The glucagon‐like peptide‐1 receptor agonist Exendin‐4, ameliorates contrast‐induced nephropathy through suppression of oxidative stress,vascular dysfunction and apoptosis independent of glycaemia

Contrast‐induced nephropathy (CIN) is a leading cause of hospital‐acquired acute kidney injury, particularly in diabetic patients. Previous studies have shown renoprotective effects of glucagon‐like peptide‐1 (GLP‐1) signalling; however, its role in CIN remains unexplored. This study investigates the prophylactic effect of exendin‐4, a GLP‐1R agonist, against CIN in a rat model mimicking both healthy and diabetic conditions. Animals were randomly divided into 7 groups: a control sham group (n = 8), and 2 identical sets of 3 disease groups, one received exendin‐4 before exposure to contrast medium (CM), while the other served as untreated control. The 3 disease groups represented diabetes (n = 8), CIN (n = 8), or diabetes and CIN combined (n = 8). Untreated groups showed deteriorating renal function as indicated by significantly higher levels of serum creatinine and blood urea nitrogen, malondialdehyde, and endothelin‐1 and caspase‐3 expression compared to the sham control group. This was accompanied by a significant decrease in tissue reserves of reduced glutathione, superoxide dismutase, nitrate and endothelin nitric oxide synthase as well as deteriorating renal histology. The CM‐induced changes in diabetic rats indicate impaired renal function, oxidative stress, vascular dysfunction, and apoptosis, and were significance higher in intensity compared to non‐diabetic rats. Pretreatment with exendin‐4 ameliorated all the aforementioned CM‐induced nephropathic effects independent of the glycemic state. To our knowledge, this is the first study describing the prophylactic renoprotective effects of exendin‐4 against CIN. With the current pharmaceutical use of exendin‐4 as a hypoglycaemic agent, the GLP‐1R agonist becomes an interesting candidate for human clinical trials on CIN prevention.     

DPP-4 inhibitor plus SGLT-2 inhibitor as combination therapy for type 2 diabetes: from rationale to clinical aspects

Introduction: Type 2 diabetes (T2D) is a complex disease with multiple defects, which generally require a combination of several pharmacological approaches to control hyperglycemia. Combining a dipeptidyl peptidase-4 inhibitor (DPP-4i) and a sodium-glucose cotransporter type 2 inhibitor (SGT2i) appears to be an attractive approach.

Area covered: An extensive literature search was performed to analyze the pharmacokinetics, pharmacodynamics and clinical experience of different gliptin-gliflozin combinations.

Expert opinion: There is a strong rationale for combining a DPP-4i and a SGLT2i in patients with T2D because the two drugs exert different and complementary glucose-lowering effects. Dual therapy (initial combination or stepwise approach) is more potent than either monotherapy in patients treated with diet and exercise or already treated with metformin. Combining the two pharmacological options is safe and does not induce hypoglycemia. The additional glucose-lowering effect is more marked when a gliflozin is added to a gliptin than when a gliptin is added to a gliflozin. Two fixed-dose combinations (FDCs) are already available (saxagliptin-dapagliflozin and linagliptin-empagliflozin) and others are in current development. Bioequivalence of the two compounds given as FDC tablets was demonstrated when compared with coadministration of the individual tablets. FDCs could simplify the anti-hyperglycaemic therapy and improve drug compliance.     

Adjunctive Role of Glucagon‐Like Peptide‐1 Receptor Agonists in the Management of Type 1 Diabetes Mellitus

Glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) are commonly used in combination with insulin to manage type 2 diabetes mellitus, and four agents are currently approved for this indication: exenatide, liraglutide, dulaglutide, and albiglutide. The distinctive properties of GLP‐1 RAs—potential hemoglobin A_1c (A1C) reduction, weight loss, potential to reduce insulin doses, and lower hypoglycemia risk—have made these agents potential treatment options for patients with type 1 diabetes mellitus (T1DM) as well. These positive effects are due to glucose‐dependent insulin secretion, reduced glucagon secretion, increased satiety, and delayed gastric emptying. Patients with T1DM are unable to suppress glucagon during meals, which contributes to postprandial hyperglycemia and may be improved with GLP‐1 therapy. In this review, we evaluated the available literature on the clinical efficacy and safety of GLP‐1 RAs in patients with T1DM. We conducted a search of the PubMed (1966–May 2016) and Ovid (1946–May 2016) databases. Abstracts presented at the scientific and clinical sessions of the American Diabetes Association and the American Association of Clinical Endocrinologists were also searched. The references of the published articles were also reviewed to identify additional studies appropriate for inclusion. All identified articles published in English were evaluated. Studies were included if they evaluated the clinical use or safety of GLP‐1 RAs in patients with T1DM. Twelve studies were included, with four evaluating exenatide, one evaluating exenatide extended release, and seven evaluating liraglutide. Both exenatide and liraglutide showed significant reductions in hemoglobin A1C, plasma glucose concentration, body weight, and insulin doses when administered to patients with T1DM already receiving insulin therapy, without increasing the occurrence of hypoglycemia. Adverse effects were mostly gastrointestinal in nature but were mild and transient. Patients who may benefit most are those experiencing adverse effects from insulin, those not at their A1C goal but hypoglycemia prevents insulin titration, and those who may benefit from weight loss.     

