Dipeptidyl Peptidase 4 Inhibition for Prophylaxis of Acute Graft-versus-Host Disease.

BACKGROUND: Dipeptidyl peptidase 4 (DPP-4; also known as CD26), a transmembrane receptor expressed on T cells, has a costimulatory function in activating T cells. In a mouse model, down-regulation of CD26 prevented graft-versus-host disease (GVHD) but preserved graft-versus-tumor effects. Whether inhibition of DPP-4 with sitagliptin may prevent acute GVHD after allogeneic stem-cell transplantation is not known. METHODS: We conducted a two-stage, phase 2 clinical trial to test whether sitagliptin plus tacrolimus and sirolimus would reduce the incidence of grade II to IV acute GVHD from 30% to no more than 15% by day 100. Patients received myeloablative conditioning followed by mobilized peripheral-blood stem-cell transplants. Sitagliptin was given orally at a dose of 600 mg every 12 hours starting the day before transplantation until day 14 after transplantation. RESULTS: A total of 36 patients who could be evaluated, with a median age of 46 years (range, 20 to 59), received transplants from matched related or unrelated donors. Acute GVHD occurred in 2 of 36 patients by day 100; the incidence of grade II to IV GVHD was 5% (95% confidence interval [CI], 1 to 16), and the incidence of grade III or IV GVHD was 3% (95% CI, 0 to 12). Nonrelapse mortality was zero at 1 year. The 1-year cumulative incidences of relapse and chronic GVHD were 26% (95% CI, 13 to 41) and 37% (95% CI, 22 to 53), respectively. GVHD-free, relapse-free survival was 46% (95% CI, 29 to 62) at 1 year. Toxic effects were similar to those seen in patients undergoing allogeneic stem-cell transplantation. CONCLUSIONS: In this nonrandomized trial, sitagliptin in combination with tacrolimus and sirolimus resulted in a low incidence of grade II to IV acute GVHD by day 100 after myeloablative allogeneic hematopoietic stem-cell transplantation. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT02683525.).

Cofrogliptin once every 2 weeks as add-on therapy to metformin versus daily linagliptin in patients with type 2 diabetes in China: A randomized, double-blind, non-inferiority trial.

AIM: We evaluated the efficacy and safety of cofrogliptin, a novel dipeptidyl peptidase-4 inhibitor taken once every 2 weeks (Q2W), compared with linagliptin (taken daily) in patients with type 2 diabetes inadequately controlled on metformin in China. MATERIALS AND METHODS: In this phase 3 randomized, double-blind, active-controlled, multicentre study, patients were randomly assigned 1:1:1 to receive cofrogliptin 10 mg Q2W, cofrogliptin 25 mg Q2W, or linagliptin 5 mg daily, all as an add-on treatment to metformin, for 24 weeks. Eligible patients could enter an open-label extension period and receive cofrogliptin 25 mg Q2W for an additional 28 weeks. The primary endpoint was change in glycated haemoglobin from baseline to 24 weeks, with a non-inferiority margin of 0.4% for cofrogliptin versus linagliptin treatment. RESULTS: Overall, 465 patients entered the 24-week treatment period (median age: 57.0 years). The least-squares mean (standard error) change in glycated haemoglobin from baseline to week 24 was -0.96 (0.063), -0.99 (0.064) and -1.07 (0.065) for the cofrogliptin 10 mg, cofrogliptin 25 mg and linagliptin 5 mg groups, respectively. The between-group difference met the predefined margin for non-inferiority of cofrogliptin (10 and 25 mg) versus linagliptin treatment. The incidence of common adverse events (≥5% patients) during the 24-week treatment period was similar between treatment groups. There were no serious hypoglycaemic events. CONCLUSION: In Chinese patients with type 2 diabetes inadequately controlled on metformin, the glucose-lowering effect of cofrogliptin (Q2W) was non-inferior to linagliptin (daily), with a similar safety profile maintained over 52 weeks of treatment.

