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1.
Sci Rep ; 14(1): 7749, 2024 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-38565703

RESUMO

DPP4 inhibitors can control glucose homeostasis by increasing the level of GLP-1 incretins hormone due to dipeptidase mimicking. Despite the potent effects of DPP4 inhibitors, these compounds cause unwanted toxicity attributable to their effect on other enzymes. As a result, it seems essential to find novel and DPP4 selective compounds. In this study, we introduce a potent and selective DPP4 inhibitor via structure-based virtual screening, molecular docking, molecular dynamics simulation, MM/PBSA calculations, DFT analysis, and ADMET profile. The screened compounds based on similarity with FDA-approved DPP4 inhibitors were docked towards the DPP4 enzyme. The compound with the highest docking score, ZINC000003015356, was selected. For further considerations, molecular docking studies were performed on selected ligands and FDA-approved drugs for DPP8 and DPP9 enzymes. Molecular dynamics simulation was run during 200 ns and the analysis of RMSD, RMSF, Rg, PCA, and hydrogen bonding were performed. The MD outputs showed stability of the ligand-protein complex compared to available drugs in the market. The total free binding energy obtained for the proposed DPP4 inhibitor was more negative than its co-crystal ligand (N7F). ZINC000003015356 confirmed the role of the five Lipinski rule and also, have low toxicity parameter according to properties. Finally, DFT calculations indicated that this compound is sufficiently soft.


Assuntos
Inibidores da Dipeptidil Peptidase IV , Simulação de Dinâmica Molecular , Inibidores da Dipeptidil Peptidase IV/farmacologia , Simulação de Acoplamento Molecular , Sítios de Ligação , Dipeptidil Peptidase 4 , Teoria da Densidade Funcional , Ligantes
2.
Acta Derm Venereol ; 104: adv26663, 2024 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-38576104

RESUMO

Drug-associated bullous pemphigoid has been shown to follow long-term gliptin (dipeptidyl-peptidase 4 inhibitors) intake. This study aimed at identifying risk factors for gliptin-associated bullous pemphigoid among patients with type 2 diabetes. A retrospective study was conducted in a tertiary centre among diabetic patients exposed to gliptins between the years 2008-2021. Data including demographics, comorbidities, medications, and laboratory results were collected using the MDClone platform. Seventy-six patients with type 2 diabetes treated with dipeptidyl-peptidase 4 inhibitors who subsequently developed bullous pemphigoid were compared with a cohort of 8,060 diabetic patients exposed to dipeptidyl-peptidase 4 inhibitors who did not develop bullous pemphigoid. Based on a multivariable analysis adjusted for age and other covariates, Alzheimer's disease and other dementias were significantly more prevalent in patients with bullous pemphigoid (p = 0.0013). Concomitant use of either thiazide or loop diuretics and gliptin therapy was associated with drug-associated bullous pemphigoid (p < 0.0001 for both). While compared with sitagliptin, exposure to linagliptin and vildagliptin were associated with bullous pemphigoid with an odds ratio of 5.68 and 6.61 (p < 0.0001 for both), respectively. These results suggest gliptins should be prescribed with caution to patients with type 2 diabetes with coexisting Alzheimer's and other dementias, or patients receiving long-term use of thiazides and loop diuretics. The use of sitagliptin over linagliptin and vildagliptin should be preferred in these patients.


Assuntos
Demência , Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Penfigoide Bolhoso , Humanos , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Vildagliptina/efeitos adversos , Penfigoide Bolhoso/induzido quimicamente , Penfigoide Bolhoso/diagnóstico , Penfigoide Bolhoso/epidemiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Linagliptina/efeitos adversos , Estudos Retrospectivos , Inibidores de Simportadores de Cloreto de Sódio e Potássio/uso terapêutico , Fatores de Risco , Fosfato de Sitagliptina/efeitos adversos , Demência/induzido quimicamente , Demência/tratamento farmacológico
4.
Expert Opin Pharmacother ; 25(2): 189-202, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38488824

