Selective Dipeptidyl Peptidase-4 Inhibitor Research Articles

Sitagliptin Reduces Endothelial Dysfunction and Apoptosis Induced by High-Fat Diet and Palmitate in Thoracic Aortas and Endothelial Cells via ROS-ER Stress-CHOP Pathway

Macrovascular disease is tightly associated with obesity-induced metabolic syndrome. Sitagliptin (SIT), an orally stable selective inhibitor of Dipeptidyl peptidase-4 (DPP-4), has protective effects on endothelium. However, the mechanisms enabling SIT to exhibit resistance to diet-induced obesity (DIO) related with reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress in the aorta and endothelial cells have not been reported yet. Therefore, the present study was conducted to determine if SIT exerts protective role in the thoracic aortas isolated from the high-fat diet (HFD)-treated rats and palmitate (PA)-treated endothelial cells by alleviating ROS and ER stress. Male Sprague Dawley rats were randomly divided into standard chow diet (SCD), HFD and HFD plus sitagliptin administration (HFD + SIT) groups. The rats of latter two groups were given HFD fodder for 12 weeks, then the HFD + SIT rats were treated with SIT (10 mg/kg/d) by intragastric administration for another 8 weeks. The body mass, vascular tension, serum oxidative stress indices and inflammatory parameters, pathological changes, protein expression of endothelial nitric oxide synthase (eNOS), the genes associated with ER stress and apoptosis in the thoracic aorta were measured. Furthermore, cell proliferation, ROS and the protein expression associated with ER stress (especially CHOP) and apoptosis were assessed in human umbilical vein endothelial cells (HUVECs) incubated with SIT and PA. Compared to the SCD rats, the HFD rats had higher serum lipid levels, decreased vascular tension, increased inflammation, oxidative and ER stress, and apoptosis of endothelial cells. PA promoted ROS generation, ER stress and apoptosis, inhibited cell proliferation in HUVECs. SIT treatment obviously ameliorated apoptosis via alleviating ROS and ER stress in the thoracic aortas isolated from HFD-fed rats and PA-treated HUVECs. The results suggest that SIT improved endothelial function via promoting cell proliferation and alleviating ROS-ER stress-CHOP pathway both in vivo and in vitro.

Omarigliptin Prevents TNF-α-Induced Cellular Senescence in Rat Aorta Vascular Smooth Muscle Cells.

Cellular senescence is one of the most significant factors involved in aging and age-related diseases. Senescence of vascular smooth muscle cells (VSMCs) adversely affects the function of the cardiovascular system and contributes to the development of atherosclerosis, hypertension, and other cardiovascular diseases. Glucagon-like peptide-1 (GLP-1) is an important incretin hormone involved in insulin release and vascular tone. GLP-1 is quickly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4). Omarigliptin is a new DPP-4 inhibitor that has demonstrated anti-inflammatory and antioxidative stress properties. In the present study, we investigated the effects of the selective DPP-4 inhibitor omarigliptin (OMG) on VSMCs exposed to insult from tumor necrosis factor-α (TNF-α), one of the main inflammatory signaling molecules involved in cellular senescence. We found that OMG could suppress TNF-α-induced expression of pro-inflammatory cytokines (interleukin-1β (IL-1β), IL-6, and IL-8) and inhibit oxidative stress by reducing the production of H2O2 and protein carbonyl. OMG ameliorated the increase in senescence-associated β-galactosidase (SA-β-gal) and telomerase activity induced by TNF-α. The plasminogen activator inhibitor-1 (PAI-1)/p53/p21 pathway is a key inducer of cellular senescence. OMG ameliorated the acetylation of p53 at lysine 382 (K382) and subsequent activation of p21 via inhibition of PAI-1. Importantly, our experiments revealed that blockage of silent information-regulator 1 (SIRT1) abolished the inhibitory effects of OMG on p53 acetylation, SA-β-gal activity, and telomerase activity in VSMCs. These results suggest that OMG may have the potential to delay or prevent the progression of age-related cardiovascular diseases by modulating the activity of SIRT1.

