Efficacy and Safety of Vildagliptin for Type 2 Diabetes in Patients With Diabetic Kidney Disease.

BACKGROUND/AIM: Vildagliptin is one of the dipeptidyl peptidase-4 (DPP-4) inhibitors that have been shown to improve hyperglycemia in clinical trials among patients with type 2 diabetes. However, few studies have examined the efficacy of vildagliptin in patients with diabetic kidney disease (DKD). PATIENTS AND METHODS: Eight patients with DKD received oral vildagliptin 50-100 mg/day. The duration of diabetes was 6.7±5.9 years and observation period was 23.6±9.8 months. Changes in fasting blood glucose, and hemoglobin A1c (HbA1c), estimated glomerular filtration rate (eGFR), and urine protein-to-creatinine ratio (UPCR) were studied before and after the administration of vildagliptin. RESULTS: Vildagliptin treatment significantly decreased fasting blood glucose and HbA1c, compared to baseline (132±56 mg/dl, p=0.036, 6.0±0.3, p=0.041, respectively). UPCR tended to be decreased, albeit without statistical significance. However, eGFR was decreased after the administration of vildagliptin. No significant adverse effects were observed in all patients during the study. CONCLUSION: Although the sample size was limited and the observation period was brief, vildagliptin was found to be an effective and reasonably well-tolerated treatment for patients with DKD.

Cost-Effectiveness of Dipeptidylpeptidase-4 Inhibitors Added to Metformin in Patients With Type 2 Diabetes in China.

Purpose: Dipeptidylpeptidase-4 (DPP-4) inhibitors, including linagliptin, alogliptin, saxagliptin, sitagliptin, and vildagliptin, are used for the treatment of type 2 diabetes mellitus (T2DM) patients in China. This study assessed the economic outcomes of different DPP-4 inhibitors in patients with T2DM inadequately controlled with metformin in the Chinese context. Materials and Methods: In this study, the validated Chinese Outcomes Model for T2DM (COMT) was conducted to project economic outcomes from the perspective of Chinese healthcare service providers. Efficacy and safety, medical expenditure, and utility data were derived from the literature, which were assigned to model variables. The primary outputs of the model included the lifetime costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER). One-way and probability sensitivity analysis was conducted to assess the potential uncertainties of parameters. Results: Of the five competing strategies, alogliptin 25 mg strategy yielded the most significant health outcome, which associated with improvements in discounted QALY of 0.007, 0.014, 0.011, and 0.022 versus linagliptin 5 mg, saxagliptin 5 mg, sitagliptin 100 mg and vildagliptin50 mg, respectively. The sitagliptin 100 mg strategy was the cheapest option. The ICER of alogliptin 25 mg against sitagliptin 100 mg strategy was $6,952 per additional QALY gained, and the rest of the strategies were dominated or extended dominated. The most influential parameters were the cost of DPP-4 inhibitors and their treatment efficacy. Conclusions: These results suggested that alogliptin was a preferred treatment option compared with other DPP-4 inhibitors for Chinese patients whose T2DM are inadequately controlled on metformin monotherapy.

Effect of Dosage Reduction of Hypoglycemic Multidrug Regimens on the Incidences of Acute Glycemic Complications in People With Type 2 Diabetes Who Fast During Ramadan: A Randomized Controlled Trial.