RESUMO

INTRODUCTION: Despite the notable success of tyrosine kinase inhibitors (TKIs) in treating chronic myeloid leukemia (CML), a subset of patients experiences resistance, or relapse after discontinuation. This challenge is attributed to the Ph+ leukemia stem cells (LSCs) pool not fully involved in the inhibition process due to the current therapeutic approach. AREAS COVERED: Current pharmacological advancements in CML therapy focus on targeting LSCs, intervening in self-renewal pathways, and exploiting biological vulnerabilities. Beyond BCR::ABL1 inhibition, innovative approaches include immunotherapy, epigenetic modulation, and interference with microenvironmental mechanisms. EXPERT OPINION: Diverse therapeutic strategies beyond TKIs are under investigation. Immunotherapy with interferon-α (IFN-α) shows some biological effects, although further research is needed for optimal application in enhancing discontinuation rates. Other compounds were able to mobilize Ph+ LSCs from the bone marrow niche (DPP-IV inhibitor vildagliptin or PAI-1 inhibitor TM5614) increasing the LSC clearance or target the CD26, a Ph+ specific surface receptor. It is noteworthy that the majority of these alternative strategies still incorporate TKIs. In conclusion, novel therapeutic perspectives are emerging for CML, holding the potential for substantial advancements in disease treatment.


Assuntos
Inibidores da Dipeptidil Peptidase IV , Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Vildagliptina , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Células-Tronco Neoplásicas/metabolismo , Proteínas de Fusão bcr-abl
5.
Food Funct ; 15(7): 3778-3790, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38511218

RESUMO

Brewer's spent yeast (BSY) hydrolysates are a source of antidiabetic peptides. Nevertheless, the impact of in vitro gastrointestinal digestion of BSY derived peptides on diabetes has not been assessed. In this study, two BSY hydrolysates were obtained (H1 and H2) using ß-glucanase and alkaline protease, with either 1 h or 2 h hydrolysis time for H1 and H2, respectively. These hydrolysates were then subjected to simulated gastrointestinal digestion (SGID), obtaining dialysates D1 and D2, respectively. BSY hydrolysates inhibited the activity of α-glucosidase and dipeptidyl peptidase IV (DPP-IV) enzymes. Moreover, although D2 was inactive against these enzymes, D1 IC50 value was lower than those found for the hydrolysates. Interestingly, after electrophoretic separation, D1 mannose-linked peptides showed the highest α-glucosidase inhibitory activity, while non-glycosylated peptides had the highest DPP-IV inhibitory activity. Kinetic analyses showed a non-competitive mechanism in both cases. After peptide identification, GILFVGSGVSGGEEGAR and IINEPTAAAIAYGLDK showed the highest in silico anti-diabetic activities among mannose-linked and non-glycosylated peptides, respectively (AntiDMPpred score: 0.70 and 0.77). Molecular docking also indicated that these peptides act as non-competitive inhibitors. Finally, an ex vivo model of mouse jejunum organoids was used to study the effect of D1 on the expression of intestinal epithelial genes related to diabetes. The reduction of the expression of genes that codify lactase, sucrase-isomaltase and glucose transporter 2 was observed, as well as an increase in the expression of Gip (glucose-dependent insulinotropic peptide) and Glp1 (glucagon-like peptide 1). This is the first report to evaluate the anti-diabetic effect of BSY peptides in mouse jejunum organoids.


Assuntos
Diabetes Mellitus , Inibidores da Dipeptidil Peptidase IV , Animais , Camundongos , Saccharomyces cerevisiae/metabolismo , Manose , Simulação de Acoplamento Molecular , alfa-Glucosidases , Inibidores da Dipeptidil Peptidase IV/química , Peptídeos/farmacologia , Peptídeos/química , Digestão , Dipeptidil Peptidase 4/genética , Dipeptidil Peptidase 4/química , Hidrolisados de Proteína/química
6.
Food Funct ; 15(7): 3848-3863, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38512162

RESUMO

To better understand the hypoglycemic potential of wheat gluten (WG), we screened dipeptidyl peptidase IV (DPP-4) inhibitory active peptides from WG hydrolysates. WG hydrolysates prepared by ginger protease were found to have the highest DPP-4 inhibitory activity among the five enzymatic hydrolysates, from which a 1-3 kDa fraction was isolated by ultrafiltration. Further characterization of the fraction with nano-HPLC-MS/MS revealed 1133 peptides. Among them, peptides with P'2 (the second position of the N-terminal) and P2 (the second position of the C-terminal) as proline residues (Pro) accounted for 12.44% and 43.69%, respectively. The peptides including Pro-Pro-Phe-Ser (PPFS), Ala-Pro-Phe-Gly-Leu (APFGL), and Pro-Pro-Phe-Trp (PPFW) exhibited the most potent DPP-4 inhibitory activity with IC50 values of 56.63, 79.45, and 199.82 µM, respectively. The high inhibitory activity of PPFS, APFGL, and PPFW could be mainly attributed to their interaction with the S2 pocket (Glu205 and Glu206) and the catalytic triad (Ser630 and His740) of DPP-4, which adopted competitive, mixed, and mixed inhibitory modes, respectively. After comparative analysis of PPFS, PPFW, and PPF, Ser was found to be more conducive to enhancing the DPP-4 inhibitory activity. Interestingly, peptides with P2 as Pro also exhibited good DPP-4 inhibitory activity. Meanwhile, DPP-4 inhibitory peptides from WG showed excellent stability, suggesting a potential application in type 2 diabetes (T2DM) therapy or in the food industry as functional components.


