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There is no stability-indicating specific related substances high-performance liquid chromatography (HPLC) method for anagliptin active pharmaceutical ingredients in the presence of its degradation products. Hence, there is a necessity to have a specific stability-indicating HPLC method for the quantification of anagliptin-related substances in the presence of its forced degradation products. The aim of the research work is to develop an innovative simple, accurate, precise, and selective HPLC method with the lesser use of organic solvents, for the quantification of anagliptin-related substances in the presence of its forced degradation products. The chromatographic separation was achieved on a YMC Pro C18 reversed-phase HPLC column (250 mm × 4.6 mm, 5 μ) with a runtime of 50 min. Mobile phase A and mobile phase B were chlorate buffer with pH 3.2 and acetonitrile respectively. The HPLC column oven temperature was set at 28°C and the photodiode array detector was set at 205 nm. The proposed test procedure has shown excellent linearity within the concentration range 0.081–6.296 μg/mL with correlation coefficient (r) about 0.9998. The limit of detection of anagliptin and related substances was observed within the range 0.052–0.106) μg/mL and the limit of quantification was observed within the range 0.156–0.317 μg/mL. The developed test procedure was successfully utilized for the quantification of related substances of anagliptin bulk drug without any interference with the degradation compounds. Hence, the test procedure can be utilized successfully in pharmaceutical organizations for the separation and quantification of anagliptin-related substances. [ABSTRACT FROM AUTHOR]

Shosaku Nomura,1 Akira Shouzu,2 Takehito Taniura,3 Yoshinori Okuda,4 Seitaro Omoto,5 Masahiko Suzuki,6 Tomoki Ito,7 Nagaoki Toyoda8 1Center of Thrombosis and Hemostasis, Kansai Medical University Medical Center, Moriguchi, Japan; 2Division of Diabetes, Saiseikai Izuo Hospital, Osaka, Japan; 3Division of Internal Medicine, Daiwa Hospital, Osaka, Japan; 4Division of Internal Medicine, Meisai Kinen Hospital, Osaka, Japan; 5Division of Internal Medicine, Yukeikai Hospital, Neyagawa, Japan; 6Division of Internal Medicine, Katano Hospital, Katano, Japan; 7First Department of Internal Medicine, Kansai Medical University, Hirakata, Japan; 8Second Department of Internal Medicine, Kansai Medical University, Hirakata, JapanCorrespondence: Shosaku Nomura, Center of Thrombosis and Hemostasis, Kansai Medical University Medical Center, 10-15 Fumizono-cho, Moriguchi, Osaka, 570-8507, Japan, Tel + 81 6 6992 1001, Fax + 81 6 6992 1066, Email shosaku-n@mbp.ocn.ne.jpPurpose: In people with type 2 diabetes mellitus (T2DM), both glucose metabolism abnormalities and atherosclerosis risk are significant concerns. This study aims to investigate the effects of the sodium-glucose cotransporter 2 inhibitor tofogliflozin (TOFO) and the dipeptidyl peptidase-4 inhibitor anagliptin (ANA) on markers of glucose metabolism and atherosclerosis when administered individually or in combination.Methods: Fifty T2DM patients were divided into two groups (receiving either TOFO or ANA monotherapy) and observed for 12 weeks (observation points: 0 and 12 weeks). The TOFO and ANA groups were then further treated with ANA and TOFO, respectively, and the patients were observed for an additional 36 weeks (observation points: 24 and 48 weeks). Therapeutic effects and various biomarkers were compared between the two groups at the observation points.Results: Combination therapy led to significant improvements in HbA1c levels and atherosclerosis markers. Additionally, the TOFO pretreatment group exhibited significant reductions in sLOX-1 and IL-6 levels.Conclusion: The increase in sLOX-1 and IL-6 levels, which indicates the response of scavenger receptors to oxidized low-density lipoproteins in people with T2DM, is mitigated following TOFO and ANA combination therapy. TOFO alone or in combination with ANA may be beneficial for preventing atherosclerosis development in people with T2DM, in addition to its effect on improving HbA1c levels.Keywords: tofogliflozin, anagliptin, type 2 diabetes mellitus, atherosclerosis, soluble LOX-1

