Vildagliptin Treatment Ameliorates Renal Interstitial Fibrosis in a Murine Model of Unilateral Ureteral Obstruction.

Renal interstitial fibrosis in mice can be modeled using unilateral ureteral obstruction (UUO). Here, we investigated the anti-fibrotic effects of the dipeptidyl peptidase-4 inhibitor vildagliptin in this model. We found that vildagliptin given in the drinking water at 10.6 ± 1.5 mg/kg/d prevented fibrosis. Mechanistically, UUO was associated with extracellular signal-regulated kinase (ERK) phosphorylation and with the accumulation of the toxic lipid peroxidation product expression of 4-hydroxy-2-nonenal (4-HNE). Both were significantly inhibited by vildagliptin. Similarly, UUO caused reductions in heme oxygenase-1 (HO-1) mRNA in the kidney, whereas interleukin-6 (IL-6) and cyclooxygenase-1 (COX-1) mRNA were increased; these effects were also prevented by vildagliptin. Taking these data together, we propose that vildagliptin reduces renal interstitial fibrosis resulting from UUO by means of its effects on ERK phosphorylation and the amounts of 4-HNE, HO-1, IL-6 and COX-1 in the kidney.

Addressing stability issues of vildagliptin: Method optimization and validation for accurate analysis in human plasma.

This research paper introduces novel strategies to address the stability issues arising with vildagliptin, marking the first attempt to tackle this challenge comprehensively. The study incorporates malic acid into the human plasma, a crucial step in stabilizing vildagliptin and preventing its degradation. Additionally, optimization of the elution process on a C18 Asentis Express column, fine-tuned with a combination of acetonitrile and ammonium trifluoroacetate 5mM, ensures optimal chromatographic conditions. For detection and quantification, electrospray ionization (ESI) is employed, monitoring multiple reactions for vildagliptin (304.2 → 154.2) and vildagliptin D7 (311.1 → 161.2). Meticulous validation of the method demonstrates high accuracy (97.30%-104.15%) and precision [(0.32%-3.09% coefficient of variance (CV)] for vildagliptin calibration curve standards (CC STD), establishing its sensitivity and reliability in measuring vildagliptin levels. This refined methodology offers numerous advantages, including the elimination of stability concerns, reduced human plasma sample volume (100 µL), exceptional reproducibility, shortened run time (~2.2 min), and a wide concentration range (1.00 to 851.81 ng/mL). These attributes make it exceptionally well-suited for diverse research applications, spanning from extensive sampling in therapeutic drug monitoring units to bioequivalence and bioavailability studies, as well as pharmacokinetic investigations of vildagliptin.

In situ evaluation of the impact of metformin or verapamil coadministration with vildagliptin on its regional absorption from the rabbit's intestine.

This research aims to identify regional differences in vildagliptin absorption across the intestinal membrane. Furthermore, it was to investigate the effect of verapamil or metformin on vildagliptin absorptive clearance. The study utilized an in situ rabbit intestinal perfusion technique to determine vildagliptin oral absorption from duodenum, jejunum, ileum, and ascending colon. This was conducted both with and without perfusion of metformin or verapamil. The findings revealed that the vildagliptin absorptive clearance per unit length varied by site and was in the order as follows: ileum < jejunum < duodenum < ascending colon, implying that P-gp is significant in the reduction of vildagliptin absorption. Also, the arrangement cannot reverse intestinal P-gp, but the observations suggest that P-gp is significant in reducing vildagliptin absorption. Verapamil co-perfusion significantly increased the vildagliptin absorptive clearance by 2.4 and 3.2 fold through the jejunum and ileum, respectively. Metformin co-administration showed a non-significant decrease in vildagliptin absorptive clearance through all tested segments. Vildagliptin absorption was site-dependent and may be related to the intestinal P-glycoprotein content. This may aid in understanding the important elements that influence vildagliptin absorption, besides drug-drug interactions that can occur in type 2 diabetic patients taking vildagliptin in conjunction with other drugs that can modify the P-glycoprotein level.