Assuntos
Cisteína Proteases , Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Proteínas de Plantas , Triticum/química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Espectrometria de Massas em Tandem , Hidrólise , Inibidores da Dipeptidil Peptidase IV/química , Peptídeos/química , Glutens , Digestão , Dipeptidil Peptidase 4/química
7.
Medicina (Kaunas) ; 60(3)2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-38541119

RESUMO

This review summarizes the complex relationship between medications used to treat type 2 diabetes and bone health. T2DM patients face an increased fracture risk despite higher bone mineral density; thus, we analyzed the impact of key drug classes, including Metformin, Sulphonylureas, SGLT-2 inhibitors, DPP-4 inhibitors, GLP-1 agonists, and Thiazolidinediones. Metformin, despite promising preclinical results, lacks a clear consensus on its role in reducing fracture risk. Sulphonylureas present conflicting data, with potential neutral effects on bone. SGLT-2 inhibitors seem to have a transient impact on serum calcium and phosphorus, but evidence on their fracture association is inconclusive. DPP-4 inhibitors emerge as promising contributors to bone health, and GLP-1 agonists exhibit positive effects on bone metabolism, reducing fracture risk. Thiazolidinediones, however, demonstrate adverse impacts on bone, inducing loss through mesenchymal stem cell effects. Insulin presents a complex relationship with bone health. While it has an anabolic effect on bone mineral density, its role in fracture risk remains inconsistent. In conclusion, a comprehensive understanding of diabetes medications' impact on bone health is crucial. Further research is needed to formulate clear guidelines for managing bone health in diabetic patients, considering individual profiles, glycemic control, and potential medication-related effects on bone.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Fraturas Ósseas , Metformina , Inibidores do Transportador 2 de Sódio-Glicose , Tiazolidinedionas , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Densidade Óssea , Hipoglicemiantes/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Fraturas Ósseas/etiologia , Fraturas Ósseas/prevenção & controle , Metformina/uso terapêutico , Compostos de Sulfonilureia/efeitos adversos , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Tiazolidinedionas/uso terapêutico
8.
Clin Drug Investig ; 44(4): 271-284, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38507188

RESUMO

BACKGROUND: The efficacy of once-weekly (OW) glucagon-like peptide-1 receptor agonists (GLP-1RAs) has been established in several trials in people with type 2 diabetes mellitus (T2DM); however, real-world evidence on their effectiveness is limited. This study evaluated the effectiveness of OW GLP-1RA regarding glycemic and weight outcomes, and relative to DPP-4i in a comparator analysis. METHODS: This observational cohort study evaluated glycated hemoglobin (HbA1c) and weight outcomes in people with T2DM with two or more prescription claims for the same OW GLP-1RA using a pre-post study design (including for a semaglutide OW T2DM subgroup, hereafter referred to as semaglutide). Comparator analysis for the same outcome was performed for OW GLP-1RAs versus DPP-4i and semaglutide subgroup versus DPP-4i. A linked patient population from the IQVIA PharMetrics® Plus database and the Ambulatory Electronic Medical Records (AEMR) database was analyzed using data from January 2017 to April 2022. HbA1c and weight were assessed at baseline and at the end of the 12-month post-index period. Inverse probability of treatment weighting (IPTW) was used to adjust for imbalances in baseline patient characteristics in the comparator analysis. RESULTS: In the pre-post analysis, a greater numerical reduction in HbA1c and weight was observed for the semaglutide subgroup (N = 354) relative to the OW GLP-1RA cohort (N = 921). In the semaglutide subgroup, 52.5% and 34.2% of patients achieved HbA1c of < 7.0% and ≥ 5% weight loss, respectively. For the comparator analysis, the OW GLP-1RAs (N = 651) were significantly more effective (p < 0.001) in reducing HbA1c (- 1.5% vs. -  1.0%) and weight (- 3.2 kg vs. -  1.0 kg) than the DPP-4is (N = 431). Similarly, the semaglutide cohort (N = 251) also displayed more effectiveness (p < 0.001) in reducing HbA1c (- 1.7% vs. -  0.9%) and weight (- 4.1 kg vs. -  1.3 kg) than the respective DPP-4i cohort (N = 417). Patients initiating OW GLP-1RAs, including the semaglutide cohort, were at least twice as likely to achieve HbA1c and weight outcomes as well as composite outcomes compared with those initiating DPP-4is. CONCLUSION: The study reinforces that OW GLP-1RAs are more effective in glycemic control and weight reduction compared with DPP-4is in people with T2DM in the real-world setting. These findings align with the recommendation in the current guidelines for utilizing glucose-lowering treatment regimens that support weight-management goals in people with T2DM.