In vitro study of the drug–drug interaction potential of cetagliptin and clinical study of pharmacokinetic interaction of cetagliptin and metformin in healthy volunteers

Cetagliptin is an oral, potent, and newly developed selective inhibitor of dipeptidyl peptidase-4 (DPP-4). We evaluated the in vitro drug–drug interaction (DDI) potential of cetagliptin, as well as the pharmacokinetics of cetagliptin and metformin and the interaction between cetagliptin and metformin. Cetagliptin did not inhibit CYP1A2, CYP2C8, CYP2B6, CYP2C9, CYP2C19, and CYP3A4, only has a moderate inhibitory effect on CYP2D6, and did not induce CYP1A2, CYP2B6, and CYP3A4. Plasma protein binding of cetagliptin didn’t have species differences or concentration dependence. Cetagliptin was a substrate for P-glycoprotein (P-gp). The 34 healthy subjects enrolled were randomly divided into two sequences (A and B) with 17 subjects in each sequence. Coadministration with metformin had no effect on cetagliptin AUC0–120 (GMR, 99.25%; 90% CI, 95.96%–102.65%). There was a slightly increase in cetagliptin C max (GMR, 117.33%; 90% CI, 102.54%–134.25%). Coadministration with cetagliptin did not affect the metformin’s AUC0–24 (GMR, 108.54%; 90% CI, 101.41%–116.17%) or C max (GMR, 97.67%; 90% CI, 90.96%–104.89%). Based on in vitro study results, cetagliptin is unlikely to cause CYP-mediated, clinically relevant DDI. Although the possibility of transporter-mediated, clinically relevant DDI cannot be ruled out, there is little or no risk of side effects. Coadministration of cetagliptin and metformin had no clinically meaningful effect on the pharmacokinetics of each drug. There was no drug–drug interaction between cetagliptin and metformin. Both monotherapies and combination therapy were well tolerated. No serious AEs and hypoglycaemia was reported.

Novel Potent and Selective DPP-4 Inhibitors: Design, Synthesis and Molecular Docking Study of Dihydropyrimidine Phthalimide Hybrids.

Background: Dipeptidyl peptidase-4 (DPP-4) inhibitors have emerged as anti-hyperglycemic agents that improve glycemic control in type 2 diabetic patients, either as monotherapy or in combination with other antidiabetic drugs. Methods: A novel series of dihydropyrimidine phthalimide hybrids was synthesized and evaluated for their in vitro and in vivo DPP-4 inhibition activity and selectivity using alogliptin as reference. Oral glucose tolerance test was assessed in type 2 diabetic rats after chronic treatment with the synthesized hybrids ± metformin. Cytotoxicity and antioxidant assays were performed. Additionally, molecular docking study with DPP-4 and structure activity relationship of the novel hybrids were also studied. Results: Among the synthesized hybrids, 10g, 10i, 10e, 10d and 10b had stronger in vitro DPP-4 inhibitory activity than alogliptin. Moreover, an in vivo DPP-4 inhibition assay revealed that 10g and 10i have the strongest and the most extended blood DPP-4 inhibitory activity compared to alogliptin. In type 2 diabetic rats, hybrids 10g, 10i and 10e exhibited better glycemic control than alogliptin, an effect that further supported by metformin combination. Finally, 10j, 10e, 10h and 10d had the highest radical scavenging activity in DPPH assay. Conclusions: Hybrids 10g, 10i and 10e are potent DPP-4 inhibitors which may be beneficial for T2DM treatment.

Activation of autophagy by sitagliptin attenuates cadmium-induced testicular impairment in rats: Targeting AMPK/mTOR and Nrf2/HO-1 pathways

