Effects Of Linagliptin Research Articles

Crosstalk between SIRT1/Nrf2 signaling and NLRP3 inflammasome/pyroptosis as a mechanistic approach for the neuroprotective effect of linagliptin in Parkinson’s disease

In recent years, special attention has been paid to highlighting the antiparkinsonian effect of linagliptin. However, the mechanism of its action has not yet been well investigated. The present study aimed to verify the neuroprotective effect of linagliptin in the rotenone model of Parkinson’s disease (PD) and further explore its potential molecular mechanisms. Rats were intoxicated with rotenone (2 mg/kg/day; sc) and treated with linagliptin (10 mg/kg/day; po) for 14 consecutive days. The present finding showed that linagliptin ameliorated the histopathological changes of rotenone on substantia nigra and striata. Linagliptin decreased α-synuclein immunoreactivity along with an increase in tyrosine hydroxylase immunoreactivity and striatal dopamine content. This was reflected in the marked improvement of the behavior and motor deficits in rotenone-intoxicated rats. On the molecular level, linagliptin upregulated sirtuin 1 (SIRT1)/ nuclear factor erythroid 2–related factor 2 (Nrf2) signaling, reduced ionized calcium‐binding adaptor molecule 1 (Iba1) protein expression, restored glutathione (GSH) content, and elevated heme oxygenase-1 (HO-1) level in rats with rotenone intoxication. Moreover, linagliptin inhibited NOD-like receptor protein 3 (NLRP3)/caspase-1/interleukin-1β (IL-1β) cascade with subsequent reduction in gasdermin D (GSDMD) expression. Therefore, the present study reveals the ability of linagliptin, through the activation of SIRT1/Nrf2 signaling, to suppress NLRP3 inflammasome-mediated pyroptosis and protect against rotenone-induced parkinsonism.

Machine learning assessment of vildagliptin and linagliptin effectiveness in type 2 diabetes: Predictors of glycemic control.

Differential effects of linagliptin and vildagliptin may help us personalize treatment for Type 2 Diabetes Mellitus (T2DM). The current study compares the effect of these drugs on glycated hemoglobin (HbA1c) in an artificial neural network (ANN) model. Patients with T2DM who received either vildagliptin or linagliptin, with predefined exclusion criteria, qualified for the study. Two input variable datasets were constructed: with or without imputation for missing values. The primary outcome was HbA1c readings between 3 to 12 months or the reduction in HbA1c levels. The cohort comprised 191 individuals (92 vildagliptin and 99 linagliptin). Linagliptin group had significantly higher disease burden. For imputed dataset, HbA1c was lower with linagliptin at 3 to 12 months (7.442 ± 0.408 vs. 7.626 ± 0.408, P < 0.001). However, there was a small yet significant difference in HbA1c reduction favoring vildagliptin over linagliptin (-1.123 ± 0.033 vs. -1.111 ± 0.043, P < 0.001). LDL level, uric acid, and the drug group were identified as predictors for HbA1c levels. In the non-imputed dataset HbA1c at 3 to 12 months was lower with linagliptin (median ± IQR: 7.489 ± 0.467 vs. 7.634 ± 0.467, P-value < 0.001). However, both linagliptin and vildagliptin exhibited similar reductions in HbA1c levels (both median ± IQR of -1.07 ± 0.02). Predictors for HbA1c levels included eGFR level and the drug group. Linagliptin effectively lowers HbA1c levels more than vildagliptin including in patients with comorbidities. DPP4-I choice is a constant predictor of HbA1c in all models.