In type 2 diabetes mellitus (T2DM), glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used for managing blood sugar levels and major adverse cardiovascular event risk reduction. In clinical trials, once-weekly (OW) GLP-1RAs showed better control of blood sugar levels and body weight than those administered daily, as well as another class of daily T2DM medications called dipeptidyl peptidase-4 inhibitors (DPP-4is). However, there is limited evidence of OW GLP-1RAs-based routine care to confirm these findings. This study gathered prescription and outcomes data for people with T2DM (January 2017­April 2022) from two linked US databases. Body weight measurements and glycated hemoglobin (HbA1c) test results (measuring average blood sugar levels) were used to evaluate the effectiveness of OW GLP-1RAs (exenatide, dulaglutide, and semaglutide) via a pre-post analysis, and compare OW GLP-1RAs with DPP-4is. We found that treatment with semaglutide lowered body weight and blood sugar levels to a greater extent than OW GLP-1RAs in the pre-post analysis. In the comparator analysis, people receiving OW GLP-1RAs, including semaglutide, were at least twice as likely to achieve reduced HbA1c levels and body weight compared with those receiving DPP-4is. People receiving OW GLP-1RAs were three times more likely than those on DPP-4is to achieve the recommended target of HbA1c < 7.0% and weight loss ≥ 5%, while treatment with semaglutide increased this likelihood by > 4.6 times. This study shows clear benefits of OW GLP-1RAs, building on current evidence for integration of this treatment into overall management of T2DM.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Humanos , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hipoglicemiantes/uso terapêutico , Controle Glicêmico , Redução de Peso , Dipeptidil Peptidases e Tripeptidil Peptidases , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas
9.
Physiol Rep ; 12(5): e15976, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38472161

RESUMO

Small animal models have shown improved cardiac function with DPP-4 inhibition, but many human studies have shown worse outcomes or no benefit. We seek to bridge the gap by studying the DPP-4 inhibitor sitagliptin in a swine model of chronic myocardial ischemia using proteomic analysis. Thirteen Yorkshire swine underwent the placement of an ameroid constrictor on the left coronary circumflex artery to model chronic myocardial ischemia. Two weeks post-op, swine received either sitagliptin 100 mg daily (SIT, n = 5) or no drug (CON, n = 8). After 5 weeks of treatment, swine underwent functional measurements and tissue harvest. In the SIT group compared to CON, there was a trend towards decreased cardiac index (p = 0.06). The non-ischemic and ischemic myocardium had 396 and 166 significantly decreased proteins, respectively, in the SIT group compared to CON (all p < 0.01). This included proteins involved in fatty acid oxidation (FAO), myocardial contraction, and oxidative phosphorylation (OXPHOS). Sitagliptin treatment resulted in a trend towards decreased cardiac index and decreased expression of proteins involved in OXPHOS, FAO, and myocardial contraction in both ischemic and non-ischemic swine myocardium. These metabolic and functional changes may provide some mechanistic evidence for outcomes seen in clinical studies.