Stability-indicating HPLC for remogliflozin, vildagliptin, and metformin: Method development, validation, and greenness.

OBJECTIVE: The present work represents a reverse-phase high-performance liquid chromatography method in addition to stability studies for sequential estimation of remogliflozin etabonate, vildagliptin, and metformin HCl in tablet formulation. METHOD: The mentioned method utilizes a Phenomenex Luna C18 column (250×4.6mm, 5µm). It consists of a column oven's temperature of 35°C. Mobile phase includes a mixture of 50% phosphate buffer (pH - 6.8) and 50% acetonitrile along with a flow rate of 0.8mL/min and 20minutes of run time. The injection volume was 20µL; 217nm is a detection wavelength, and a PDA detector is used for detection. RESULTS: The suggested technique was proven and validated per the ICH Q2 (R1) guideline. The combination was put under stress conditions that included acid, base, thermal, photolytic, and oxidative degradation. The combination was considerably degraded under oxidative, acidic, and basic circumstances for deterioration, and the degradation results were accurately identified from the observed peaks, demonstrating the method's effectiveness in detecting stability. CONCLUSION: The technique was quick, precise, sensitive, and accurate; as a result, it may be used in quality control laboratories and the pharmaceutical industry for routine quality monitoring of tablets containing all three medications.

Green polymer altered in-situ gel oral liquid sustainable release preparation of vildagliptin suitable for dysphagic diabetic patients: assessment in-vitro & in-vivo.

PURPOSE: This work aimed to fabricate alginate based in-situ gelling matrix of vildagliptin improved by calcium and carboxy methyl cellulose (CMC) for appropriate adjustment of the onset and duration of action. This easy-to-swallow thickened liquid preparation aimed to improve compliance for dysphagic or elderly diabetic patients. METHODS: Vildagliptin dispersions containing alginate were fabricated in the presence or absence of calcium chloride to assess the effect of calcium ion, then a matrix containing 1.5% w/v of sodium alginate with calcium was further examined after the addition of CMC with different concentrations ranging from 0.1% to 0.3%. The viscosity, gelling forming property, Differential scanning calorimetry, and in-vitro drug release were assessed before monitoring the hypoglycemic effect of the selected formulation. RESULTS: In-situ gel matrixes were fabricated at gastric pH with and without calcium ions. The best formula concerning viscosity and the gel-forming property was achieved with higher CMC concentrations, which in turn decreased the rate of vildagliptin release in stimulated gastric pH. In-vivo results confirmed the extended hypoglycemic effect of the vildagliptin in-situ gelling matrix compared to the vildagliptin aqueous solution. CONCLUSION: This study represents a green polymeric-based in-situ gel as a liquid oral retarded release preparation intended for reducing dose frequency, easier administration of vildagliptin, and improving compliance in geriatric and dysphagic diabetic patients.

Mechanistic Study on the Effect of Renal Impairment on the Pharmacokinetics of Vildagliptin and its Carboxylic Acid Metabolite.

PURPOSE: To clarify the mechanism of renal impairment leading to different degrees of increased plasma exposure to dipeptidyl peptidase 4 inhibitor vildagliptin and its major metabolite, M20.7. METHODS: The 5/6 nephrectomized (5/6 Nx) rat model, to simulate chronic renal failure (CRF) patients, combined with kidney slices and transporter studies in vitro were used to assess this pharmacokinetic differences. RESULTS: After intragastric administration to 5/6 Nx rats, vildagliptin showed increased plasma levels by 45.8%, and M20.7 by 7.51 times, which was similar to patients with severe renal impairment. The recovery rate of M20.7 in urine and feces increased by less than 20%, showing limited effect of renal impairment on vildagliptin metabolism. In vitro studies found M20.7 to be the substrate for organic anion transporter 3 (OAT3). However, the active uptake of M20.7 in renal slices showed no difference between the 5/6 Nx and normal rats. In OAT3 overexpressed cells, the protein-bound uremic toxins, 3-carboxy-4-methyl-5propyl-2-furanpropionate (CMPF), hippuric acid (HA) and indoxyl sulfate (IS), which accumulate in CRF patients, inhibited M20.7 uptake with IC50 values of 5.75, 29.0 and 69.5 µM respectively, far lower than plasma concentrations in CRF patients, and showed a mixed inhibition type. CONCLUSIONS: The large increase in plasma exposure of M20.7 could be attributed to the accumulation of uremic toxins in CRF patients, which inhibited OAT3 activity and blocked renal excretion of M20.7, while vildagliptin, with high permeability, showed a slight increase in plasma exposure due to reduced glomerular filtration.