Lixisenatide as add-on to insulin glargine for the treatment of type 2 diabetes mellitus

Introduction: As type 2 diabetes mellitus (T2DM) advances, patients receiving basal insulin will eventually require another agent on top of their current regimen in order to achieve glycemic control. One such agent that can be administered in combination with basal insulin is the glucagon-like peptide-1 receptor agonist (GLP-1 RA) lixisenatide. GLP-1 RAs, such as lixisenatide, and basal insulin offer complementary mechanisms of action in their ability to provide glycemic control, thus providing a strong rationale for using them in combination with each other for the treatment of T2DM.

Areas covered: The current data available on the use of lixisenatide added to basal insulin for the management of T2DM is reviewed.

Expert opinion: Lixisenatide as add-on to basal insulin provides overall glycemic control as well as offering a number of other treatment benefits, such as a reduction in both body weight and the risk of hypoglycemia. Therefore, when basal insulin becomes inadequate in managing T2DM, lixisenatide should be considered as an add-on agent to help patients achieve glycemic targets with a low risk of hypoglycemic events.     

胰高血糖素样肽1受体激动剂治疗2型糖尿病患者疗效的网状Meta分析

目的：系统评价胰高血糖素样肽1受体激动剂治疗2型糖尿病的临床疗效。方法：根据PICOS原则制定检索策略,计算机检索MEDLINE、EMBASE、CENTRAL等数据库,检索时限从建库至2018年8月。严格按照纳入排除标准筛选随机双盲对照试验,提取纳入文献的基本信息和结局指标,采用Corchrane偏倚风险评估工具对文献进行方法学质量评价。采用软件STATA14.0对各效应指标进行网状Meta分析,连续性变量用均数差（MD）及95% CI计算,二分类变量用比值比（OR）及95% CI计算。结果：共纳入51篇英文研究,合计22 360例患者,涉及19个干预措施。网状Meta分析显示,在疗效方面,索马鲁肽1.0 mg降低糖化血红蛋白、提高HbA1c<7%达标率、降低空腹血糖、减轻体质量、降低收缩压最明显,艾塞那肽10 μg降低舒张压最明显。结论：胰高血糖素样肽1受体激动剂治疗2型糖尿病有良好的疗效。     

Mechanism-based population pharmacokinetic modelling in diabetes: vildagliptin as a tight binding inhibitor and substrate of dipeptidyl peptidase IV

AIMS

To assess the pharmacokinetics of vildagliptin at different doses and build a mechanism-based population model that simultaneously describes vildagliptin pharmacokinetics and its effects on DPP-4 activity based on underlying physiology and biology.

METHODS

Vildagliptin concentrations and DPP-4 activity vs. time from 13 type 2 diabetic patients after oral vildagliptin 10, 25 or 100 mg and placebo twice daily for 28 days were co-modelled. NONMEM VI and S-ADAPT were utilized for population modelling.

RESULTS

A target-mediated drug disposition (TMDD) model accounting for capacity-limited high affinity binding of vildagliptin to DPP-4 in plasma and tissues had good predictive performance. Modelling the full time course of the vildagliptin-DPP-4 interaction suggested parallel vildagliptin dissociation from DPP-4 by a slow first-order process and hydrolysis by DPP-4 to an inactive metabolite as a disposition mechanism. Due to limited amounts of DPP-4, vildagliptin concentrations increased slightly more than dose proportionally. This newly proposed model and the parameter estimates are supported by published in vitro studies. Mean parameter estimates (inter-individual coefficient of variation) were: non-saturable clearance 36 l h⁻¹ (25%), central volume of distribution 22 l (37%), half-life of dissociation from DPP-4 1.1 h (94%) and half-life of hydrolysis 6.3 h (81%).