AimsCadmium (Cd) is a prevalent environmental contaminant that incurs deleterious health effects, including testicular impairment. Sitagliptin, a selective dipeptidyl peptidase-4 (DPP-4) inhibitor, has demonstrated marked cardio-, hepato-, and reno-protective actions, however, its impact on Cd-triggered testicular dysfunction has not been formerly investigated. Hence, the present study aimed to explore the probable beneficial impact of sitagliptin against Cd-evoked testicular impairment which may add to its potential clinical utility. The underlying mechanisms pertaining to the balance between testicular autophagy and apoptosis were explored, including the AMPK/mTOR and Nrf2/HO-1 pathways. Materials and methodsThe testicular tissues were examined using histopathology, immunohistochemistry, Western blotting, and ELISA. Sitagliptin (10 mg/kg/day, by gavage) was administered for 4 consecutive weeks. Key findingsSitagliptin attenuated the testicular impairment via improvement of the relative testicular weight, sperm count/motility, sperm abnormalities, and serum testosterone. Additionally, sitagliptin counteracted Cd-induced histologic aberrations/disrupted spermatogenesis. Interestingly, sitagliptin augmented the defective autophagy as demonstrated by upregulating Beclin 1 protein expression and lowering p62 SQSTM1 protein accumulation. These effects were mediated via the activation of testicular AMPK/mTOR pathway as proven by increasing p-AMPK (Ser485, Ser491)/total AMPK and diminishing p-mTOR (Ser2448)/total mTOR protein expression. Additionally, sitagliptin suppressed the testicular apoptotic events via downregulating Bax and upregulating Bcl-2 protein expression. In tandem, sitagliptin suppressed the oxidative stress through lowering lipid peroxides and activating Nrf2/HO-1 pathway via upregulating the protein expression of Nrf2, and the downstream effectors HO-1 and GPx. SignificanceSitagliptin attenuated Cd-induced testicular injury via boosting the autophagy/apoptosis ratio through activation of AMPK/mTOR and Nrf2/HO-1 pathways.

Hepatoprotective effect of dipeptidyl peptidase-4 inhibitor sitagliptin against carbon tetrachloride-induced liver fibrosis in mice

Background and Aim Sitagliptin is a selective dipeptidyl peptidase-4 inhibitor that is used worldwide to ameliorate hyperglycemia and insulin insensitivity-induced dysmetabolism. The current study assessed the effect of sitagliptin as well as silymarin (the standard hepatoprotective drug) against experimentally carbon tetrachloride (CCl4)-induced liver toxicity in male mice. Materials and methods Mice chronic liver fibrosis models were established and divided into olive oil-induced control group, CCl4-induced model group, silymarin-treated group, and sitagliptin-treated group. Hepatic fibrotic changes were evaluated by measuring hepatic enzymes (alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase), histopathological score, activation of hepatic stellate cells (α-smooth muscle actin expression with special stain), and oxidative stress (malondialdehyde, glutathione, total nitrate/nitrite, and manganese superoxide dismutase levels). Results The injection of mice with CCl4 for 7 weeks resulted in a marked elevation of hepatic fibrotic changes and reduction of glutathione level; both silymarin and sitagliptin therapy showed a significant decrease in the fibrotic changes and a significant increase in endogenous antioxidants. Conclusion This study shows that sitagliptin ameliorates hepatic fibrosis in mice and announces a new strategy for treating hepatic fibrosis in humans.

Effects and Safety of Sitagliptin in Non-Alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis.

Non-alcoholic fatty liver disease (NAFLD) is currently the most common cause of chronic liver disease. However, the treatment is limited. The aim of this meta-analysis was to evaluate the effects and safety of sitagliptin, a selective inhibitor of dipeptidyl peptidase-4 (DPP-4I), in treating NAFLD. Studies were sourced from electronic databases including PubMed, CENTRAL (Cochrane Controlled Trials Register), Embase, Medline, Web of Science, Clinical Trials, and CNKI to identify all randomized controlled clinical trials (RCTs) and non-RCTs in adult patients with NAFLD. Key outcomes were changes in serum levels of liver enzymes and improvement in hepatic histology and fat content measured by imaging or liver biopsy. Stata14.0 and RevMan5.3 were used for the meta-analysis. Seven studies with 269 NAFLD patients were included. Compared to the control group, sitagliptin treatment improved serum gamma-glutamyl transpeptidase (GGT) levels in the RCT subgroup (SMD = 0.79, 95% CI: 0.01-1.58). However, there was no significant improvement in serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels following sitagliptin treatment. Four of the included studies performed liver imaging, but sitagliptin treatment did not result in a significant reduction in liver fat content. Only five participants developed sitagliptin-related gastrointestinal discomfort. Our study suggests that sitagliptin effects individuals with NAFLD by improving serum GGT. Although sitagliptin is safe and well tolerated in NAFLD patients, it exerts no beneficial effects on liver transaminase and liver fat content in these patients.