Background Music therapy, as an emerging treatment, has a gradually evolving role in the rehabilitation of chronic diseases and is gaining increasing attention. But there are few studies on the effects of music therapy on diabetes rehabilitation. Objective To observe the effects of music assisted anagliptin on glycolipid metabolism in patients with type 2 diabetes. Methods Sixty five type 2 diabetic patients with poor glycemic control on oral agents who visited the outpatient clinic of Department of Endocrinology, Boai Hospital, China Rehabilitation Research Center, from October 2019 to February 2021 were selected. Patients were divided into group A (n=35) and group B (n=30) by random numbers, and patients in both groups maintained their original diet and exercise habits. Group A was treated with anagliptin tablets in combination with the original treatment (drug type, dose unchanged) , while group B was given music adjuvant therapy on the basis of group A. Patients in both groups were treated continuously for 12 weeks. Fasting plasma glucose (FPG) , glycated hemoglobin (HbA1c) , low-density lipoprotein cholesterol (LDL-C) , total cholesterol (TC) , triacylglycerol (TG) , high-density lipoprotein cholesterol (HDL-C) , uric acid (UA) , 2 h postprandial plasma glucose (2 hPG) , hypersensitivity C-reactive protein (hs-CRP) , free fatty acids (FFA) , insulin resistance index (HOMA-IR) , β Cell function secretion index (HOMA-β) before and 12 weeks after treatment were compared between the two groups. The patients were observed for the occurrence of adverse reactions during the treatment. Results One patient was eliminated from the trial because of adverse drug reactions during the course of the trial in both groups, and 34 and 29 patients finally completed the trial in groups A and B, respectively. Patients in group B had lower 2 hPG than those in group A after 12 weeks of treatment (P

Introduction: The effects of switching DPP-4 inhibitors in type 2 diabetes mellitus (T2DM) patients are being widely studied. However, information of which factors affect the therapeutic response is limited. We evaluated the difference in HbA1c lowering effect by comorbidity and other variables after switching to anagliptin in patients with T2DM inadequately controlled by other DPP-4 inhibitors. Methods: In a multicenter, open-label, single-arm, prospective observational study, patients with T2DM, HbA1c ≥ 7.0% who have taken DPP-4 inhibitors other than anagliptin, either alone or in combination (DPP-4 inhibitors + metformin/sulfonylurea (SU)/thiazolidinedione (TZD)/insulin), for at least 8 weeks were enrolled. After the switch to anagliptin, HbA1c and available clinical characteristics were determined. Results: The change in HbA1c levels from baseline to week 12 and 24 was − 0.40% and − 0.42% in all patients. However, comparing the subgroups without and with comorbidities, the change in HbA1c levels at weeks 12 and 24 was − 0.68% and − 0.89% vs. − 0.27% and 0.22%, respectively. In addition, the proportion of patients achieving HbA1c < 7% from baseline to week 12 and 24 was increased to 70% and 70% vs. 20% and 24%, respectively. Duration of T2DM and different subtype classes of DPP-4 inhibitor did not significantly contribute to the change in HbA1c. Conclusion: In patients with T2DM poorly controlled by other DPP-4 inhibitors, HbA1c levels were significantly decreased after switching to anagliptin. Given that the change in HbA1c was greater in patients without comorbidities than in patients with comorbidities, switching to anagliptin before adding other oral hypoglycemic agents (OHAs) may be an option in patients without comorbidities. [ABSTRACT FROM AUTHOR]

Introduction: The combination tablets of dipeptidyl peptidase-4 (DPP-4) inhibitors and metformin are used for both once-daily and twice-daily agents in Japan. If there is no difference in effectiveness between the once-daily and twice-daily DPP-4 inhibitor/metformin combination tablets, the once-daily agent is advantageous in terms of frequency of administration. The aim of this study was to compare the effectiveness of once-daily alogliptin/metformin combination tablet (alogliptin 25 mg/metformin 500 mg) and twice-daily anagliptin/metformin combination tablet low dose (LD) (anagliptin 100 mg/metformin 250 mg). Methods: Forty-eight Japanese patients with type 2 diabetes whose metformin administration of 250 mg twice daily had remained unchanged for at least 8 weeks, except when using DPP-4 inhibitors, glucagon-like peptide-1 receptor agonists, or insulin, were randomized to either the once-daily alogliptin/metformin combination tablet group or the twice-daily anagliptin/metformin combination tablet LD group. The primary endpoint was the difference in glycosylated hemoglobin (HbA1c) levels from baseline to week 12 of administration, whereas the secondary endpoints were fasting blood glucose, body mass index (BMI), and adherence. Results: Forty-four patients completed the study, and intention-to-treat analyses were performed. The adjusted mean value (standard error) for the change in HbA1c from week 0 to 12, was − 0.75 (0.109)% for the once-daily alogliptin/metformin combination tablet group and − 0.65 (0.109)% for the twice-daily anagliptin/metformin combination tablet LD group, with an intergroup difference of − 0.10% (95% confidence interval, CI − 0.407, 0.215). The upper limit of the bilateral 95% CI was 0.215%, below the 0.40% pre-defined as the non-inferiority margin. Fasting blood glucose, BMI, and adherence were not significantly different between the groups. Conclusions: The once-daily alogliptin/metformin combination tablet was non-inferior to the twice-daily anagliptin/metformin combination tablet LD in Japanese patients with type 2 diabetes. Trial Registration: University Hospital Medical Information Network Clinical Trial Registry (UMIN-CTR) (registration number: UMIN000034951). [ABSTRACT FROM AUTHOR]

