| Objective 1. The aim of this study was to investigate the antiatherogenic effects of the DPP-4 inhibitor, sitagliptin and explore the relevant mechanisms. 2. The aim of clinical trial was to compare the effects of a dipeptidyl peptidase-4 (DPP-4) inhibitor, sitagliptin,with an alpha-glucosidase inhibitor, acarbose, on the progression of coronary atherosclerosis in patients with type 2 diabetes.Methods 1. Eight-week-old low-dose streptozotocin (STZ)-induced diabetic ApoE-/-mice fed a high-fat diet were administered a DPP-4 inhibitor, sitagliptin, 200mg/kg/day,in drinking water or Lantus insulin by daily subcutaneous injection of 1 unit/mouse over a period of 12 weeks. Aortic atherosclerosis and apoptosis in the plague were determined.2. This was a prospective, single-center, open-label, randomized, controlled 12-month clinical trial in patients with coronary disease and type 2 diabetes. A total of 88 patients,who had at least 1 atherosclerotic plaque with 20% to 80% luminal narrowing in a coronary artery that had not undergone intervention during a clinically indicated coronary angiography or percutaneous coronary intervention, were randomized to receive sitagliptin (sitagliptin group), 100mg, once per day, or acarbose (control group),50mg, three times per day, for 12 months. The primary outcome was change in percent atheroma volume(PAV) from baseline to study completion measured by repeat three-dimension quantitative coronary angiography(3D-QCA). Secondary outcomes included change in normalized total atheroma volume (TAV), late lumen loss (LLL) and change in target lesion length.Results 1. Mean PAV decreased 1.99% (SD, 7.74%)with sitagliptin and increased 3.62%(SD,7.01%)with control group (P =0.014). The secondary outcome of change in TAV in patients treated with sitagliptin decreased 1.4 mm3 (95%CL,-4.07 to 3.06 mm3) and increased 0.8 mm3 (95%CL,-1.91?11.06 mm3) , however, no significant difference between groups was observed(P =0.153). Patients treated with sitagliptin were more likely to have significantly higher LLL as compared with acarbose and (or) other conventional antidiabetics (0.01,95%CL, -0.19 to 0.10 vs. -0.09, -0.45 to -0.05mm,P=0.011). Changes in the target lesions length of the coronary arteries were significantly decreased in sitagliptin group than control group (-0.51, 95%CL, -1.15 to 0.48 vs. 0.89,0.03 to 1.90mm, P =0.007).2. Sitagliptin significantly reduced atherosclerotic lesion area(7.00±0.13 vs. 12.80±2.7%,P =0.003)and suppressed vascular smooth muscle cell(2.30±1.34 vs.4.8±1.93%,P=0.003, n=10)and macrophage(6.50±2.99 vs. 12.50±3.44%,P <0.01,n=10)associated with increased intraplaque neovessels(32.2±6.23 vs. 9.60±3.06,P<0.001,n=6)compared with vehicle treatment. In addition, sitagliptin significantly increased the expression of ?-catenin in the aortic tissue (0.56±0.13 vs.0.17±0.02,P=0.008) compared with vehicle treatment.Conclusions 1. DPP-4 inhibitor, sitagliptin, exhibited anti-atherogenic effects through suppressing cell apoptosis in the atherosclerotic plague, possibly mediated by the?-catenin / Survivin pathways.2. In patients with coronary disease and type 2 diabetes, treatment with sitagliptin resulted in a significantly lower rate of progression of coronary atherosclerosis compared with acarbose. |
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