Objective: We aimed to investigate the effect of dosage reduction of four hypoglycemic multidrug regimens on the incidences of acute glycemic complications in people with type 2 diabetes who fast during Ramadan. Methods: We conducted an open-label, parallel-group, randomized controlled trial at a tertiary care center in Amman, Jordan. We recruited adults with type 2 diabetes who expressed an intention to fast during Ramadan and were adherent to one of four regimens-namely: metformin and glimepiride; metformin and vildagliptin; metformin and insulin glargine U100; or, metformin, insulin glargine U100, and human regular insulin. We randomly assigned participants in a 2:1 ratio to low- or regular-dosage therapy. The primary outcomes were the incidences of hypoglycemia and hyperglycemia during the 29 days of Ramadan 2017, and the secondary outcomes were the incidences of diabetic ketoacidosis and hyperosmolar hyperglycemic state during the same period. Results: We randomly assigned 687 participants to low-dosage therapy (n = 458) or regular-dosage therapy (n = 229) and included 678 (452 and 226, respectively) in the final analysis. The incidence of hypoglycemia was lower in the low-dosage group compared with the regular-dosage group (19 [4.2%] vs. 52 [23.0%], respectively; OR, 0.15 [95% CI, 0.08-0.26]; P < 0.001). The incidence of hyperglycemia did not differ between the low- and regular-dosage groups (319 [70.6%] vs. 154 [68.1%], respectively; OR, 1.12 [95% CI, 0.79-1.58]; P = 0.5). No participants experienced diabetic ketoacidosis or hyperosmolar hyperglycemic state. Each 1% decrease in the baseline HbA1c concentration was associated with a 19.9-fold (95% CI, 9.6-41.5; P < 0.001) increase in the odds of hypoglycemia, and each 1% increase in the baseline HbA1c concentration was associated with a 15.7-fold (95% CI, 10.0-24.6; P < 0.001) increase in the odds of hyperglycemia. Conclusion: Dosage reduction decreases the incidence of hypoglycemia without a concomitant increase in the incidences of hyperglycemia, diabetic ketoacidosis, and hyperosmolar hyperglycemic state in people with type 2 diabetes who fast during Ramadan. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT04237493.

Augmentation of RBP4/STRA6 signaling leads to insulin resistance and inflammation and the plausible therapeutic role of vildagliptin and metformin.

A role of Retinol Binding Protein-4 (RBP4) in insulin resistance is widely studied. However, there is paucity of information on its receptor viz., Stimulated by Retinoic Acid-6 (STRA6) with insulin resistance. To address this, we investigated the regulation of RBP4/STRA6 expression in 3T3-L1 adipocytes exposed to glucolipotoxicity (GLT) and in visceral adipose tissue (VAT) from high fat diet (HFD) fed insulin-resistant rats. 3T3-L1 adipocytes were subjected to GLT and other experimental maneuvers with and without vildagliptin or metformin. Real-time PCR and western-blot experiments were performed to analyze RBP4, STRA6, PPARγ gene and protein expression. Adipored staining and glucose uptake assay were performed to evaluate lipid and glucose metabolism. Oral glucose tolerance test (OGTT) and Insulin Tolerance Test (ITT) were performed to determine the extent of insulin resistance in HFD fed male Wistar rats. Total serum RBP4 was measured by quantitative sandwich enzyme-linked immunosorbent assay kit. Adipocytes under GLT exhibited significantly increased RBP4/STRA6 expressions and decreased insulin sensitivity/glucose uptake. Vildagliptin and metformin not only restored the above but also decreased the expression of IL-6, NFκB, SOCS-3 along with lipid accumulation. Furthermore, HFD fed rats exhibited significantly increased serum levels of RBP4 along with VAT expression of RBP4, STRA6, PPARγ, IL-6. These molecules were significantly altered by the vildagliptin/ metformin treatment. We conclude that RBP4/STRA6 pathway is primarily involved in mediating inflammation and insulin resistance in adipocytes and visceral adipose tissues under glucolipotoxicity and in insulin resistant rats.

Rapamycin Plus Vildagliptin to Recover ß-Cell Function in Long-Standing Type 1 Diabetes: A Double-Blind, Randomized Trial.

AIM: The aim of this study was to investigate whether treatment with rapamycin plus vildagliptin restores ß-cell function in patients with long-standing type 1 diabetes. METHODS: A phase 2, single-center, randomized, double-blind, placebo-controlled study was conducted in long-standing type 1 diabetes patients randomly assigned (1:1:1) to 4 weeks of rapamycin (group 2), 4 weeks of rapamycin plus 12 weeks of vildagliptin (group 3), or double placebo (group 1). The primary outcome was the proportion of participants with a positive response to the Mixed-Meal Tolerance Test (C-peptide at 90 minutes > 0.2 nmol/L) at weeks 4 and 12. Secondary end points included insulin requirement, standard measures of glycemic control, and hormonal and immunological profile. RESULTS: Fifty-five patients were randomly assigned to group 1 (n = 18), group 2 (n = 19), or group 3 (n = 18). No patient in any group showed a positive C-peptide response, and there was no significant difference at 4 and 12 weeks for the primary outcome. At 4 weeks, insulin requirement decreased from 0.54 to 0.48 U/kg/day in group 2 (P = .013), from 0.59 to 0.51 U/kg/day in group 3 (P < .001), whereas it did not change in group 1. At 12 weeks, glycated hemoglobin significantly decreased both in group 2 (from 7.3% [56 mmol/mol] to 7% [53 mmol/mol]; P = .045] and in group 3 (from 7.2% [55.5 mmol/mol] to 6.9% [52 mmol/mol]; P = .001]. Rapamycin treatment was associated with a decrease in insulin antibody titer and changes in hormonal/immunological profile. CONCLUSIONS: Rapamycin reduced insulin requirement, but did not restore ß-cell function in patients with long-standing type 1 diabetes.

