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Objectives: Uncertainties remain regarding the effect of elevated glucose levels on lymphatic metastasis of cancer cells. Our study elucidated the mechanisms linking high glucose to lymphangiogenesis and lymphatic barrier‐related factors and investigated the protective role of linagliptin against lymphatic barrier dysfunction. Materials and Methods: A CAL‐27‐LEC co‐culture system was established. Sodium fluorescein permeability assay observed lymphatic endothelial cell permeability. Western blotting and RT‐qPCR detected protein and mRNA expression under different conditions, respectively. CCK‐8, scratch wound healing, and transwell assays revealed cell migration and proliferation. Tube formation experiment tested capacity for endothelial tube formation. Immunohistochemical staining analyzed tissue sections from 43 oral cancer individuals with/without diabetes. Results: In high‐glucose co‐culture system, we observed increased lymphatic barrier permeability and decreased expression of ZO‐1 and occludin, two tight‐junction proteins; conversely, the expression of PAR2, a high permeability‐related protein, was increased. Following linagliptin treatment, the expression levels of VEGF‐C, VEGFR‐3, and PAR2 decreased, while those of ZO‐1 and occludin increased. Considerably higher levels of LYVE‐1 expression in individuals with diabetes than in those without diabetes. Conclusions: By ameliorating the high glucose‐induced disruption of the lymphatic endothelial barrier, linagliptin may reduce lymphangiogenesis and exhibit an inhibitory effect on lymphatic metastasis in oral cancer patients with diabetes. [ABSTRACT FROM AUTHOR]

This research paper presents an electroanalytical investigation utilizing voltammetry to quantify the antidiabetic drug linagliptin with an unmodified boron-doped diamond electrode. Using cyclic voltammetry, linagliptin exhibited a single, distinct, irreversible oxidation peak at around + 1.03 V (vs. Ag/AgCl) in a 0.1 mol dm−3 phosphate buffer solution at pH 7.4. The square-wave voltammetry technique achieved acceptable linearity at approximately + 0.94 V in PBS (pH 7.4). The methodology demonstrated linearity within the concentration range of 1.0 and 50.0 μg cm−3 (equivalent to 2.1 × 10–6–1.1 × 10–4 mol dm−3) and yielded a limit of detection of 0.28 μg cm−3 (equivalent to 5.9 × 10–7 mol dm−3). The investigation of the proposed method's applicability was ultimately conducted through the sensing of linagliptin in drug formulations. The established methodologies can serve as viable alternatives to other analytical techniques due to their cost-effectiveness, user-friendliness, efficiency, and ability to yield reliable and repeatable results. [ABSTRACT FROM AUTHOR]

Dipeptidyl-peptidase 4 (DPP-4) inhibitors are one of the most commonly used anti-diabetic drugs because of their established safety and efficacy. Bullous pemphigoid which is an autoimmune blister skin disorder associated with DPP-4 inhibitors is a recognized adverse drug reaction (ADR) reported in some Southeast Asian Nations but has not been reported earlier from India. It is an uncommon, serious treatment with emergent adverse effects. Here, we report a series of five cases of DPP-4 inhibitor Linagliptin-induced bullous pemphigoid reaction in Type 2 diabetes mellitus patients. We are reporting five cases that showed various clinical manifestations in terms of gender (males 4), duration of diabetes (average 7.2 years), glycemic control (average HbA1C 6.7%), and latency period (average 3.6 weeks) for development of the ADR. Quality of life and treatment satisfaction were severely impacted by this ADR. Withdrawal of Linagliptin, use of topical and oral steroids and immunosuppressant like azathioprine were prescribed and effective for improving the lesions of all the cases. As per the World Health Organization-Uppsala Monitoring Center scale, causality was established as "probable" for all the cases. This case series serves to bring to the notice of prescribers regarding this important cutaneous ADR with the use of Linagliptin. This case intends to improve awareness among clinicians regarding the possibility of this cutaneous ADR among diabetic patients to facilitate early diagnosis and intervention. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: The current study aimed to compare the renal effects of Empagliflozin with Linagliptin combined with Metformin in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease. Materials and Methods: We conducted a randomized clinical trial on diabetic patients aged over 18 years with chronic renal failure and an EGFR between 20 to 60 ml/minutes/1.73 m2 corrected with the MDRD equation. Between January and December 2023, a total of 150 cases in Imam Hossein Hospital were randomized into two study arms of 75 cases receiving Empagliflozin (10 mg/day) and metformin or Linagliptin (5mg/day) and metformin for 6 months. The primary outcome was a change in chronic kidney disease (CKD) stage, while serum creatinine, fasting blood sugar (FBS), proteinuria, and blood pressure were evaluated at baseline, 3 and 6 months later. Results: The mean age of participants was 62.20 (± 4.45) years and 50% of them were females. Study indices including serum creatinine (P: 0.001), estimated glomerular filtration rate (eGFR) (P: 0.001), FBS (P: 0.001), HgA1c (P: 0.001), proteinuria (P: 0.001), and blood pressure (P: 0.001) reduced significantly over time in both groups. After adjustment for potential confounders, Empagliflozin reduced the level of serum creatinine independent of other factors. Conclusion: Empagliflozin significantly reduces the level of serum creatinine compared to Linagliptin in patients with T2DM and chronic renal failure. [ABSTRACT FROM AUTHOR]

The article describes two case scenarios in which liraglutide demonstrated glucose lowering similar to agents categorized as having very high efficacy. A 63-year-old Black man was referred to an outpatient clinic's in-house pharmacist-run diabetes education and management service while a 63-year-old White man was referred to the same clinical pharmacy service. The cases show the potential for robust A1C lowering with the use of liraglutide in patients with type 2 diabetes who overeat.

Lung cancer has the highest global fatality rate of all cancers, and most existing therapies have a wide range of toxic effects. This necessitates searching for new medications with potential anticancer properties and a better safety profile against normal cells. Dipeptidyl peptidase-4 (DPP4) inhibitors have recently shown anticancer efficacy in various malignancies such as colorectal, prostate, and renal cancer. Therefore, this study investigated the anticancer activity of sitagliptin (SITA) and linagliptin (LINA) against the lung cancer cell line A549 alone and in combination with cisplatin (CP). A549 cells were divided into six groups: control (untreated cells), CP-treated cells, SITA-treated cells, LINA-treated cells, CP plus SITA-treated cells (ratio 1:1), and CP plus LINA-treated cells (ratio 1:1). After 72 hours of incubation, a 3-(4,5-dimethylthiazol2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) test was used to determine cell viability and the concentration of 50% inhibition for cell viability (IC50) for each group. A549 cells were later seeded in six flasks and treated with the resulting IC50; cell pellets were collected and lysed to determine the malondialdehyde (MDA) level using ELISA kits. SITA and LINA therapy dramatically reduced A549 cell viability compared to the control (P < 0.0001), with results comparable to CP. When SITA and LINA were combined with CP, they demonstrated significantly higher anticancer efficacy than when used alone. Notably, both medicines lowered MDA levels when taken alone or in combination with CP. SITA and LINA showed promising anticancer and antioxidant activity against A549 cells. This may indicate a potential synergistic anticancer effect with CP. [ABSTRACT FROM AUTHOR]

The increasing occurrence of childhood overweight and obesity has been followed by a substantial increase in youth-onset type 2 diabetes (T2D). Pharmacological treatment options for youth-onset T2D remain limited, with a clear unmet need for additional oral agents. This summary of research reports on the efficacy and safety of empagliflozin and linagliptin on glycaemic control in children and adolescents aged 10–17 years with T2D in the randomised, double-blind, parallel group, phase 3 DINAMO trial. Empagliflozin provided a clinically relevant, statistically significant, and durable improvement in glycaemic control; however, linagliptin did not. The safety profile of both empagliflozin and linagliptin was comparable to those observed in studies in adults. These results suggest that empagliflozin could be a new oral therapy option for youth-onset T2D. [ABSTRACT FROM AUTHOR]