Neuroprotective Effects of the DPP4 Inhibitor Vildagliptin in In Vivo and In Vitro Models of Parkinson's Disease.

Parkinson's disease (PD) is characterized by loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) of the midbrain. Restoration of nigrostriatal dopamine neurons has been proposed as a potential therapeutic strategy for PD. Because currently used PD therapeutics only help relieve motor symptoms and do not treat the cause of the disease, highly effective drugs are needed. Vildagliptin, a dipeptidyl peptidase 4 (DPP4) inhibitor, is an anti-diabetic drug with various pharmacological properties including neuroprotective effects. However, the detailed effects of vildagliptin against PD are not fully understood. We investigated the effects of vildagliptin on PD and its underlying molecular mechanisms using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model and a 1-methyl-4-phenylpyridium (MPP+)-induced cytotoxicity model. Vildagliptin (50 mg/kg) administration significantly attenuated MPTP-induced motor deficits as evidenced by rotarod, pole, and nest building tests. Immunohistochemistry and Western blot analysis revealed that vildagliptin increased tyrosine hydroxylase-positive cells in the SNpc and striatum, which was reduced by MPTP treatment. Furthermore, vildagliptin activated MPTP-decreased PI3k/Akt and mitigated MPTP-increased ERK and JNK signaling pathways in the striatum. Consistent with signaling transduction in the mouse striatum, vildagliptin reversed MPP+-induced dephosphorylation of PI3K/Akt and phosphorylation of ERK and JNK in SH-SY5Y cells. Moreover, vildagliptin attenuated MPP+-induced conversion of LC3B-II in SH-SY5Y cells, suggesting its role in autophagy inhibition. Taken together, these findings indicate that vildagliptin has protective effects against MPTP-induced motor dysfunction by inhibiting dopaminergic neuronal apoptosis, which is associated with regulation of PI3k/Akt, ERK, and JNK signaling transduction. Our findings suggest vildagliptin as a promising repurposing drug to treat PD.

Dipeptidyl Peptidase-4 Inhibitor-Related Bullous Pemphigoid: Clinical, Laboratory, and Histological Features, and Possible Pathogenesis.

Dipeptidyl peptidase-4 inhibitor (DPP4i) is a widely used antidiabetic agent. Emerging cases of DPP4i-associated bullous pemphigoid (DBP), whose pathogenesis remains unclear, have been reported. Thus, a retrospective study was conducted from January 2016 to June 2021 to determine the clinical, laboratory, and histopathological features of DBP and idiopathic bullous pemphigoid (IBP). We set up in vitro experiments using vildagliptin-treated HaCaT keratinocytes to validate what we found by analyzing published RNA sequencing data about the genes related to the dermal-epidermal junction. We also observed IL-6 expression by HaCaT cells treated with vildagliptin. We enrolled 20 patients with DBP and 40 patients with IBP. The total Bullous Pemphigoid Disease Area Index (BPDAI) score was similar in both groups. However, the BPDAI score of erosions and blisters in DBP was significantly higher than that in IBP (24.6 vs. 16.68, p = 0.0189), and the score for urticaria and erythema was lower in DBP (12 vs. 19.05, p = 0.0183). The pathological features showed that the mean infiltrating eosinophil number per high-power field was significantly lower in DBP than in IBP (16.7 vs. 27.08, p = 0.023). The expression of LAMA3, LAMB3, LAMC2, DST, and COL17A1 decreased significantly in vildagliptin-treated human keratinocytes. On the other hand, IL-6, the hallmark cytokine of bullous pemphigoid (BP) severity, was found to be upregulated in HaCaT cells by vildagliptin. These experimental findings imply less of a requirement for eosinophil infiltration to drive the inflammatory cascades in DBP blistering. Both immunologic and non-immunologic pathways could be employed for the development of DBP. Our findings may help explain the higher incidence of non-inflammatory BP that was observed in DBP.