A case of anti-BP230 antibody-positive bullous pemphigoid receiving DPP-4 inhibitor.

Bullous pemphigoid (BP) is a cutaneous autoimmune blistering disorder. Recently, it has been reported that dipeptidyl peptidase-4 inhibitors (DPP4i) is associated with the development of BP (DPP4i-BP). Patients with DPP4i-BP have autoantibodies (autoAbs) preferentially targeting full-length BP180, but not the BP180NC16a domain. In this report, we described a case of anti-BP230 antibody (Ab)-positive BP receiving DPP4i. A 78-year-old male with a medical history of type 2 diabetes receiving vildagliptin at 100 mg daily for 38 months was referred to our hospital with itching blisters on his body and extremities. Skin biopsy showed subepidermal bulla with eosinophil infiltration. Direct immunofluorescence staining revealed a linear staining pattern with complement C3 and IgG at the subepidermal basement membrane zone. By laboratory testing, autoAbs against BP180NC16a and full-length BP180 were negative by enzyme-linked immunosorbent assay (ELISA); however, anti-BP230 Abs were positive by ELISA (index: 123.91). His HLA genotype was DQB1*04:01 and 05:01. Based on these results, we diagnosed the patient with anti-BP230 Abs-positive BP associated with DPP4i. To the best of our knowledge, this is the first case of DPP4i-BP with only anti-BP230 Abs. Further accumulation of DPP4i-BP cases is needed to clarify the relationship between overall features of DPP4i-BP and anti-BP230 Abs.

Vildagliptin vs. insulin treatment alone in diabetic acute coronary syndrome patients.

BACKGROUND: Vildagliptin, an oral antidiabetic of the dipeptidyl peptidase-4 (DPP-4) inhibitor drugs, exhibits an overall low risk of hypoglycemia with less frequent hypoglycemic events in type 2 diabetes mellitus (T2DM) patients than other antidiabetic drugs. We hypothesized that among hospitalized acute coronary syndrome (ACS) patients, the addition of vildagliptin to subcutaneous insulin therapy would reduce the risk of hypoglycemic events. METHODS: One hundred ACS T2DM adult patients naive to DPP-4 inhibitors were enrolled during admission to the ICCU. Patients were divided into two randomized controlled groups: a subcutaneous rapid-acting insulin-only therapy group and an oral vildagliptin plus subcutaneous insulin group. The trial was open label with no placebo arm. Mean glucose values, insulin values given for correction per hospitalization, and the number of hypoglycemic events (glucose < 70 mg/dL) were documented. RESULTS: Eight hypoglycemia events occurred in the insulin-only group and none in the insulin plus DPP-4 inhibitor group (P < 0.001). Patients with acute myocardial infarction experienced a higher number of hypoglycemic events compared with unstable angina diagnosed patients. No significant differences were found regarding glucose level (P = 0.462) and administered insulin units (P = 0.639). CONCLUSIONS: In T2DM patients, the addition of DPP-4 inhibitors to routine subcutaneous insulin therapy may significantly reduce hypoglycemic events while maintaining acceptable recommended ranges of glucose. Further studies on a larger scale are required to verify these results and to support that DPP-4 inhibitors added to today's standard insulin-only treatment in hospitalized diabetic ACS patients may improve overall glycemic control and provide a potential treatment option in this challenging clinical setting.