Effectiveness of switching from dipeptidyl peptidase-4 inhibitor to oral glucagon-like peptide-1 receptor agonist in Japanese participants with type 2 diabetes mellitus: Prospective observational study using propensity score matching.

AIM: Recently, the development of the oral glucagon-like peptide-1 receptor agonist semaglutide has drawn a great deal of attention. This study aimed to compare the effectiveness of oral glucagon-like peptide-1 receptor agonist semaglutide and dipeptidyl peptidase-4 (DPP-4) inhibitors on glycaemic control and several metabolic parameters in patients with type 2 diabetes mellitus over a 6-month period. METHODS: Fifty-nine participants were included, and we compared various clinical parameters between before and after switching from DPP-4 inhibitors to oral semaglutide in 'study 1' (pre-post comparison) and set the control group using the propensity score matching method in 'study 2'. RESULTS: In 'study 1', 6 months after the switching, the glycated haemoglobin value was significantly reduced from 7.5% to 7.0%, and the body mass index was also decreased from 29.7 kg/m2 to 28.8 kg/m2. Such effects were more clearly observed in participants whose glycaemic control was poor. In 'study 2', after 1:1 propensity score matching, 51 participants from each group were matched, and glycaemic control as well as body weight management were improved in the switching group compared with the DPP-4 inhibitor continuation group over the 6-month observation period. CONCLUSION: In this study, including obese participants with poor glycaemic control, switching DPP-4 inhibitors to oral semaglutide showed more beneficial effects on both glycaemic and weight control, irrespective of age, body weight and diabetes duration. Therefore, we should bear in mind that it would be better to start using an oral semaglutide in clinical practice, particularly in obese participants with poor glycaemic control with DPP-4 inhibitors.

Sustained linagliptin administration: superior glycemic control and less pancreatic injury in diabetic rats.

While linagliptin is the most potent dipeptidyl peptidase 4 inhibitor, its use is limited due to poor bioavailability and the potential risk of pancreatic injury. Here, we investigated whether the sustained weekly administration of linagliptin could provide better effect compared to frequent daily oral administration. Type 2 diabetes was induced by feeding rats a high fructose/fat/salt diet followed by STZ injection. Compared to the partial glycemic control achieved with daily oral linagliptin, a weekly subcutaneous injection containing about one-fourth of the oral dose produced superior glycemic control, as evidenced by the 4-week postprandial glucose follow-up and oral glucose tolerance test. This was confirmed by the significant increase in serum insulin in the case of the sustained linagliptin administration. Higher levels of the anti-inflammatory cytokine adiponectin and lower triglyceride levels were observed after sustained linagliptin administration compared with daily oral linagliptin. In addition, sustained linagliptin displayed a significant increase in ß-cells' insulin immunoreactivity when compared with daily linagliptin. More reduction in collagen deposition and caspase-3 immunoreactivity in pancreatic tissue were observed in sustained linagliptin compared with oral linagliptin. In conclusion, sustained linagliptin administration provided superior glycemic control, which seems to be mediated by more reduction in pancreatic injury.

Evaluating the efficacy and safety of empagliflozin addition to insulin and oral antidiabetic medication (OAD) regimen in poorly controlled type 2 diabetes and obese patients.

Insulin resistance complicates diabetes care. Its effectiveness and tolerability as an addition to metformin, DPP4 inhibitor and insulin treatment in type 2 diabetic patients will be examined in this research. Participants with type 2 diabetes from poor socio-economic backgrounds had HbA1c values ≥8.5% when using Insulin+Metformin+DPP-4 inhibitors. They received 10mg Empagliflozin daily for 12 weeks (n=143). The main outcome was change in HbA1c at 12th week from baseline. Secondary outcomes were baseline weight and week 12 FPG. Adjusted mean (SE) HbA1c increases at week 12 were: Mean ± SD 10.38 (6.8-17.0) vs. Mean±SD 9.05±1.77 (5.60-16.0) with empagliflozin 10mg. When added to the regimen, empagliflozin significantly reduced FPG, systolic and diastolic blood pressure. The mean (SE) BMI increases from baseline were 31.28±5.89 (16.0-66.0) and 29.73±5.47 (3.0-46.0) with 10mg empagliflozin. Two individuals experienced urinary tract infections as AEs, but no genital infections. Adding empagliflozin 10mg daily to metformin+DPP4 inhibitor+insulin improved glycemic control, body weight and blood pressure for 12 weeks. The intervention was well-tolerated, highlighting empagliflozin's therapeutic potential.