Alogliptin inhibits IL-1β-induced inflammatory response in fibroblast-like synoviocytes

Excessive production of pro-inflammatory cytokines such as interleukin (IL)-1β plays an important role in the chronic inflammation in fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA). Alogliptin, an important selective dipeptidyl peptidase-4 (DPP-4) inhibitor licensed for the treatment of type 2 diabetes, has displayed a wide range of pharmacological capacities. In the present study, we aimed to investigate whether alogliptin possessed a protective effect against IL-1β-induced insult in FLS. Our results indicate that alogliptin treatment ameliorated IL-1β-induced production of reactive oxygen species, the expression of matrix metalloproteinase-3 (MMP-3) and MMP-13, secretions of tumor necrosis factor-α (TNF-α), IL-6, and IL-8. Additionally, we found that alogliptin inhibited c-Jun N-terminal kinase (JNK)/activator protein 1 (AP-1) signaling by reducing IL-1β-induced phosphorylation of JNK, the expression of c-Jun and c-Fos, and the luciferase activity of AP-1. Importantly, alogliptin suppressed IL-1β-induced activation of IκBα/NF-κB signaling by preventing the phosphorylation and degradation of IκBα, nuclear translocation of NF-κB p65, as well as the luciferase activity of AP-1. These findings suggest that alogliptin might have therapeutic potential for the treatment of chronic inflammation in RA.

Antidiabetic Effect of Pumpkin Seeds and Gum Arabic and/or Vildagliptin on type 2 Induced Diabetes in Male Rats

Metabolic syndrome is the accompaniment of multiple risk factors for atherosclerotic cardiovascular disease and type 2 diabetes (T2D) including glucose intolerance, hypertension and dyslipidemia where obesity is the basic element at this syndrome. T2DM is a heterogeneous metabolic syndrome resulting from genomic-environment complex interaction. Pumpkin seeds and gum Arabic are two natural products with an obvious hypoglycemic role. Vildagliptin is a selective inhibitor of dipeptidylpeptidase-4 (DPP-IV), and a certified therapy for T2DM. This study has been destined to assess in vivo the hypoglycemic impact of pumpkin seeds and gum Arabic in compare with vildagliptin and their combination treatments. 70 male albino rats were randomly separated into seven groups of ten each: control non-diabetic, control non-treated diabetic, diabetic treated with pumpkin seed extract (300mg/kg/day), diabetic treated with gum Arabic (500mg/kg/day), diabetic treated with vildagliptin (10mg/kg/day), diabetic treated with a combination of pumpkin seed extract and vildagliptin, and diabetic treated with a combination of gum Arabic and vildagliptin.T2DM was stimulated by feeding rats on high fat-high fructose/sucrose diet regimen (HFHF/S) for 12 weeks. Biochemical assessment has revealed that pumpkin seed extract, gum Arabic and vildagliptin can alleviate the severity of hyperglycemia, insulin resistance, dyslipidemia and depress glucagon secretion.

Protective effect of saxagliptin against renal ischaemia reperfusion injury in rats

Saxagliptin is an effective and selective dipeptidyl peptidase-4 (DPP-4) inhibitor. This study was designed to determine possible protective effects of saxagliptin against damage caused by renal ischaemia/reperfusion (I/R) in rats. In this study, 40 rats were divided into 4 groups (n = 10 for each). Group 1 (Control), Group 2 (I/R) in both kidneys ischaemia of 45 min was performed, and then reperfusion was applied for 24 h. Saxagliptin (Group 3: 2 mg/kg and Group 4: 10 mg/kg) was administered by oral gavage to the animals in treatment groups, before the I/R. Saxagliptin decreased the markers (BUN, Cre, NGAL, KIM-1 and IL-18) of acute renal damage in blood and kidney tissue. Saxagliptin provided increase in antioxidant enzyme levels and decrease in MDA and apoptosis. Histological results showed that the administration of saxagliptin exhibited a protective effect against renal damage caused by I/R. These results indicates that saxagliptin provide protection against kidney injury caused by I/R.