Incretins as a Potential Treatment Option for Gestational Diabetes Mellitus.

Gestational diabetes mellitus (GDM) is a metabolic disease affecting an increasing number of pregnant women around the world. It is not only associated with numerous perinatal complications but also has long-term consequences impacting maternal health and fetal development. To prevent them, it is important to keep glucose levels under control. As much as 15-30% of GDM patients will require treatment with insulin, metformin, or glyburide. With that in mind, it is crucial to keep searching for novel and improved pharmacotherapies. Nowadays, there are ongoing studies investigating the use of other groups of drugs that have proven successful in the treatment of T2DM. Glucagon-like peptide-1 (GLP-1) receptor agonist and dipeptidyl peptidase-4 (DPP-4) inhibitor are among the drugs targeting the incretin system and are currently receiving significant attention. The aim of our review is to demonstrate the potential of these medications in treating GDM and preventing its later complications. It seems that both groups may be successful in the GDM management used alone or as an addition to better-known drugs, including metformin and glyburide. However, more clinical trials are needed to confirm their importance in GDM treatment and to demonstrate effective therapeutic strategies.

An Experimental Design Approach to Quantitative Expression for Quality Control of a Multicomponent Antidiabetic Formulation by the HILIC Method.

A rapid and reproducible hydrophilic liquid chromatography (HILIC) process was established for concomitant determination of remogliflozin etabonate (RE), vildagliptin (VD), and metformin (MF) in a formulation. A face-centered central composite experimental design was employed to optimize and predict the chromatographic condition by statistically studying the surface response model and design space with desirability close to one. A HILIC column with a simple mobile phase of acetonitrile (65% v/v) and 20 mM phosphate buffer (35% v/v, pH 6, controlled with orthophosphoric acid) was used to separate RE, VD, and MF. RE, VD, and MF were separated in 3.6 min using an isocratic mode mobile phase flow at a flow rate of 1.4 mL at room temperature, and the analytes were examined by recording the absorption at 210 nm. The developed HILIC method was thoroughly validated for all parameters recommended by ICH, and linearity was observed in the ranges 20−150 µg/mL, 10−75 µg/mL, and 50−750 µg/mL for RE, VD, and MF, respectively, along with excellent regression coefficients (r2 > 0.999). The calculated percentage relative deviation and relative error ascertained the precision and accuracy of the method. The selectivity and accuracy were further confirmed by the high percentage recovery of added standard drugs to the formulation using the standard addition technique. The robustness of the HILIC processes was confirmed by developing a half-normal probability plot and Pareto chart, as the slight variation of a single factor had no significant influence on the assay outcomes. Utilization of the optimized HILIC procedure for concurrent quantification of RE, VD, and MF in solid dosage forms showed accurate and reproducible results. Hence, the fast HILIC method can be regularly employed for the quality assurance of pharmaceutical preparations comprising RE, VD, and MF.

Physiologically Based Biopharmaceutics Model of Vildagliptin Modified Release (MR) Tablets to Predict In Vivo Performance and Establish Clinically Relevant Dissolution Specifications.