Improved Erythrocyte Deformability Induced by Sodium-Glucose Cotransporter 2 Inhibitors in Type 2 Diabetic Patients.

PURPOSE: Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are antidiabetic drugs that improve cardiovascular outcomes. Hemoglobin and hematocrit values increase after SGLT-2 inhibitor administration. Although these factors increase blood viscosity and the risk of cardiovascular disease, SGLT-2 inhibitors have protective effects on the cardiovascular system. The mechanisms for this paradoxical phenomenon remain unclear, and the effect of SGLT-2 inhibitors on hemorheology has not been studied. METHODS: We evaluated the hemorheological parameters of 63 patients of whom 38 received metformin with a dipeptidyl peptidase 4 (DPP-4) inhibitor, while 25 received metformin with SGLT-2 inhibitor. Blood viscosity was measured using a cone-and-plate viscometer, erythrocyte aggregation was measured using a modified erythrocyte sedimentation rate method, and erythrocyte membrane fluctuation was measured as deformability, using a diffraction optical tomography. RESULTS: Both blood viscosity and erythrocyte aggregation increased in the SGLT-2 inhibitor group, although erythrocyte deformability was significantly improved compared with that of the DPP-4 inhibitor group (DPP-4 inhibitor 43.71 ± 5.13 nm; SGLT-2 inhibitor 53.88 ± 4.88 nm; p < 0.001). When the two groups were compared after propensity score matching, no differences in blood viscosity at high shear rates and erythrocyte aggregation were observed, although erythrocyte deformability was significantly improved in the SGLT-2 inhibitor group (DPP-4 inhibitor 45.01 ± 5.28 nm; SGLT-2 inhibitor 53.14 ± 4.72 nm; p = 0.001). CONCLUSION: This study demonstrates that erythrocyte deformability was improved in the SGLT-2 inhibitor group compared with that in the DPP-4 inhibitor group. This improvement in erythrocyte deformability is expected to have a protective effect on the cardiovascular system.

Sitagliptin and Narrow-Band Ultraviolet-B for Moderate Psoriasis (DINUP): A Randomised Controlled Clinical Trial.

BACKGROUND: Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor licensed for the treatment of type 2 diabetes mellitus (T2DM), has been reported to improve psoriasis. OBJECTIVE: We compared the effects of sitagliptin treatment, a DPP-4 inhibitor, in combination with narrow-band ultraviolet-B (NB-UVB) phototherapy compared to NB-UVB alone on psoriasis severity, quality of life, cardiovascular disease risk factors and immune parameters in people with moderate psoriasis without T2DM. METHODS: In this 39-week, single-centre, randomised controlled trial, people were allocated randomly to receive sitagliptin for 24 weeks with NB-UVB or NB-UVB alone. The primary endpoint was the change in Psoriasis Area and Severity Index (PASI) from baseline to 24 weeks. We estimated that 120 participants would be needed to have 80% power to find a significant difference between the groups. RESULTS: A total of 118 patients were randomised. The median (IQR) baseline PASI was 8.8 (7.5-11.6). At 24 weeks, the mean difference from baseline in PASI (-1.0 [95% CI -2.0 to 0.0]) was significantly larger in the sitagliptin/NB-UVB arm than in the NB-UVB-alone arm (p = 0.044). There were significant differences in the change in Hospital Anxiety and Depression Scale (-2.5 [95% CI -4.0 to -1.0]; p = 0.002) and EuroQol 5-item questionnaire (0.1 [95% CI 0.0-0.1]; p = 0.036) values from baseline to 24 weeks between the sitagliptin/NB-UVB and the NB-UVB-alone arm. There were no treatment-related serious adverse events. CONCLUSION: Sitagliptin therapy combined with NB-UVB phototherapy significantly improved psoriasis severity, albeit modestly, compared to NB-UVB phototherapy alone in patients with moderate psoriasis without T2DM.