Linagliptin mitigates cisplatin-induced kidney impairment via mitophagy regulation in rats, with emphasis on SIRT-3/PGC-1α, PINK-1 and Parkin-2

Cisplatin (CDDP) often leads to kidney impairment, limiting its effectiveness in cancer treatment. The lack of mitophagy in proximal tubules exacerbates this issue. Hence, targeting SIRT-3 and PGC1-α shows promise in mitigating CDDP-induced kidney damage. The potential renoprotective effects of linagliptin, however, remain poorly understood. This study represents the first exploration of linagliptin's impact on CDDP-induced kidney impairment in rats, emphasizing its potential role in mitophagic pathways. The experiment involved four rat groups: Group (I) received saline only, Group (II) received a single intraperitoneal injection of CDDP at 6 mg/kg. Groups (III) and (IV) received linagliptin at 6 and 10 mg/kg p.o., respectively, seven days before CDDP administration, continuing for an additional four days. Various parameters, including renal function tests, oxidative stress, TNF-α, IL-1β, IL-6, PGC-1α, FOXO-3a, p-ERK1, and the gene expression of SIRT-3 and P62 in renal tissue, were assessed. Linagliptin improved renal function, increased antioxidant enzyme activity, and decreased IL-1β, TNF-α, and IL-6 expression. Additionally, linagliptin significantly upregulated PGC-1α and PINK-1/Parkin-2 expression while downregulating P62 expression. Moreover, linagliptin activated FOXO-3a and SIRT-3, suggesting a potential enhancement of mitophagy. Linagliptin demonstrated a positive impact on various factors related to kidney health in the context of CDDP-induced impairment. These findings suggest a potential role for linagliptin in improving cancer treatment outcomes. Clinical trials are warranted to further investigate and validate its efficacy in a clinical setting.

Metabolic Analysis and Renal Protective Effects of Linagliptin and Empagliflozin in Alport Syndrome.

We previously demonstrated that Empagliflozin (Empa), a sodium-glucose cotransporter-2 (SGLT2) inhibitor, reduces intrarenal lipid accumulation and slows kidney function decline in experimental Alport syndrome (AS). In this study, we aimed to evaluate the renal protective benefits of Linagliptin (Lina), a dipeptidyl peptidase-4 (DPP4) inhibitor in AS and compare it to Empa. Metabolite distribution in kidney cortices was assessed using mass spectrometry imaging. We examined albuminuria and histological changes in kidneys from AS mice treated with Lina and/or Empa or vehicle. Several metabolites, including adrenic acid (AdA) and glucose, were increased in renal cortices of AS mice when compared to wildtype (WT) mice, while eicosapentaenoic acid (EPA) levels were decreased. In addition, a redistribution of AdA from the glomerular compartment in WT mice to the tubulointerstitial compartment in AS mice was observed. Both Lina and Empa treatments were found to reduce albuminuria, to extend the survival of AS mice for about 10 days, and to decrease glomerulosclerosis and tubulointerstitial fibrosis compared to WT mice. There were no significant differences with regard to the renal phenotype observed between Empa and Lina treated AS mice, and the combination of Lina and Empa was not superior to individual treatments. In vitro experiments revealed that DPP4 is expressed in podocytes and tubular cells derived from both AS and WT mice. Differently from what we have reported for Empa, Lina treatment was found to reduce glucose-driven respiration in AS tubular cells, but not in AS podocytes. Renal expression patterns and spatial distribution of several metabolites differ in AS compared to WT mice. While Lina and Empa treatments similarly partially slow the progression of kidney disease in AS, the metabolic mechanisms conferring the protective effect may be different.

Linagliptin ameliorates tacrolimus-induced renal injury: role of Nrf2/HO-1 and HIF-1α/CTGF/PAI-1