Abstract Background Fatty acid-binding protein 4 (FABP4) acts as a novel adipokine, and elevated FABP4 concentration is associated with obesity, insulin resistance and atherosclerosis. Dipeptidyl peptidase-4 (DPP-4) inhibitors, a class of antidiabetic drugs, have distinct structures among the drugs, possibly leading to a drug class effect and each drug effect. Sitagliptin, a DPP-4 inhibitor, has been reported to decrease FABP4 concentration in drug-naïve and sulfonylurea-treated patients with type 2 diabetes mellitus. Anagliptin, another DPP-4 inhibitor, was shown to decrease low-density lipoprotein cholesterol (LDL-C) level to a greater extent than that by sitagliptin in the Randomized Evaluation of Anagliptin vs. Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) trial. Aim and methods As a sub-analysis study using data obtained from the REASON trial, we investigated the effects of treatment with anagliptin (n = 148, male/female: 89/59) and treatment with sitagliptin (n = 159, male/female: 93/66) for 52 weeks on FABP4 concentration in patients with type 2 diabetes mellitus at a high risk for cardiovascular events who were receiving statin therapy. Results The DPP-4 inhibitor had been administered in 82% of the patients in the anagliptin group and 81% of the patients in sitagliptin group prior to randomization. Serum FABP4 level was significantly decreased by 7.9% by treatment with anagliptin (P = 0.049) and was not significantly decreased by treatment with sitagliptin (P = 0.660). Change in FABP4 level was independently associated with basal FABP4 level and changes in waist circumference and creatinine after adjustment of age, sex and the treatment group. Conclusion Anagliptin decreases serum FABP4 concentration independent of change in hemoglobin A1c or LDL-C in patients with type 2 diabetes mellitus and dyslipidemia who are on statin therapy. Trial registration ClinicalTrials.gov number NCT02330406. Registered January 5, 2015, https://clinicaltrials.gov/ct2/show/NCT02330406

Cardiovascular complications are the leading cause of mortality and morbidity in type 2 diabetes patients. Diabetes greatly increases the risk of heart disease; therefore, the management of diabetes often involves the prevention of heart disease. DPP-4 inhibitors have been proven to be the effective therapeutic agents of glycaemic control. Recent studies have shown that certain types of DPP-4 inhibitors could also have cardiovascular benefits. In this study, we examined the protective role of the newly developed DPP-4 inhibitor anagliptin in cultured cardiac myocytic cell line H9C2 cells. Our data show that exposure of H9C2 cells to hypoxic conditions induced higher expression of DPP-4, indicating that DPP-4 is a hypoxia-inducible factor. The inhibition of DPP-4 by anagliptin ameliorates hypoxia-induced cytotoxicity and induction of the pro-inflammatory cytokines IL-6 and MCP-1. Anagliptin also suppresses hypoxia-induced oxidative stress as revealed by the detected levels of cellular ROS and reduced GSH. Moreover, anagliptin protects myocytes from hypoxia-associated reduced mitochondrial membrane potential. Mechanistically, we show that anagliptin promotes hypoxia-induced NFR2/HO1 induction but suppresses HMGB1 and MyD88 generation. Collectively, our data indicate that anagliptin-mediated DPP-4 inhibition is a protective mechanism in cardiomyocytes and imply that the DDP-4 inhibitor anagliptin plays dual roles by lowering glucose and protecting cardiomyocytes.

Abstract Background Anagliptin, a dipeptidyl peptidase-4 inhibitor, is reported to reduce the level of low-density lipoprotein cholesterol (LDL-C). The underlying mechanism of this effect and effect on lipid metabolism however remains uncertain. Aim and methods We therefore evaluate the effects of anagliptin on lipid metabolism-related markers compared with those of sitagliptin. The study was a secondary analysis using data obtained from the Randomized Evaluation of Anagliptin versus Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) trial. This trial in patients with type 2 diabetes at a high risk of cardiovascular events and on statin therapy showed that anagliptin reduced LDL-C levels to a greater extent than sitagliptin. Cholesterol absorption (campesterol and sitosterol) and synthesis (lathosterol) markers were measured at baseline and 52 weeks in the study cohort (n = 353). Results There was no significant difference in the changes of campesterol or sitosterol between the two treatment groups (p = 0.85 and 0.55, respectively). Lathosterol concentration was increased significantly at 52 weeks with sitagliptin treatment (baseline, 1.2 ± 0.7 μg/mL vs. 52 weeks, 1.4 ± 1.0 μg/mL, p = 0.02), whereas it did not change in the anagliptin group (baseline, 1.3 ± 0.8 μg/mL vs. 52 weeks, 1.3 ± 0.7 μg/mL, p = 0.99). The difference in absolute change between the two groups showed a borderline significance (p = 0.06). Conclusion These findings suggest that anagliptin reduces LDL-C level by suppressing excess cholesterol synthesis, even in combination with statin therapy. Trial registration ClinicalTrials.gov number NCT02330406. https://clinicaltrials.gov/ct2/show/NCT02330406; registered January 5, 2015.