Hypoglycemic peptide-enriched hydrolysates of Corbicula fluminea and Chlorella sorokiniana possess synergistic hypoglycemic activity through inhibiting α-glucosidase and dipeptidyl peptidase-4 activity.

BACKGROUND: The prevalence of diabetes mellitus worldwide has increased in recent decades. Maintaining the level of blood glucose is the most basic and important issue for diabetics. This study aimed to investigate the hypoglycemic activity of a combination of hypoglycemic peptide-enriched hydrolysates of Corbicula fluminea (ACH) and Chlorella sorokiniana (PCH). RESULTS: Combined supplementation of ACH and PCH synergistically inhibited α-glucosidase and DPP4 activities in vitro. After 4 weeks of treatment with ACH and/or PCH, the plasma glucose concentration and insulin, homeostasis model assessment-estimated insulin resistance (HOMA-IR), total cholesterol (TC) and triglyceride (TG) levels significantly decreased. The hypoglycemic peptides in ACH and PCH were purified and assayed for α-glucosidase and DPP4 activity. The hypoglycemic peptides in ACH and PCH effectively decreased α-glucosidase and DPP4 activities. In silico assays showed that these two peptide types have different docking poses, which determined their inhibitory effect against α-glucosidase and DPP4 activity. CONCLUSION: Combined treatment with hypoglycemic peptide-enriched ACH and PCH could modulate blood glucose by synergistically inhibiting α-glucosidase and DPP4 activities. © 2021 Society of Chemical Industry.

Optimization and validation of a fluorogenic dipeptidyl peptidase 4 enzymatic assay in human plasma.

During the development of a specific dipeptidyl peptidase 4 (DPP4) inhibitor to treat type 2 diabetes, a fluorogenic kinetic analysis for DPP4 enzymatic activity using Gly-Pro-Aminomethylcoumarin (AMC) as a substrate was optimized and validated for recombinant DPP4 and human plasma samples. The sensitivity, calibration curve, detection range, accuracy, precision, recovery efficiency, Km constant, short/long-term stability, and stability after freezing-thawing cycles were analyzed. DPP4 enzymatic activity (mU/min) was measured as the initial velocity (Vo) of the enzymatic reaction over time. The sensitivity of the Vo value was 14,488 mU/min for recombinant DPP4 and 17,995 mU/min for human plasma samples. The dynamic ranges of the calibration curve were linear and reliable between 1.11 × 104-1.86 × 106 mU/min of the mean Vo value and in the DPP4 concentration range of 23.4-3,000 ng/mL. The assay's accuracy and precision met acceptance criteria for all samples. Plasma DPP4 was stable under various storage temperatures, even after three freeze-thaw cycles. Our optimized, validated bioanalytic method for measuring DPP4 activity in plasma samples was successfully employed to evaluate the effect of evogliptin (DA-1229) tartrate, which irreversibly and dose-dependently inhibits DPP4 enzymatic activity, without the dilution effect of human plasma samples and irrespective of the co-treated metformin.

Diabetes medications and risk of Parkinson's disease: a cohort study of patients with diabetes.