Assuntos
Inibidores da Dipeptidil Peptidase IV , Isquemia Miocárdica , Suínos , Humanos , Animais , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Proteoma/metabolismo , Fosforilação Oxidativa , Fosfato de Sitagliptina/uso terapêutico , Proteômica/métodos , Miocárdio/metabolismo , Hipoglicemiantes/uso terapêutico , Modelos Animais de Doenças
10.
Int J Mol Sci ; 25(5)2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38474255

RESUMO

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


Assuntos
Inibidores da Dipeptidil Peptidase IV , Linagliptina , Ratos , Animais , Linagliptina/farmacologia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Serotonina , Dopamina , Norepinefrina , Dipeptidil Peptidase 4/metabolismo , Hipocampo/metabolismo , Neurotransmissores , RNA Mensageiro
11.
Int J Mol Sci ; 25(5)2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38474306

RESUMO

Type 2 diabetes is a chronic metabolic disorder characterized by high blood glucose levels due to either insufficient insulin production or ineffective utilization of insulin by the body. The enzyme dipeptidyl peptidase IV (DPP IV) plays a crucial role in degrading incretins that stimulate insulin secretion. Therefore, the inhibition of DPP IV is an established approach for the treatment of diabetes. Hemorphins are a class of short endogenous bioactive peptides produced by the enzymatic degradation of hemoglobin chains. Numerous in vitro and in vivo physiological effects of hemorphins, including DPP IV inhibiting activity, have been documented in different systems and tissues. However, the underlying molecular binding behavior of these peptides with DPP IV remains unknown. Here, computational approaches such as protein-peptide molecular docking and extensive molecular dynamics (MD) simulations were employed to identify the binding pose and stability of peptides in the active site of DPP IV. Findings indicate that hemorphins lacking the hydrophobic residues LVV and VV at the N terminal region strongly bind to the conserved residues in the active site of DPP IV. Furthermore, interactions with these critical residues were sustained throughout the duration of multiple 500 ns MD simulations. Notably, hemorphin 7 showed higher binding affinity and sustained interactions by binding to S1 and S2 pockets of DPP IV.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Humanos , Inibidores da Dipeptidil Peptidase IV/farmacologia , Simulação de Acoplamento Molecular , Dipeptidil Peptidase 4/metabolismo , Peptídeos/química , Insulina , Simulação de Dinâmica Molecular
12.
Cell Biochem Funct ; 42(2): e3967, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38480622

RESUMO

A drug interaction is a condition in which two or more drugs are taken at the same time. Type 2 diabetes mellitus is a significant contributor to polypharmacy. Proton pump inhibitors (PPIs) are often prescribed in combination with metformin or DPP-4 inhibitors (sitagliptin, saxagliptin, linagliptin, and alogliptin) or a combined dose of metformin and DPP-4 inhibitor to treat gastritis in diabetic patients. This review article mainly focused on evaluating the potential drug-drug interactions (DDIs) between PPIs (i.e. esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole) with metformin and PPIs with DPP-4 inhibitors. The findings demonstrated the existence of pharmacokinetic and pharmacodynamic DDIs between the aforementioned PPIs with metformin and DPP-4 inhibitors, which could impact the biological activities (i.e., hypoglycemia) of these drugs. Moreover, this review suggested that esomeprazole could be the best drug in the PPI group to be prescribed simultaneously with metformin and DPP-4 inhibitors, as most of the antidiabetic drugs of this study did not show any interaction with esomeprazole. The findings of this study also revealed that both antidiabetic drugs and PPIs could have positive interactions as PPIs have the potential to lessen the gastrointestinal side effects of metformin and DPP-4 inhibitors. To achieve the greatest therapeutic impact with the fewest side effects, careful dose control of these drugs is required. So, more extensive research on both human and animal subjects are needed to ascertain the veracity of this hypothesis.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Metformina , Animais , Humanos , Inibidores da Bomba de Prótons/farmacocinética , Inibidores da Dipeptidil Peptidase IV/farmacologia , Esomeprazol/farmacologia , Metformina/farmacologia , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Interações Medicamentosas
13.
J Diabetes ; 16(3): e13547, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38501220