BackgroundTacrolimus (TAC) is a frequently used immunosuppressive medication in organ transplantation. However, its nephrotoxic impact limits its long-term usage. This study aims to investigate the effect of linagliptin (Lina) on TAC-induced renal injury and its underlying mechanisms.Methods and resultsThirty-two Sprague Dawley rats were treated with TAC (1.5 mg/kg/day, subcutaneously) and/or Lina (5 mg/kg/day, orally) for 4 weeks. Histological examination was conducted, and serum and urinary biomarkers were measured to assess kidney function and integrity. Furthermore, ELISA, Western blot analysis and immunohistochemical assay were employed to determine signaling molecules of oxidative stress, profibrogenic, hypoxic, and apoptotic proteins. Tacrolimus caused renal dysfunction and histological deterioration evidenced by increased serum creatinine, blood urea nitrogen (BUN), urinary cystatin C, and decreased serum albumin as well as elevated tubular injury and interstitial fibrosis scores. Additionally, TAC significantly increased the expression of collagen type-1, alpha-smooth muscle actin (α-SMA), plasminogen activator inhibitor-1 (PAI-1), and transforming growth factor-beta1 (TGF-β1) renal content. Moreover, TAC decreased the expression of nuclear factor erythroid-2-related factor2 (Nrf2), heme oxygenase 1 (HO-1), and mitochondrial superoxide dismutase (SOD2). In addition, TAC increased protein expression of hypoxia-inducible factor1-alpha (HIF-1α), connective tissue growth factor (CTGF), inducible nitric oxide synthase (iNOS), 8-hydroxy-2-deoxyguanosine (8-OHdG), as well as nitric oxide (NO), 4-hydroxynonenal, caspase-3 and Bax renal contents. Furthermore, TAC decreased Bcl-2 renal contents. The Lina administration markedly attenuated these alterations.ConclusionLina ameliorated TAC-induced kidney injury through modulation of oxidative stress, hypoxia, and apoptosis related proteins.

Linagliptin decreased the tumor progression on glioblastoma model

PurposeDipeptidyl peptidase-4 (DPP-4) inhibitors are oral hypoglycemic drugs and are used for type II diabetes. Previous studies showed that DPP-4 expression is observed in several tumor types and DPP-4 inhibitors suppress the tumor progression on murine tumor models. In this study, we evaluated the role of DPP-4 and the antitumor effect of a DPP-4 inhibitor, linagliptin, on glioblastoma (GBM). MethodsWe analyzed DPP-4 expression in glioma patients by the public database. We also analyzed DPP-4 expression in GBM cells and the murine GBM model. Then, we evaluated the cell viability, cell proliferation, cell migration, and expression of some proteins on GBM cells with linagliptin. Furthermore, we evaluated the antitumor effect of linagliptin in the murine GBM model. ResultsThe upregulation of DPP-4 expression were observed in human GBM tissue and murine GBM model. In addition, DPP-4 expression levels were found to positively correlate with the grade of glioma patients. Linagliptin suppressed cell viability, cell proliferation, and cell migration in GBM cells. Linagliptin changed the expression of phosphorylated NF-kB, cell cycle, and cell adhesion-related proteins. Furthermore, oral administration of linagliptin decreases the tumor progression in the murine GBM model. ConclusionInhibition of DPP-4 by linagliptin showed the antitumor effect on GBM cells and the murine GBM model. The antitumor effects of linagliptin is suggested to be based on the changes in the expression of several proteins related to cell cycle and cell adhesion via the regulation of phosphorylated NF-kB. This study suggested that DPP-4 inhibitors could be a new therapeutic strategy for GBM.

DPP-4 inhibition by linagliptin ameliorates age-related mild cognitive impairment by regulating microglia polarization in mice

Extensive preclinical evidence demonstrates a causative link between insulin signaling dysfunction and the pathogenesis of Alzheimer's disease (AD), and diabetic drugs may represent a promising approach to fighting AD. However, it remains to be determined which antidiabetic drugs are more effective in preventing cognitive impairment. Thus, the present study investigated the effect of dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin on cognitive impairment in middle-aged mice by comparing it with the effect of metformin. We found that DPP-4 activity increased in the hippocampus of middle-aged mice, and DPP-4 was mainly expressed by microglia rather than astrocytes and oligodendrocytes. DPP-4 directly regulated M1/M2 microglia polarization following LPS or IL-4 stimulation, while DPP-4 inhibitor, linagliptin, suppressed M1-polarized activation and induced M2-polarized activation. Both linagliptin and metformin enhanced cognitive ability, increased hippocampal synaptic plasticity and neurogenesis, and decreased age-related oxidative stress and inflammation by regulating microglia polarization in the hippocampus of middle-aged mice. The combination of linagliptin and metformin showed a maximum protective effect compared to the individual drugs alone. Loss of macrophage inflammatory protein-1α (MIP-1α), a DPP-4 substrate, abrogated the cognitive protection and anti-inflammation effects of linagliptin. Therefore, the current investigation exhibits a potential utility for DPP-4 inhibition in attenuating microglia-mediated inflammation and preventing mild cognitive impairment (MCI) in middle-aged mice, and the effect was partly mediated by MIP-1α.