The objective of the study was to predict pharmacokinetic (PK) and pharmacodynamic (PD) parameters of matrix-based modified release (MR) drug product of vildagliptin. Physiologically based biopharmaceutics modeling (PBBM) was developed using GastroPlus™ based on the available data including immediate-release (IR) drug product of vildagliptin. In vitro-in vivo correlation (IVIVC) was developed using mechanistic deconvolution to predict plasma concentration-time profile and PK parameters for a MR drug product planned for clinical use. Both methods, i.e., PBBM and IVIVC, were compared for the predicted PK parameters. Integration of DDDPlus™ and GastroPlus™ modeling was performed to explore clinically relevant dissolution specifications for vildagliptin MR tablets. The bioequivalence (BE) between batches with different dissolution specifications was evaluated using virtual clinical trials. The PD effect of dipeptidyl peptidase-IV (DPP-IV) inhibition was simulated utilizing PDPlus™ model in GastroPlus™. The results indicated that IVIVC best correlated the simulated PK parameters with those observed with the clinical study. The outcomes highlight the importance of integration of in vitro and in silico tools towards predictability of PK and PD parameters for a MR drug product. However, the post absorptive phase was found to be more dependent on the demographics of the healthy subjects.

DPP4 reduces proinflammatory cytokine production in human rheumatoid arthritis synovial fibroblasts.

Rheumatoid arthritis (RA) is an autoimmune disorder that is characterized by increasing levels of proinflammatory cytokines. The ubiquitous enzyme dipeptidyl peptidase-4 (DPP4, also known as CD26) regulates different immune disorders, although the effects of DPP4 in RA are uncertain. Here, we found lower levels of DPP4 in RA synovial tissues compared with normal tissues. DPP4 levels were also lower in a rat collagen-induced arthritis model than in control (healthy) rats. Overexpression of DPP4 or exogenous treatment of RA synovial fibroblasts with DPP4 reduced levels of proinflammatory interleukin (IL)-1ß, IL-6, and IL-13, and increased anti-inflammatory IL-10 synthesis, while DPP4 inhibitors sitagliptin and vildagliptin increased proinflammatory cytokine production, indicating an enhanced risk of RA development. The evidence suggests that increasing DPP4 expression is a novel strategy for RA disease.

DPP-4 inhibitor reduces striatal microglial deramification after sensorimotor cortex injury induced by external force impact.

Dipeptidyl peptidase-4 inhibitors (or gliptins), a class of antidiabetic drugs, have recently been shown to have protective actions in the central nervous system. Their cellular and molecular mechanisms responsible for these effects are largely unknown. In the present study, two structurally different gliptins, sitagliptin and vildagliptin, were examined for their therapeutic actions in a controlled cortical impact (CCI) model of moderate traumatic brain injury (TBI) in mice. Early post-CCI treatment with sitagliptin, but not vildagliptin, significantly reduced body asymmetry, locomotor hyperactivity, and brain lesion volume. Sitagliptin attenuated post-CCI microglial deramification in the ipsilateral dorsolateral (DL) striatum, while vildagliptin had no effect. Sitagliptin also reduced striatal expression of galectin-3 and monocyte chemoattractant protein 1(MCP-1), and increased the cortical and striatal levels of the anti-inflammatory cytokine IL-10 on the ipsilateral side. These data support a differential protective effect of sitagliptin against TBI, possibly mediated by an anti-inflammatory effect in striatum to preserve connective network. Both sitagliptin and vildagliptin produced similar increases of active glucagon-like peptide-1 (GLP-1) in blood and brain. Increasing active GLP-1 may not be the sole molecular mechanisms for the neurotherapeutic effect of sitagliptin in TBI.

Early combination therapy delayed treatment escalation in newly diagnosed young-onset type 2 diabetes: A subanalysis of the VERIFY study.