Reprotoxic activities of vildagliptin administration in male Wistar rats

Vildagliptin is an oral hypoglycemic agent used in the management of diabetes. Some oral antidiabetic drugs have been implicated in reproductive toxicity.The objective of this study was to investigate the effects of daily administration of vildagliptin at different dosages (0.35 mg/kg B.W., 0.70 mg/kg B.W. and 1.40 mg/kg B.W.) to male Wistar rats for 8 weeks. Sperm parameters, serum concentrations of testosterone, follicle stimulating hormone and luteinizing hormone and the histology of the testis of the rats were assessed. Another set of rats were also treated for 8 weeks and allowed to recover and the same parameters were assessed in them. Fertility study was conducted by determining their litter size. The results showed that vildagliptin administration significantly reduced sperm count and motility of the treated rats. It also significantly increased the number of abnormal sperms. Serum level of testosterone was significantly decreased while luteinizing hormone and follicle stimulating hormone levels showed no significant change. The histoarchitecture of the testis of the treated rats appeared visibly normal. The litter size was also significantly reduced. Most of the changes observed were dose dependent. However, these parameters were restored towards normal in the recovery group. Our results suggest that vildagliptin adversely affected sperm parameters, affected litter size and disrupted the pituitary - gonadal axis. These changes were however reversed upon cessation of drug administration.

Comparative clinical study evaluating the effect of adding Vildagliptin versus Glimepiride to ongoing Metformin therapy on diabetic patients with symptomatic coronary artery disease.

BACKGROUND AND OBJECTIVE: Cardiovascular diseases (CVDs) remain the most identified cause of death in patients with diabetes mellitus (DM). This study aimed to evaluate the effect of adding Vildagliptin versus Glimepiride to ongoing Metformin on the biomarkers of inflammation, thrombosis, and atherosclerosis in T2DM patients with symptomatic coronary artery disease (CAD). METHODS: This study included 80 patients with uncontrolled T2DM and symptomatic CAD who were randomized to add either Vildagliptin 50 mg/day "group I" or Glimepiride 4 mg/day "group II" to ongoing Metformin therapy (1000 mg/day). Blood samples were collected at baseline and 3 months after intervention for biochemical analysis of HbA1c %, IL-1ß, adiponectin, hsCRP and lipid profile. Additionally atherogenic index (AI) and coronary risk index (CRI) were determined. RESULTS: Three months after intervention and as compared to group II (Glimepiride/Metformin), group 1 (Vildagliptin/Metformin) showed significantly lower BMI (28.73 ± 3.48 versus 30.55 ± 3.15; p = 0.02), HbA1c (6.05 ± 0.72 versus 7.06 ± 0.89; p < 0.0001), hsCRP (0.96 ± 0.20 versus 1.72 ± 0.38; p < 0.0001), IL-1ß (34.95 ± 10.01 versus 45.13 ± 10.26; p < 0.0001), TC (136 ± 23.45 versus 169 ± 35.72; p < 0.0001), TG (116 ± 29.10 versus 146 ± 56.58; p = 0.005), and CRI (2.47 ± 0.90 versus 3.65 ± 1.19; p < 0.0001) which was associated with significantly higher adiponectin and HDL-C (4.42 ± 1.29 versus 2.52 ± 1.86; p < 0.0001 and 61 ± 23.04 versus 48 ± 12.92; p = 0.003 respectively). CONCLUSION: In patients with T2DM and symptomatic CAD, the addition of Vildagliptin to ongoing metformin showed better glycemic control, lower inflammatory markers (IL-1ß and hsCRP), higher protective markers (adiponectin and HDL-C) and improved lipid profile compared to Glimepiride/metformin therapy.

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

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

Cardiovascular safety and effectiveness of vildagliptin in patients with type 2 diabetes mellitus: a 3-year, large-scale post-marketing surveillance in Japan.