Neuroprotective Cognitive Effects of Nose-to-brain Delivered Linagliptin Loaded Polymeric Nanosuspension in Animal Model

Objective: Insulin resistance is a common link between diabetes mellitus (DM) and dementia. The current work emphasizes the effect of linagliptin on dementia with its neuroprotective effects, which occur directly at the neuronal level, as GLP-1 receptors are exclusively expressed in neurons. Methods: The objective of the study was to formulate linagliptin-loaded polymeric nanosuspension (LS) by nanoprecipitation method and further study their pharmaceutical, pharmacodynamics, scintigraphic, and neuroprotective effects following nose-to-brain delivery in the rat model of dementia. Results: Developed LS were spherical with z-average (250.7 nm), charge (-16.3 mV), % entrapment efficiency (95.8 ± 1.45%), and % drug loading (35.78 ± 0.19%). In vitro dissolution rate (88.56 ± 1.24%) and ex vivo permeation (81.59 ± 1.06%) of LS showed a better-sustained release profile than pure linagliptin. The spatial learning/memory in the treated group of Sprague-Dawley rats were significantly improved compared with those in the control group. Conclusion: Histopathological study of LS produced no toxicity or structural damage to the nasal mucosa. Optimum pharmaceutical characterization results improved pharmacodynamic studies/ histopathological data, and gamma-scintigraphic images proved that polymeric nanosuspensions stand out as wellappreciated approaches to deliver linagliptin more efficiently to the brain via intranasal route, thereby enhancing the neuroprotective efficacy in dementia.

A Quantitative Systems Pharmacology Model of the Incretin Hormones GIP and GLP1, Glucagon, Glucose, Insulin, and the Small Molecule DPP-4 Inhibitor, Linagliptin

In the current study, we established a comprehensive quantitative systems pharmacology (QSP) model using linagliptin as the model drug, where drug disposition, drug intervention on dipeptidyl peptidase-4 (DPP-4), glucose-dependent insulinotropic peptide (GIP), Glucagon-like peptide-1 (GLP-1), glucagon, glucose, and insulin are integrated together with the cross talk and feedback loops incorporated among the whole glycemic control system. In the final linagliptin QSP model, the complicated disposition of linagliptin was characterized by a 2-compartment pharmacokinetic (PK) model with an enterohepatic cycling (EHC) component as well as target-mediated drug disposition (TMDD) processes occurring in both tissues and plasma, and the inhibitory effect of linagliptin on DPP-4 was determined by the linagliptin-DPP-4 complex in the central compartment based on target occupancy principle. The integrated GIP-GLP1-glucagon-glucose-insulin system contains five indirect response models as the “skeleton” structure with 12 feedback loops incorporated within the glucose control system. Our model adequately characterized the substantial nonlinear PK of linagliptin, time course of DPP-4 inhibition, as well as the kinetics of GIP, GLP-1, glucagon, and glucose simultaneously in humans. Our model provided valuable insights on linagliptin pharmacokinetics/pharmacodynamics and complicated glucose homeostasis. Since the glucose regulation modeling framework within the QSP model is “drug-independent”, our model can be easily adopted by others to evaluate the effect of other DPP-4 inhibitors on the glucose control system. In addition, our QSP model, which contains more components than other reported glucose regulation models, can potentially be used to evaluate the effect of combination antidiabetic therapy targeting different components of glucose control system.