We analysed glycaemic durability (sustained glycaemic control) with early combination therapy (metformin plus vildagliptin) versus metformin monotherapy, among patients with type 2 diabetes diagnosed before (young-onset [YOD]) and after (late-onset [LOD]) the age of 40 years, enrolled in the VERIFY trial. The primary endpoint was time to initial treatment failure (TF), defined as HbA1c of 7.0% or higher at two consecutive scheduled visits after randomization. The time to secondary TF was assessed when both groups were receiving and failing on the combination. A total of 186 (9.3%) patients had YOD and 1815 (90.7%) had LOD with a mean age difference of 20.4 years. Compared with metformin monotherapy, early combination reduced the risk of time to initial TF for both YOD (48%, P < .0006) and LOD (46%, P < .0001). With early combination, risk for time to secondary TF was reduced by 48% (P < .0035) in YOD and 24% (P < .0009) in LOD. Both treatment approaches were well tolerated with no unexpected safety concerns. In treatment-naïve patients with YOD (HbA1c 6.5%-7.5%), an early combination strategy improved attainment of the glycaemic target with durability and delayed treatment escalation compared with initial metformin monotherapy.

Early combination versus initial metformin monotherapy in the management of newly diagnosed type 2 diabetes: An East Asian perspective.

Type 2 diabetes (T2D) in the East Asian population is characterized by phenotypes such as low body mass index, an index of ß-cell dysfunction, and higher percentage of body fat, an index of insulin resistance. These phenotypes/pathologies may predispose people to early onset of diabetes with increased risk of stroke and renal disease. Less than 50% of patients with T2D in East Asia achieve glycaemic targets recommended by national or regional guidelines, which may be attributable to knowledge and/or implementation gaps. Herein, we review the latest evidence with special reference to East Asian patients with T2D and present arguments for the need to use early combination therapy to intensify glycaemic control. This strategy is supported by the 5-year worldwide VERIFY study, which reported better glycaemic durability in newly diagnosed patients with T2D with a mean HbA1c of 6.9% treated with early combination therapy of vildagliptin plus metformin versus those treated with initial metformin monotherapy followed by addition of vildagliptin only with worsening glycaemic control. This paradigm shift of early intensified treatment is now recommended by the American Diabetes Association and the European Association for the Study of Diabetes. In order to translate these evidence to practice, increased awareness and strengthening of the healthcare system are needed to diagnose and manage patients with T2D early for combination therapy.

The association of bullous pemphigoid with dipeptidyl-peptidase 4 inhibitors: a ten-year prospective observational study.

BACKGROUND: Bullous pemphigoid is the most common bullous chronic autoimmune skin disease. Recent studies have suggested dipeptidyl-peptidase 4 inhibitors as possible predisposing agents of bullous pemphigoid. The objective of our study was to prospectively estimate the association between gliptins and the development of bullous pemphigoid. METHODS: We conducted a prospective study which included all patients diagnosed with biopsy-proven bullous pemphigoid in the Dermatology Department of our hospital between April 1, 2009 and December 31,2019. The diagnosis of bullous pemphigoid was based on specific clinical, histological and immunological features. RESULTS: Overall 113 consecutive patients (age 75 ± 13 years, 62 females) with the diagnosis of bullous pemphigoid were enrolled. Seventy-six patients (67.3%) suffered from type 2 Diabetes and 52 (46%) were treated with dipeptidyl-peptidase 4 inhibitors. The most frequent prescribed gliptin was vildagliptin, being administered to 45 cases (39.8% of total patients enrolled, 86.5% of the patients treated with gliptins). Gliptins were withdrawn immediately after the diagnosis of bullous pemphigoid, which together with steroid administration led to remission of the rash. CONCLUSIONS: This study revealed that treatment with dipeptidyl-peptidase 4 inhibitors, especially vildagliptin, is significantly associated with an increased risk of bullous pemphigoid development.

The impact of vildagliptin on the daily glucose profile and coronary plaque stability in impaired glucose tolerance patients with coronary artery disease: VOGUE-A multicenter randomized controlled trial.