The elevated risk of Parkinson's disease in patients with diabetes might be mitigated depending on the type of drugs prescribed to treat diabetes. Population data for risk of Parkinson's disease in users of the newer types of drugs used in diabetes are scarce. We compared the risk of Parkinson's disease in patients with diabetes exposed to thiazolidinediones (glitazones), glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase 4 (DPP4) inhibitors, with the risk of Parkinson's disease of users of any other oral glucose lowering drugs. A population-based, longitudinal, cohort study was conducted using historic primary care data from The Health Improvement Network. Patients with a diagnosis of diabetes and a minimum of two prescriptions for diabetes medications between January 2006 and January 2019 were included in our study. The primary outcome was the first recording of a diagnosis of Parkinson's disease after the index date, identified from clinical records. We compared the risk of Parkinson's disease in individuals treated with glitazones or DPP4 inhibitors and/or GLP-1 receptor agonists to individuals treated with other antidiabetic agents using a Cox regression with inverse probability of treatment weighting based on propensity scores. Results were analysed separately for insulin users. Among 100 288 patients [mean age 62.8 years (standard deviation 12.6)], 329 (0.3%) were diagnosed with Parkinson's disease during the median follow-up of 3.33 years. The incidence of Parkinson's disease was 8 per 10 000 person-years in 21 175 patients using glitazones, 5 per 10 000 person-years in 36 897 patients using DPP4 inhibitors and 4 per 10 000 person-years in 10 684 using GLP-1 mimetics, 6861 of whom were prescribed GTZ and/or DPP4 inhibitors prior to using GLP-1 mimetics. Compared with the incidence of Parkinson's disease in the comparison group (10 per 10 000 person-years), adjusted results showed no evidence of any association between the use of glitazones and Parkinson's disease [incidence rate ratio (IRR) 1.17; 95% confidence interval (CI) 0.76-1.63; P = 0.467], but there was strong evidence of an inverse association between use of DPP4 inhibitors and GLP-1 mimetics and the onset of Parkinson's disease (IRR 0.64; 95% CI 0.43-0.88; P < 0.01 and IRR 0.38; 95% CI 0.17-0.60; P < 0.01, respectively). Results for insulin users were in the same direction, but the overall size of this group was small. The incidence of Parkinson's disease in patients diagnosed with diabetes varies substantially depending on the treatment for diabetes received. The use of DPP4 inhibitors and/or GLP-1 mimetics is associated with a lower rate of Parkinson's disease compared to the use of other oral antidiabetic drugs.

Anticipatory guidance and systematic review of prescribing combination incretin therapy in the treatment of type 2 diabetes.

WHAT IS KNOWN AND OBJECTIVE: Few studies have evaluated the efficacy and safety of combining a glucagon-like peptide-1 receptor agonist and dipeptidyl peptidase-4 inhibitor in patients with type 2 diabetes mellitus. Clinicians may frequently encounter this drug therapy combination in practice and should be aware of clinical evidence and risks associated with its use. METHODS: A literature search was conducted in Embase (1947-April 20, 2020), Medline - Ovid (1946-April 21, 2020), Medline - PubMed (1946-April 21, 2020), Cochrane Library CENTRAL Register of Controlled Trials (1991-April 20, 2020) and Web of Science (1900-April 17, 2020). Databases were searched using keywords and subject headings to identify studies assessing efficacy and safety of combination incretin therapy. The search identified 1255 studies. Of these, 383 were excluded for duplicate citations. Articles were then excluded based on title and abstract screen. RESULTS AND DISCUSSION: Six studies were included. A small reduction in haemoglobin A1c and weight loss was found by combining incretin therapy. Adverse effects such as hypoglycaemia, gastrointestinal upset and pancreatitis were infrequent. WHAT IS NEW AND CONCLUSION: On current evidence, the small benefit in glycaemic control that may be realized by using combination incretin therapy is unlikely to be offset by the potential increased risk of pancreatitis or additional cost. Additional long-term prospectively designed studies are needed to better understand the efficacy and safety of combination incretin therapy.

Study on the Mechanism of the Blood-Glucose-Lowering Effect of Collagen Peptides from Sturgeon By-Products.

In a previous study, we found that the collagen peptides prepared from the by-products of Bester sturgeon had an inhibitory effect on elevated blood glucose levels in a glucose tolerance test with ICR mice. In the present study, we examine the mechanism of the effect of sturgeon collagen peptides (SCPs) in detail. When glucose was orally administered to mice along with the SCPs, it was found that the glucose remained in the stomach for a longer time. In the above tests, the amount of glucose excreted in the feces of mice also increased. On the contrary, it was revealed that the SCPs have a dipeptidyl-peptidase-IV (DPP-IV) inhibitory ability in an in vitro test. In subsequent oral and intravenous glucose administration tests, glucagon-like peptide-1 (GLP-1) and insulin levels in the blood of mice were maintained at high levels. These results suggested the following three mechanisms: SCPs slow the rate of transportation of glucose from the stomach into the small intestine, resulting in delayed glucose absorption; SCPs suppress the absorption of glucose in the small intestine and excrete it from the body; SCPs inhibit DPP-IV in the blood and maintain a high GLP-1 level in blood, which in turn stimulates insulin secretion.