Pylorus ligation-induced hyperacidity: synergistic prophylactic effects of linagliptin and L-arginine via up-regulation of EP4 receptor subtype and improvement of vascular endothelial damage.

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 6mg/kg), L-arginine (LA; 150 and 300mg/kg) and their combination (LN 3 + LA 150mg/kg), respectively for 7days. 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.

DPP-4 Inhibitors Attenuate Fibrosis After Glaucoma Filtering Surgery by Suppressing the TGF-β/Smad Signaling Pathway.

This study investigated the effect of dipeptidyl peptidase-4 inhibitors (DPP-4is) on fibrosis after glaucoma filtering surgery with clinical data and an in vitro model that used transforming growth factor-β (TGF-β) to induce human Tenon's fibroblast (HTF) fibrosis. The medical records of 41 eyes of 35 patients with diabetes with neovascular glaucoma (NVG) who received initial trabeculectomy were retrospectively reviewed. The surgical success rate was compared between cases that received (n = 23) and did not receive (n = 18) DPP-4i treatment for diabetes. The antifibrotic effects of linagliptin (a DPP-4i) were evaluated with quantitative real-time PCR for fibrosis markers (α-smooth muscle actin, collagen Iα, and fibronectin), a scratch assay, and a collagen gel contraction assay of primary cultured HTFs treated with TGF-β1 and linagliptin. Western blotting analysis was performed to evaluate the levels of phosphorylated Smad2 and Smad3 in the presence of linagliptin. The Kaplan-Meier curve for bleb survival was higher in patients who received DPP-4is (P = 0.017, log-rank test). The in vitro experiments demonstrated that treatment with linagliptin attenuated the elevated levels of fibrosis markers induced by TGF-β1 in HTFs. Linagliptin treatment also prevented the migration and gel contraction of HTFs. Linagliptin inhibited the phosphorylation of Smad2 and Smad3, which is the canonical pathway of TGF-β signaling. The current study indicates the potential effect of DPP-4is for maintaining bleb function after glaucoma filtering surgery in patients with diabetes with NVG. Our results demonstrate that linagliptin attenuates fibrotic change in HTFs by inhibiting TGF-β/Smad signaling.

The effect of linagliptin on microalbuminuria in patients with diabetic nephropathy: a randomized, double blinded clinical trial

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.

Linagliptin counteracts rotenone’s toxicity in non-diabetic rat model of Parkinson’s disease: Insights into the neuroprotective roles of DJ-1, SIRT-1/Nrf-2 and implications of HIF1-α

While all current therapies’ main focus is enhancing dopaminergic effects and remission of symptoms, delaying Parkinson’s disease (PD) progression remains a challenging mission. Linagliptin, a Dipeptidyl Peptidase-4 (DPP-4) Inhibitor, exhibited neuroprotection in various neurodegenerative diseases. This study aims to evaluate the neuroprotective effects of Linagliptin in a rotenone-induced rat model of PD and investigate the possible underlying mechanisms of Linagliptin’s actions. The effects of two doses of Linagliptin (5 and 10 mg/kg) on spontaneous locomotion, catalepsy, coordination and balance, and histology were assessed. Then, after Linagliptin showed promising results, it was further tested for its potential anti-inflammatory, antiapoptotic effects, and different pathways for oxidative stress. Linagliptin prevented rotenone-induced motor deficits and histological damage. Besides, it significantly inhibited the rotenone-induced increase in pro-inflammatory cytokines: Tumor Necrosis Factor-α (TNF-α) and Interleukin-6 (IL-6) and decrease in caspase 3 levels. These effects were associated with induction in the levels of Protein deglycase also known as DJ-1, Hypoxia-inducible factor 1-alpha (HIF-1α), potentiation in the Sirtuin 1 (SIRT-1)/Nuclear factor erythroid-2-related factor 2 (Nrf-2)/Heme oxygenase-1 (HO-1) pathway, and an increase in the antioxidant activity of catalase which provided neuroprotection to the neurons from rotenone-induced PD. Collectively, these results suggest that Linagliptin might be a suitable candidate for the management of PD.