BACKGROUND: The impact of reduction in glycemic excursion on coronary plaques remains unknown. This study aimed to elucidate whether a dipeptidyl peptidase 4 inhibitor could reduce the glycemic excursion and stabilize the coronary plaques compared with conventional management in coronary artery disease (CAD) patients with impaired glucose tolerance (IGT). METHODS: This was a multicenter, randomized controlled trial including CAD patients with IGT under lipid-lowering therapy receiving either vildagliptin (50 mg once a day) or no medication (control group) regarding glycemic treatment. The primary endpoint was changes in the minimum fibrous cap thickness and lipid arc in non-significant native coronary plaques detected by optical coherence tomography at 6 months after intervention. Glycemic variability expressed as the mean amplitude of glycemic excursion (MAGE) measured with a continuous glucose monitoring system was evaluated before and 6 months after intervention. RESULTS: A total of 20 participants with 47 lesions were allocated to either the vildagliptin group (10 participants, 22 lesions) or the control group (10 participants, 25 lesions). The adjusted difference of mean changes between the groups was - 18.8 mg/dl (95% confidence interval, - 30.8 to - 6.8) (p = 0.0064) for the MAGE (vildagliptin, - 20.1 ± 18.0 mg/dl vs. control, 2.6 ± 12.7 mg/dl), - 22.8° (- 40.6° to - 5.1°) (p = 0.0012) for the mean lipid arc (vildagliptin, - 9.0° ± 25.5° vs. control, 15.8° ± 16.8°), and 42.7 µm (15.3 to 70.1 µm) (p = 0.0022) for the minimum fibrous cap thickness (vildagliptin, 35.7 ± 50.8 µm vs. control, - 15.1 ± 25.2 µm). CONCLUSIONS: Vildagliptin could reduce the MAGE at 6 months and may be associated with the decreased lipid arc and increased minimum FCT of the coronary plaques in CAD patients with IGT as compared with the control group. These findings may represent its potential stabilization effect on coronary plaques, which are characteristic in this patient subset. Trial registration Registered in the UMIN clinical trial registry (UMIN000008620), Name of the registry: VOGUE trial, Date of registration: Aug 6, 2012, URL: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000010058.

Efficacy and safety profile of sitagliptin, vildagliptin, and metformin in newly diagnosed type 2 diabetic subjects.

Type 2 diabetes mellitus (T2DM) is a chronic and progressive disease that requires long-term management. Thus, dipeptidyl peptidase-4 inhibitors (DPP-4) need more investigations about their efficacy and safety profile as there is still no evidence of whether DPP-4 inhibitors can be used as a first line option for T2DM drug-naïve patients. In this randomized case-controlled study, 60 drug-naïve T2DM subjects were randomized into three groups, each group comprising 20 subjects. Group 1 was given sitagliptin 100 mg once daily, Group 2 was given vildagliptin 50 mg twice daily, and Group 3 served as the control group and was given metformin 1 g twice daily. Efficacy endpoints included changes in glycosylated haemoglobin (HbA1c), fasting plasma glucose (FPG), and 2-hr postprandial plasma glucose (PPG), and the secondary endpoints were related to safety profile were the assessment of liver and kidney function tests and complete blood count (CBC). All treatment regimens had comparable efficacy and safety profiles with the non-significant relative superiority of vildagliptin in lowering HbA1c more than sitagliptin but significant (p = 0.011) regarding FPG reduction, vildagliptin significantly decreased HbA1c by -1.02% (p < 0.001), sitagliptin significantly decreased HbA1c by -0.96% (p < 0.001), and control significantly decreased HbA1c by -0.90% (p < 0.001) compared with baseline. The studied drugs showed moderate efficacy in lowering HbA1c levels with the non-significant relative higher efficacy of DPP-4 inhibitors. DPP-4 inhibitors and metformin showed favourable effects on improving metabolic syndrome by decreasing blood pressure, serum triglycerides (TG), low-density lipoprotein (LDL), total cholesterol, and increasing high-density lipoprotein (HDL), plus their positive impacts on weight. As a final conclusion, the three medications are highly comparable.