RESUMO

OBJECTIVE: To assess the association between glucagon-like peptide-1 receptor agonists (GLP-1RA) treatment and the risk of suicide attempts in people with type 2 diabetes (T2D), with a focus on subgroups with and without a history of depression or suicide attempts. METHODS: This retrospective cohort study utilized TriNetX, a federated network of real-world data. Using the Global Collaborative Network data, we collected electronic medical records from 113 health care organizations with 135 million patient records with 8 million with T2D, 83% from the United States. The four cohorts were identified based on age, medication, diagnosis, and presence of depression or suicide attempts. Analytic methods included measures of association and number of Instances, with propensity score matching employed to mitigate potential confounders. The primary outcome was the incidence of suicide attempts among people with T2D with GLP-1RA treatment in comparison with dipeptidyl peptidase-4 inhibitor (DPP-4i) treatment. RESULTS: People with T2D treated with GLP-1RA consistently exhibited a lower risk of suicide attempts compared to those treated with DPP-4i. This was particularly significant in people with a history of depression or suicide attempts. The risk and odds ratios were significantly lower in the GLP-1RA-treated cohorts than in DPP-4i across all analyses. CONCLUSION: As compared with DPP-4i, our analysis shows a protective effect associated with GLP-1RA treatment on the risk of suicide attempts among people with T2D. However, further research, particularly prospective and randomized studies, is necessary to confirm these observations and understand the underlying mechanisms.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Adulto , Humanos , Estados Unidos/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Estudos Retrospectivos , Tentativa de Suicídio , Estudos Prospectivos , Hipoglicemiantes/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas
15.
Sci Rep ; 14(1): 7227, 2024 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-38538694

RESUMO

There is a scarcity of information on the population with diabetes mellitus type 2 and cardiomyopathy (PDMC) in COVID-19, especially on the association between anti-diabetic medications and COVID-19 outcomes. Study is designed as a retrospective cohort analysis covering 2020 and 2021. Data from National Diabetes Registry (CroDiab) were linked to hospital data, primary healthcare data, the SARS-CoV-2 vaccination database, and the SARS-CoV-2 test results database. Study outcomes were cumulative incidence of SARS-CoV-2 positivity, COVID-19 hospitalizations, and COVID-19 deaths. For outcome predictors, logistic regression models were developed. Of 231 796 patients with diabetes mellitus type 2 in the database, 14 485 patients had cardiomyopathy. The two2-year cumulative incidence of all three studies' COVID-19 outcomes was higher in PDMC than in the general diabetes population (positivity 15.3% vs. 14.6%, p = 0.01; hospitalization 7.8% vs. 4.4%, p < 0.001; death 2.6% vs. 1.2%, p < 0.001). Sodium-Glucose Transporter 2 (SGLT-2) inhibitors therapy was found to be protective of SARS-CoV-2 infections [OR 0.722 (95% CI 0.610-0.856)] and COVID-19 hospitalizations [OR 0.555 (95% CI 0.418-0.737)], sulfonylureas to be risk factors for hospitalization [OR 1.184 (95% CI 1.029-1.362)] and insulin to be a risk factor for hospitalization [OR 1.261 (95% CI 1.046-1.520)] and death [OR 1.431 (95% CI 1.080-1.897)]. PDMC are at greater risk of acquiring SARS-CoV-2 infection and having worse outcomes than the general diabetic population. SGLT-2 inhibitors therapy was a protective factor against SARS-CoV-2 infection and against COVID-19 hospitalization, sulfonylurea was the COVID-19 hospitalization risk factor, while insulin was a risk factor for all outcomes. Further research is needed in this diabetes sub-population.


Assuntos
COVID-19 , Cardiomiopatias , Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Hipoglicemiantes/uso terapêutico , Estudos Retrospectivos , Vacinas contra COVID-19/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , COVID-19/complicações , SARS-CoV-2 , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Compostos de Sulfonilureia/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Insulina/uso terapêutico , Cardiomiopatias/induzido quimicamente
16.
Front Endocrinol (Lausanne) ; 15: 1359407, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38529396