The role of linagliptin, a selective dipeptidyl peptidase-4 inhibitor, in the morphine rewarding effects in rats

Linagliptin is a selective dipeptidyl peptidase-4 (DPP-4) inhibitor which suppresses the rapid degradation of endogenous glucagon-like peptide-1 (GLP-1). In clinical practice, it is used as an antidiabetic drug, but recent studies have confirmed its role in the activity of the central nervous system (CNS). The reported study focused on the role of linagliptin (10 and 20 mg/kg, ip) in the morphine rewarding effect, analyzing how the agent had influenced the conditioned place preference (CPP) in rats via the expression, acquisition, extinction and reinstatement of the morphine rewarding effect. The obtained results clearly demonstrated linagliptin to inhibit the expression and acquisition, to accelerate the extinction and, eventually, to reduce the reinstatement of morphine-induced CPP. The undertaken experiments significantly extended our knowledge on the mechanisms behind the morphine rewarding effect.

Efficacy and safety of evogliptin in the treatment of type 2 diabetes mellitus in a Brazilian population: a randomized bridging study

BackgroundEvogliptin (EVO) is a potent and selective dipeptidyl peptidase-4 inhibitor (DPP4i) developed for the treatment of type 2 diabetes mellitus (T2DM). DPP4is are known to exhibit a better glucose-lowering effect in Asians compared to other ethnic groups. Once EVO’s clinical development program was conducted in Asian patients, this bridging study was designed to validate for the Brazilian population the efficacy and safety of the approved dose regimen (once-daily 5.0 mg).MethodsIn this randomized, double-blind, double-dummy, parallel trial, 146 patients with T2DM with inadequate glycemic control on diet and exercise (7.5% ≤ HbA1c ≤ 10.5%) were randomly assigned to a 12-week once-daily treatment with EVO 2.5 mg (N = 35), EVO 5 mg (N = 36), EVO 10 mg (N = 36), or sitagliptin (SITA) 100 mg (N = 39). Absolute changes (Week 12—baseline) in HbA1c, fasting plasma glucose (FPG) and body weight (BW) were obtained. One-sided one sample t test was used to determine if mean HbA1c reduction in each group was < − 0.5% (beneficial metabolic response). An analysis of covariance estimated the change in HbA1c and FPG adjusted by baseline HbA1c, FPG, body mass index (BMI) and study site. Response rates to treatment were also established. No between-group statistical comparisons were planned.ResultsHbA1c mean reductions were − 1.26% (90% CI − 1.7%, − 0.8%), − 1.12% (90% CI − 1.4%, − 0.8%), − 1.29% (90% CI − 1.6%, − 1.0%), and − 1.15% (90% CI − 1.5%, − 0.8%) in groups EVO 2.5 mg, EVO 5 mg, EVO 10 mg, and SITA 100 mg, respectively. FPG levels showed a mean increase of 10.89 mg/dL in group EVO 2.5 mg, with significant mean reductions of − 18.94 mg/dL, − 21.17 mg/dL, and − 39.90 mg/dL in those treated with EVO 5 mg, EVO 10 mg, and SITA 100 mg, respectively. BW showed significant reductions of approximately 1 kg in patients treated with EVO 5 mg, EVO 10 mg, and SITA 100 mg. Mean adjusted reductions of HbA1c and FPG levels confirmed the significant clinical benefit of all study treatments. The clinical benefit of EVO’s “target” dose (5 mg) was confirmed. No safety concerns were identified.ConclusionsThese results validate for the Brazilian population the approved dose regimen of EVO (once-daily 5 mg).Trial registration ClinicalTrials.gov Identifier: NCT02689362 (first posted on 02/23/2016).

EFFICACY AND SAFETY OF TENELIGLIPTIN AS ADD-ON THERAPY TO CONVENTIONAL THERAPY IN INDIAN PATIENTS WITH TYPE 2 DIABETES MELLITUS