Development and validation of an ultrasensitive LC-MS/MS method for the quantification of cetagliptin in human plasma and its application in a microdose clinical trial.

This study established and validated an LC-MS/MS method for the ultrasensitive determination of cetagliptin in human plasma. Sample pretreatment was achieved by liquid-liquid extraction with ethyl acetate, and chromatographic separation was performed on an XB-C18 analytical column (50 × 2.1 mm, 5 µm) with gradient elution (0.1% formic acid in acetonitrile and 0.1% formic acid) at a flow rate of 1.0 mL/min. For mass spectrometric detection, multiple reaction monitoring was used, and the ion transitions monitored were m/z 421.2-86.0 for cetagliptin and m/z 424.2-88.0 for cetagliptin-d3. Method validation was performed according to the U.S. Food and Drug Administration Bioanalytical Method Validation Guidance, for which the calibration curve was linear in the range of 50.0-2000 pg/mL. All of the other results, such as selectivity, lower limit of quantitation, precision, accuracy, matrix effect, recovery, and stability, met the acceptance criteria. The validated method was successfully applied in a microdose clinical trial to systematically investigate the pharmacokinetic profile of cetagliptin in healthy subjects. Both rapid absorption and prolonged duration demonstrate the potential value of cetagliptin for diabetes treatment.

Vildagliptin, a DPP-4 inhibitor, attenuates carbon tetrachloride-induced liver fibrosis by targeting ERK1/2, p38α, and NF-κB signaling.

Mitogen-activated protein kinases (MAPKs) and nuclear factor (NF)-ĸB signaling have been recognized for their causal connection with liver fibrosis. Hence, it is encouraging to discover drugs that can modify the interactions between these signaling cascades. It has been suggested that glucagon-like peptide-1 receptors (GLP-1Rs) might have a role in the observed hepatoprotection of dipeptidyl peptidase-4 inhibitors other than vildagliptin (VLD). Consequently, we aimed to elucidate the mechanisms underlying its potential antifibrotic activity in a CCl4-intoxicated mouse model. VLD increased the percentage of viable CCl4-intoxicated primary rat hepatocytes in vitro. It also attenuated hepatic fibrosis, improved liver function, and prolonged survival of CCl4-intoxicated mice in a dose-dependent manner. This hepatoprotection might be mediated mainly through interference with extracellular signal-regulated protein kinase 1/2 phosphorylation, the most downstream signal of the MAPK pathway. In addition, VLD hepatoprotective activity could be partially mediated through inhibition of p38α phosphorylation and phosphorylation-induced NF-ĸB activation. As a result, VLD downregulated profibrogenic mediators, such as tumor necrosis factor α, transforming growth factor ß, tissue inhibitor of metalloproteinase 1 and platelet-derived growth factor BB. Consequently, decreased expression levels of fibrosis markers, such as hydroxyproline and α smooth muscle actin, were confirmed. VLD showed a strong trend toward increasing the antioxidant defense machinery of fibrotic tissue, and we confirmed that GLP-1Rs were not implicated in the observed hepatoprotection. Since VLD poses little risk of hypoglycemia and is a safe drug for patients with liver injury, it may be a hopeful candidate for adjuvant treatment of liver fibrosis in humans.

Safety, tolerability, pharmacokinetics and pharmacodynamics of parenterally administered dutogliptin: A prospective dose-escalating trial.