Osteoporosis is a common debilitating bone disease characterized by loss of bone mass and degradation of the bone architecture, which is primarily driven by dysregulated differentiation of mesenchymal stem cells into bone-producing osteoblasts. Osteoblasts contribute to bone formation by secreting various proteins that guide the deposition of bone extracellular matrix, such as alkaline phosphatase (ALP), osteocalcin (OCN), and osteopontin (OPN). The Wnt/β-catenin pathway is widely recognized as a regulator of bone mass and is required to maintain bone homeostasis. Hormones have long been recognized as playing a key role in bone metabolism, and in recent years, growing evidence has shown that diabetes is a risk factor for osteoporosis. In the present study, we investigated the effects of the antidiabetic drug anagliptin on the differentiation and mineralization of osteoblasts induced by osteogenic medium. Anagliptin promotes insulin production via inhibition of dipeptidyl peptidase IV (DPP-4), an enzyme that targets the incretin hormone glucagon-like peptide 1 (GLP-1) for degradation. Our findings show that anagliptin significantly increases the differentiation of MSCs into osteoblasts via activation of RUNX2. Anagliptin significantly increased matrix deposition and mineralization by osteoblasts, as evidenced by elevated levels of ALP, OCN, OPN, and BMP-2. We further demonstrate that anagliptin activates the canonical and noncannonical Wnt signaling pathways and that silencing of Wnt/β-catenin signaling completely abolished the effects of anagliptin. Thus, anagliptin might be a safe, effective therapy for type II diabetes that might show promise as a therapy against osteoporosis.

Platelet-derived growth factor-B (PDGF-B) is a main factor to promote adipose tissue angiogenesis, which is responsible for the tissue expansion in obesity. In this process, PDGF-B induces the dissociation of pericytes from blood vessels; however, its regulatory mechanism remains unclear. In the present study, we found that stromal cell-derived factor 1 (SDF1) plays an essential role in this regulatory mechanism. SDF1 mRNA was increased in epididymal white adipose tissue (eWAT) of obese mice. Ex vivo pharmacological analyses using cultured adipose tissue demonstrated that physiological concentrations (1–100 pg/mL) of SDF1 inhibited the PDGF-B-induced pericyte dissociation from vessels via two cognate SDF1 receptors, CXCR4 and CXCR7. In contrast, higher concentrations (> 1 ng/mL) of SDF1 alone caused the dissociation of pericytes via CXCR4, and this effect disappeared in the cultured tissues from PDGF receptor β (PDGFRβ) knockout mice. To investigate the role of SDF1 in angiogenesis in vivo, the effects of anagliptin, an inhibitor of dipeptidyl peptidase 4 (DPP4) that degrades SDF1, were examined in mice fed a high-fat diet. Anagliptin increased the SDF1 levels in the serum and eWAT. These changes were associated with a reduction of pericyte dissociation and fat accumulation in eWAT. AMD3100, a CXCR4 antagonist, cancelled these anagliptin effects. In flow-cytometry analysis, anagliptin increased and decreased the PDGF-B expression in endothelial cells and macrophages, respectively, whereas anagliptin reduced the PDGFRβ expression in pericytes of eWAT. These results suggest that SDF1 negatively regulates the adipose tissue angiogenesis in obesity by altering the reactivity of pericytes to PDGF-B. [ABSTRACT FROM AUTHOR]

Aims: To investigate the effect of anagliptin (Ana), a dipeptidyl peptidase‐4 (DPP‐4) inhibitor, on acute ischemia‐induced bladder dysfunction in rats. Methods: Eight‐week‐old female Wistar‐ST rats were randomly assigned into four groups: (a) sham; (b) ligation (Lig); (c) Lig + Ana; and (d) Lig + Liraglutide (a glucagon‐like peptide‐1 [GLP‐1] receptor agonist; Lira). Rats in the Lig, Lig + Ana, and Lig + Lira groups underwent ligature of the bilateral internal iliac arteries. Ana was orally administered mixed with the CE‐2 diet. Lira was subcutaneously administered once a day. Blood glucose levels, plasma dipeptidyl peptidase 4 (DPP‐4) activity, GLP‐1 levels, and bladder function were measured in all groups. Bladder blood flow was measured in the sham, Lig, and Lig + Ana groups, 4 weeks postsurgery. Results: No differences in blood glucose levels among the groups were observed. DPP‐4 activity decreased in the Lig + Ana group (P <.01). GLP‐1 levels in the Lig + Ana and Lig + Lira groups were higher than those in the sham and Lig groups (P <.01). Intercontraction intervals (ICIs) were longer in the Lig and Lig + Lira groups than in the sham group (P <.05), but similar to those observed in the Lig + Ana and sham groups. The Lig group exhibited reduced bladder blood flow relative to the sham group (P <.01); however, this measure improved in the Lig + Ana group (P <.01). Conclusions: Ana administration improved ICIs and bladder blood flow after acute bladder ischemia through a GLP‐1 receptor‐independent signaling pathway, without altering the blood glucose levels. Therefore, Ana dosing might be useful to prevent ischemia‐induced bladder dysfunctions. [ABSTRACT FROM AUTHOR]