Objective: Teneligliptin is a novel, highly selective dipeptidyl peptidase-4 inhibitor. The objective of the present study was to investigate the efficacy and safety of teneligliptin as add-on therapy in patients with type 2 diabetes mellitus (T2DM) who are inadequately controlled by conventional therapy (metformin/glimepiride) in India.&#x0D; Methods: Clinical study protocol was approved by the Institutional Ethics Committee. T2DM patients (male/female) whose glycated hemoglobin (HbA1c) &gt;7% were randomized to receive following group treatments, namely, Treatment A: Metformin/glimepiride plus add-on teneligliptin 20 mg and Treatment B: Metformin/glimepiride for 24 weeks. A pre-designed case report form was used to collect information from the prescribing physicians regarding the efficacy and safety of teneligliptin. Efficacy variables included change in plasma blood glucose (fasting and postprandial) and HbA1c from baseline to week 24. Treatment emergent adverse events were assessed.&#x0D; Results: A total of 120 type 2 diabetes patients were analyzed. Teneligliptin as add-on therapy with metformin/glimepiride significantly reduced plasma glucose (HbA1c, fasting, and postprandial) concentration as compared to conventional therapy.&#x0D; Conclusion: Add-on therapy with teneligliptin was found superior over conventional therapy in reducing plasma glucose concentration (fasting and postprandial) and HbA1c levels significantly in patients with T2DM. Further, it was found effective and well tolerated in Indian patients with T2DM who are inadequately controlled with conventional therapy.

1163-P: Comparison of Glycemic Variability between Gemigliptin and Dapagliflozin in Patients with Type 2 Diabetes Mellitus: A Randomized, Active-Controlled, Multicenter, 12-Week Clinical Trial (STABLE II Study)

The aim of this study was to evaluate the effect of gemigliptin, a potent and selective dipeptidyl peptidase-4 inhibitor versus dapagliflozin, a sodium glucose co-transporter-2 inhibitor on glycemic variability in patients with type 2 diabetes mellitus (T2DM). This randomized, parallel group, blinded end-point, multicenter, 12-week clinical trial was conducted in 71 patients with T2DM inadequately controlled with metformin alone or drug naïve patients. Subjects were randomized to receive gemigliptin 50mg (N=35) or dapagliflozin 10mg (N=36) daily for 12 weeks. Glycemic variability parameters such as mean amplitude of glycemic excursions (MAGE), standard deviation (SD) and coefficient of variation (CV) were evaluated during 6-day continuous glucose monitoring at baseline and after 12 weeks of treatment. The primary efficacy endpoint was change in MAGE after 12 weeks compared to baseline. Measures of glycemic control, oxidative stress and inflammation, as well as safety profiles were assessed. Adjusted mean change ± standard error in MAGE after 12 weeks were -27.2 ± 4.4 mg/dL (P&amp;lt;0.001) in the gemigliptin group and -7.9 ± 4.9 mg/dL (P=0.160) in the dapagliflozin group. The between-group comparison showed that gemigliptin group had significantly larger reduction in MAGE compared to dapagliflozin group (-19.2 mg/dL, 95% CI -31.3 to -7.2, P=0.002). Other glycemic variability parameters including SD and CV also showed significantly larger reduction in the gemigliptin group. Glycemic control estimated by HbA1c, fasting glucose and safety profiles were comparable between the two groups. In conclusion, gemigliptin significantly improved glycemic variability than dapagliflozin with similar glycemic efficacy and safety profiles in patients with T2DM inadequately controlled with metformin alone or drug naïve patients. ClinicalTrials.gov Identifier: NCT03202563. Disclosure Y. Hwang: None. J. Kim: None. S. Kwak: None. S. Kim: None. J. Won: None. J. Bae: None. H. Kim: None. S. Suh: None. E. Lee: None. S. Lee: Employee; Self; LG Chem. Funding LG Chem, Ltd.

The Unique Pharmacological and Pharmacokinetic Profile of Teneligliptin: Implications for Clinical Practice.

Teneligliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor that was approved for the treatment of type 2 diabetes mellitus (T2DM) in Japan and Korea and is being researched in several countries. Teneligliptin is a potent, selective, and long-lasting DPP-4 inhibitor with a t½ of approximately 24 h and unique pharmacokinetic properties: it is metabolized by cytochrome P450 (CYP) 3A4 and flavin-containing monooxygenase 3 (FMO3), or excreted from the kidney in an unchanged form. Because of its multiple elimination pathways, dose adjustment is not needed in patients with hepatic or renal impairment, and it is considered to have a low potential for drug–drug interactions. Clinical studies and postmarketing surveillance show that teneligliptin, administered as monotherapy and/or in combination with antihyperglycemic agents, is effective and well tolerated in T2DM patients, including in elderly patients and those with renal impairment. Furthermore, teneligliptin has antioxidative properties, which induce the antioxidant cascade, as well as ·OH scavenging properties. In addition, it has shown endothelial protective effects in several non-clinical and clinical studies. From its unique profile and clinical data, teneligliptin represents a potential therapeutic option in a wide variety of patients, including elderly diabetic patients and those with renal impairment. The fixed-dose combination (FDC) tablet of teneligliptin and canagliflozin has been approved in Japan; this is the first FDC tablet of a DPP-4 inhibitor and sodium glucose co-transporter 2 inhibitor in Japan, and the third globally. The FDC tablet may also provide additional prescribing and adherence benefits.