AIMS: Animal studies suggest that inhibition of dipeptidyl peptidase 4 (DPP-IV) may improve heart function and survival after myocardial infarction by increasing cardiac myocytes' regenerative capacity. Parenterally administered dutogliptin may provide continuous strong DPP-IV inhibition to translate these results into humans. This trial investigated the safety and tolerability, as well as pharmacokinetics and pharmacodynamics, of parenterally administered dutogliptin after single and repeated doses. METHODS: In an open-label trial, volunteers received dutogliptin at increasing doses of 30-120 mg subcutaneously or 30 mg intravenously in the single-dose cohorts. Subjects in the multiple-dose cohort received 60, 90 or 120 mg dutogliptin subcutaneously once daily on 7 consecutive days. RESULTS: Forty healthy males were included in the trial. No related serious adverse events occurred. Mild local injection site reactions with no requirement for intervention comprised 147 of 153 (96%) related adverse events. Subcutaneous bioavailability was approximately 100%. Multiple injections at daily intervals did not lead to the accumulation of the study drug. The accumulation ratios based on AUC0-24h range from 0.90 to 1.03, supporting this argument. All subjects receiving ≥60 mg dutogliptin yielded a maximum DPP-IV inhibition >90%. The duration of DPP-IV inhibition over time increased in a dose-dependent manner and was highest in the 120-mg multiple-dosing cohort with a maximum AUEC0-24h of 342 h % (standard deviation: 73), translating into 86% DPP-IV inhibition 24 hours after dosing. CONCLUSION: Parenteral injection of dutogliptin was safe and subcutaneous bioavailability is excellent. DPP-IV inhibition increased dose dependently to >86% over 24 hours after multiple doses of 120 mg dutogliptin.

Association between dipeptidyl peptidase-4 inhibitor and aspiration pneumonia: disproportionality analysis using the spontaneous reporting system in Japan.

PURPOSE: Dipeptidyl peptidase-4 inhibitor (DPP-4-Is), a kind of drug used for the treatment of diabetes, is considered to prevent the degradation of substance P that suppresses the occurrence of dysphagia. On the other hand, DPP-4 inhibitors are also known to act on the immune system. In this study, we used a spontaneous reporting system to evaluate the signals for dysphagia and aspiration pneumonia with DPP-4-Is. METHODS: We calculated reporting odds ratio (ROR) and information coefficients (IC) as disproportionality analysis to evaluate DPP-4-Is induced dysphagia and aspiration pneumonia using the Japanese Adverse Drug Event Report (JADER) database. RESULTS: For DPP-4-Is as a class, no signals were detected for dysphagia, but the signal for aspiration pneumonia was detected at ROR 1.67 (95% confidence interval [95% CI]: 1.20 to 2.34) and IC 0.70 (95% CI: 0.21 to 1.19). For aspiration pneumonia, trelagliptin was the only drug among the DPP-4-Is for which both ROR and IC signals were detected (ROR 9.99, 95% CI: 4.10 to 24.36; IC: 1.98, 95% CI: 0.78 to 3.18). ROR signals, but not IC signals, were detected for linagliptin (ROR 2.66, 95% CI: 1.19 to 5.94; IC: 1.09, 95% CI: - 0.004 to 2.19) and sitagliptin (ROR 1.84, 95% CI: 1.04 to 3.25; IC: 0.78, 95% CI: - 0.03 to 1.58). CONCLUSION: Since DPP-4 inhibitors prevent the degradation of substance P involved in swallowing reflex, DPP-4 inhibitors were expected to prevent dysphagia and aspiration pneumonia. However, this study revealed that DPP-4 inhibitors strongly were associated with onset rather than preventing aspiration pneumonia. This result suggests that DPP-4 inhibitors may affect the immune function associated with the development of aspiration pneumonia. Furthermore, there is a possibility that the amount of DPP-4-Is used clinically cannot increase the amount of substance P in sufficient quantity to prevent aspiration pneumonia.

Target-mediated exposure enhancement: a previously unexplored limit of TMDD.

