Long-term treatment with Sitagliptin, a dipeptidyl peptidase-4 inhibitor, reduces colon carcinogenesis and reactive oxygen species in 1,2-dimethylhydrazine-induced rats

Cyclosporine A (CyA) is an immunosuppressive agent that induces nephrotoxicity with long-term treatment. The roles of DPP-4 and its inhibitors in cyclosporine nephrotoxicity are not fully understood. Therefore, we investigated the effects of a novel DPP-4 inhibitor, DA-1229, on the progression of renal disease in an experimental cyclosporine nephrotoxicity model. Chronic cyclosporine nephrotoxicity was induced in six-week-old male ICR mice by subcutaneous injections of CyA at a dose of 30 mg/kg for four weeks. Animals were treated with DA-1229 at a dose of 300 mg/kg per day in food for four weeks. Although DPP-4 activity did not increase in the kidneys of mice with induced cyclosporine nephrotoxicity, DA-1229 treatment significantly suppressed DPP-4 activity in both plasma and renal tissues. DPP-4 inhibition by DA-1229 led to significantly decreased albuminuria and urinary excretion of 8-isoprosatane. DPP-4 inhibition also substantially suppressed pro-inflammatory effects, profibrotic molecules, and macrophage infiltration, and led to the improvement in renal structural changes. Our results suggest that DPP-4 inhibition by DA-1229 provides renoprotective effects in an animal model of cyclosporine nephrotoxicity via antioxidant, anti-inflammatory, and anti-fibrotic mechanisms. DPP-4 inhibition may be a useful new therapeutic approach for the management of progressive renal disease in cyclosporine nephrotoxicity.

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Abstract 15107: Long-Term Treatment With Sitagliptin Provides Multiple Ultrasonic-Evaluated Antiatherosclerotic Effects Independent of Diabetic Improvement for Type-2 Diabetics

Circulation ◽

10.1161/circ.132.suppl_3.15107 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Tatsuaki Murakami ◽

Sumio Mizuno

Keyword(s):

Intima Media Thickness ◽

Term Treatment ◽

Dipeptidyl Peptidase 4 ◽

Type 2 Dm ◽

Dipeptidyl Peptidase 4 Inhibitor ◽

Type 2 Diabetics ◽

Long Term Treatment ◽

High Resolution Ultrasonography

Introduction: Diabetes mellitus (DM) is thought to be highly involved in complex atherothrombogenic processes, but the long-term antiatherosclerotic therapies in patients with type-2 DM have not been established. Hypothesis: Therefore we assessed hypothesis long-term treatment sitagliptin, a dipeptidyl peptidase-4 inhibitor recently developed antidiabetic agent, chronically inhibits atherosclerotic progression in patients with type-2 DM. Methods: Thirty-two type-2 diabetic patients with stable coronary artery disease were randomized to group-S where they received sitagliptin (50mg/day), or to group-C where they received enhanced antidiabetic therapy without a dipeptidyl peptidase-4 inhibitor for 2 years. We quantified flow-mediated endothelium-dependent dilation of right brachial artery after 5 minutes forearm occlusion (BFMD), and intima-media thickness of brachial artery (BIMT) using high-resolution ultrasonography. We also quantified intima-media thickness of common carotid artery (CIMT) using high-resolution ultrasonography. Changes in BFMD, BIMT, and CIMT were compared between the two study groups. Results: Group-S (n=16) manifested good compliance to the long-term treatment and improvements in diabetic and lipid variables represented by HbA1c and LDL after long-term medication of sitagliptin, while there were no improvements in group-C. BFMD (%) improved after medication in group-S (from 3.9±1.8 to 6.4±2.6, p<0.01) and BIMT (mm) decreased in group-SG (from 0.35±0.10 to 0.32±0.11, p=0.03), while both remained unchanged in group-C (BFMD; from 4.1±2.0 to 4.1±1.9, p=0.88, BIMT; from 0.34±0.13 to 0.35±0.12, p=0.54). CIMT (mm) did not increase in group-S (from 1.10±0.35 to 1.08±0.39, p=0.16) but increased in group-C (from 1.09±0.46mm to 1.16±0.47mm, p<0.01). Changes of BFMD or BIMT in group-S did not correlate to those of HbA1c (BFMD: r=0.17, p=0.79, BIMT: r=0.11, p=0.85). Conclusions: This study suggests that long-term treatment of sitagliptin safely improves arterial function and inhibits progression of wall thickness independent of reversal for diabetic status, which may have beneficial potentials for long-term management of atherosclerosis in type-2 diabetics.

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