Objectives: The dipeptidyl peptidase-4 (DPP-4) inhibitor vildagliptin is indicated for type 2 diabetes mellitus (T2DM). However, the long-term safety, effectiveness, and clinical relationship with cardiovascular events of vildagliptin have not been evaluated in Japan.Methods: The authors conducted post-marketing surveillance (PMS) to evaluate the safety and effectiveness of vildagliptin in more than 3000 Japanese T2DM patients for up to 3 years. Main assessments included demographics, major adverse cardiovascular events (MACE), adverse events (AEs), adverse drug reactions (ADRs), and glycated hemoglobin (HbA1c).Results: In this PMS, 3831 patients (775 sites) were registered in April 2010 - April 2012. The safety analysis population comprised 3769 patients; 2085 patients were aged ≥65 years, and 240, 411, and 114 had renal impairment, hepatic impairment, and heart failure, respectively. The median treatment duration was 2.7 years. The incidence of MACE was 6.04 cases/1000 person-years, mostly attributable to cerebrovascular events (4.27 cases/1000 person-years). The AE and ADR incidences were 26.0% and 5.3%, respectively. The incidence of hypoglycemia was 0.6%. No significant changes in body weight occurred and mean change in HbA1c from baseline at final assessment was -0.74 ± 1.41% (p < 0.0001).Conclusions: In real-world clinical settings, vildagliptin was well tolerated, with similar profiles as previously reported.

Regimen-dependent synergism and antagonism of treprostinil and vildagliptin in hematopoietic cell transplantation.

The cell dose in umbilical cord blood units is a major determinant for the outcome of hematopoietic cell transplantation. Prostaglandin analogs and dipeptidylpeptidase-4 (DPP4/CD26)-inhibitors enhance the ability of hematopoietic stem cells (HSCs) to reconstitute hematopoiesis. Here we explored the synergism between treprostinil, a stable prostaglandin agonist, and the DPP4/CD26-inhibitor vildagliptin. The combination of treprostinil and forskolin caused a modest but statistically significant increase in the surface levels of DPP4/CD26 on hematopoietic stem and progenitor cells (HSPCs) derived from murine bone and human cord blood. Their migration towards stromal cell-derived factor-1 (SDF-1/CXCL12) was enhanced, if they were pretreated with treprostinil and forskolin, and further augmented by vildagliptin. Administration of vildagliptin rescued 25% of lethally irradiated recipient mice injected with a limiting number of untreated HSPCs, but 90 to 100% of recipients injected with HSPCs preincubated with treprostinil and forskolin. The efficacy of vildagliptin surpassed that of treprostinil (60% rescue). Surprisingly, concomitant administration of vildagliptin and treprostinil resulted in poor survival of recipients indicating mutual antagonism, which was recapitulated when homing of and colony formation by HSPCs were assessed. These observations of regimen-dependent synergism and antagonism of treprostinil and vildagliptin are of translational relevance for the design of clinical trials. KEY MESSAGES: Pretreatment with treprostinil increases surface levels of DPP4/CD26 in HSPCs. Vildagliptin enhances in vitro migration of pretreated HSPCs. Vildagliptin enhances in vivo homing and engraftment of pretreated HSPCs. Unexpected mutual antagonism in vivo by concomitant administration of vildagliptin and treprostinil.

Safety and efficacy of vildagliptin: 52-week post-marketing surveillance of Japanese patients with type 2 diabetes in combination with other oral antidiabetics and insulin.

Background: Vildagliptin is a dipeptidyl peptidase-4 inhibitor that reduces glycemia in patients with type 2 diabetes mellitus (T2DM). When approved in 2013, data on vildagliptin combined with >750 mg/day metformin in Japanese patients were limited. There is a need to confirm the safety and efficacy of vildagliptin in combination with oral antidiabetic drugs (OADs).Research design and methods: This 52-week post-marketing surveillance (PMS) observational study in Japanese T2DM patients evaluated the safety and efficacy of vildagliptin in combination with OADs including high-dose metformin or insulin but excluding combination with sulfonylureas alone.Results: During this survey of 3006 Japanese T2DM patients, 13.61% of patients experienced adverse events (AEs) and 2.20% reported a serious AE (SAE). The frequency of AEs/SAEs was similar when in combination with biguanides (12.93%/1.46%), metformin ≥1000 mg/day (12.92%/1.22%), metformin <1000 mg/day (12.62%/1.54%), thiazolidine derivatives (16.71%/2.86%), α-glucosidase inhibitors (13.18%/1.90%), rapid-acting insulin secretagogues  (glinides) (20.41%/5.71%), or insulin (15.87%/2.47%). The mean ± SD changes from baseline at endpoint in glycated hemoglobin and fasting blood glucose were -0.76 ± 1.27% and -23.3 ± 57.3 mg/dL, respectively, and these changes were consistent, regardless of concomitant OAD.Conclusions: Long-term vildagliptin combination therapy is safe and effective in Japanese T2DM patients in real-world settings.

