Mechanism of lipid‐lowering action of the dipeptidyl peptidase‐4 inhibitor, anagliptin, in low‐density lipoprotein receptor‐deficient mice

Yano, Wataru; Inoue, Noriyuki; Ito, Shiori; Ito, Takahiro; Yasumura, Misako; Yoshinaka, Yasunobu; Hagita, Sumihiko; Goto, Minoru; Nakagawa, Takashi; Inoue, Kentaro; Tanabe, Seiichi; Kaku, Kohei

doi:10.1111/jdi.12593

Cited by 31 publications

(36 citation statements)

References 30 publications

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“…The present study showed that in type 2 diabetes mellitus patients treated with ANA, the %change in LDL-C level at 24 weeks correlated significantly with the %change in apoB-100 levels (Spearman, P = 0.028, r = 0.424), but not with that in apoB-48 levels (Spearman, P = 0.951, r = -0.013). This finding suggests that the mechanism of action of ANA involves the suppression of cholesterol synthesis in the liver, similar to the possible mechanism reported by Yano et al 17 .…”

Section: Discussionsupporting

confidence: 90%

“…Yano et al . showed that in LDL‐C receptor‐deficient mice, ANA did not affect sterol regulatory element‐binding protein 1c (SREBP1c), a transcription factor involved in TG synthesis in the liver, but reduced sterol regulatory element‐binding protein 2, a transcription factor involved in cholesterol synthesis in the liver.…”

Section: Discussionmentioning

confidence: 99%

“…Yano et al 17 showed that in LDL-C receptor-deficient mice, ANA did not affect sterol regulatory element-binding protein 1c (SREBP1c), a transcription factor involved in TG synthesis in the liver, but reduced sterol regulatory element-binding protein 2, a transcription factor involved in cholesterol synthesis in the liver. The present study showed that in type 2 diabetes mellitus patients treated with ANA, the %change in LDL-C level at 24 weeks correlated significantly with the %change in apoB-100 levels (Spearman, P = 0.028, r = 0.424), but not with that in apoB-48 levels (Spearman, P = 0.951, r = -0.013).…”

Section: Discussionmentioning

confidence: 99%

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Comparison of effects of anagliptin and alogliptin on serum lipid profile in type 2 diabetes mellitus patients

Kurozumi

Okada

Arao

et al. 2017

J of Diabetes Invest

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IntroductionAnagliptin (ANA) improves dyslipidemia in addition to blood glucose levels. However, there are no comparative studies on the effects of ANA and other dipeptidyl peptidase‐4 inhibitors on serum lipid profile. We compared the effects of ANA on serum lipid profile with those of alogliptin (ALO) in type 2 diabetes mellitus outpatients.Materials and MethodsThe study participants were 87 type 2 diabetes mellitus patients who had been treated with dipeptidyl peptidase‐4 inhibitors for ≥8 weeks and had a low‐density lipoprotein cholesterol (LDL‐C) level of ≥120 mg/dL. Participants were switched to either 200 mg/day ANA or 25 mg/day ALO for 24 weeks.ResultsThere was no significant difference in percentage change in LDL‐C level at 24 weeks between the ANA and ALO groups. Treatment with ANA for 12 weeks significantly decreased LDL‐C levels, one of the secondary end‐points. Treatment with ANA for 24 weeks significantly improved apolipoprotein B‐100 levels, and the percentage change in LDL‐C levels at 24 weeks correlated significantly with the percentage change in apolipoprotein B‐100 levels in the ANA group.ConclusionsThe LDL‐C‐lowering effects of ANA and ALO at 24 weeks were almost similar in patients with type 2 diabetes mellitus. However, the results showed a tendency for a decrease in LDL‐C level at 24 weeks in the ANA group, and that such improvement was mediated, at least in part, through the suppression of apolipoprotein B‐100 synthesis.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Comparison of effects of anagliptin and alogliptin on serum lipid profile in type 2 diabetes mellitus patients

Kurozumi

Okada

Arao

et al. 2017

J of Diabetes Invest

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“…First of all, we confirmed the lipid‐lowering effect of anagliptin in the mice, just as in a previous clinical study, with anagliptin treatment reducing the serum total cholesterol and non‐HDL‐C concentrations. Similar effects of anagliptin have been shown in ApoE‐deficient mice, LDL receptor knockout mice and cholesterol‐fed rabbits. Yano et al .…”