CONCLUSIONS

Vildagliptin is both an inhibitor and substrate for DPP-4. By utilizing the TMDD approach, slow dissociation of vildagliptin from DPP-4 was found in patients and the half-life of hydrolysis by DPP-4 estimated. This model can be used to predict DPP-4 inhibition effects of other dosage regimens and be modified for other DPP-4 inhibitors to differentiate their properties.     

Design,Synthesis and Biological Evaluation of Imidazo[1,2‐a]pyridine Derivatives as Novel DPP‐4 Inhibitors

A new series of DPP‐4 inhibitors with imidazo[1,2‐a]pyridine scaffold were designed by exploiting scaffold hopping strategy and docking study. Based on docking binding model, structural modifications of 2‐benzene ring and pyridine moieties of compound 5a led to the identification of compound 5d with 2, 4‐dichlorophenyl group at the 2‐position as a potent (IC₅₀ = 0.13 μm ), selective (DPP‐8/DPP‐4 = 215 and DPP‐9/DPP‐4 = 192) and in vivo efficacious DPP‐4 inhibitor. Further, molecular docking revealed that compound 5d could retain key binding features of DPP‐4 with the pyridine moiety of imidazo[1,2‐a]pyridine ring providing an additional π?π interaction with Phe357 of DPP‐4. Compound 5d might be a promising lead for further development of novel DPP‐4 inhibitor treating T2DM.     

Concentration‐dependent plasma protein binding of the novel dipeptidyl peptidase 4 inhibitor BI 1356 due to saturable binding to its target in plasma of mice,rats and humans

Objectives The purpose of this study was to characterise the plasma protein binding of BI 1356. Methods BI 1356 (proposed trade name ONDERO) is a novel dipeptidyl peptidase 4 (DPP‐4) inhibitor, which is under clinical development for the treatment of type 2 diabetes. DPP‐4 is expressed in various tissues but soluble DPP‐4 is also present in plasma. Therefore, binding to soluble DPP‐4 may influence the pharmacokinetics of BI 1356. Plasma protein binding of BI 1356 was determined in vitro for wild type mice and rats and the results compared with those for DPP‐4 knockout mice and DPP‐4 deficient Fischer rats. In addition, protein binding of BI 1356 was examined in plasma from healthy human volunteers and renal excretion of the compound in the DPP‐4 knockout mice was compared with that occurring in wild type mice. Key findings The results showed that BI 1356 exhibited a prominent concentration‐dependent plasma protein binding due to a saturable high affinity binding to the DPP‐4 target in plasma. Differences in renal excretion of BI 1356 between DPP‐4 knockout mice and wild type mice suggested that saturable binding of BI 1356 to DPP‐4 in the body also influenced elimination. Conclusions High affinity, but readily saturable binding of BI 1356 to its target DPP‐4 accounted primarily for the concentration‐dependent plasma protein binding at therapeutic plasma concentrations of BI 1356.     

二肽基肽酶Ⅳ抑制剂辅助胰岛素治疗1型糖尿病的研究进展

二肽基肽酶Ⅳ（DPP-4）抑制剂为一类在2型糖尿病中应用广泛的口服降糖药,其疗效确切、给药方便、总体耐受性好,但目前尚未被批准用于1型糖尿病。国内外相关文献表明在1型糖尿病患者体内DPP-4抑制剂可以辅助胰岛素改善血糖、保护胰岛β细胞功能、降低谷氨酸脱羧酶抗体（GADA）滴度、减少胰岛素剂量,且不增加低血糖风险和体质量。因此,DPP-4抑制剂可能可作为1型糖尿病患者胰岛素的辅助治疗,作用机制可能源于其抑制胰岛α细胞分泌胰高血糖素,通过免疫机制使胰岛β细胞免受摧毁。     

Adding prandial GLP-1 receptor agonists to basal insulin: a promising option for type 2 diabetes therapy

Background: Diabetes mellitus is a serious and increasingly prevalent condition in Canada and around the world. Treatment strategies have become increasingly complex, with a widening array of pharmacological agents available for glycemic management in type 2 diabetes mellitus (T2DM). New therapies that act in concert with available basal insulins may represent alternatives to basal insulin intensification with prandial or pre-mixed insulin. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have recently shown promise as useful additions to basal insulin, with significant reductions in glycated hemoglobin and potentially beneficial effects on body weight. This review will focus on pivotal clinical trials to assess the potential benefits of adding prandial GLP-1 RAs to basal insulin in patients with T2DM.