Effects of Linagliptin and Pioglitazone on Fracture Healing in an Experimental Type 2 Diabetes Rat Model.

Our study aimed to examine the effects of Linagliptin, Pioglitazone, and their combination on fracture healing in a diabetes rat femur fracture model. Type 2 diabetes mellitus (T2DM) induced rats were randomly divided into four groups: non-treated diabetes group (TD), Pioglitazone group (P), Linagliptin group (L), and Pioglitazone and Linagliptin group (PL). Daily oral dosage of pioglitazone (10 mg/kg/day), linagliptin (10 mg/kg/day), and their combination were administered. Femur fractures were stabilized intramedullary. At weeks 2 and 6, rats were sacrificed for evaluation radiologically, biomechanically, histopathologically, histomorphometrically, and immunohistochemically. Flexural strength of the L and PL groups were significantly higher compared to the P group. The highest healing score was in the L group and lowest in the P group, while the highest inflammation score was in the P group and lowest in the L group. A cluster of differentiation (CD) CD 34 reactivity was highest in the L group and lowest in the PL group. Linagliptin treatment significantly increased histological healing scores, callus volume, biomechanical strength, and vascularity, however, minimized the inflammatory process, which was increased by pioglitazone. The combination of linagliptin and pioglitazone restored BMD and increased biomechanical strength. Linagliptin monotherapy is rarely indicated; hence, T2DM patients with a high risk of bone fractures can be considered for combined therapy of pioglitazone and linagliptin.

Linagliptin and Vitamin D3 Synergistically Rescue Testicular Steroidogenesis and Spermatogenesis in Cisplatin-Exposed Rats: The Crosstalk of Endoplasmic Reticulum Stress with NF-κB/iNOS Activation.

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.

Long-term safety and effectiveness of linagliptin by baseline body mass index in Japanese patients with type 2 diabetes: a 3-year post-marketing surveillance study

ABSTRACT Background A recent 3-year post-marketing surveillance (PMS) study reaffirmed the safety and effectiveness of linagliptin in linagliptin-naïve Japanese patients with type 2 diabetes (T2D). We present further analyses from this study by body mass index (BMI). Research design and methods Safety and effectiveness were assessed across BMI subgroups (<25, 25 to <30, and ≥30 kg/m2). Results Data were available for 876, 566, and 201 patients in the BMI subgroups, respectively. Incidence of adverse drug reactions [ADR] with linagliptin was 11.42%, 11.31%, 10.45%, respectively. The most common ADR of special interest was hepatic disorders (n [%]: 6 [0.68], 7 [1.24], and 3 [1.49], respectively). Additional use of glucose-lowering drugs (GLDs) increased with BMI (15.0%, 19.1%, 24.4% of patients; P < 0.001). In the overall population, HbA1c change (adjusted mean %±SE) until week 156 was –0.71±0.04, –0.68±0.04 and –0.74±0.09. In patients receiving linagliptin with no additional GLDs, HbA1c changes were –0.58%±0.04, –0.62%±0.04, and –0.77%±0.11. Conclusions In this study of linagliptin in Japanese patients with T2D, across BMI subgroups no new safety concerns were observed. The proportion of patients with additional GLD use increased with baseline BMI. Decreases in HbA1c were observed in all subgroups, including in patients with no additional GLD use. ClinicalTrials.gov NCT01650259

The dipeptidyl peptidase-4 inhibitor linagliptin ameliorates LPS-induced acute lung injury by maintenance of pulmonary microvascular barrier via activating the Epac1/AKT pathway