Section: Discussionsupporting

confidence: 55%

Dipeptidyl peptidase 4 inhibitor anagliptin ameliorates hypercholesterolemia in hypercholesterolemic mice through inhibition of intestinal cholesterol transport

Goto

Furuta

Yamashita

et al. 2018

J of Diabetes Invest

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Aims/IntroductionRecent data showed that dipeptidyl peptidase 4 (DPP‐4) inhibitors exert a lipid‐lowering effect in diabetes patients. However, the mechanism of action is not yet clearly understood. We investigated the effect of anagliptin on cholesterol metabolism and transport in the small intestine using non‐diabetic hyperlipidemic animals, to clarify the mechanisms underlying the cholesterol‐lowering action.Materials and MethodsMale apolipoprotein E (ApoE)‐deficient mice were orally administered anagliptin in the normal chow. Serum cholesterol levels and lipoprotein profiles were measured, and cholesterol transport was assessed by measuring the radioactivity in the tissues after oral loading of 14C‐labeled cholesterol (14C‐Chol). In additional experiments, effects of exendin‐4 in mice and of anagliptin in DPP‐4‐deficient rats were assessed. Effects on target gene expressions in the intestine were analyzed by quantitative polymerase chain reaction in normal mice.ResultsThe serum total and non‐high‐density lipoprotein cholesterol concentrations decreased after anagliptin treatment in the ApoE‐deficient mice. The cholesterol‐lowering effect was predominantly observed in the chylomicron fraction. The plasma 14C‐Chol radioactivity was significantly decreased by 26% at 2 h after cholesterol loading, and the fecal 14C‐Chol excretion was significantly increased by 38% at 72 h. The aforementioned effects on cholesterol transport were abrogated in rats lacking DPP‐4 activity, and exendin‐4 had no effect on the 14C‐Chol transport in ApoE‐deficient mice. Furthermore, significant decreases of the intestinal cholesterol transport‐related microsomal triglyceride transfer protein, acyl‐coenzyme A:cholesterol acyltransferase 2, ApoA2 and ApoC2 messenger ribonucleic acid expressions were observed in the mice treated with repeated doses of anagliptin.ConclusionsThese findings suggest that anagliptin might exert a cholesterol‐lowering action through DPP‐4‐dependent and glucagon‐like peptide 1‐independent suppression of intestinal cholesterol transport.

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“…Anagliptin treatment significantly decreased the plasma total cholesterol (14% reduction, p<0.01) and triglyceride levels (27% reduction, p<0.01). The results indicated that the DPP4 inhibitor, anagliptin, exhibited a lipid-lowering effect in a hyperlipidemic animal model, and suggested that the down regulation of hepatic lipid synthesis was involved in the effect [31].…”

Section: Dpp4 Inhibitors In the Management Of Hyperlipidemiamentioning

confidence: 88%

Dipeptidyl Peptidase-4 Inhibitors: Potential for Treatment of Metabolic Syndrome and Developed Formulation Approaches

Mishra

Dhole

2017

Asian J Pharm Clin Res

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This review article deals with the pre-clinical and clinical findings reviewed or investigated by the researchers on dipeptidyl peptidase-4 (DPP4) inhibitors as a potential in the treatment of metabolic syndrome. Most of the researchers reported the activity of DPP4 inhibitors in the management of obesity, hyperlipidemia, hypertension, atherosclerosis, and in cardiometabolic risk which are summarized in the article. This article also focuses on the formulation approaches in which the formulators have reported and used in the designing or development of DPP4 inhibitors as dosage form. The formulation approaches which are commonly employed on DPP4 inhibitors are immediate release, sustain release, and combination therapy.

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Mechanism of lipid‐lowering action of the dipeptidyl peptidase‐4 inhibitor, anagliptin, in low‐density lipoprotein receptor‐deficient mice

Cited by 31 publications

References 30 publications

Comparison of effects of anagliptin and alogliptin on serum lipid profile in type 2 diabetes mellitus patients

Comparison of effects of anagliptin and alogliptin on serum lipid profile in type 2 diabetes mellitus patients

Dipeptidyl peptidase 4 inhibitor anagliptin ameliorates hypercholesterolemia in hypercholesterolemic mice through inhibition of intestinal cholesterol transport

Dipeptidyl Peptidase-4 Inhibitors: Potential for Treatment of Metabolic Syndrome and Developed Formulation Approaches

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