Background: Fatty acid-binding protein 4 (FABP4) acts as a novel adipokine, and elevated FABP4 concentration is associated with obesity, insulin resistance and atherosclerosis. Dipeptidyl peptidase-4 (DPP-4) inhibitors, a class of antidiabetic drugs, have distinct structures among the drugs, possibly leading to a drug class effect and each drug effect. Sitagliptin, a DPP-4 inhibitor, has been reported to decrease FABP4 concentration in drug-naïve and sulfonylurea-treated patients with type 2 diabetes mellitus. Anagliptin, another DPP-4 inhibitor, was shown to decrease low-density lipoprotein cholesterol (LDL-C) level to a greater extent than that by sitagliptin in the Randomized Evaluation of Anagliptin vs. Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) trial. Aim and methods: As a sub-analysis study using data obtained from the REASON trial, we investigated the effects of treatment with anagliptin (n = 148, male/female: 89/59) and treatment with sitagliptin (n = 159, male/female: 93/66) for 52 weeks on FABP4 concentration in patients with type 2 diabetes mellitus at a high risk for cardiovascular events who were receiving statin therapy. Results: The DPP-4 inhibitor had been administered in 82% of the patients in the anagliptin group and 81% of the patients in sitagliptin group prior to randomization. Serum FABP4 level was significantly decreased by 7.9% by treatment with anagliptin (P = 0.049) and was not significantly decreased by treatment with sitagliptin (P = 0.660). Change in FABP4 level was independently associated with basal FABP4 level and changes in waist circumference and creatinine after adjustment of age, sex and the treatment group. Conclusion: Anagliptin decreases serum FABP4 concentration independent of change in hemoglobin A1c or LDL-C in patients with type 2 diabetes mellitus and dyslipidemia who are on statin therapy. Trial registration ClinicalTrials.gov number NCT02330406. Registered January 5, 2015, https://clinicaltrials.gov/ct2/show/NCT02330406 [ABSTRACT FROM AUTHOR]

To investigate the regulatory effects of anagliptin, a DPP‐IV inhibitor used to treat type 2 diabetes mellitus (T2DM), on myoblast differentiation and mitochondrial biogenesis in C2C12 mouse skeletal muscle cells. C2C12 myoblasts were differentiated into myotubes and then treated with anagliptin (10, 25, and 50 μmol/L) for 24 hours. In C2C12 myotubes, anagliptin treatment was significantly increased the expression of MHC, PGC1α, Sirt‐1, NRF‐1, and TFAM and the phosphorylation of AMPK and ACC in a concentration‐dependent manner. Anagliptin also significantly increased the total ATP levels in the myotubes. These results suggest that anagliptin can help prevent skeletal muscle dysfunction in T2DM by promotion of myoblast differentiation and enhancement of energy production via upregulation of mitochondrial biogenetic factors and activation of the AMPK/ACC signalling pathway. [ABSTRACT FROM AUTHOR]

Cardiovascular complications are the leading cause of mortality and morbidity in type 2 diabetes patients. Diabetes greatly increases the risk of heart disease; therefore, the management of diabetes often involves the prevention of heart disease. DPP-4 inhibitors have been proven to be the effective therapeutic agents of glycaemic control. Recent studies have shown that certain types of DPP-4 inhibitors could also have cardiovascular benefits. In this study, we examined the protective role of the newly developed DPP-4 inhibitor anagliptin in cultured cardiac myocytic cell line H9C2 cells. Our data show that exposure of H9C2 cells to hypoxic conditions induced higher expression of DPP-4, indicating that DPP-4 is a hypoxia-inducible factor. The inhibition of DPP-4 by anagliptin ameliorates hypoxia-induced cytotoxicity and induction of the pro-inflammatory cytokines IL-6 and MCP-1. Anagliptin also suppresses hypoxia-induced oxidative stress as revealed by the detected levels of cellular ROS and reduced GSH. Moreover, anagliptin protects myocytes from hypoxia-associated reduced mitochondrial membrane potential. Mechanistically, we show that anagliptin promotes hypoxia-induced NFR2/HO1 induction but suppresses HMGB1 and MyD88 generation. Collectively, our data indicate that anagliptin-mediated DPP-4 inhibition is a protective mechanism in cardiomyocytes and imply that the DDP-4 inhibitor anagliptin plays dual roles by lowering glucose and protecting cardiomyocytes. [ABSTRACT FROM AUTHOR]