Cardiovascular outcomes of vildagliptin in patients with type 2 diabetes mellitus after acute coronary syndrome or acute ischemic stroke.

AIMS/INTRODUCTION: The cardiovascular (CV) outcomes of vildagliptin - a dipeptidyl peptidase-4 inhibitor - in patients with type 2 diabetes mellitus after acute coronary syndrome or acute ischemic stroke are unclear. MATERIALS AND METHODS: We analyzed data from the Taiwan National Health Insurance Research Database on 3,750 type 2 diabetes mellitus patients with acute coronary syndrome or acute ischemic stroke within 3 months between 1 August 2011 and 31 December 2013. Clinical outcomes were evaluated by comparing 1,250 participants receiving vildagliptin with 2,500 propensity score-matched participants. The primary composite outcome included CV death, non-fatal myocardial infarction and non-fatal stroke. RESULTS: The primary composite outcome occurred in 122 patients (9.8%) in the vildagliptin group and 263 patients (10.5%) in the control group (hazard ratio [HR] 0.90, 95% confidence interval [CI] 0.72-1.11) with a mean follow-up period of 9.9 months. No significant between-group differences were observed for CV death (HR 0.93, 95% CI 0.56-1.52), non-fatal myocardial infarction (HR 0.79, 95% CI 0.46-1.36) and non-fatal stroke (HR 0.96, 95% CI 0.74-1.24). The vildagliptin group was at similar risks of hospitalization for heart failure (HF) or coronary intervention to the control group (P = 0.312 and 0.430, respectively). For patients with HF at baseline, the risk of hospitalization for HF was similar between the vildagliptin and control groups (HR 1.04, 95% CI 0.57-1.88). CONCLUSIONS: Among patients with type 2 diabetes mellitus after a recent acute coronary syndrome or acute ischemic stroke, treatment with vildagliptin was not associated with increased risks of CV death, non-fatal myocardial infarction, non-fatal stroke and hospitalization for HF.

Vildagliptin Attenuates Huntington's Disease through Activation of GLP-1 Receptor/PI3K/Akt/BDNF Pathway in 3-Nitropropionic Acid Rat Model.

Vildagliptin (Vilda), a dipeptidyl peptidase-4 (DPP-4) inhibitor, has been highlighted as a promising therapeutic agent for neurodegenerative diseases as Alzheimer's and Parkinson's diseases. Vilda's effect is mostly linked to PI3K/Akt signaling in CNS. Moreover, PI3K/Akt activation reportedly enhanced survival and dampened progression of Huntington's disease (HD). However, Vilda's role in HD is yet to be elucidated. Thus, the aim of the study is to uncover the potentiality of Vilda in HD and unfold its link with PI3K/Akt pathway in 3-nitropropionic acid (3NP) rat model. Rats were randomly assigned into 4 groups; group 1 received saline, whereas, groups 2, 3 and 4 received 3NP (10 mg/kg/day; i.p.) for 14 days, concomitantly with Vilda (5 mg/kg/day; p.o.) in groups 3 and 4, and wortmannin (WM), a PI3K inhibitor, (15 µg/kg/day; i.v.) in group 4. Vilda improved cognitive and motor perturbations induced by 3NP, as confirmed by striatal histopathological specimens and immunohistochemical examination of GFAP. The molecular signaling of Vilda was estimated by elevation of GLP-1 level and protein expressions of survival proteins; p85/p55 (pY458/199)-PI3K, pS473-Akt. Together, it boosted striatal neurotrophic factors and receptor; pS133-CREB, BDNF, pY515-TrKB, which subsequently maintained mitochondrial integrity, as indicated by enhancing both SDH and COX activities, and the redox modulators; Sirt1, Nrf2. Such neuroprotection restored imbalance of neurotransmitters through increasing GABA and suppressing glutamate as well PDE10A. These effects were reversed by WM pre-administration. In conclusion, Vilda purveyed significant anti-Huntington effect which may be mediated, at least in part, via activation of GLP-1/PI3K/Akt pathway in 3NP rat model.

