Journal of the American College of Cardiology

2012

DOI: 10.1016/j.jacc.2011.07.053

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A Dipeptidyl Peptidase-4 Inhibitor, Des-Fluoro-Sitagliptin, Improves Endothelial Function and Reduces Atherosclerotic Lesion Formation in Apolipoprotein E–Deficient Mice

Junichi Matsubara

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Koichi Sugamura

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et al.

Abstract: A DPP-4 inhibitor, DFS, exhibited antiatherogenic effects through augmenting GLP-1 activity in macrophages and endothelium.

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атеротромбоз тэла неотложная кардиология1

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Cited by 249 publications

(231 citation statements)

References 17 publications

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“…In addition, these agents have potential antiatherosclerotic properties. In a rodent model of atherosclerosis, GLP-1 and GLP-1 receptor agonists were reported to inhibit atherosclerosis and inflammation (6)(7)(8)(9), and DPP-4 inhibitors, including alogliptin, inhibit these pathological processes in GLP-1-dependent and -independent manners (10)(11)(12).…”

mentioning

confidence: 99%

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)

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et al. 2015

Diabetes Care

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OBJECTIVERecent experimental studies have shown that dipeptidyl peptidase 4 (DPP-4) inhibitors have antiatherosclerotic benefits in glucagon-like peptide 1-dependent and -independent manners. The current study investigated the effects of alogliptin, a DPP-4 inhibitor, on the progression of carotid atherosclerosis in patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODSThis prospective, randomized, open-label, blinded-end point, multicenter, parallelgroup, comparative study included 341 patients with T2DM free of a history of apparent cardiovascular diseases recruited at 11 clinical units and randomly allocated to treatment with alogliptin (n = 172) or conventional treatment (n = 169). Primary outcomes were changes in mean common and maximum intima-media thickness (IMT) of the carotid artery measured by carotid arterial echography during a 24-month treatment period. RESULTSAlogliptin treatment had a more potent glucose-lowering effect than the conventional treatment (20.3 6 0.7% vs. 20.1 6 0.8%, P = 0.004) without an increase of hypoglycemia. Changes in the mean common and the right and left maximum IMT of the carotid arteries were significantly greater after alogliptin treatment than after conventional treatment (20.026 mm [SE 0.009] CONCLUSIONSAlogliptin treatment attenuated the progression of carotid IMT in patients with T2DM free of apparent cardiovascular disease compared with the conventional treatment.

“…In addition, these agents have potential antiatherosclerotic properties. In a rodent model of atherosclerosis, GLP-1 and GLP-1 receptor agonists were reported to inhibit atherosclerosis and inflammation (6)(7)(8)(9), and DPP-4 inhibitors, including alogliptin, inhibit these pathological processes in GLP-1-dependent and -independent manners (10)(11)(12).…”

mentioning

confidence: 99%

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)

¹

,

²

,

³

et al. 2015

Diabetes Care

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OBJECTIVERecent experimental studies have shown that dipeptidyl peptidase 4 (DPP-4) inhibitors have antiatherosclerotic benefits in glucagon-like peptide 1-dependent and -independent manners. The current study investigated the effects of alogliptin, a DPP-4 inhibitor, on the progression of carotid atherosclerosis in patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODSThis prospective, randomized, open-label, blinded-end point, multicenter, parallelgroup, comparative study included 341 patients with T2DM free of a history of apparent cardiovascular diseases recruited at 11 clinical units and randomly allocated to treatment with alogliptin (n = 172) or conventional treatment (n = 169). Primary outcomes were changes in mean common and maximum intima-media thickness (IMT) of the carotid artery measured by carotid arterial echography during a 24-month treatment period. RESULTSAlogliptin treatment had a more potent glucose-lowering effect than the conventional treatment (20.3 6 0.7% vs. 20.1 6 0.8%, P = 0.004) without an increase of hypoglycemia. Changes in the mean common and the right and left maximum IMT of the carotid arteries were significantly greater after alogliptin treatment than after conventional treatment (20.026 mm [SE 0.009] CONCLUSIONSAlogliptin treatment attenuated the progression of carotid IMT in patients with T2DM free of apparent cardiovascular disease compared with the conventional treatment.

