DPP-4 Inhibitor Teneligliptin Improves Insulin Resistance and Serum Lipid Profile in Japanese Patients with Type 2 Diabetes

Kusunoki, Masataka; Sato, Daisuke; Nakamura, Toshio; Oshida, Yoshiharu; Tsutsui, Hideyo; Natsume, Yukie; Tsutsumi, K.; Miyata, T.

doi:10.1055/s-0034-1390419

Cited by 23 publications

(19 citation statements)

References 21 publications

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“…Importantly, no significant differences were found between teneligliptin and sitagliptin in lipid profiles or glycaemic variability. Both teneligliptin and sitagliptin improved insulin resistance, based on HOMA‐β, which is in line with previous data showing the positive impact of teneligliptin on insulin resistance …”

Section: Discussionsupporting

confidence: 91%

Teneligliptin versus sitagliptin in Korean patients with type 2 diabetes inadequately controlled with metformin and glimepiride: A randomized, double‐blind, non‐inferiority trial

Kim

Kang

Jang

et al. 2018

Diabetes Obesity Metabolism

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Aim To assess the efficacy and safety of add‐on therapy with the dipeptidyl peptidase‐4 inhibitor teneligliptin compared with sitagliptin in patients with type 2 diabetes (T2DM) inadequately controlled with metformin and glimepiride. Materials and Methods This was a phase 3, randomized, double‐blind, non‐inferiority study of adult Korean subjects with T2DM (n = 201), with HbA1c ranging from 7.0% to 11.0%, on stable doses of metformin plus glimepiride. Subjects were randomized in a 1:1 fashion to receive either oral teneligliptin 20 mg or sitagliptin 100 mg for 24 weeks. The primary endpoint was change from baseline in HbA1c. Results At baseline, mean age was 60.56 ± 9.41 years, body mass index was 25.23 ± 2.85 kg/m 2 and HbA1c was 8.11% ± 0.79%. At 24 weeks, both groups achieved significant reductions from baseline in HbA1c (teneligliptin, −1.03% ± 0.10% [ P < 0.0001]; sitagliptin, −1.02% ± 0.10% [ P < 0.0001]). The inter‐group difference was −0.01% (95% confidence interval [CI]: −0.28, 0.26; P = 0.9497); the upper limit of the 95% CI was within the preset limit for non‐inferiority (0.4%). There were no significant differences between groups in the proportion of patients achieving HbA1c targets, or changes from baseline in fasting plasma glucose, body weight or lipid levels at 24 weeks. Rates of adverse events (teneligliptin, n = 63 [61.76%]; sitagliptin, n = 61 [62.24%]; P = 0.9442) and hypoglycaemia (teneligliptin, n = 32 [31.37%]; sitagliptin, n = 28 [28.57%]; P = 0.6656) were similar. Conclusion Teneligliptin was non‐inferior to sitagliptin in the context of triple therapy for T2DM and is an important option in this setting.

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Section: Discussionsupporting

confidence: 91%

Teneligliptin versus sitagliptin in Korean patients with type 2 diabetes inadequately controlled with metformin and glimepiride: A randomized, double‐blind, non‐inferiority trial

Kim

Kang

Jang

et al. 2018

Diabetes Obesity Metabolism

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“…This study is the first to demonstrate this causal relationship using ETIrs2KO mice; we showed that chronic treatment with anagliptin enhanced insulin-induced capillary recruitment and interstitial insulin concentrations, thereby improving the skeletal muscle glucose uptake in vivo, by directly acting on endothelial cells via NO-and GLP-1-dependent mechanisms. The findings of our study may be of clinical relevance, as GLP-1R agonists and DPP4 inhibitors have been reported to attenuate insulin resistance in humans [9][10][11]40]. Taken together, these data suggest that anagliptin might be a promising agent to improve skeletal muscle insulin resistance in obese patients with type 2 diabetes.…”

Section: Discussionsupporting

confidence: 62%

Anagliptin increases insulin-induced skeletal muscle glucose uptake via an NO-dependent mechanism in mice

Satō

Kubota

et al. 2016

Diabetologia

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Aims/hypothesis Recently, incretin-related agents have been reported to attenuate insulin resistance in animal models, although the underlying mechanisms remain unclear. In this study, we investigated whether anagliptin, the dipeptidyl peptidase 4 (DPP-4) inhibitor, attenuates skeletal muscle insulin resistance through endothelial nitric oxide synthase (eNOS) activation in the endothelial cells. We used endothelium-specific Irs2-knockout (ETIrs2KO) mice, which show skeletal muscle insulin resistance resulting from a reduction of insulin-induced skeletal muscle capillary recruitment as a consequence of impaired eNOS activation. Methods In vivo, 8-week-old male ETIrs2KO mice were fed regular chow with or without 0.3% (wt/wt) DPP-4 inhibitor for 8 weeks to assess capillary recruitment and glucose uptake by the skeletal muscle. In vitro, human coronary arterial endothelial cells (HCAECs) were used to explore the effect of glucagon-like peptide 1 (GLP-1) on eNOS activity. Results Treatment with anagliptin ameliorated the impaired insulin-induced increase in capillary blood volume, interstitial insulin concentration and skeletal muscle glucose uptake in ETIrs2KO mice. This improvement in insulin-induced glucose uptake was almost completely abrogated by the GLP-1 receptor (GLP-1R) antagonist exendin-(9-39). Moreover, the increase in capillary blood volume with anagliptin treatment was also completely inhibited by the NOS inhibitor. GLP-1 augmented eNOS phosphorylation in HCAECs, with the effect completely disappearing after exposure to the protein kinase A (PKA) inhibitor H89. These data suggest that anagliptin treatment enhances insulin-induced capillary recruitment and interstitial insulin concentrations, resulting in improved skeletal muscle glucose Hiroyuki Sato, Naoto Kubota and Tetsuya Kubota contributed equally to this work. Electronic supplementary material The online version of this article