Methods: Clinical studies combining prandial GLP-1 RAs and basal insulin (published between 2011 and July 2017) were identified and reviewed in PubMed, the Cochrane Central Register of Clinical Trials (Issue 6, June 2017), and clinicaltrials.gov.

Results: Most of the studies presented in this review show that the addition of a prandial GLP-1 RA to basal insulin results in equal or slightly superior efficacy compared to the addition of prandial insulin, together with weight loss and less hypoglycemia.

Conclusions: The results of the studies suggest that a prandial GLP-1 RA as an add-on to basal insulin may be a safe and effective treatment intensification option (vs basal-plus or basal-bolus insulin).     

Effects of active and passive smoking on the development of cardiovascular disease as assessed by a carotid intima‐media thickness examination in patients with type 2 diabetes mellitus

Carotid intima‐media thickness has been widely used as a surrogate end‐point for cardiovascular disease, myocardial infarction, and stroke. This study aimed to assess the effects of active and passive smoking exposure on the development of cardiovascular disease in patients with type 2 diabetes mellitus. Seven hundred twenty‐two patients with type 2 diabetes mellitus were recruited for the study. A standardized questionnaire on smoking status, pack‐years of smoking, and the number of years of smoking cessation was provided to the patients, and their responses were collected for analysis. The carotid intima‐media thickness, carotid plaque, and the internal diameter of the common carotid artery were determined by high‐resolution B‐mode ultrasonography. Compared to non‐smokers, passive female smokers had a higher risk of cardiovascular disease (odds ratio = 3.50, 95% confidence interval: 1.29–9.49, P = 0.009); they also had a significantly larger common carotid artery (P = 0.041) and risk of carotid plaque (odds ratio = 2.20, 95% confidence interval: 1.1980–4.0505, P = 0.01). Both active and passive male smokers had a significantly greater carotid intima‐media thickness than non‐smokers (P = 0.003 and P = 0.005, respectively). Male active smokers had a significantly higher risk of carotid plaque (odds ratio = 2.88, 95% confidence interval: 1.4788–5.6094, P = 0.001). In conclusion, cumulative active and passive smoking exposures are significant risk factors for carotid atherosclerosis in patients with type 2 diabetes mellitus. Our results highlight the importance of endorsing a smoke‐free environment for patients with type 2 diabetes mellitus.     

Treatment preference for weekly versus daily DPP-4 inhibitors in patients with type 2 diabetes mellitus: outcomes from the TRINITY trial

Abstract

Objective: To examine patient preference for treatment with the oral once-weekly dipeptidyl peptidase-4 inhibitor (DPP-4i), trelagliptin, and oral once-daily DPP-4i, alogliptin, administered for 8?weeks each in patients with type 2 diabetes mellitus prescribed a daily DPP-4i.

Methods: In this randomized, open-label, two-way crossover study, patients received trelagliptin followed by alogliptin (T-A group) or alogliptin followed by trelagliptin (A-T group), for 8?weeks each (NCT03231709, JapicCTI-173662). Treatment preference was assessed using a standardized questionnaire in the overall population and by baseline characteristics. Other outcomes included patient satisfaction with diabetes treatment (assessed using the Diabetes Treatment Satisfaction Questionnaire [DTSQ]), hemoglobin A1c (HbA1c) levels after 8?weeks of treatment with each agent, and safety.

Results: Sixty patients from two clinical sites were randomized 1:1 to T-A and A-T groups (each n?=?30); baseline characteristics were similar between groups. After 16?weeks of treatment, 51.7% of patients preferred treatment with alogliptin compared with 30.0% selecting trelagliptin (p?=?.014); preference for alogliptin was consistently greater than for trelagliptin in the secondary analyses by baseline characteristics. DTSQ score and HbA1c levels were similar between treatments after 8?weeks of therapy. Both treatments demonstrated favorable safety and tolerability profiles.

Conclusions: Patients expressed a significantly greater treatment preference for once-daily alogliptin than once-weekly trelagliptin, although patient satisfaction and HbA1c levels were similar across treatments. The decision to administer a once-weekly or once-daily DPP-4i is likely to depend on patient preference, patient-physician discussions, and treatment practices of the prescribing physician.

Trial registration: ClinicalTrials.gov identifier: NCT03231709.