Objective: Lung cancer (LC) has the highest mortality rate globally. Most chemotherapeutic medicines now in use are cytotoxic, prompting the search for novel compounds with anticancer properties and improved safety profiles for normal cells. Dipeptidyl peptidase-4 inhibitors have demonstrated anticancer effects and apoptotic properties by specifically inhibiting dipeptidyl peptidase-4, a glycoprotein found in various organs that support the spread of cancer and tumor formation. Based on that, this study aimed to evaluate the cytotoxicity and apoptotic activity of sitagliptin (SITA) and linagliptin (LINA) against the lung cancer cell line (A549) alone and in combination with cisplatin (CP). Methods: A549 cells were categorized into six groups: control (untreated cells), CP-treated cells, SITA-treated cells, LINA-treated cells, CP plus SITA treated cells (1:1 ratio), and CP plus LINA treated cells (1:1 ratio). After 72 hours of incubation, cell viability (or cytotoxicity) and concentration required to inhibit 50% of cell viability (IC50) for each group were determined using an MTT assay. This method is safe and easy to use, has more reproducibility, and is commonly used for cell viability and cytotoxicity tests. Later, A549 cells were cultured in six flasks and exposed to the IC50 for 36 hours. Afterward, the cells were harvested and centrifuged, and the supernatant was removed. The remaining cell pellets were collected and lysed using a lysis buffer to measure B-cell lymphoma type 2 (BCL-2) levels with ELISA test kits. The data was collected and subjected to statistical analysis techniques. Results: MTT assay results determined that SITA and LINA significantly increased A549 cell cytotoxicity compared to the control group (P<0.0001). Moreover, combining SITA or LINA with CP showed markedly increased antitumor efficacy and more significant cytotoxicity directed toward A549 cells. Additionally, these combinations highly reduced IC50 in comparison to monotherapy. Considerably, both drugs showed remarkable apoptotic activity on A549 cells when used alone or combined with CP by decreasing BCL2 levels. Consequently, it potentiates apoptotic effects and cytotoxicity of CP against cancer cells. Interestingly, Lina was more potent than Sita regarding cytotoxicity and apoptotic activity on A549 cells. Conclusion: SITA and Lina exhibited significant cytotoxic and apoptotic effects against A549 cells through the induction of apoptosis. Notably, the results suggest a potential synergistic anticancer impact on CP. [ABSTRACT FROM AUTHOR]

The article focuses on the use of semaglutide in patients receiving hemodialysis, highlighting unexpected benefits for managing hyperphosphatemia and hyperkalemia, despite limited treatment options for type 2 diabetes due to renal impairment and complex physiology. It reports illustrate significant improvements in phosphate levels in patients who initiated semaglutide alongside their hemodialysis treatment.

Linagliptin is a selective dipeptidyl peptidase-4 (DPP-4) inhibitor that indirectly elevates the glucagon-like peptide-1 (GLP-1) level. The aim of the present study was to check whether linagliptin has an influence on neurotransmission in rat brain. Rats were acutely and chronically exposed to linagliptin (10 and 20 mg/kg, intraperitoneally (i.p.)). Twenty-four hours later, the striatum and hippocampus were selected for further studies. In neurochemical experiments, using high-performance liquid chromatography with electrochemical detection (HPLC-ED), the concentrations of three major neurotransmitters—dopamine, serotonin and noradrenaline—and their metabolites were measured. The analysis of mRNA expression of dopamine (D1 and D2), serotonin (5-HT-1 and 5-HT-2) and noradrenaline (α1 and α2a) receptors was also investigated using real-time quantitative reverse transcription polymerase chain reaction (RQ-PCR) in the same brain areas. Linagliptin has the ability to influence the dopaminergic system. In the striatum, the elevation of dopamine and its metabolites was observed after repeated administration of that linagliptin, and in the hippocampus, a reduction in dopamine metabolism was demonstrated. Acute linagliptin exposure increases the serotonin level in both areas, while after chronic linagliptin administration a tendency for the mRNA expression of serotoninergic receptors (5-HT1A and 5-HT2A) to increase was observed. A single instance of exposure to linagliptin significantly modified the noradrenaline level in the striatum and intensified noradrenaline turnover in the hippocampus. The recognition of the interactions in the brain between DPP-4 inhibitors and neurotransmitters and/or receptors is a crucial step for finding novel discoveries in the pharmacology of DPP-4 inhibitors and raises hope for further applications of DPP-4 inhibitors in clinical practices. [ABSTRACT FROM AUTHOR]

As part of the development and production of pharmaceuticals, the purity of Active Pharmaceutical Ingredients stands as a fundamental parameter that significantly influences the quality, safety, and efficacy of the final drug product. Impurities in Active Pharmaceutical Ingredients are various unwanted substances that can appear during the whole manufacturing process, from raw materials to the final product. These impurities can stem from multiple sources, including starting materials, intermediates, reagents, solvents, and even degradation products resulting from exposure to environmental factors such as heat, light, or moisture. Their presence can potentially compromise the therapeutic effect of the drug, introduce unexpected side effects, or even pose safety risks to patients. This study aims to conduct the forced degradation of linagliptin and subsequently attempt to identify the resulting degradants. The degradation procedures were carried out in accordance with the guidelines of the International Committee for Harmonization. The degradation profile of linagliptin was investigated under various conditions, including acid hydrolysis, alkaline hydrolysis, oxidation, heat, and light exposure, utilizing ultra-performance liquid chromatography connected to a photo array detector. Identification and characterization of the degradation products were achieved using an ultra-performance liquid chromatography coupled with a single quadrupole detector mass spectrometer and also a liquid chromatography coupled with a high-resolution mass spectrometry. The identified degradation products demonstrate that linagliptin is particularly susceptible to degradation when exposed to acid and peroxide. Whereas, no significant degradation effects were observed under alkali, thermolytic, and photolytic conditions. [ABSTRACT FROM AUTHOR]

Type 1 diabetes mellitus (T1DM) is one of the main causes of ovarian atresia, but its molecular effect on the ovaries is not fully understood. Accumulating evidence suggests that T1DM causes excessive endoplasmic reticulum (ER) stress and insufficient adaptive unfolded protein response that triggers proapoptotic signaling pathways in ovarian tissue. In addition, problems such as amenorrhea and infertility, which are frequently seen in women with T1DM, continue despite the intensification of insulin therapy and improvement of metabolic control. Therefore new, and adjunctive treatments for women with T1DM need to be explored. We aimed to examine how the use of linagliptin, which has blood sugar‐lowering effects and high antioxidant activity, together with insulin affects the expression levels of proteins and genes that play a role in ER stress in type 1 diabetic mouse ovaries. Eighty‐four Balb/C 6‐week‐old female mice were randomly divided into seven groups: control, vehicle, diabetes + insulin, diabetes + linagliptin, diabetes + linagliptin + insulin, diabetes + TUDCA, and diabetes + TUDCA + insulin. TUDCA (an inhibitor of ER stress) groups are positive control groups created to compare linagliptin groups in terms of ER stress. Linagliptin and TUDCA were given by oral gavage and 1U insulin was administered subcutaneously for 2 weeks. A significant decrease was observed in the MDA and NOX1 levels and the number of atretic follicles in the ovaries of the diabetes + linagliptin + insulin group compared to the diabetes + insulin group. The use of linagliptin and insulin increased the expression of pro‐survival XBP1s transmembrane protein and decreased the expression of proapoptotic ATF4, pJNK1/2, cleaved caspase 12, and cleaved caspase 3 in mouse ovaries. Our study provides new therapeutic evidence that linagliptin administered in addition to insulin induces ER stress mechanism‐dependent survival in ovaries with type 1 diabetes. Significance Statement: In our study, we aimed to answer the question whether the use of linagliptin, a DPP4 inhibitor with high antioxidant activity, and insulin triggers the survival pathway or the apoptotic pathway of unfolded protein response (UPR) signaling activated by endoplasmic reticulum (ER) stress in type 1 diabetes mellitus (T1DM) mouse ovaries to reach new therapeutic targets. Our results showed that the addition of linagliptin to insulin induced pro‐survival UPR by decreasing ATF4 and increasing XBP1s proteins, while suppressing proapoptotic UPR by decreasing p‐JNK1 + JNK2, cleaved caspase 12, and cleaved caspase 3 proteins. This study will contribute to the literature in terms of the discovery of new methods to be used in the treatment of ovarian pathologies associated with diabetes‐induced ER stress. [ABSTRACT FROM AUTHOR]