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“…Thus, anagliptin treatment may improve insulin resistance in OLETF rats. Indeed, previous studies showed that another DPP-4 inhibitor, teneligliptin, improved insulin resistance in type 2 diabetic patients (26) and that anagliptin ameliorated insulin resistance in the mouse liver (27). The issue of whether treatment with miglitol or anagliptin ameliorates insulin resistance in OLETF rats should be further assessed using insulin tolerance tests.…”

Section: Discussionmentioning

confidence: 99%

Treatment with DPP-4I Anagliptin or α-GI Miglitol Reduces IGT Development and the Expression of CVD Risk Factors in OLETF Rats

Imai

Harazaki

Inoue

et al. 2015

J Nutr Sci Vitaminol

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Recent cohort studies such as Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe (DECODE) in Europe and FUNAGATA in Japan have demonstrated that postprandial hyperglycemia is a strong independent risk factor for the development of cardiovascular diseases (CVD) in subjects with impaired glucose tolerance (IGT), reflecting pre-diabetic subjects, or type 2 diabetes (1, 2). Furthermore, the Study To Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM) trial reported that suppression of postprandial hyperglycemia in subjects with IGT, the pre-diabetic stage, by treatment with the a-glucosidase inhibitor (a-GI) acarbose, which suppresses postprandial hyperglycemia by inhibiting the carbohydrate digestion in the small intestine, reduces the incidence of CVD as well as the development of type 2 diabetes (3). These lines of evidence indicate that inhibition of postprandial hyperglycemia from the pre-diabetic stage could inhibit CVD development.Many previous studies have shown that CVDs are related to activation of leukocytes such as neutrophils, monocytes, and macrophages, and associated disorders of vascular endothelial function. Postprandial hyperglycemia activates the leukocytes through the production of reactive oxygen species (ROS) by activated neutrophils and enhanced glucose metabolism in mitochondria (4). The activated leukocytes secrete inflammatory cytokines such as interleukin (IL)-1b and tumor necrosis factor (TNF)-a (5, 6). These inflammatory cytokines Summary It has been reported that postprandial hyperglycemia from the pre-diabetic stage, especially from the impaired glucose tolerance (IGT) stage, is positively associated with subsequent incidences of cardiovascular diseases (CVD) and type 2 diabetes. In this study, we aimed to investigate whether treatment with a dipeptidyl peptidase-4 inhibitor (DPP-4I) or an a-glucosidase inhibitor (a-GI), either of which suppresses postprandial hyperglycemia, reduces the expression of CVD risk factors in an IGT animal model. A DPP-4I, anagliptin (1,200 ppm), or an a-GI, miglitol (600 ppm), in the diet was administered for 47 wk to Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model for spontaneously-developed type 2 diabetes, at the IGT stage. We examined whether each treatment reduced the expression of CVD risk factors such as inflammatory cytokines/cytokine-like factors in peripheral leukocytes and adhesion molecules in the aortic tissues and circulation. Treatment with either drug reduced IGT development and repressed expression of the interleukin-1b, tumor necrosis factor-a, S100a9, and S100a11 genes in peripheral leukocytes in the fasting state at weeks 25 and 39. The mRNA levels of E-selectin in aortic tissues and protein levels of the soluble forms of E-selectin and ICAM-1 in arterial blood were significantly lower in the anagliptin and miglitol groups than in the control group. Our results suggest that long-term treatment with anagliptin or miglitol in OLETF rats at the IGT stage suppresses the expression of inflammatory ...

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DPP-4 Inhibitor Teneligliptin Improves Insulin Resistance and Serum Lipid Profile in Japanese Patients with Type 2 Diabetes

Cited by 23 publications

References 21 publications

Teneligliptin versus sitagliptin in Korean patients with type 2 diabetes inadequately controlled with metformin and glimepiride: A randomized, double‐blind, non‐inferiority trial

Teneligliptin versus sitagliptin in Korean patients with type 2 diabetes inadequately controlled with metformin and glimepiride: A randomized, double‐blind, non‐inferiority trial

Anagliptin increases insulin-induced skeletal muscle glucose uptake via an NO-dependent mechanism in mice

Treatment with DPP-4I Anagliptin or α-GI Miglitol Reduces IGT Development and the Expression of CVD Risk Factors in OLETF Rats

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DPP-4 Inhibitor Teneligliptin Improves Insulin Resistance and Serum Lipid Profile in Japanese Patients with Type 2 Diabetes

Cited by 23 publications

References 21 publications

Teneligliptin versus sitagliptin in Korean patients with type 2 diabetes inadequately controlled with metformin and glimepiride: A randomized, double‐blind, non‐inferiority trial

Teneligliptin versus sitagliptin in Korean patients with type 2 diabetes inadequately controlled with metformin and glimepiride: A randomized, double‐blind, non‐inferiority trial

Anagliptin increases insulin-induced skeletal muscle glucose uptake via an NO-dependent mechanism in mice

Treatment with DPP-4I Anagliptin or &alpha;-GI Miglitol Reduces IGT Development and the Expression of CVD Risk Factors in OLETF Rats

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Treatment with DPP-4I Anagliptin or α-GI Miglitol Reduces IGT Development and the Expression of CVD Risk Factors in OLETF Rats