Background: Anagliptin, a dipeptidyl peptidase-4 inhibitor, is reported to reduce the level of low-density lipoprotein cholesterol (LDL-C). The underlying mechanism of this effect and effect on lipid metabolism however remains uncertain. Aim and methods: We therefore evaluate the effects of anagliptin on lipid metabolism-related markers compared with those of sitagliptin. The study was a secondary analysis using data obtained from the Randomized Evaluation of Anagliptin versus Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) trial. This trial in patients with type 2 diabetes at a high risk of cardiovascular events and on statin therapy showed that anagliptin reduced LDL-C levels to a greater extent than sitagliptin. Cholesterol absorption (campesterol and sitosterol) and synthesis (lathosterol) markers were measured at baseline and 52 weeks in the study cohort (n = 353). Results: There was no significant difference in the changes of campesterol or sitosterol between the two treatment groups (p = 0.85 and 0.55, respectively). Lathosterol concentration was increased significantly at 52 weeks with sitagliptin treatment (baseline, 1.2 ± 0.7 μg/mL vs. 52 weeks, 1.4 ± 1.0 μg/mL, p = 0.02), whereas it did not change in the anagliptin group (baseline, 1.3 ± 0.8 μg/mL vs. 52 weeks, 1.3 ± 0.7 μg/mL, p = 0.99). The difference in absolute change between the two groups showed a borderline significance (p = 0.06). Conclusion: These findings suggest that anagliptin reduces LDL-C level by suppressing excess cholesterol synthesis, even in combination with statin therapy. Trial registration ClinicalTrials.gov number NCT02330406. https://clinicaltrials.gov/ct2/show/NCT02330406; registered January 5, 2015. [ABSTRACT FROM AUTHOR]

Highlights • Anagliptin attenuates high glucose- induced cell death, mitochondrial ROS, and NOX-4. • Anagliptin attenuates high glucose- induced expression of TXNIP. • Anagliptin inhibits NLRP3 inflammasome activation and IL-1β/IL-18 maturation. • The effects of Anagliptin on NLRP3 inflammasome activation are mediated by SIRT1. Abstract High glucose- induced endothelial dysregulation has been recognized as an initiation of vascular complications in Type 2 diabetes mellitus (T2DM). Anagliptin is a novel licensed dipeptidyl peptidase-4 (DPP-4) inhibitor for the treatment of T2DM. The effects of anagliptin in high glucose- induced endothelial dysfunction are less reported. In the current study, we found that treatment with anagliptin prevented high glucose- induced reduction of cell viability and increase in LDH release in human umbilical vein endothelial cells (HUVECs). Our results indicate that anagliptin- reduced high glucose- induced increase in mitochondrial ROS and NOX-4 expression. Additionally, anagliptin treatment inhibited high glucose- induced expressions of TXNIP in HUVECs. Importantly, anagliptin treatment downregulated high glucose- induced NLRP3 inflammasome activation, as evidenced by reducing the expressions of NLRP3, ASC, and cleaved caspase-1 (P10). Also, ELISA results demonstrate that anagliptin treatment significantly abolished high glucose- induced maturation of IL-1β and IL-18. Mechanistically, we found that anagliptin treatment restored high glucose- induced reduction of SIRT1 expression. Silencing of SIRT1 by transfection with SIRT1 siRNA abolished the inhibitory effects of anagliptin in NLRP3 inflammasome activation. These results display that anagliptin may confer protection against high glucose- induced endothelial injury via SIRT1-dependent inhibition of NLRP3 infammasome activation. [ABSTRACT FROM AUTHOR]

A gradient-specific stability indicating HPLC method was developed and validated for the determination of the antidiabetic agent anagliptin in laboratory mixtures. Reversed-phase chromatography was performed using a Shimadzu LC-20 AD pump (binary), Shimadzu PDA M-20A diode array detector, and Waters Symmetry C-18 column (150 × 4.6 mm, 3.5 µm) maintained at a column oven temperature of 40 °C with UV detection at 247 nm. A gradient program was run at flow rate of 1 mL min−1. Mobile phase A consisted of a mixture of acetate buffer(10 mm) pH 5/methanol/acetonitrile in the ratio of 90:5:5. Mobile phase B consisted of a mixture of acetate buffer (10 mm) pH 5/methanol/acetonitrile in the ratio of 50:25:25. The method was validated according International Conference of Harmonization (ICH) guidelines. Linearity was observed in the concentration range of 10-120 µg/mL with regression coefficient r2(0.999). The LOD was found to be 7.8 µg/mL and LOQ was found to be 22.68 µg/mL. Anagliptin was subjected to stresses such as acidic, alkali, oxidation, photolysis, and thermal conditions. The proposed method was validated as per ICH guidelines and was found to be accurate, precise, and specific. The drug showed significant degradation in alkaline and oxidative conditions. Alkaline and oxidative degradation followed first-order kinetics. Degradation rate constant and half-lives were determined. Degradation products in alkaline and oxidative conditions were identified by LC-MS. One major degradation product was isolated from each condition by preparative HPLC. These degradation products were characterized by 1H NMR, 13C NMR, DEPT, D2O exchange, MS/MS, HRMS, and IR techniques. From the spectral data the alkaline degradation product was characterized as 1-{2-[1-(2-methylpyrazolo[1,5-a]pyrimidine-6-carboxamido)-methyl-propan-2-yl-amino]acetyl}pyrrolidine-2-carboxamide. The oxidative degradation product was characterized as N-[2-({2-[(2S)-2-cyanopyrrolidin-1-yl]-2-oxoethyl}amino)-2-methylpropyl]-2-methylpyrazolo-[1,5-a]pyrimidine-N-oxido-6-carboxamide. [ABSTRACT FROM AUTHOR]