RESUMO

Aims: To evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of cetagliptin (CAS number:2243737-33-7) in Chinese patients with type 2 diabetes mellitus (T2DM). A population PK/PD model was developed to quantify the PK and PD characteristics of cetagliptin in patients. Materials and methods: 32 Chinese adults with T2DM were enrolled in this study. The subjects were randomly assigned to receive either cetagliptin (50 mg or 100 mg), placebo, or sitagliptin (100 mg) once daily for 14 days. Blood samples were collected for PK and PD analysis. Effects on glucose, insulin, C-peptide, and glucagon were evaluated following an oral glucose tolerance test (OGTT) (day15). Effects on HbA1c and glycated albumin (GA), and safety assessments were also conducted. Meanwhile, a population PK/PD model was developed by a sequential two-step analysis approach using Phoenix. Results: Following multiple oral doses, cetagliptin was rapidly absorbed and the mean half-life were 34.9-41.9 h. Steady-state conditions were achieved after 1 week of daily dosing and the accumulation was modest. The intensity and duration of DPP-4 inhibition induced by 50 mg cetagliptin were comparable with those induced by sitagliptin, and 100 mg cetagliptin showed a much longer sustained DPP-4 inhibition (≥80%) than sitagliptin. Compared with placebo group, plasma active GLP-1 AUEC0-24h increased by 2.20- and 3.36-fold in the 50 mg and 100 mg cetagliptin groups. A decrease of plasma glucose and increase of insulin and C-peptide were observed following OGTT in cetagliptin groups. Meanwhile, a tendency of reduced GA was observed, whereas no decreasing trend was observed in HbA1c. All adverse events related to cetagliptin and sitagliptin were assessed as mild. A population PK/PD model was successfully established. The two-compartment model and Sigmoid-Emax model could fit the observed data well. Total bilirubin (TBIL) was a covariate of volume of peripheral compartment distribution (V2), and V2 increased with the increase of TBIL. Conclusions: Cetagliptin was well tolerated, inhibited plasma DPP-4 activity, increased plasma active GLP-1 levels, and exhibited a certain trend of glucose-lowering effect in patients with T2DM. The established population PK/PD model adequately described the PK and PD characteristics of cetagliptin.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Adulto , Humanos , Hipoglicemiantes/efeitos adversos , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Hemoglobinas Glicadas , Peptídeo C , Glicemia , Fosfato de Sitagliptina/farmacologia , Fosfato de Sitagliptina/uso terapêutico , Peptídeo 1 Semelhante ao Glucagon , Insulina/uso terapêutico
17.
Int J Mol Sci ; 25(6)2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38542317

RESUMO

The probability of acute kidney injury (AKI) is higher in septic diabetic patients, which is associated with, among other factors, proximal tubular cell (PTC) injury induced by the hypoxic/hyperglycemic/inflammatory microenvironment that surrounds PTCs in these patients. Here, we exposed human PTCs (HK-2 cells) to 1% O2/25 mM glucose/inflammatory cytokines with the aim of studying the role of prostaglandin uptake transporter (PGT) and dipeptidyl peptidase-4 (DPP-4, a target of anti-hyperglycemic agents) as pharmacological targets to prevent AKI in septic diabetic patients. Our model reproduced two pathologically relevant mechanisms: (i) pro-inflammatory PTC activation, as demonstrated by the increased secretion of chemokines IL-8 and MCP-1 and the enhanced expression of DPP-4, intercellular leukocyte adhesion molecule-1 and cyclo-oxygenase-2 (COX-2), the latter resulting in a PGT-dependent increase in intracellular prostaglandin E2 (iPGE2); and (ii) epithelial monolayer injury and the consequent disturbance of paracellular permeability, which was related to cell detachment from collagen IV and the alteration of the cell cytoskeleton. Most of these changes were prevented by the antagonism of PGE2 receptors or the inhibition of COX-2, PGT or DPP-4, and further studies suggested that a COX-2/iPGE2/DPP-4 pathway mediates the pathogenic effects of the hypoxic/hyperglycemic/inflammatory conditions on PTCs. Therefore, inhibitors of PGT or DPP-4 ought to undergo testing as a novel therapeutic avenue to prevent proximal tubular damage in diabetic patients at risk of AKI.


Assuntos
Injúria Renal Aguda , Diabetes Mellitus , Inibidores da Dipeptidil Peptidase IV , Humanos , Ciclo-Oxigenase 2/metabolismo , Diabetes Mellitus/tratamento farmacológico , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/prevenção & controle , Dipeptidil Peptidases e Tripeptidil Peptidases , Prostaglandinas , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Dipeptidil Peptidase 4
18.
Europace ; 26(3)2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38484180