The worldwide incidence of type 2 diabetes mellitus (T2DM), a chronic metabolic disorder, is increasing rapidly. A newer category of oral hypoglycemic medications called dipeptidyl peptidases-4 (DPP-4) inhibitors has come into existence for the management of T2DM. DPP-4 inhibitors, i.e., linagliptin, saxagliptin, and sitagliptin, belong to BCS class III, while alogliptin belongs to BCS class I. These drugs have high aqueous solubility and, therefore, short elimination half-life which necessitates the need for multiple daily dosing. Furthermore, the unrestrained drug release from conventional tablets can cause elevation in systemic drug concentrations which might instigate gastrointestinal side effects. The poor membrane permeability of BCS class III drugs also results in their poor oral bioavailability. Therefore, clinical compliance and therapeutic efficacy of DPP-4 inhibitors can be enhanced by nanotechnology-based techniques. This research paper has described various risk factors and pathophysiology of T2DM and also explained about the mode of action of DPP-4 inhibitors. The main objectives and rationale of this review include the exploration of preclinical pharmacological investigations and the summarization of developed nanoformulations of DPP-4 inhibitors researched in previous decades. The nanoformulations which has been synthesized for DPP-4 inhibitors in the past few decades for the management of T2DM include polymeric nanoparticle, solid lipid nanoparticle, transferosomes, niosomes, mucoadhesive nanoparticle, and self-microemulsifying drug delivery systems. [ABSTRACT FROM AUTHOR]

To investigate the mechanism of linagliptin on stromal cell-derived factor 1 and vascular endothelial growth factor protein after molar pulp revascularization in rats. 45 specific-pathogen free male Sprague-Dawley rats were divided into 5 groups based on the average body weight, with 9 rats in each group. The control group did not establish the rat model of molar pulp revascularization, and model group, low-linagliptin group, mediumlinagliptin group, and high-linagliptin group all established the rat model of molar pulp revascularization. On d 1 after modeling, rats in low-linagliptin group, medium-linagliptin group, and high-linagliptin group were gavaged with 1, 2, and 3 mg/ml linagliptin, respectively. Rats in control group and model group were gavaged with 0.9 % normal saline at equal volume, once a day for 28 d. After the last gavage, the rats were detected for the body weight and fasting blood glucose, and superoxide dismutase and serum oxidative stress indicators malondialdehyde were detected by kit; hematoxylin and eosin staining was employed to detect the pathological morphology of dental pulp tissue, immunohistochemistry and immunoblot were applied to detect the positive expression of vascular endothelial growth factor and stromal cell-derived factor 1 and the protein content. No significant differences were found in fasting blood glucose and body weight between the groups (p>0.05). In control group, loose connective tissue was found in the root canal of rats, and a large number of long spindle forming fibrocytes were distributed; in model group, a large number of inflammatory cells are found under the dental pulp, with the majority of neutrophils; in comparison with model group, inflammatory cells in pulp tissue of low-linagliptin group, medium-linagliptin group and high-linagliptin group gradually decreased, and scattered restorative dentin could be found in the pulp, and there was no inflammatory expression in the middle and lower tissues of the pulp. Dipeptidyl peptidase 4 inhibitor linagliptin has no effect on rats' body weight and blood glucose after revascularization, but it can improve the level of oxidative stress and accelerate revascularization and perhaps its mechanism links to the up-regulation of vascular endothelial growth factor and stromal cell-derived factor 1 expression. [ABSTRACT FROM AUTHOR]

A well-made chitosan-PVP block copolymer platform was equipped with highly ordered and uniform nano-channels. This highly adhesive block copolymer platform was designed to ensure the efficient co-delivery of two synergistic-acting hypoglycemic drugs. Linagliptin oral bioavailability is 30% due to poor permeability and intestinal degradation. Its pharmacokinetics shows a non-linear profile. Empagliflozin exhibited decreased permeability and decreased solubility in aqueous media between pH 1 and 7.5. Cubosomes were functionalized as a good microdomain to guest and improve the physicochemical characteristics of drug molecules with decreased permeability and solubility. Cubosomes loaded with linagliptin (linagliptin cubosomes (LCs)) and empagliflozin (empagliflozin cubosomes ECs) were separately prepared using the top-down method and optimized by applying 23 factorial design. Optimized cubosomal systems LCs (F3) and ECs (F4) were incorporated into a chitosan-PVP gel to obtain dual cubosome-loaded platforms (LECF) optimized through 22 factorial design. The permeation study from the optimized LECF (C1) ensured enhanced empagliflozin permeation alongside continued efflux for linagliptin, resolving potential risks due to its non-linear plasma profile. The in-vivo study revealed that AUC(0–∞) of linagliptin and empagliflozin was enhanced by 2- and threefold, respectively. Therefore, the chitosan-PVP block copolymer platform buccal application for the co-delivery of linagliptin and empagliflozin could contribute to enhanced clinical effectiveness in treating diabetes. Graphical abstract showing dual cubosome-loaded platform tested in-vivo using a rabbit model [ABSTRACT FROM AUTHOR]

Gastric hyperacidity and ulceration are chronic diseases characterized by repeated healing followed by re-exacerbation. The study aims to protect against gastric hyperacidity without interfering with gastric acid secretion. Pylorus ligation–induced hyperacidity is commonly utilized in the induction of gastric ulcers. Forty-two rats were distributed into seven groups (n = 6). Group I comprised sham-operated group. Group II served as pylorus-ligation group. Groups III–VII were given oral Linagliptin (LN; 3 and 6 mg/kg), L-arginine (LA; 150 and 300 mg/kg) and their combination (LN 3 + LA 150 mg/kg), respectively for 7 days. On the 8th day, groups II–VII were subjected to pylorus-ligation. Treatment of pylorus-ligated rats with LN, LA and their combination improved the gastric hyperacidity as exhibited by a marked reduction in the gastric juice volume, total and free acidities and pepsin contents with a noticeable increase in pH. Pre-treatment with LN, LA and their combination showed a marked alleviation in the gastric inflammatory indicators evidenced by reduction in the gastric levels of MCP-1and Il-1β as well as elevation of eNOS levels versus the sham-operated group. A marked up-regulation in the gastric gene expression of PGE, EP4 and VEGF accompanied by an improvement of the histopathologic pictures/scores, and TNF-α and caspase-3 immuno-staining were also recorded. By estimating the combination-index, it can be concluded that combining LN with LA exhibited prophylactic synergistic effects in ameliorating pylorus ligated-induced hyperacidity, mainly via up-regulation of EP4 receptor and improvement of vascular endothelial damage through VEGF expression in gastric mucosa. [ABSTRACT FROM AUTHOR]

Introduction: The aim of the study was to evaluate the efficacy and safety of fixed-dose combination (FDC) of dapagliflozin (10 mg) and linagliptin (5 mg) in comparison to linagliptin 5 mg (Trajenta) in patients with insufficiently controlled type 2 diabetes mellitus (T2DM) on metformin monotherapy. Methods: The double-blind, randomized, multicentric, parallel-group phase III trial screened 287 adult patients with T2DM (age 18–65 years) from 16 sites across India. The recruited subjects were undergoing metformin monotherapy ≥ 1000 mg/day for at least 28 days. Patients with HbA1c of 7.5–10.5% (58–91 mmol/l) (n = 232) after 2 weeks of run-in period with linagliptin monotherapy and placebo dapagliflozin/linagliptin on metformin monotherapy were randomized (1:1) in parallel to once daily dapagliflozin/linagliptin 10/5 mg or linagliptin 5 mg for 16 weeks. Patients were stratified on the basis of HbA1c (≤ 9.0% and > 9.0%; ≤ 75 mmol/l and > 75 mmol/l)). A total of 225 subjects completed 16 weeks of treatment, 115 patients in the test group and 110 patients in the reference group. Results: Dapagliflozin/linagliptin (p = 0.0003) exhibited a greater change in HbA1c from baseline than linagliptin (p < 0.0001) in 16 weeks (mean reduction, − 1.28% vs − 0.83%). Test group showed a significant decrease in fasting plasma glucose (FPG), postprandial plasma glucose (PPG) and body weight compared to the reference group. The FDC was well tolerated with adverse events being more frequent in the reference group. No serious adverse events (SAEs) were reported in the study. Conclusion: Dapagliflozin/linagliptin combination is a novel dipeptidyl peptidase 4 (DPP4)/sodium-glucose co-transporter 2 (SGLT2) inhibitor FDC approved in India for patients with T2DM. Potential limitations of this study are a small dose of dapagliflozin (10 mg) in the FDC, a short study duration (30 weeks) and a high minimum threshold for HbA1c (≤ 7.5%; ≤ 53 mmol/l). Results indicate the FDC to be a superior therapeutic option over linagliptin for patients with T2DM on metformin monotherapy. Trial Registration: CTRI/2022/08/044563; 01/08/2022. [ABSTRACT FROM AUTHOR]