Pulmonary microvascular endothelial cells (PMVECs) barrier dysfunction is a main pathophysiological feature of sepsis-related acute lung injury (ALI). This study aimed to investigate whether the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin could protect against LPS-induced PMVECs barrier disruption and its underlying molecular mechanisms. A classical ALI animal model and LPS-treated PMVECs were applied and all were treated with or without linagliptin. Cellular experiments demonstrated that linagliptin could mitigate LPS-induced PMVECs hyperpermeability and intercellular junction (VE-cadherin, β-catenin, and ZO-1) disruption in a dose-dependent manner. Correspondingly, it was observed that linagliptin pretreatment distinctly relieved LPS-induced lung injury, oxidative stress, and pulmonary edema in vivo. Furthermore, we found that the inhibition of oxidative stress by linagliptin may be achieved by reversing impaired mitochondrial function. Mechanistically, linagliptin administration promoted the activation of the Epac1 pathway and its downstream AKT pathway, while inhibition of the Epac1/Akt signaling pathway significantly alleviated the above-mentioned protective effect of linagliptin on the PMVECs barrier. Taken together, these data suggest that linagliptin can effectively reserve PMVECs barrier dysfunction and inhibit oxidative stress to protect against ALI via activating the Epac1/AKT signaling pathway, and thus may become a potential clinical therapeutic strategy for ALI.

Linagliptin in Combination With Metformin Ameliorates Diabetic Osteoporosis Through ModulatingBMP-2 and Sclerostin in the High-Fat Diet Fed C57BL/6 Mice.

BackgroundDiabetic osteoporosis is a poorly managed serious skeletal complication, characterized by high fracture risk, increased bone resorption, reduced bone formation, and disrupted bone architecture. There is a need to investigate drugs that can improve bone health along with managing glycemic control. DPP-4 inhibitors and metformin have proven benefits in improving bone health. Here, we investigated the effects of linagliptin, a DPP inhibitor, and metformin alone and in combination to treat diabetic osteoporosis in high-fat-fed mice.MethodsC57BL/6 mice were kept on the high-fat diet (HFD) for 22 weeks to induce diabetic osteoporosis. Linagliptin (10mg/Kg), metformin (150mg/Kg), and their combination were orally administered to the diabetic mice from the 18th-22nd week. Femur and tibial bone microarchitecture together with bone mineral density (BMD) were evaluated using µCT and histopathological changes were assessed. Further, bone turnover biomarkers namely bone morphogenetic protein-2 (BMP-2), sclerostin, tartrate-resistant acid phosphatase (TRAP), osteocalcin, alkaline phosphatase (ALP), calcium, and pro-inflammatory cytokines were assessed. Additionally, metabolic parameters including body weight, fasting blood glucose (FBG), glucose & insulin tolerance, lipids profile, and leptin were measured.ResultsHFD feeding resulted in impaired bone microarchitecture, reduced BMD, distorted bone histology, and altered bone turnover biomarkers as indicated by the significant reduction in bone ALP, BMP-2, osteocalcin, and an increase in sclerostin, TRAP, and serum calcium. Interestingly, treatment with linagliptin and its combination with metformin significantly reverted the impaired bone architecture, BMD, and positively modulated bone turnover biomarkers, while metformin alone did not exhibit any significant improvement. Further, HFD induced diabetes and metabolic abnormalities (including an increase in body weight, FBG, impaired glucose and insulin tolerance, leptin, triglycerides, cholesterol), and pro-inflammatory cytokines (TNF-alpha and IL-1β) were successfully reversed by treatment with linagliptin, metformin, and their combination.ConclusionLinagliptin and its combination with metformin successfully ameliorated diabetic osteoporosis in HFD-fed mice possibly through modulation of BMP-2 and sclerostin. The study provides the first evidence for the possible use of linagliptin and metformin combination for managing diabetic osteoporosis.

Repositioning Linagliptin for the Mitigation of Cadmium-Induced Testicular Dysfunction in Rats: Targeting HMGB1/TLR4/NLRP3 Axis and Autophagy.

