) | 31 (79.5%) |
| The duration of statin use (months) | 53.9 (27.1) | 52.8 (33.8) |
| Fasting blood sugar (mg/dL) | 106.4 (8.8) | 108.2 (11.5) |
| Immunoreactive insulin | 11.2 (8.6) | 10.2 (12.1) |
| 75-g oral glucose tolerance test (120 minutes) | 181.7 (38.0) | 177.4 (39.7) |
| Homeostasis model assessment ratio | 2.99 (4.9) | 2.73 (2.9) |
| Homeostatic model assessment of beta cell function | 89.5 (134.2) | 86.4 (125.3) |
| Glycosylated hemoglobin (%) | 5.77 (0.31) | 5.49 (0.29) |
| Lipid profile | ||
| Total cholesterol (mg/dL) | 161.6 (27.3) | 165.7 (31.1) |
| Triglycerides (mg/dL) | 110.3 (46.9) | 107.3 (60.4) |
| High-density lipoprotein cholesterol (mg/dL) | 51.9 (13.3) | 53.3 (15.2) |
| Low-density lipoprotein cholesterol (mg/dL) | 94.6 (17.0) | 93.0 (19.1) |
| Intima-media thickness (mm) | 1.11 (0.42) | 1.07 (0.42) |
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 = 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 = 0.02, Figure 2 ). In addition, the sitagliptin group had greater reductions in body weight (2.2%, p = 0.03), 2-hour glucose levels on the 75-g OGTT (17.3%, p <0.001), HbA 1c (4.7%, p <0.001), and LDL-C levels (7.9%, p = 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.
| Variables | Sitagliptin Group | Control Group | ||||
|---|---|---|---|---|---|---|
| Baseline | 12 Months | p | Baseline | 12 Months | p | |
| Systolic blood pressure (mm Hg) | 130.2 (7.2) | 128.5 (9.8) | 0.32 | 128.9 (9.8) | 133.3 (10.1) | 0.08 |
| Weight (kg) | 65.8 (12.5) | 64.3 (12.4) | 0.02 | 61.6 (11.6) | 61.4 (11.3) | 0.69 |
| Body mass index (kg/m 2 ) | 25.4 (3.9) | 23.2 (7.5) | 0.05 | 23.8 (3.1) | 24.3 (3.1) | 0.14 |
| Fasting blood sugar (mg/dL) | 106.4 (8.8) | 104.2 (21.0) | 0.52 | 108.2 (11.5) | 107.4 (11.8) | 0.80 |
| 75-g oral glucose tolerance test (120) | 181.7 (38.0) | 156.3 (44.5) | <0.01 | 177 (39.3) | 182 (45.9) | 0.48 |
| Immunoreactive insulin (μU/ml) | 11.2 (8.6) | 8.63 (5.5) | 0.39 | 10.2 (12.1) | 7.7 (6.0) | 0.05 |
| Homeostasis model assessment ratio | 2.99 (4.9) | 2.73 (2.01) | 0.49 | 2.73 (2.9) | 2.08 (1.8) | 0.03 |
| Homeostatic model assessment of beta cell function | 89.5 (134.2) | 69.7 (34.6) | 0.38 | 86.4 (125.3) | 62.8 (54.7) | 0.10 |
| Glycosylated hemoglobin (%) | 5.77 (0.31) | 5.49 (0.31) | <0.01 | 5.76 (0.40) | 5.68 (0.42) | 0.02 |
| Total cholesterol | 161.4 (30.2) | 155.8 (28.8) | 0.12 | 168.0 (33.8) | 164.2 (34.3) | 0.55 |
| Triglycerides | 110.3 (46.9) | 108.9 (51.3) | 0.84 | 110.3 (62.5) | 107.3 (52.3) | 0.62 |
| High-density lipoprotein cholesterol | 51.9 (13.3) | 51.5 (10.4) | 0.82 | 53.6 (15.1) | 55.9 (13.7) | 0.02 |
| Low-density lipoprotein cholesterol | 94.6 (17.0) | 85.9 (20.89) | <0.01 | 94.4 (20.8) | 93.9 (23.4) | 0.88 |
| Intima-media thickness (mm) | 1.11 (0.43) | 1.09 (0.42) | 0.43 | 1.02 (0.44) | 1.07 (0.41) | 0.04 |
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