The new drug linagliptin belongs to the class of dipeptidyl peptidase‐4 enzyme inhibitors. Linagliptin is used to treat type 2 diabetes and is taken orally either alone or in combination with other drugs. In this instance, a new, simple, and economical technique for analyzing linagliptin was developed by the effective use of a pyrrolidone derivative. The primary amine group of linagliptin permits its condensation with ninhydrin (0.14% w/v) to produce a fluorescent product in the presence of phenylacetaldehyde (0.02% v/v). All experimental parameters were carefully examined and adjusted in order to monitor the generation of the pyrrolidone derivative at excitation and emission wavelengths of 385 and 475 nm, respectively. The calibration graph was made by plotting the intensity of the fluorescence in relation to linagliptin concentration. A significant linearity was found for values ranging from 20 to 460 ng/mL. The process's validity has been verified by a thorough assessment of the instructions provided by the International Conference on Harmonization (ICH). The results indicate excellent uniformity with a reference method, showing that there is no substantial difference in precision and accuracy. The proposed approach was utilized for determining linagliptin in real rat plasma successfully owing to its high sensitivity. Additionally, the proposed approach was evaluated using the Eco‐Scale evaluation tool and showed a high degree of eco‐friendliness (86/100). [ABSTRACT FROM AUTHOR]

The purpose of this study was to compare the effects of pioglitazone and linagliptin on glycemic control, lipid profile and high-sensitivity C-reactive protein (hs-CRP) parameters in patients with type 2 diabetes treated with metformin. The present randomized clinical trial was conducted on 60 patients with type 2 diabetes treated with metformin in the age range of 30–60 years. The participants with informed consent were randomly assigned to receive pioglitazone or linagliptin. The first intervention group (n=30) received 30 mg of pioglitazone daily and the second intervention group (n=30) received 5 mg of linagliptin daily for 12 weeks. Fasting blood samples were taken from patients at the baseline and after 12 weeks to measure related variables. The current study was approved in Kashan University of Medical Sciences (with the code of ethics of IR.KAUMS.MEDNT.REC.1398.016), and the Iranian Registry of Clinical Trials (with the registration number of IRCT20170513033941N66). The linagliptin administration significantly reduced serum levels of fasting blood sugar (p=0.03), blood sugar 2 h after a meal (p=0.02), glycosylated hemoglobin (p=0.02) and hs-CRP (p=0.005) after 12 weeks compared with pioglitazone. In contrast, the pioglitazone administration significantly decreased triglyceride levels (p=0.01) and increased HDL-cholesterol (p=0.002) compared to linagliptin. In addition, the administration of both linagliptin and pioglitazone drugs had no significant effect on LDL-cholesterol, total cholesterol, systolic and diastolic blood pressure, creatinine and blood urea. The present study demonstrated the superiority of linagliptin over pioglitazone for glycemic control, although pioglitazone compared to linagliptin showed greater efficacy in reducing triglycerides and raising HDL-cholesterol. [ABSTRACT FROM AUTHOR]

Patients with diabetic kidney disease (DKD) are at increased risk to develop post-contrast acute kidney injury (AKI). Diabetic patients under dipeptidyl peptidase 4 inhibitors (DPP4Is) experience a lower propensity to develop AKI. We speculated that linagliptin as a single agent or in combination with allopurinol may reduce the incidence of post-contrast AKI in stage 3–5 chronic kidney disease (CKD) patients with underlying DKD. Out of 951 DKD patients eligible for this study, 800 accepted to sign informed consent. They were randomly allocated to 4 equal groups that received their prophylaxis for 2 days before and after radiocontrast. The first control group received N-acetyl cysteine and saline, the 2nd received allopurinol, the 3rd group received linagliptin, and the 4th received both allopurinol and linagliptin. Post-procedure follow-up for kidney functions was conducted for 2 weeks in all patients. 20, 19, 14, and 8 patients developed post-contrast AKI in groups 1 through 4, respectively. Neither linagliptin nor allopurinol was superior to N-acetyl cysteine and saline alone. However, the combination of the two agents provided statistically significant renal protection: post-contrast AKI in group 4 was significantly lower than in groups 1 and 2 (p < 0.02 and <0.03, respectively). None of the post-contrast AKI cases required dialysis. Linagliptin and allopurinol in combination may offer protection against post-contrast AKI in DKD exposed to radiocontrast. Further studies are needed to support this view. NCT03470454 [ABSTRACT FROM AUTHOR]

Background: Cardiac hypertrophy (CH) is one of the contributing causes of morbidity and mortality. Hyperhomocysteinemia (HHcy) is one of the diseases which may predispose hyperlipidemia and CH. Linagliptin (Lina) and secoisolariciresinol diglucoside (SDG) are known to alleviate a variety of illnesses by reducing oxidative stress and inflammation. Aim: This study aimed to study the effect of HHcy on cardiac tissues, with a special focus on endoplasmic reticulum (ER) stress as a mainstay pathophysiological pathway. In addition, our study examined the protective effect of Lina, SDG, and their combination against HHcy-induced hyperlipidemia and CH in rats. Methods: Seventy-five male Sprague–Dawley rats were randomly divided into five groups, and for 60 days, the following regimen was administered: Group I: rats received distilled water; Group II: rats received methionine (MET) (2 g/kg/day, p.o.); groups III and IV: rats received Lina (3 mg/kg/day, p.o.) and SDG (20 mg/kg/ day, p.o.), respectively, followed by MET (2 g/kg/day, p.o.); Group V: rats received Lina and SDG, followed by MET (2 g/kg/day, p.o.). Results: Pretreatment with Lina, SDG, and their combination showed a significant decrease in serum levels of HHcy and an improved lipid profile compared to the MET group. Moreover, both drugs improved cardiac injury, as evidenced by the substantial improvement in ECG parameters, morphological features of the cardiac muscle, and reduced serum levels of cardiac markers. Additionally, Lina and SDG significantly attenuated cardiac oxidative stress, inflammation, and apoptosis. Furthermore, Lina, SDG, and their combination remarkably downregulated the enhanced expression of endoplasmic reticulum (ER) stress markers, GRP78, PERK, ATF-4, CHOP, NF-κB, and SREBP1c compared to the METgroup. Conclusion: Lina and SDG showed cardioprotective effects against HHcy-induced heart hypertrophy and hyperlipidemia in rats. [ABSTRACT FROM AUTHOR]

Objective: To assess the effectiveness and safety of evogliptin versus linagliptin in type 2 diabetic patients. Method: 200 individuals with type 2 diabetes with HbA1c levels between 7.1% and 10.1% were divided equally into two groups and given daily doses of either linagliptin 5 mg or evogliptin 5 mg for a period of 12 weeks. The change from baseline HbA1c at week 11 served as the primary efficacy outcome. The change in the mean amplitude of glycaemic excursion (MAGE), as determined by continuous glucose monitoring, served as the secondary endpoint. Evogliptin 5 mg daily was given to both groups in the extension study during the course of the subsequent 11 weeks: the evogliptin/evogliptin group (n = 100) and the linagliptin/evogliptin group (n = 100). Results: The mean change in HbA1c in the linagliptin and evogliptin groups after 11 weeks of treatment was 0.84 and 0.74 percent, respectively. Based on a non-inferiority margin of 0.3%, the between-group difference was 0.11% (95% CI: -0.31 to 0.10), indicating noninferiority. In the evogliptin group, the change in MAGE was 24.5 mg/dL, whereas in the linagliptin group, it was 16.6 mg/dL. These numbers were significantly below the starting points in both groups' data. However, there was little difference between the two groups. At week 25, HbA1c decreased by 0.93% in the evogliptin/evogliptin group, with HbA1c values of 7.1% in 80.1% of the patients. For 25 weeks, there was no significant difference in the frequency or kind of adverse events between the two groups. Conclusion: Evogliptin's ability to reduce blood sugar in this study was non-inferior to linagliptin's. A 0.93% decrease in HbA1c at week 25 allowed for its maintenance. In patients with type 2 diabetes, evogliptin medication increased glycaemic variability without resulting in any severe side effects. [ABSTRACT FROM AUTHOR]