Glycaemic durability of an early combination therapy with vildagliptin and metformin versus sequential metformin monotherapy in newly diagnosed type 2 diabetes (VERIFY): a 5-year, multicentre, randomised, double-blind trial.

BACKGROUND: Early treatment intensification leading to sustained good glycaemic control is essential to delay diabetic complications. Although initial combination therapy has been suggested to offer more opportunities than a traditional stepwise approach, its validity remains to be determined. METHODS: Vildagliptin Efficacy in combination with metfoRmIn For earlY treatment of type 2 diabetes (VERIFY) was a randomised, double-blind, parallel-group study of newly diagnosed patients with type 2 diabetes conducted in 254 centres across 34 countries. The study consisted of a 2-week screening visit, a 3-week metformin-alone run-in period, and a 5-year treatment period, which was further split into study periods 1, 2, and 3. Patients aged 18-70 years were included if they had type 2 diabetes diagnosed within 2 years prior to enrolment, and centrally confirmed glycated haemoglobin A1c (HbA1c) of 48-58 mmol/mol (6·5-7·5%) and a body-mass index of 22-40 kg/m2. Patients were randomly assigned in a 1:1 ratio either to the early combination treatment group or to the initial metformin monotherapy group, with the help of an interactive response technology system and simple randomisation without stratification. Patients, investigators, clinical staff performing the assessments, and data analysts were masked to treatment allocation. In study period 1, patients received either the early combination treatment with metformin (stable daily dose of 1000 mg, 1500 mg, or 2000 mg) and vildagliptin 50 mg twice daily, or standard-of-care initial metformin monotherapy (stable daily dose of 1000 mg, 1500 mg, or 2000 mg) and placebo twice daily. If the initial treatment did not maintain HbA1c below 53 mmol/mol (7·0%), confirmed at two consecutive scheduled visits which were 13 weeks apart, patients in the metformin monotherapy group received vildagliptin 50 mg twice daily in place of the placebo and entered study period 2, during which all patients received the combination therapy. The primary efficacy endpoint was the time from randomisation to initial treatment failure, defined as HbA1c measurement of at least 53 mmol/mol (7·0%) at two consecutive scheduled visits, 13 weeks apart from randomisation through period 1. The full analysis set included patients who received at least one randomised study medication and had at least one post-randomisation efficacy parameter assessed. The safety analysis set included all patients who received at least one dose of randomised study medication. This study is registered with ClinicalTrials.gov, NCT01528254. FINDINGS: Trial enrolment began on March 30, 2012, and was completed on April 10, 2014. Of the 4524 participants screened, 2001 eligible participants were randomly assigned to either the early combination treatment group (n=998) or the initial metformin monotherapy group (n=1003). A total of 1598 (79·9%) patients completed the 5-year study: 811 (81·3%) in the early combination therapy group and 787 (78·5%) in the monotherapy group. The incidence of initial treatment failure during period 1 was 429 (43·6%) patients in the combination treatment group and 614 (62·1%) patients in the monotherapy group. The median observed time to treatment failure in the monotherapy group was 36·1 (IQR 15·3-not reached [NR]) months, while the median time to treatment failure time for those receiving early combination therapy could only be estimated to be beyond the study duration at 61·9 (29·9-NR) months. A significant reduction in the relative risk for time to initial treatment failure was observed in the early combination treatment group compared with the monotherapy group over the 5-year study duration (hazard ratio 0·51 [95% CI 0·45-0·58]; p<0·0001). Both treatment approaches were safe and well tolerated, with no unexpected or new safety findings, and no deaths related to study treatment. INTERPRETATION: Early intervention with a combination therapy of vildagliptin plus metformin provides greater and durable long-term benefits compared with the current standard-of-care initial metformin monotherapy for patients with newly diagnosed type 2 diabetes. FUNDING: Novartis.

Design, synthesis and evaluation of DNA nano-cubes as a core material protected by the alginate coating for oral administration of anti-diabetic drug.