Target-mediated drug disposition (TMDD) is often observed for targeted therapeutics, and manifests as decreases in clearance and volume of distribution with increasing dose as a result of saturable, high affinity target binding. In the present work, we demonstrate that classically defined TMDD is just one of the characteristic features of the system. In fact, for molecules with rapid non-specific elimination relative to target-mediated elimination, binding to target may actually lead to improved exposure at sub-saturating doses. This feature, which we refer to as target-mediated exposure enhancement (TMEE), produces the opposite trend to classical TMDD, i.e., with increasing dose levels, clearance and volume of distribution will also increase. The general model of TMDD was able to well-characterize the pharmacokinetics of two molecules that display TMEE, ALX-0081 and linagliptin. Additional fittings using the commonly reported TMDD model approximations revealed that both the quasi-equilibrium and quasi-steady-state approximations were able to well-describe TMEE; however, the Michaelis-Menten approximation was unable to describe this behavior. With the development of next-generation therapeutics with high affinity for target and rapid non-specific elimination, such as antibody fragments and peptides, this previously unexplored limit of TMDD is anticipated to become increasingly relevant for describing pharmacokinetics of investigational therapeutics.

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).

Objective: 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.

Prediction of saxagliptin stability using a new approach based on Partial Least Squares and Design of Experiments.

The objective of this study was to assess the possibility of applying Partial Least Squares (PLS) statistics with the use of experimental design approach towards stability evaluation of the Saxagliptin drug product. The influences of temperature, time, dose, packaging, batch, and oxygen protection were analyzed for identification of critical factors responsible for degradation of saxagliptin and prediction of impurity levels at various storage conditions. Predicted levels of the impurity DP-2 were lower for at least 0.2 % when the drug product was protected from oxygen after its manufacture. Additionally, the PLS model revealed that the lower strength is at least twice less stable concerning impurity DP-1. Based on this analysis shelf life for Zone II was proposed at 24 months with high reliability. Comparison of the PLS model estimates with the measured stability data at shelf life revealed good predictive ability of the developed model. Moreover, PLS predictions of DP-1 and Total impurities were more accurate than those obtained with a standard linear least squares regression, while DP-2 predictions were at least as accurate. We can thus propose a more extensive use of this approach for stability evaluation of pharmaceuticals.

Lipospheres for Simultaneous Controlled Release and Improved Pharmacokinetic Profiles of Saxagliptin-Enalapril: Formulation, Optimization, and Comparative In Vitro-In Vivo Evaluation.

The current study aims at formulating and optimizing lipospheres (LS) by the Box-Behnken design (BBD) from safe biodegradable carnauba wax (CW) to co-administer saxagliptin (SG) and enalapril (EP) for co-existing chronic hypertensive diabetes in order to overcome inadequacies of conventional modes of drug administration. Optimized liposphere formulation (OLF) was selected by a numerical optimization procedure and a comparative in vivo pharmacokinetic study of OLF and commercial brands was also performed. Discrete, free-flowing, spherical, smooth-surface LS having a size range of 5-10 µm and zeta potential of - 20 to - 30 mV were successfully formulated. Compatibility studies by FTIR and DSC proved the lack of interaction of components while XRD suggested the transformation of crystalline drugs to amorphous form. Outcomes of dependent optimizing variables like percentage yield (30-90%), EP-release (32-92%), and SG-release (28-95%) followed a polynomial quadratic model. Pharmacokinetics studies indicated a significantly lower Cmax of EP (125.22 ± 6.32) and SG (75.63 ± 3.85) and higher mean Tmax values (9.4 h for EP and 10.73 h for SG) from OLF in comparison with reference brands of EP (257.54 ± 8.23 ng/mL) and SG (393.66 ± 2.97 ng/mL). Additionally, a potential rise in half-life and MRT of SG and EP was achieved reaching approximately 2- to 3-fold higher than noted for reference brands. Importantly, the enhanced Tmax and AUC0-24 specified the achievement of enhanced bioavailability of both drugs from LS. Consequently, such an innovative approach could not only control drug release in both in vitro and in vivo analyses but also maintain plasma drug concentration for a longer time without maximizing Cmax leading towards effective management of chronic illnesses.