The aim of this study is to reveal the effects of the use of linagliptin, a DPP‐4 inhibitor due to its beneficial cardiovascular effects, on endoplasmic reticulum stress (ERS) signaling, which is involved in the pathogenesis of cardiovascular complications related to type 1 diabetes. BALB/c female mice (n = 72) were divided into six groups: control, diabetes+insulin, diabetes+linagliptin, diabetes+linagliptin+insulin, diabetes+TUDCA, and diabetes+TUDCA+insulin. Immunohistochemistry and western blot method, qRT‐PCR, ELISA method, and malondialdehyde (MDA) measurements were performed. Linagliptin administered to the type 1 diabetic mouse heart significantly reduced the expression levels of the total and cleaved forms of ATF6, ATF4, and p‐JNK, caspase 3. Immunohistochemical and western blot analyses revealed that cleaved caspase 3 protein expression was significantly increased in the diabetes+insulin group compared to the other groups. According to ELISA findings, TUDCA was more effective in reducing NOX 1 and MDA levels than linagliptin. While linagliptin decreased the Chop mRNA level, no change was observed in the Grp78 mRNA level. Our findings showed that there was not much difference between the administration of linagliptin alone or in combination with insulin. Our study reveals that linagliptin is an effective therapeutic agent on ERS and apoptotic UPR in type 1 diabetic hearts. [ABSTRACT FROM AUTHOR]

When human serum albumin binds firmly with a drug molecule, the impact will be greater on its half-life and other important pharmacokinetic properties. Linagliptin is an antidiabetic drug candidate with a good safety profile. The interaction mechanism of linagliptin with HSA is not reported so far. In the present study, various spectroscopic investigations (UV, fluorescence, FTIR and CD) and molecular docking were performed to determine the binding constant and the other binding characteristics of the interaction between HSA and drug molecule. The binding constant obtained from the UV-spectroscopic results (0.98x103 M-1), revealed weak binding between the protein and linagliptin structure. Fluorescence spectroscopy results showed quenching of intrinsic fluorescence of HSA through static quenching. The binding constant value was Ksv=1.26×10-4 M-1. In the FTIR and circular dichroism spectra minor changes were observed in peak positions and peak intensities. Molecular docking revealed that linagliptin was stabilized at site-I primarily with Pi-Pi stacking and the binding mode was similar that of R-warfarin. [ABSTRACT FROM AUTHOR]

In this research study, we developed a new rapid and simple HPLC quantitative approach for comprehensively measuring related substance impurities (LNGN N formyl; LNGN acetamide; LNGN N Boc; LNGN amino) in Linagliptin. The related substance impurities were studied by PDA detection at 225 nm after being separated on the Kromasil C18 column stationary phase. The isocratic mode elution and a flow velocity of 1.0 mL/min were performed with the 0.1% phosphoric acid having pH 2.5 and acetonitrile. The proposed approach was appropriately verified in agreement with the "International Conference on Harmonization". Linearity was demonstrated for values ranging from LOQ quantity ppm to 150% quantity ppm, with variance coefficients 0.99. The precision varied from 0.128 to 0.969% RSD and accuracy varied from 99.13% to 101.76% for four related substance impurities. The proposed approach was appropriately implemented in the quality control analysis of the linagliptin API. Stress testing on the linagliptin API is also part of this investigation. One degradant with a 10.273 min Rt was found during oxidative stress testing on linagliptin. Using LC-MS this peak was discovered to be an adduct. [ABSTRACT FROM AUTHOR]

The glucagon-like peptide 1 receptor agonists, together with sodium-glucose cotransporter-2 inhibitors, are antidiabetic drugs known for their beneficial effects on the cardiovascular system; many phase 3 trials also support this conclusion. However, it can be thought that they may cause an increase in the risk of tachyarrhythmia due to the stimulation of their receptors in the sympathetic nervous system and sinoatrial cells. We report a case of a 71-year-old woman with no history of arrhythmia who presented with new-onset atrial fibrillation after an exenatide injection during clinical follow-up. [ABSTRACT FROM AUTHOR]

2 Martin CL, Albers JW, Pop-Busui R. Neuropathy and related findings in the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. Effects of baricitinib, empagliflozin, linagliptin and telmisartan on cardiovascular autonomic neuropathy in type 1 diabetes: An exploratory, randomized, open-label, crossover trial The primary aim was to determine the individual albuminuria-lowering response of four albuminuria-lowering drug classes in persons with type 1 diabetes. Keywords: clinical trial; diabetes complications; diabetic neuropathy; empagliflozin; linagliptin; SGLT2 inhibitor EN clinical trial diabetes complications diabetic neuropathy empagliflozin linagliptin SGLT2 inhibitor 3064 3067 4 09/06/23 20231001 NES 231001 INTRODUCTION Cardiovascular autonomic neuropathy (CAN) is a prevalent complication in type 1 diabetes and a risk factor for cardiovascular mortality.[1] CAN is preventable to some extent: Intensive glucose control demonstrated a 45% risk reduction of CAN in persons with type 1 diabetes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC).[2] To our knowledge, however, no treatment is available when CAN is incident. [Extracted from the article]

Alzheimer's disease (AD) is an age-related, multifactorial progressive neurodegenerative disorder manifested by cognitive impairment and neuronal death in the brain areas like hippocampus, yet the precise neuropathology of AD is still unclear. Continuous failure of various clinical trial studies demands the utmost need to explore more therapeutic targets against AD. Type 2 Diabetes Mellitus and neuronal insulin resistance due to serine phosphorylation of Insulin Receptor Substrate-1 at 307 exhibits correlation with AD. Dipeptidyl Peptidase-4 inhibitors (DPP-4i) have also indicated therapeutic effects in AD by increasing the level of Glucagon-like peptide-1 in the brain after crossing Blood Brain Barrier. The present study is hypothesized to examine Linagliptin, a DPP-4i in intracerebroventricular streptozotocin induced neurodegeneration, and neuroinflammation and hippocampal insulin resistance in rat model of AD. Following infusion on 1st and 3rd day, animals were treated orally with Linagliptin (0.513 mg/kg, 3 mg/kg, and 5 mg/kg) and donepezil (5 mg/kg) as a standard for 8 weeks. Neurobehavioral, biochemical and histopathological analysis was done at the end of treatment. Dose-dependently Linagliptin significantly reversed behavioral alterations done through locomotor activity (LA) and morris water maze (MWM) test. Moreover, Linagliptin augmented hippocampal GLP-1 and Akt-ser473 level and mitigated soluble Aβ (1–42), IRS-1 (s307), GSK-3β, TNF-α, IL-1β, IL-6, AchE and oxidative/nitrosative stress level. Histopathological analysis also exhibited neuroprotective and anti-amylodogenic effect in Hematoxylin and eosin and Congo red staining respectively. The findings of our study concludes remarkable dose-dependent therapeutic potential of Linagliptin against neuronal insulin resistance via IRS-1 and AD-related complication. Thus, demonstrates unique molecular mechanism that underlie AD. [ABSTRACT FROM AUTHOR]

Cadmium is an environmental contaminant associated with marked neurotoxicity and cognitive impairment. Linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, has demonstrated promising neuroprotection against cerebral ischemia and diabetic dementia. However, there has been no study of its effect on cadmium-induced cognitive deficits. In the present work, linagliptin's prospective neuroprotective effects against cadmium-evoked cognitive decline were examined in vivo in rats. The molecular pathways related to oxidative stress, apoptosis, and autophagy were investigated. Histology, immunohistochemistry, ELISA, and biochemical assays were performed on brain hippocampi after receiving linagliptin (5 mg/kg/day). The current findings revealed that cadmium-induced learning and memory impairment were improved by linagliptin as seen in the Morris water maze, Y-maze, and novel object recognition test. Moreover, linagliptin lowered hippocampal neurodegeneration as seen in histopathology. At the molecular level, linagliptin curtailed hippocampal DPP-4 and augmented GLP-1 levels, triggering dampening of the hippocampal neurotoxic signals Aβ42 and p-tau in rats. Meanwhile, it enhanced hippocampal acetylcholine and GABA and diminished the glutamate spike. The behavioral recovery was associated with dampening of the hippocampal pro-oxidant response alongside SIRT1/Nrf2/HO-1 axis stimulation. Meanwhile, linagliptin counteracted hippocampal apoptosis markers and inhibited the pro-apoptotic kinase GSK-3β. In tandem, linagliptin activated hippocampal autophagy by lowering SQSTM-1/p62 accumulation, upregulating Beclin 1, and stimulating AMPK/mTOR pathway. In conclusion, linagliptin's antioxidant, antiapoptotic, and pro-autophagic properties advocated its promising neuroprotective impact. Thus, linagliptin may serve as a management approach against cadmium-induced cognitive deficits. [ABSTRACT FROM AUTHOR]