Multicenter prospective observational study of teneligliptin, a selective dipeptidyl peptidase-4 inhibitor, in patients with poorly controlled type 2 diabetes: Focus on glycemic control, hypotensive effect, and safety Chikushi Anti-Diabetes Mellitus Trial-Teneligliptin (CHAT-T)

ABSTRACTObjective: We purpose to confirm the effect of teneligliptin (Tenelia), a selective dipeptidyl peptidase-4 (DPP-4) inhibitor, on glycemic control and non-glucose risk factors for macroangiopathy, including blood pressure, lipid metabolism, and body weight.Methods: In a prospective, multicenter, open-label, observational study, teneligliptin (20 mg/day) was administered to type 2 diabetic patients with poor glycemic control (HbA1c ≥ 6.5% to <10%) at our hospitals. The safety of teneligliptin and its impact on blood glucose, blood pressure, and the lipid profile were assessed after administration for 3 and 6 months.Results: One hundred and sixty-two patients were enrolled between February 2014 and August 2015. HbA1c was 7.6% at baseline and showed significant reduction to 7.1% after 3 months of treatment and to 6.9% after 6 months (both p < 0.01). Patients with poorly controlled hypertension (systolic blood pressure [SBP] ≥130 mmHg and/or diastolic blood pressure [DBP] ≥80 mmHg) at study initiation were extracted to investigate the effect of teneligliptin on blood pressure. SBP showed a significant decrease from 141.2 ± 9.8 mmHg at baseline to 131.1 ± 14.3 mmHg after 3 months and 133.9 ± 11.5 mmHg after 6 months (both p < 0.001). DBP also decreased significantly from 85.8 ± 5.7 mmHg at baseline to 78.4 ± 10.0 mmHg after 3 months and 79.7 ± 10.1 mmHg after 6 months (both p < 0.001). Adverse events were pruritus in four patients, and cerebral infarction was reported as a cerebrovascular event in one patient.Conclusions: Teneligliptin therapy was safe and improved glycemic control irrespective of baseline HbA1c. Blood pressure was also improved in patients with concomitant hypertension.

THE IN VITRO CYTOTOXICITY, GENOTOXICITY AND OXIDATIVE DAMAGE POTENTIAL OF THE ORAL DIPEPTIDYL PEPTIDASE-4 INHIBITOR, LINAGLIPTIN, ON CULTURED HUMAN MONONUCLEAR BLOOD CELLS.

Linagliptin (LNG) is a selective dipeptidyl peptidase-4 (DPP-4) inhibitor that ameliorates blood glucose control of patients with type 2 diabetes, without developing hypoglycemic risk and weight gain with a good clinical and biological tolerance profile. To the best of our knowledge, its cytotoxic, genotoxic and oxidative effects have never been studied on any cell line. To evaluate the in vitro cytotoxic, genotoxic damage potential and antioxidant/oxidant activity of LNG in cultured peripheral blood mononuclear cells (PBMC). After exposure to different doses (from 0.5 to 500 mg/L) of LNG, cell viability was measured by the MTT (3,(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and lactate dehydrogenase (LDH) leakage tests. The antioxidant activity was assessed by the total antioxidant capacity (TAC) and total oxidative stress (TOS) assays. To evaluate the genotoxic damage potential, chromosomal aberration (CA) frequencies and 8-oxo-2'-deoxyguanosine (8-oxo-dG) levels were determined. Treatment with LNG did not cause statistically significant decreases of cell viability at lower concentrations than 100 mg/L as compared to untreated cultures. However, LNG exhibited cytotoxic action at 250 and 500 mg/L. Also, IC20 and IC50 values of LNG were determined as 8.827 and 70.307 mg/L, respectively. In addition, the oxidative analysis revealed that LNG supported antioxidant capacity at concentrations of 2.5, 5, 10, 25, 50 and 100 mg/L without generating oxidative stress. Besides, the results of CA and 8-oxo-dG assays showed in vitro non-genotoxic feature of LNG. As a conclusion, our findings clearly revealed that LNG had no cytotoxic and genotoxic actions, but exhibited antioxidative activity. In conclusion, therefore it is suggested that LNG use in diabetic patients is safe and provides protection against diabetic vascular and oxidative complications.