Cadmium, a ubiquitous environmental toxicant, disrupts testicular function and fertility. The dipeptidyl peptidase-4 inhibitor linagliptin has shown pronounced anti-inflammatory and anti-apoptotic features; however, its effects against cadmium-evoked testicular impairment have not been examined. Herein, the present study investigated targeting inflammation, apoptosis, and autophagy by linagliptin for potential modulation of cadmium-induced testicular dysfunction in rats. After 60 days of cadmium chloride administration (5 mg/kg/day, by gavage), testes, epididymis, and blood were collected for analysis. The present findings revealed that linagliptin improved the histopathological lesions, including spermatogenesis impairment and germ cell loss. Moreover, it improved sperm count/motility and serum testosterone. The favorable effects of linagliptin were mediated by curbing testicular inflammation seen by dampening of HMGB1/TLR4 pathway and associated lowering of nuclear NF-κBp65. In tandem, linagliptin suppressed the activation of NLRP3 inflammasome/caspase 1 axis with consequent lowering of the pro-inflammatory IL-1β and IL-18. Jointly, linagliptin attenuated testicular apoptotic responses seen by Bax downregulation, Bcl-2 upregulation, and suppressed caspase 3 activity. With respect to autophagy, linagliptin enhanced the testicular autophagy flux seen by lowered accumulation of p62 SQSTM1 alongside upregulation of Beclin 1. The observed autophagy stimulation was associated with elevated AMPK (Ser487) phosphorylation and lowered mTOR (Ser2448) phosphorylation, indicating AMPK/mTOR pathway activation. In conclusion, inhibition of testicular HMGB1/TLR4/NLRP3 pro-inflammatory axis and apoptosis alongside stimulation of autophagy were implicated in the favorable actions of linagliptin against cadmium-triggered testicular impairment.

DPP-4 inhibitor linagliptin ameliorates imiquimod-induced psoriasis-like skin alterations in type 2 diabetic mice by inhibiting the MAPK/NF-κB inflammatory pathway.

Studies have shown that the DPP-4 inhibitor was effective in improving skin damage in patients with psoriasis, but the exact mechanism was not known. To investigate the therapeutic effects of linagliptin in mice with type 2 diabetes mellitus (T2DM) with psoriasis and its possible therapeutic mechanisms. A total of 32 db/db mice and 16 db/m mice were randomly divided into six groups: normal group, psoriasis group, diabetes group, diabetes combined with psoriasis group, linagliptin-treated diabetes group, and linagliptin-treated diabetes combined with psoriasis group. The levels of serum fasting blood glucose, total cholesterol(TC), triglyceride (TG), high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were measured; the levels of serum FINS were determined by enzyme-linked immunoassay and the insulin resistance index was calculated. Basic parameters of diabetes, Psoriasis Area and Severity Index, histopathology of skin, the expression of interleukin (IL)-17A, IL-23, IL-22, and tumor necrosis factor(TNF)-α, and expression levels of measuring p-ERK, p-MAPK and p-nuclear factor kappa B (NF-κB) in skin tissues were measured. After treatment with linagliptin, insulin resistance, and TC and TG levels were reduced in mice with T2DM and psoriasis (p < .05). Moreover, the degree of epidermal tissue thickening, number of keratinized layers, and inflammatory cell infiltration were also reduced (p < .05), as well as the expression levels of inflammatory factors: TNF-α, IL-1β, IL-17A, IL-23, and p-P38/P38, p-ERK/ERK, p-P65/P65 proteins (p < .05). Linagliptin significantly reduced the extent of skin lesions and skin inflammation. The underlying mechanism of this compound may be related to the inhibition of MAPK/NF-κB inflammatory pathways and the consequential improvement of insulin resistance.Significance Statement: In this study, we evaluated the therapeutic effect of the DPP-4 inhibitor linagliptin using a murine model of type 2 diabetes combined with psoriasis, and its potential mechanisms of action were further explored. The results of this study will help to uncover the pathogenesis of type 2 diabetes and psoriasis and, more importantly, provide a theoretical basis for the search for safe and effective drugs in the treatment of this specific patient population.