The differences in baseline could be explained by the differences in pathophysiology as type 1 diabetes is primarily characterized as an autoimmune disease, whereas type 2 diabetes is characterized by chronic inflammation. *p < 0.05; **p < 0.01 gl CONCLUSIONS Previous studies have established the anti-inflammatory effects of ARBs, DPP-4 inhibitors, SGLT2 inhibitors and baricitinib in individuals with type 1 diabetes or type 2 diabetes. Keywords: ARB; baricitinib; DPP-4 inhibitor; empagliflozin; inflammation; inflammatory markers; JAK-STAT inhibitor; linagliptin; SGLT2 inhibitor; telmisartan EN ARB baricitinib DPP-4 inhibitor empagliflozin inflammation inflammatory markers JAK-STAT inhibitor linagliptin SGLT2 inhibitor telmisartan 2413 2418 6 07/04/23 20230801 NES 230801 BACKGROUND Inflammation plays an important role in the initiation and progression of kidney function decline in individuals with diabetes.[1] In experimental models of diabetes and chronic kidney disease (CKD), interventions with drugs commonly used to treat cardiovascular and kidney complications have shown anti-inflammatory effects, including angiotensin receptor blockers (ARBs),[[2], [4]] sodium-glucose co-transporter-2 (SGLT2) inhibitors,[[5], [7]] dipeptidyl peptidase-4 (DPP-4) inhibitors,[[8], [10]] and Janus kinase-signal transducer and activator of transcription (JAK-STAT) inhibitors.[[11]] In clinical studies, treatment with renin-angiotensin-aldosterone-system inhibitors, SGLT2 inhibitors, DPP-4 inhibitors and JAK-STAT inhibitors has also been shown to exert anti-inflammatory effects.[[5], [11], [13], [15]] The follow-up of most previous studies was more than 6 months. Overall, the concentrations of the inflammation markers were lower in participants with type 1 diabetes compared with those with type 2 diabetes (Table 1). 1 TABLE Baseline characteristics of the total, ROTATE-1 and ROTATE-2 participants. [Extracted from the article]

The work introduces green and white sustainable micellar electrokinetic chromatography (MEKC) procedure that could analyze therapeutically related drugs, empagliflozin (EMP), linagliptin (LIN) and metformin (MET) which are antidiabetic drugs with different mechanism of action, in their different pharmaceutical combinations. The method not only comply with the green analytical concepts, but also it is in line with sustainable analytical concepts as it is economic by applying the same operating conditions to analyze different pharmaceuticals in quality control (QC) labs which is a crucial step in QC labs and research centers to save time, effort, and money. Moreover, the method functionality regarding its scope with its achieved levels of accuracy, precision, low detection, and quantitation limits is tested using white assessment tool and compared with reported methods. The proposed MEKC coupled with a diode array detector (DAD) has been developed and validated for micro estimation of EMP and LIN in their low critical concentrations with MET in a ratio of (EMP: MET, 1:40) and (LIN: MET, 1:200). Separation was achieved within 6 min using fused silica capillary (40 cm × 50 µm id) using 20 mM Tris buffer (pH 10) in presence of 50 mM sodium dodecyl sulphate and 10% v/v methanol. The concentration ranges of the studied anti-diabetic drugs were 10–500, 10–100 and 2.5–100 µg. mL−1 for MET, EMP and LIN, respectively. The developed method is the first MEKC for concurrent determination of EMP, LIN and MET with high separation efficiency, low solvent consumption and regard as an easy green and white analytical tool. Moreover, Greenness and whiteness assessment were done via the most widely used Analytical Eco-Scale, the innovative AGREE tool and the RGB 12 algorithm. [ABSTRACT FROM AUTHOR]

Aims/Introduction: Linagliptin is a selective dipeptidyl peptidase (DPP)‐4 inhibitor capable of successfully regulating blood glucose levels. The cardiovascular protective effects of several DPP‐4 inhibitors have been shown in preclinical studies; however, the detailed influence of DPP‐4 inhibitors on diabetic pathological alterations in cardiac tissue has not yet been elucidated. Materials and Methods: We combined laboratory‐based experiments and bioinformatics techniques to identify suitable candidate targets with significant biological pathways. Mice with streptozotocin‐induced insulin deficiency diabetic model were utilized for in vivo experiments. Mice were euthanized at 24 weeks after the induction of diabetes; linagliptin intervention was carried out for 4 weeks before euthanasia. Microarray analysis of heart samples was carried out. Results: Mice with streptozotocin‐induced diabetes, but not control mice, showed cardiac fibrosis with an endothelial–mesenchymal transition program, and myocardial fiber and sarcomere disruption; linagliptin alleviated these diabetes‐associated pathological alterations without altering blood glucose levels. Bioinformatics analysis utilizing a microarray dataset identified 10 hub genes that were confirmed to have human disease relevance by Gene Expression Omnibus analysis. Among these hub genes, we focused on the Sox9–necroptosis axis as a therapeutic target in diabetic hearts. Indeed, diabetic mice showed the induction of necroptosis‐associated genes and the phosphorylation of RIP3 and mixed lineage kinase domain‐like protein. Conclusions: Linagliptin showed excellent heart protection in mice with streptozotocin‐induced diabetes associated with alterations in human disease‐relevant hub genes. Further investigation is required to determine why DPP‐4 inhibitors do not show similar superior organ‐protective effects in the clinical setting. [ABSTRACT FROM AUTHOR]

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To develop an approach to reduce the type 2 diabetic osteoporosis, this study investigated the protective effects of the combination of linagliptin and metformin against osteoporosis. Micro-CT and dynamic biomechanical measurements were used to determine the bone microstructure in the type 2 diabetes mellitus (T2DM) rats. MC3T3-E1 cells were cultured in high glucose environments. In addition, we used qRT-PCR and Western blotting to assess osteogenic markers and p38 and extracellular signal-regulated kinase (ERK) protein expression. The combination of linagliptin and metformin treatment significantly restored bone micro-architecture and femoral mechanical properties in the T2DM rats. In contrast, bone markers including osteocalcin, NH2-terminal propeptide of type I procollagen, COOH-terminal telopeptide of type I collagen and tartrate-resistant acid phosphatase were significantly reduced by the combination of linagliptin and metformin treatment. We used high glucose treated MC3T3-E1 cells to mimic the condition of T2DM. Linagliptin combined with metformin treatment significantly inhibited the phosphorylation of p38 and ERK induced by high glucose treatment. In conclusion, the linagliptin combined with metformin treatment improved the rats' bone mineral density, bone structure, and osteogenic markers. Both p38 and ERK phosphorylation were reduced in high glucose MC3T3-E1 cells. Our findings highlight the potential of linagliptin combined with metformin for the treatment of T2DM-related osteoporosis. [ABSTRACT FROM AUTHOR]

A new precise and accurate GC-ALS method was developed and validated for quantitative determination of hazardous high boiling solvents impurities i.e. acetic acid and dimethyl sulphoxide in Linagliptin drug molecule using direct injection technique by GC-ALS with the help of Flame ionization detector (FID). The column used was Agilent J & W DB-FFAP, 30M X 0.530 mm X 1μm capillary column. The stationary phase of the column was nitro terephthalic acid-modified polyethylene glycol (PEG). The method was validated for specificity, precision, LOD, LOQ, accuracy, linearity, range, solution stability, and robustness. The detection limit and quantitation limit obtained for acetic acid was 83.3 μg/g and 252.4 μg/g respectively. For Dimethyl sulphoxide detection limit and quantitation limit obtained were 83.7 μg/g and 253.7 μg/g respectively. The method was found to be linear in the range between 253.9 μg/g to 7616.9 μg/g for acetic acid and 253.5 μg/g to 7605.8 μg/g for dimethyl sulphoxide. The average recoveries obtained were 85.20% and 89.69% at LOQ level for acetic acid and dimethyl sulphoxide respectively, and for 150% level recovery were 94.26% and 100.43% for acetic acid and dimethyl sulphoxide respectively. The developed method was found to be robust, specificity was also demonstrated, and standard and the spiked solution was stable for up 20 Hrs. Thus, the method is used for routine analysis of their intended use. For quantification of Acetic acid and Dimethyl sulphoxide in Linagliptin, no pharmacopeial method is available so developed this simple method for laboratory use. [ABSTRACT FROM AUTHOR]