Poor control towards glycemic levels among diabetic patients may lead to severe micro/macro-vascular and neuropathic complexities. Proper functioning of alpha-beta cells of pancreases is required to attain long term glycemic control among type 2 diabetics. The recent developments to manage diabetes are focused on controlling the insulin-glucagon secretions from the pancreases. DPP-4 inhibitors class of drugs after elevating GLP-1/GIP (incretins) levels in the blood, not only raise the insulin levels but also suppress the glucagon level. Vildagliptin (VI) is a potent DPP-4 inhibitor with least adverse events compared to other DPP-4 inhibitors. We encapsulated VI into 3D nanocube that gets bind to the DNA due to secondary amine in its chemical structure. DNA-nanocube being negatively charged was incubated with the PLL to attain positive surface. Ultimately VI loaded nanocubes were coated with the negatively charged Na-alginate via electrostatic attraction method to get stable spherical nanospheres for oral delivery of VI. Nanospheres were evaluated physically through native PAGE analysis, DSC, TGA, dissolution testing, XRD and FTIR. We attained uniformed and spherical nanospheres with stable topology, nanoscale size precision (40-150 nm in diameter), Entrapment efficiency (up to 90%), prolonged drug release (13 ± 4 h) at basic pH, and superior oral antidiabetic effects with improved GLP1 and glycemic levels. The formulated nanospheres attained size uniformity and better therapeutic outcomes in terms of reduced adverse events and better control of glycemic levels than previously reported methods with decreased dosage frequency tested in Db/Db mice.

Identification of Novel Metabolites of Vildagliptin in Rats: Thiazoline-Containing Thiol Adducts Formed via Cysteine or Glutathione Conjugation.

Vildagliptin (VG), a dipeptidyl peptidase-4 inhibitor, is used for treating type 2 diabetes. On rare occasions, VG causes liver injury as an adverse reaction. One case report suggested the involvement of immune responses in the hepatotoxicity, but the underlying mechanisms are unknown. We recently reported that VG binds covalently in vitro to l-cysteine to produce a thiazoline acid metabolite, M407, implying that the covalent binding may trigger the immune-mediated hepatotoxicity. There was no evidence, however, that such a thiazoline acid metabolite was formed in vivo. In the present study, we administered a single oral dose of VG to male Sprague-Dawley rats, and detected M407 in plasma. The sum of urinary and fecal excretions of M407 reached approximately 2% of the dose 48 hours postdosing. Using bile duct-cannulated rats, we demonstrated that M407 was secreted into bile as a glucuronide, designated as M583. Another newly identified thiazoline metabolite of VG, the cysteinylglycine conjugate M464, was detected in urine, feces, and bile. The formation of M464 was confirmed by in vitro incubation of VG with glutathione even in the absence of metabolic enzymes. A glutathione adduct against the nitrile moiety M611 was also detected in vitro but not in vivo. In summary, we found three new thiazoline-containing thiol adduct metabolites in VG-administered rats. Nonenzymatic covalent binding of VG would likely occur in humans, and it may be relevant to predicting adverse reactions.

DNA scaffold nanoparticles coated with HPMC/EC for oral delivery.

The control of the glycemic level among diabetes/T2 patients is very important for their long term survival and avoiding further complexities including micro/macrovascular diseases as well as diabetic neuropathy. Vildagliptin (VD) is a drug that has addressed these issues successfully with the desired safety portfolio. We used DNA-nanocubes for initial nano-encapsulation of VD followed by HPMC/EC coating. The results revealed the stable, smooth, spherical and nano-sized nanoparticles with improved size uniformity (from 100 to 400 nm in diameter) and encapsulation-efficiency (E.E.%) than previously reported (500-2000 nm) with the chemical compatibility evident in ATR/FTIR and DSC results. Animal experiments results revealed the improvement of incretin level in the serums due to potent DPP-4 inhibition compared to the free-VD/solution with better maintenance of glycemic levels after feeding. The safety of these HPMC/EC-DNA-VD nanoparticles was assessed through the histological-examination after completion of the treatment turn. The solvent evaporation technique provided the better coating of HPMC around DNA-core with gastro-resistant and effervescent property due to presence of NaHCO3 (0.01%) in the formulations that caused delayed delivery of VD as well as nanoparticles to the intestine, increasing the availability time of the drug and nanospheres at the target sites (intestine and blood) where DPP-4 enzyme is most abundant (to degrade the GLP-1 and GIP causing loss of control of the postprandial glycemic levels. So the availability of sustained release nanospheres near the target sites and prolonged DPP-4 inhibition improved the outcomes of the therapy.