Magnetic solid-phase extraction based on the adsorption of sodium dodecyl sulfate on the surface of Fe3O4 nanoparticles was used to isolate the new hypoglycemic drug anagliptin in human and mouse serum before determination by high-performance liquid chromatography. The magnetic adsorbent was characterized by transmission electron microscopy, Fourier transform infrared spectroscopy, and the zeta potential. The factors affecting the extraction performance such as the type of surfactant, the amount of adsorbent and sodium dodecyl sulfate, pH of solution, time and temperature of adsorption and elution, and eluent type were examined. Under the optimized conditions, the adsorbent could be reused for six times and the efficiency of extraction or elution was over 95.0%. The calibration curve was linear in the range of 0.050-4.00 µg mL−1, with detection limits of 0.021 and 0.023 µg mL−1 for human and mouse serum, respectively. The recovery values of 92.0-99.1% (human serum) or 94.8-105.7% (mouse serum) illustrated the accuracy of the proposed method. Moreover, it may be the first time that this extraction method has been used to determine anagliptin in biological liquids. [ABSTRACT FROM AUTHOR]

Pharmaceutical drugs are potential molecules with specific biological activity. However, long-term use of these chemical molecules can affect the human physiological system because of their increased levels in the human body. Therefore, identification and structure elucidation of impurities or degradation products should be taken into consideration in order to assure drug safety. The present study assessed the degradation behaviour of dipeptidyl peptidase-4 (DPP-4) inhibitor anagliptin under different stress conditions as per ICH guidelines Q1A (R2) followed by elucidation of the structure of degradation products. All the stress samples were analysed by using UPLC/PDA. The superior separation of drug from its degradation products was attained with time programmed gradient elution on BEH C18 (100 mm × 2.1 mm, 1.7 μm) column using 10 mM ammonium formate (aqueous) and acetonitrile (organic) as the mobile phase components. All the degradation products of anagliptin were characterized using LC/QTOF/MS/MS. In addition, the activity and toxicity of degradation products were determined through molecular docking and in silico toxicity prediction studies, respectively. The developed UPLC/PDA method was validated as per ICH guidelines in terms of specificity, accuracy, precision, linearity and robustness. [ABSTRACT FROM AUTHOR]

The present study evaluated the effect of anagliptin on intimal hyperplasia following carotid artery injury in Sprague-Dawley rats. Sprague-Dawley rats weighing 280-300 g were injured using a 2F Fogarty balloon embolectomy catheter. The rats were divided into injury-(saline) and anagliptin-(10 mg/kg/day) treated groups. vascular injuries were induced in the left carotid artery, followed by evaluation of neointima formation at 28 days. The right and left carotid arteries were harvested and evaluated with histological evaluation, and the plasma activity of glucagon-like peptide 1 receptor (GLP-1), stromal cell-derived factor (SDF)-1α, interleukin (IL)-6, IL-1β and tumor necrosis factor (TNF)-α were detected by ELISA analysis. Treatment with anagliptin decreased balloon injury-induced neointima formation, compared with the injury group (P<0.01). Body weight and food consumption did not alter following treatment with anagliptin. Anagliptin caused an increase in the serum active GLP-1 concentration, compared with the injury group. In addition, serum SDF-1α was significantly decreased by treatment with anagliptin (P<0.001). Anagliptin altered the serum activity of IL-6, IL-1β and TNF-α (P<0.01). The results of the present study demonstrated that anagliptin appeared to attenuate neointimal formation by inhibiting inflammatory cytokines and chemokines following balloon injury, and that treatment with a dipeptidyl peptidase 4 inhibitor may be useful for future preclinical studies and potentially for the inhibition of thrombosis formation following percutaneous coronary intervention. [ABSTRACT FROM AUTHOR]

This paper comprehends systematic Quality by Design (QbD) based development of Normal-Phase High-Performance Thin-Layer Chromatography (NP-HPTLC) method for qualitative and quantitative estimation of anagliptin in bulk and in-house tablets. Chromatographic separation was executed out on aluminum backed Silica gel F254 plates using dichloromethane: methanol (9.2:0.8 v/v) as a mobile phase. Densitometry scanning was accomplished at 248 nm. Quality target method profile was defined and critical analytical attributes (CAAs) for the HPTLC method set aside. The mobile phase ratio and saturation time were determinate as critical method parameters (CMPs) and systematically optimized using Central composite design, evaluating for CAAs, namely retention factor (Rf), Peak-area and Peak-height. Statistical modelization was implemented followed by response surface analysis for comprehending plausible interaction(s) among CMPs. Search for optimum solution was conducted through numerical and graphical optimization for demarcating the design space. The described method was linear. The precision, ruggedness, and robustness values were also within the prescribed limit. The studies successfully demonstrate the utility of QbD approach for developing the highly sensitive HPTLC method with enhanced method performance. [ABSTRACT FROM AUTHOR]