Pharmacokinetic Interaction Study Between Saxagliptin and Omeprazole, Famotidine, or Magnesium and Aluminum Hydroxides Plus Simethicone in Healthy Subjects: An Open-Label Randomized Crossover Study.

Saxagliptin is an orally administered, highly potent, and selective dipeptidyl peptidase-4 inhibitor for the management of type 2 diabetes mellitus. This study was conducted to determine the effect of magnesium and aluminum hydroxides plus simethicone, famotidine, and omeprazole on the pharmacokinetics of saxagliptin and its active metabolite, 5-hydroxy saxagliptin. This was an open-label, randomized, 5-treatment, 5-period, 3-way crossover study in 15 healthy subjects. Mean Cmax of saxagliptin was 26% lower, but AUC was almost unchanged when saxagliptin was coadministered with Maalox Max. Mean Cmax was 14% higher, but AUC was almost unchanged when saxagliptin was coadministered with famotidine. Changes in pharmacokinetics of 5-hydroxy saxagliptin generally paralleled the changes in saxagliptin. These pharmacokinetic changes were unlikely to be clinically meaningful. Coadministration of omeprazole did not affect saxagliptin Cmax or AUC. Saxagliptin in combination with these medicines resulted in no unexpected safety or tolerability findings in these healthy subjects. No dose adjustment of saxagliptin or separation in the time of saxagliptin dosing is necessary with medicines that raise gastric pH when coadministered with saxagliptin.

Effect of Dipeptidyl Peptidase-4 Inhibitors on Bone Metabolism and the Possible Underlying Mechanisms.

Diabetes mellitus has been demonstrated to be closely associated with osteoporosis. Accordingly, hypoglycemic therapy is considered effective in treating metabolic bone disease. Recently, the effects of dipeptidyl peptidase-4 (DPP-4) inhibitors, a new type of antidiabetic drug, on bone metabolism have been widely studied. This review mainly describes the effects of DPP-4 inhibitors on bone metabolism, including their effects on bone mineral density, bone quality, and fracture risk. In addition, the potential underlying mechanisms are discussed. Based on the current progress in this research field, DPP-4 inhibitors have been proved to reduce fracture risk. In addition, sitagliptin, a strong and highly selective DPP-4 inhibitor, showed its beneficial effects on bone metabolism by improving bone mineral density, bone quality, and bone markers. With regard to the potential underlying mechanisms, DPP-4 inhibitors may promote bone formation and reduce bone resorption through DPP-4 substrates and DPP-4-related energy metabolism. Vitamin D and other related signaling pathways also play a role in affecting bone metabolism. Although these assumptions are controversial, they provide a translational pharmacology approach for the clinical use of DPP-4 inhibitors in the treatment of metabolic diseases. Prior to the use of these drugs in clinic, further studies should be conducted to determine the appropriate type of DPP-4 inhibitor, the people who would benefit the most from this therapy, appropriate dose and duration, and the effects of the treatment.

New dipeptidyl peptidase 4 inhibitors among adamantane derivatives

Fifteen adamantane derivatives were synthesized. Preliminary evaluation of their potential as dipeptidyl peptidase 4 (DPP-4) inhibitors was performed in silico by the Microcosm informational technology, PASS system, and docking in AutoDock Vina. The DPP-4 inhibition was studied in vitro. The selectivity of action of the most active compounds was studied by the direct inhibition of human plasma DPP-4 and recombinant human DPP-8. The highest activity was found for the compounds containing a nitrogen atom in the β-position of the side chain, namely, derivatives of adamantane carboxylic acid and N-(3-adamantyl-allyl) thiourea. We demonstrated that the most active compound of the series, 3,5-dimethyladamantane 1-carboxamide, was a selective DPP-4 inhibitor with IC50 53.94 μM.