The synthesis of some novel 1,2,3-triazole-based linagliptin derivatives from the CuI catalyzed 1,3-dipolar cycloaddition reaction between N-propargyl purines and several aryl azides as described herein. All these new compounds were further evaluated for their in vitro dipeptidyl peptidase-4 (DPP-4) activity and the compounds 8-bromo-1,3-dimethyl-7-((1-(3-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-1H-purine-2,6(3H,7H)-dione, 7-(but-2-yn-1-yl)-1,3-dimethyl-8-(4-((1-(3-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methyl) piperazin-1-yl)-1H-purine-2,6(3H,7H)-dione and 7-(but-2-yn-1-yl)-8-(4-((1-(3,5-dichloro phenyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione have shown good inhibitory activity against DPP-4. Molecular docking studies were performed for the promising compounds for their binding interactions with the receptor dipeptidyl peptidase IV (PDB ID-3G0B). The most potent compound was deliberated optimal structure, and data were calculated using the density functional theory (DFT) B3LYP method on a 6-311++G (d,p) basis set. The structural parameters were derived from geometry optimization. The HOMO and LUMO energies are calculated for the molecule. [ABSTRACT FROM AUTHOR]

Background: In addition to lifestyle modifications, metformin is the recommended first-line pharmacotherapy for patients with type 2 diabetes mellitus (T2DM). The use of glimepiride or linagliptin as add-on to metformin (GM or LM) has been noticed on prescriptions in major pharmacies in Nigeria. Aims: The aim of this study was to compare the efficacy of glimepiride or linagliptin as add-on to metformin in T2DM. Methods: A preliminary case-crossover randomized experimental/observational study comprising 30 participants (i.e., 15 for each of the combination therapies) was designed and designated GM and LM groups, respectively. Baseline physiological and health-indicators of the participants were primarily observed followed by a practical/analytical drug efficacy measurement of postprandial blood glucose (PPBG) levels at 1, 2, 4, and 6 h once weekly for 2 weeks and thereafter crossover to the other regimen for another two weeks' assessment. Results: Baseline results were consistent across subgroup analyses in both treatment types. The statistical analysis demonstrated that LM achieved significant PPBG lowering potential compared to baseline blood glucose status (p<0.05). There was no significant difference in the observed physiological and biochemical indicators of organ system function for both treatments during the study. Treatment with LM was associated with reduced post-meal blood glucose compared with GM (p<0.05). Postprandial blood glucose change over measurement points were higher with LM (p<0.05). Conclusion: Blood glucose control was better achieved with LM compared to GM. Propensity to hypoglycemia was higher with LM. More studies involving larger patient population in several centres are required to validate the outcome of these findings. [ABSTRACT FROM AUTHOR]

Aim: The CAROLINA trial established non‐inferiority of linagliptin versus glimepiride for major adverse cardiovascular events in patients with relatively early type 2 diabetes at increased cardiovascular risk. In pre‐specified and post‐hoc analyses, we investigated treatment effects on total hypoglycaemic burden in CAROLINA. Materials and methods: Patients were randomized and treated with 5 mg linagliptin (n = 3014) or 1‐4 mg glimepiride (n = 3000) once daily added to standard care. Hypoglycaemia captured from investigator‐reported adverse events was analysed with Poisson and negative binomial regressions for the first and total (first plus recurrent) events, respectively. The influence of insulin initiation and glycated haemoglobin (HbA1c) change on the treatment effect for hypoglycaemia was also explored. Results: Over 6.3 years median follow‐up, average HbA1c over time did not differ between linagliptin versus glimepiride (weighted mean difference [95% confidence interval]: 0.00%, [−0.05, 0.05]), nor did insulin initiation (18.6% vs. 19.2% of patients, respectively), whereas body weight was lower with linagliptin (−1.54 kg, [−1.80, −1.28]). Hypoglycaemia frequency was lower with linagliptin across all hypoglycaemia categories, including severe episodes. Rate ratios (95% confidence interval) for first and total events for investigator‐reported hypoglycaemia were 0.21 (0.19‐0.24) and 0.12 (0.10‐0.14), respectively, with 8.7 first and 60.8 total estimated events prevented/100 patient‐years with linagliptin versus glimepiride. These differences occurred during night‐time and daytime, and in subgroup analyses of total events. Treatment differences in hypoglycaemia were neither impacted by HbA1c changes nor insulin initiation. Conclusions: Across the severity spectrum, linagliptin substantially reduced the hypoglycaemic burden versus glimepiride in patients with relatively early type 2 diabetes at increased cardiovascular risk. [ABSTRACT FROM AUTHOR]

Objectives The aim of this work was to investigate the regional difference in linagliptin intestinal membrane transport and to investigate the effects of carvedilol, atorvastatin and bile salts on intestinal absorption of linagliptin. Methods The study employed an in-situ rabbit intestinal absorption technique. The membrane transport parameters of linagliptin were determined through duodenum, jejunum, ileum and colon segments. The effect of carvedilol, atorvastatin and sodium cholate was investigated by co-perfusion of each with linagliptin through jejunum and ileum. Key findings The study reflected incomplete linagliptin absorption from the explored intestinal segments. The resulted rank indicated that the extent of absorption decreases as we move distally through the small intestine before increasing at the ascending colon. This behaviour suggests a role of P-glycoprotein (P-gp) efflux on reduced linagliptin intestinal absorption. Co-perfusion with carvedilol, atorvastatin or bile salts significantly enhanced linagliptin absorption. This elects P-gp efflux inhibition as one possible mechanism for enhanced linagliptin intestinal membrane transport. Conclusions The study confirmed the role of P-gp efflux transporters in reduced intestinal linagliptin absorption. Co-administration of linagliptin with either carvedilol or atorvastatin can modulate the oral bioavailability of linagliptin. Bile salts can be employed as a formulation excipient for enhanced oral absorption of linagliptin. [ABSTRACT FROM AUTHOR]

Background: Gliflozins and gliptins are two distinct groups of pharmacological drugs that reduce blood glucose levels in individuals with type II diabetes in various ways that may perform their functions harmoniously. Trijardy® tablet, which contains empagliflozin, linagliptin, and metformin, was recently approved. The scientific database does not yet have a method that is sensitive enough to quantify the aforementioned medications in the presence of metformin official toxic impurities melamine and cyanoguanidine. Molecular docking modeling was utilized in this work to further prove the toxicity of melamine. Methods: The five analytes listed before were quantified using RP-HPLC-diode array detector and a Zorbax® C8 column (4.6 × 250 mm, 5 μm) with isocratic mobile phase composed of acetonitrile and 0.05 M potassium dihydrogen phosphate buffer, which had been treated by ?-phosphoric acid to restore a pH of 4.0 (90:10, v/v) at a flow rate of 1.2 mL/min and the eluted peaks were scanned at 250 nm. Conclusion: The utilization of the simplest isocratic elution mode give the current technique a significant time-and cost-saving benefit. The current method can quantify the triple therapy agents in the presence of each other as well as with two official toxic impurities of metformin in one short analytical run. [ABSTRACT FROM AUTHOR]

A simple, economical, and specific analytical method has been developed for determining and validating linagliptin (LNG) in bulk. This method is based on a condensation reaction between a primary amine in LNG and an aldehyde group in P-dimethylaminobenzaldehyde (PDAB) to form the yellow Schiff base with a wavelength of 407 nm. The optimum experimental conditions for the formulation of the colored complex have been studied. The optimum conditions were 1 mL of 5% w/v reagent solution with methanol and distilled water as a solvent for both PDAB, LNG respectively, also adding 2 mL of HCl as an acidic medium, heating to 70–75 °C on a water bath for 35 min. Furthermore, the stoichiometry of the reaction has been studied according to Job's and Molar ratio method which was expressing 1:1 for LNG and PDAB. The researcher modified the method. The results show that the linearity in the concentration range (5–45 µg/mL) with correlation coefficient R2 = 0.9989 with percent recovery (99.46–100.8%) and RSD was less than 2%, LOD and LOQ 1.5815 − 4.7924 μg/mL respectively. This method can show high quality and there is no significant interference with excipients and in pharmaceutical forms. None of the studies showed the development of this method before. [ABSTRACT FROM AUTHOR]