Aims/Introduction Dipeptidyl peptidase-4 inhibitors are used for treatment of patients with type 2 diabetes. In addition to glycemic control, these agents showed beneficial effects on lipid metabolism in clinical trials. However, the mechanism underlying the lipid-lowering effect of dipeptidyl peptidase-4 inhibitors remains unclear. Here, we investigated the lipid-lowering efficacy of anagliptin in a hyperlipidemic animal model, and examined the mechanism of action. Materials and Methods Male low-density lipoprotein receptor-deficient mice were administered 0.3% anagliptin in their diet. Plasma lipid levels were assayed and lipoprotein profile was analyzed using high-performance liquid chromatography. Hepatic gene expression was examined by deoxyribonucleic acid microarray and quantitative polymerase chain reaction analyses. Sterol regulatory element-binding protein transactivation assay was carried out in vitro. Results Anagliptin treatment significantly decreased the plasma total cholesterol (14% reduction, P < 0.01) and triglyceride levels (27% reduction, P < 0.01). Both low-density lipoprotein cholesterol and very low-density lipoprotein cholesterol were also decreased significantly by anagliptin treatment. Sterol regulatory element-binding protein-2 messenger ribonucleic acid expression level was significantly decreased at night in anagliptin-treated mice (15% reduction, P < 0.05). Anagliptin significantly suppressed sterol regulatory element-binding protein activity in HepG2 cells (21% decrease, P < 0.001). Conclusions The results presented here showed that the dipeptidyl peptidase-4 inhibitor, anagliptin, exhibited a lipid-lowering effect in a hyperlipidemic animal model, and suggested that the downregulation of hepatic lipid synthesis was involved in the effect. Anagliptin might have beneficial effects on lipid metabolism in addition to a glucose-lowering effect. [ABSTRACT FROM AUTHOR]

The current research concern about the development of stereo specific normal phase high performance liquid chromatographic method for the separation and estimation of enantiopurity of anagliptin (AGT) by using Lux cellulose-3 [cellulose tris (4-benzoate)] chiral column, n-Hexane, ethanol and triethylamine (TEA) (80:20:0.5 v/v/v) solvent ratios were used as mobile phase at flow rate of 1ml/min in isocratic mode. Both AGT-(R) (desired form) and AGT-(S) (undesired form) detected at 254 nm with retention time of 9.11 min and at 8.09 min respectively, and having correlation coefficient (R2) of 0.999. Inter day and intraday precision of the developed method was < 1.0 % RSD and % mean recovery was found to be 99.074. Enantioselective method was validated for linearity, precision, accuracy, limit of detection & quantification, solution stability, robustness and ruggedness, developed method can be used for the separation and estimation of enantiopuirty of AGT-(R) in recemate mixture. [ABSTRACT FROM AUTHOR]

Anagliptin is a Dipeptidyl peptidase-4 (DPP-4) inhibitor used in the treatment of diabetes. Five simple, specific, sensitive, rapid and economical UV-Spectrophotometry methods have been established for the determination of Anagliptin in bulk and in-house tablets. All five methods of UVSpectrophotometry based upon Zero Order, First Order and Second Order derivative Spectrophotometry have been established considering amplitude and Area under Curve of the spectrum. In all five methods, Anagliptin obeyed linearity in the concentration range of 2-8 µg/mL with correlation coefficient (r2>0.999). The % amount of drug estimated in the developed methods was found to be good agreement with label claimed in in-house tablet formulation. All the methods were validated as per International conference on Harmonization (ICH) guidelines. All these proposed methods were proved to be linear, accurate, precise and rugged and also adequately sensitive. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2DM) is a progressive disease, and pharmacotherapy with a single agent does not generally provide durable glycaemic control over the long term. Sulphonylurea (SU) drugs have a history stretching back over 60 years, and have traditionally been the mainstay choice as second‐line agents to be added to metformin once glycaemic control with metformin monotherapy deteriorates; however, they are associated with undesirable side effects, including increased hypoglycaemia risk and weight gain. Dipeptidyl peptidase (DPP)‐4 inhibitors are, by comparison, more recent, with the first compound being launched in 2006, but the class now globally encompasses at least 11 different compounds. DPP‐4 inhibitors improve glycaemic control with similar efficacy to SUs, but do not usually provoke hypoglycaemia or weight gain, are relatively free from adverse side effects, and have recently been shown not to increase cardiovascular risk in large prospective safety trials. Because of these factors, DPP‐4 inhibitors have become an established therapy for T2DM and are increasingly being positioned earlier in treatment algorithms. The present article reviews these two classes of oral antidiabetic drugs (DPP‐4 inhibitors and SUs), highlighting differences and similarities between members of the same class, as well as discussing the potential advantages and disadvantages of the two drug classes. While both classes have their merits, the choice of which to use depends on the characteristics of each individual patient; however, for the majority of patients, DPP‐4 inhibitors are now the preferred choice. [ABSTRACT FROM AUTHOR]