Development and validation of an analytical method for quantitative determination of three potentially genotoxic impurities in vildagliptin drug material using HPLC-MS.

A novel high-performance liquid chromatography-mass spectrometry method was developed to determine the quantities of pyridine, 4-dimethylaminopyridine, and N, N-dimethylaniline impurities in vildagliptin drug material. These impurities are reactive bases that may be used in synthesis of vildagliptin pharmaceutical ingredients. They are considered as potentially genotoxic impurities since they contain electrophilic functional groups. Therefore, these impurities should be monitored at the allowed limits in vildagliptin. Hence a high-performance liquid chromatography-mass spectrometry method was developed to quantify the amounts of these impurities in vildagliptin. The column was KROMASIL CN (250 mm × 3.9 mm, 3.5 µm) in reversed-phase mode. The mobile phase was a mixture of water-methanol (55:45) containing 2.5 mM ammonium acetate and 0.1% formic acid. The mass spectrometer was used to detect the amounts of impurities using selected ionization monitoring mode at m/z = 80, 122, and 123 for pyridine, N, N-dimethylaniline, and 4-dimethylaminopyridine, respectively. The flow rate was 0.5 mL/min. The sensitivity of the method was excellent at levels very less than the allowed limits. The method had excellent linearity in the concentration ranges of limit of quantification-150% of the permitted level with coefficients of determination above 0.9990. The recovery ratios were in the range of 93.70-108.63%. Results showed good linearity, precision, accuracy, sensitivity, selectivity, robustness, and solution stability.

Saxagliptin and vildagliptin lowered albuminuria in patients with diabetes and hypertension independent on glycaemic control.

BACKGROUND: Preclinical data illustrated that the dipeptidyl peptidase-4(DPP-4) inhibitors did lower urinary albumin excretion in diabetes-induced rats. We evaluated the effects of saxagliptin and vildagliptin on albuminuria in patients with diabetic nephropathy on top of the renin-angiotensin-aldosterone system (RAAS) blockade therapy. METHODS: This study included 120 patients with type 2 diabetes (T2D), hypertension, and prevalent albuminuria [defined as urine albumin-to-creatinine ratio (UACR) 30-3000mg/g creatinine] on a stable dose of olmesartan as a standard RAAS blocker for diabetic nephropathy. Patients were assigned to receive either of saxagliptin 5mg/day (n = 40), vildagliptin 100mg/day (n = 40), or traditional antidiabetic therapy as control patients (n = 40) for 12 weeks. RESULTS: Each of saxagliptin and vildagliptin significantly reduced albuminuria after 12 weeks, with mean percentage changes (%) of -57.9% [95% confidence interval (CI) -66.1 to -49.8], and -55.2% (95% CI -64.9 to -45.4); P < .001, respectively, compared with the control group. Significantly, saxagliptin shifted higher proportions of patients towards lower albuminuria categories (P < .001) compared with vildagliptin despite a similar UACR rate of changes. Results of binary logistic models confirmed that the change in UACR because saxagliptin was independent of changes in systolic blood pressure (SBP), glycated hemoglobin (HbA1c ), estimated glomerular filtration rate (eGFR), or body weight (overall regression: P = .002, R2  = 0.398) vs control. Likewise, vildagliptin reduced UACR independently on other confounders (overall regression: P = .002, R2  = 0.388). Furthermore, no significant correlation was observed between the change in UACR and changes in HbA1c, SBP or eGFR with either saxagliptin or vildagliptin (Pearson coefficients: 0.203, 0.143, -0.190; P > .05, and 0.003, 0.241, 0.019; P > .05, respectively). CONCLUSIONS: DPP-4 inhibitors, saxagliptin, and vildagliptin, resulted in substantial reductions in albuminuria in patients with T2D and hypertension on top of RAAS blockade after short term therapy independently on glycaemic or hemodynamic changes. Saxagliptin was superior to vildagliptin in albuminuria-categorical shifting.