Objective: To compare the effect of glucose-lowering drugs on peripheral nerve and kidney function in prediabetes. Methods: Multicenter, randomized, placebo-controlled trial in 658 adults with prediabetes treated for 1 year with metformin, linagliptin, their combination or placebo. Endpoints are small fiber peripheral neuropathy (SFPN) risk estimated by foot electrochemical skin conductance (FESC < 70 μSiemens) and estimated glomerular filtration rate (eGFR). Results: Compared to the placebo, the proportion of SFPN was reduced by 25.1% (95% CI:16.3–33.9) with metformin alone, by 17.3% (95% CI 7.4–27.2) with linagliptin alone, and by 19.5% (95% CI 10.1–29.0) with the combination linagliptin/metformin (p < 0.0001 for all comparisons). eGFR remained +3.3 mL/min (95% CI: 0.38–6.22) higher with the combination linagliptin/metformin than with the placebo (p = 0.03). Fasting plasma glucose (FPG) decreased more with metformin monotherapy −0.3 mmol/L (95%CI: −0.48; 0.12, p = 0.0009) and with the combination metformin/linagliptin −0.2 mmol/L (95% CI: −0.37; −0.03) than with the placebo (p = 0.0219). Body weight (BW) decreased by −2.0 kg (95% CI: −5.65; −1.65, p = 0.0006) with metformin monotherapy, and by −1.9 kg (95% CI: −3.02; −0.97) with the combination metformin/linagliptin as compared to the placebo (p = 0.0002). Conclusions: in people with prediabetes, a 1 year treatment with metformin and linagliptin, combined or in monotherapy, was associated with a lower risk of SFPN, and with a lower decrease in eGFR, than treatment with placebo. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the effect of linagliptin on microalbuminuria in patients with diabetic nephropathy (DN). The present double-blind randomized placebo-controlled clinical trial was performed on 92 patients with DN who were divided into two groups. The intervention and control groups received linagliptin 5 mg and placebo for 24 weeks, respectively. Blood pressure, lipid profile, liver enzymes, fasting plasma glucose (FPG), and urine albumin-creatinine ratio (UACR) were assessed and recorded before, 12 weeks, and 24 weeks after the beginning of the intervention. The mean value of UACR decrease was significant over time in both groups, with higher decrease in linagliptin group, however, the differences between two groups were not, statistically significant (P > 0.05). However, the percentage of improvement in microalbuminuria (UACR < 30 mg/g) in the linagliptin group was significantly higher than that of the control group during 24 weeks of intervention (68.3% vs. 25%; P-value < 0.001). There was no statistically significant difference in the mean value of the UACR and other parameters between linagliptin treated and placebo treated patients with diabetic nephropathy. Further studies, with longer periods of follow-up are suggested to examine these patients' renal outcomes. [ABSTRACT FROM AUTHOR]

Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor used for the treatment of type 2 diabetes, with additional beneficial effects for the kidney. Treatment of mice with linagliptin revealed increased storage of cobalamin (Cbl, Vitamin B12) in organs if a standard Cbl diet (30 µg Cbl/kg chow) is given. In order to translate these findings to humans, we determined methylmalonic acid (MMA), a surrogate marker of functional Cbl homeostasis, in human plasma and urine samples (n = 1092) from baseline and end of trial (6 months after baseline) of the previously completed MARLINA-T2D clinical trial. We found that individuals with medium Cbl levels (MMA between 50 and 270 nmol/L for plasma, 0.4 and 3.5 µmol/mmol creatinine for urine, at baseline and end of trial) exhibited higher MMA values at the end of study in placebo compared with linagliptin. Linagliptin might inhibit the N-terminal degradation of the transcobalamin receptor CD320, which is necessary for uptake of Cbl into endothelial cells. Because we demonstrate that linagliptin led to increased organ levels of Cbl in mice, sustained constant medium MMA levels in humans, and inhibited CD320 processing by DPP-4 in-vitro, we speculate that linagliptin promotes intra-cellular uptake of Cbl by prolonging half-life of CD320. [ABSTRACT FROM AUTHOR]

Bacteria communicate with each other using quorum sensing (QS) which works in an inducer/receptor manner. QS plays the main role in orchestrating diverse bacterial virulence factors. Pseudomonas aeruginosa is one of the most clinically important bacterial pathogens that can cause infection in almost all body tissues. Besides its efficient capability to develop resistance to different antibiotics, P. aeruginosa acquires a huge arsenal of virulence factors that are controlled mainly by QS. Challenging QS with FDA-approved drugs and natural products was proposed as a promising approach to mitigate bacterial virulence enabling the host immunity to complete the eradication of bacterial infection. The present study aims to evaluate the dipeptidase inhibitor-4 inhibitor hypoglycemic linagliptin anti-QS and anti-virulence activities against P. aeruginosa in vitro, in vivo, and in silico. The current results revealed the significant ability to diminish the production of protease and pyocyanin, motility, and biofilm formation in P. aeruginosa. Furthermore, the histopathological examination of liver and kidney tissues of mice injected with linagliptin-treated bacteria showed an obvious reduction of pathogenesis. Linagliptin downregulation to QS-encoding genes, besides the virtual ability to interact with QS receptors, indicates its anti-QS activities. In conclusion, linagliptin is a promising anti-virulence and anti-QS candidate that can be used solely or in combination with traditional antimicrobial agents in the treatment of P. aeruginosa aggressive infections. [ABSTRACT FROM AUTHOR]

The present work was performed in order to study the mechanism of micellar thin layer chromatography (MTLC) and to develop a new simple and sensitive simultaneous MTLC method for separation of empagliflozin, Linagliptin and metformin hydrochloride ternary mixture. The study was done using three different surfactants; sodium dodecyl sulphate (SDS), benzalkonium chloride (BAC) and polysorbate 80 (tween 80). Chromatographic procedure was performed using micellar mobile phase that composed of aqueous solution of each surfactant and methanol (6: 4 v/v) and micellar TLC determination at λmax 237 nm. Separation using SDS (anionic surfactant) and BAC (cationic surfactant) depends on ionization potential (AMI-IP), partition coefficient (logP (o/w)) and hydrogen bond donor atoms (a-don), whereas separation using tween 80 depends mainly on the lipophilicity (R M0), solvation energy (E-sol) and Van der Waals energy (E-vdw). Quantitative structure–retention relationships study was carried out, modeled, evaluated and validated using molecular operating environment software. [ABSTRACT FROM AUTHOR]

Insulin remains the mainstay of treatment for inpatient hyperglycemia in the United States and Canada. However, some other countries commonly use noninsulin agents such as metformin and sulfonylureas, and several trials have demonstrated the efficacy and safety of incretin-based agents in patients with type 2 diabetes who are admitted to noncritical care medicine and surgery services. There is a high degree of interest in alternative glucose-lowering strategies to achieve favorable glycemic outcomes with lower risks of hypoglycemia. In this case series, we highlight the challenges of inpatient glycemic management and the need for alternatives to the traditional basal-bolus insulin regimen. Additional investigation will be imperative to validate the safety and efficacy of appropriate insulin and noninsulin treatments and to further develop guidelines that are applicable in real-world hospital settings. [ABSTRACT FROM AUTHOR]

This study investigated the therapeutic effect of linagliptin and/or vitamin D3 on testicular steroidogenesis and spermatogenesis in cisplatin-exposed rats including their impact on endoplasmic reticulum (ER) stress and NF-κB/iNOS crosstalk. Cisplatin (7 mg/kg, IP) was injected into adult male albino rats which then were orally treated with drug vehicle, linagliptin (3 mg/kg/day), vitamin D3 (10 μg/kg/day) or both drugs for four weeks. Age-matched rats were used as the control group. Serum samples and testes were collected for further analyses. Cisplatin induced testicular weight loss, deteriorated testicular architecture, loss of germ cells and declined serum and intra-testicular testosterone levels, compared to the control group. There was down-regulation of steroidogenic markers including StAR, CYP11A1, HSD3b and HSD17b in cisplatin-exposed rats, compared with controls. Cisplatin-exposed rats showed up-regulation of ER stress markers in testicular tissue along with increased expression of NF-κB and iNOS in spermatogenic and Leydig cells. These perturbations were almost reversed by vitamin D3 or linagliptin. The combined therapy exerted a more remarkable effect on testicular dysfunction than either monotherapy. These findings suggest a novel therapeutic application for linagliptin combined with vitamin D3 to restore testicular architecture, aberrant steroidogenesis and spermatogenesis after cisplatin exposure. These effects may be attributed to suppression of ER stress and NF-kB/iNOS. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "Effect of metformin and metformin/linagliptin on gut microbiota in patients with prediabetes" published in Scientific Reports. The correction states that in the original version of the article, the authors' given names and surnames were reversed. The correction has been made to the article. The authors of the article are Yoscelina Estrella Martínez-López, Daniel Neri-Rosario, Diego Armando Esquivel-Hernández, Cristian Padron-Manrique, Aarón Vázquez-Jiménez, Jean Paul Sánchez-Castañeda, David Girón-Villalobos, Cristian Mendoza-Ortíz, María de Lourdes Reyes-Escogido, Maria Lola Evia-Viscarra, Alberto Aguilar-Garcia, Osbaldo Resendis-Antonio, and Rodolfo Guardado-Mendoza. [Extracted from the article]