“…Recently, the DPP-IV inhibitors des-fluoro-sitagliptin and alogliptin have been shown to decrease atherosclerosis quantitatively in mouse studies [9,13]. However, little is known about the effects of DPP-IV inhibitors on plaque composition and on the stability of atherosclerotic plaques.…”

Section: Introductionmentioning

confidence: 99%

Sitagliptin reduces plaque macrophage content and stabilises arteriosclerotic lesions in Apoe −/− mice

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et al. 2012

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Aims/hypothesis Inhibitors of dipeptidyl peptidase-IV (DPP-IV), such as sitagliptin, increase glucagon-like peptide-1 (GLP-1) concentrations and are current treatment options for patients with type 2 diabetes mellitus. As patients with diabetes exhibit a high risk of developing severe atherosclerosis, we investigated the effect of sitagliptin on atherogenesis in Apoe −/− mice. Methods Apoe−/− mice were fed a high-fat diet and treated with either sitagliptin or placebo for 12 weeks. Plaque size and plaque composition were analysed using Oil Red O staining and immunohistochemistry. Furthermore, in vitro experiments with the modified Boyden chamber and with gelatine zymography were performed to analyse the effects of GLP-1 on isolated human monocyte migration and metalloproteinase-9 (MMP-9) release.Results Treatment of Apoe −/− mice with sitagliptin significantly reduced plaque macrophage infiltration (the aortic root and aortic arch both showing a 67% decrease; p<0.05) and plaque MMP-9 levels (aortic root showing a 69% and aortic arch a 58% reduction; both p<0.01) compared with controls. Moreover, sitagliptin significantly increased plaque collagen content more than twofold (aortic root showing an increase of 58% and aortic arch an increase of 73%; both p<0.05) compared with controls but did not change overall lesion size (8.1 ± 3.5% vs 5.1 ± 2.5% for sitagliptin vs controls; p0NS). In vitro, pretreatment of isolated human monocytes with GLP-1 significantly decreased cell migration induced by both monocyte chemotactic protein-1 and by the protein known as regulated on activation, normal T cell expressed and secreted (RANTES) in a concentration-dependent manner. Furthermore, GLP-1 significantly decreased MMP-9 release from isolated human monocyte-derived macrophages. Conclusions/interpretation Sitagliptin reduces plaque inflammation and increases plaque stability, potentially by GLP-1-mediated inhibition of chemokine-induced monocyte migration and macrophage MMP-9 release. The effects observed may provide potential mechanisms for how DPP-IV inhibitors could modulate vascular disease in high-risk patients with type 2 diabetes mellitus.

“…Interestingly, sitagliptin, an oral glucose-lowering agent currently used for treating type 2 diabetes, has been found to enhance circulating glucagon-like peptide-1 (GLP-1) levels through inhibition of dipeptidyl peptidase IV (DPP-IV) activity [24,25] which, in turn, provides cardiovascular protection probably through the anti-inflammatory and anti-atherosclerotic activities of GLP-1 [26] . Additionally, our study recently demonstrated that sitagliptin therapy enhances stromal cell-derived factor (SDF)-1α level, numbers of endothelial progenitor cells (EPCs) in circulation, and angiogenesis through inhibition of DDP-IV in CD26 cells [27] .…”

mentioning

confidence: 99%

Sitagliptin protects rat kidneys from acute ischemia-reperfusion injury via upregulation of GLP-1 and GLP-1 receptors

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et al. 2014

Acta Pharmacol Sin

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Aim: Sitagliptin, an oral glucose-lowering agent, has been found to produce cardiovascular protection possibly via anti-inflammatory and anti-atherosclerotic activities of glucagon-like peptide-1 receptor (GLP-1). The aim of this study was to investigate whether sitagliptin protected the kidney function from acute ischemia-reperfusion (IR) injury in rats. Methods: Adult male SD rats were categorized into 4 groups: sham control, IR injury, IR+sitagliptin (300 mg/kg) and IR+sitagliptin (600 mg/kg). Acute renal IR injury of both kidneys was induced by clamping the renal pedicles for 1 h. The drug was orally administered at 1, 24 and 48 h after acute IR. Blood samples and 24-h urine were collected before and at 72 h after acute IR. Then the rats were sacrificed, and the kidneys were harvested for biochemical and immunohistochemical studies. Results: Acute IR procedure markedly increased serum levels of creatinine and BUN and the ratio of urine protein to creatinine. The kidney injury score, inflammatory biomarkers (MMP-9, TNF-α and NF-κB) levels and CD68+ cells in IR kidneys were considerably increased. The expression of oxidized protein, reactive oxygen species (NOX-1, NOX-2) and apoptosis proteins (Bax, caspase-3, PARP) in IR kidneys was also significantly upregulated. All these pathological changes were suppressed by sitagliptin in a dose-dependent manner. Furthermore, the serum GLP-1 level, and the expression of GLP-1 receptor, anti-oxidant biomarkers (HO-1 and NQO-1 cells, as well as SOD-1, NQO-1 and HO-1 proteins), and angiogenesis markers (SDF-1α+ and CXCR4+ cells) in IR kidneys were significantly increased, and further upregulated by sitagliptin. Conclusion: Sitagliptin dose-dependently protects rat kidneys from acute IR injury via upregulation of serum GLP-1 and GLP-1 receptor expression in kidneys.

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