RESUMO

AIMS: Prior studies suggest that sodium-glucose cotransporter-2 inhibitors (SGLT2is) may decrease the incidence of atrial fibrillation (AF). However, it is unknown whether SGLT2i can attenuate the disease course of AF among patients with pre-existing AF and Type II diabetes mellitus (DM). In this study, our objective was to examine the association between SGLT2i prescription and arrhythmic outcomes among patients with DM and pre-existing AF. METHODS AND RESULTS: We conducted a population-based cohort study of adults with DM and AF between 2014 and 2019. Using a prevalent new-user design, individuals prescribed SGLT2i were matched 1:1 to those prescribed dipeptidyl peptidase-4 inhibitors (DPP4is) based on time-conditional propensity scores. The primary endpoint was a composite of AF-related healthcare utilization (i.e. hospitalization, emergency department visits, electrical cardioversion, or catheter ablation). Secondary outcome measures included all-cause mortality, heart failure (HF) hospitalization, and ischaemic stroke or transient ischaemic attack (TIA). Cox proportional hazard models were used to examine the association of SGLT2i with the study endpoint. Among 2242 patients with DM and AF followed for an average of 3.0 years, the primary endpoint occurred in 8.7% (n = 97) of patients in the SGLT2i group vs. 10.0% (n = 112) of patients in the DPP4i group [adjusted hazard ratio 0.73 (95% confidence interval 0.55-0.96; P = 0.03)]. Sodium-glucose cotransporter-2 inhibitors were associated with significant reductions in all-cause mortality and HF hospitalization, but there was no difference in the risk of ischaemic stroke/TIA. CONCLUSION: Among patients with DM and pre-existing AF, SGLT2is are associated with decreased AF-related health resource utilization and improved arrhythmic outcomes compared with DPP4is.


Assuntos
Fibrilação Atrial , Isquemia Encefálica , Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Insuficiência Cardíaca , Ataque Isquêmico Transitório , AVC Isquêmico , Inibidores do Transportador 2 de Sódio-Glicose , Acidente Vascular Cerebral , Adulto , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/epidemiologia , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Estudos de Coortes , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/prevenção & controle , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/farmacologia , Insuficiência Cardíaca/epidemiologia , Glucose , Sódio , Hipoglicemiantes , Estudos Retrospectivos
19.
Diabetes Obes Metab ; 26(5): 1837-1849, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38379094

RESUMO

AIM: Using a systematic review and meta-analysis of placebo-controlled cardiovascular outcome trials (CVOTs) of newer glucose-lowering agents [sodium-glucose cotransporter-2 inhibitors (SGLT-2is), glucagon-like peptide-1 receptor agonists (GLP-1RAs), and dipeptidyl peptidase-4 inhibitors (DPP-4is)] in type 2 diabetes (T2D), we aimed to determine the macrovascular and microvascular outcomes of these agents and clarify the relationships between glycated haemoglobin (HbA1c) reduction and risk of these outcomes. MATERIALS AND METHODS: Randomized controlled trials were identified from MEDLINE, Embase and the Cochrane Library until September 2023. Study-specific hazard ratios with 95% confidence intervals (CIs) were pooled, and meta-regression was used to assess the relationships between outcomes and between trial arm HbA1c reductions. RESULTS: Twenty unique CVOTs (six SGLT-2is, nine GLP-1RAs, five DPP-4is), based on 169 513 participants with T2D, were eligible. Comparing SGLT-2is, GLP-1RAs and DPP-4is with placebo, the hazard ratios (95% CIs) for 3-point major adverse cardiovascular events were 0.88 (0.82-0.94), 0.85 (0.79-0.92) and 1.00 (0.94-1.06), respectively. SGLT-2is and GLP-1RAs consistently reduced the risk of several macrovascular and microvascular complications, particularly kidney events. DPP-4is showed no macrovascular benefits. There was potential evidence of an inverse linear relationship between HbA1c reduction and 3-point major adverse cardiovascular event risk (estimated risk per 1% reduction in HbA1c: 0.84, 95% CI 0.67-1.06; p = .14; R2 = 14.2%), which was driven by the component of non-fatal stroke (R2 = 100.0%; p = .094). There were non-significant inverse linear relationships between HbA1c reduction and the risk of several vascular outcomes. CONCLUSIONS: SGLT-2is and GLP-1RAs showed consistent risk reductions in macrovascular and microvascular outcomes. The vascular benefits of SGLT-2is and GLP-1RAs in patients with T2D extend beyond mere glycaemic control.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Glucose/uso terapêutico , Hemoglobinas Glicadas , Controle Glicêmico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas
20.
Diabetes Metab Res Rev ; 40(3): e3784, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38402457

RESUMO

AIMS: Sodium-glucose cotransporter 2 inhibitors (SGLT-2is) have been demonstrated to be associated with cancer cell mechanisms. However, whether they increase the risk of cancer remains unclear. Thus, this study aimed to determine the association between SGLT-2i use and the incidence of cancer in patients with diabetes mellitus (DM) in Taiwan. MATERIALS AND METHODS: This retrospective cohort study was based on the Taiwan National Health Insurance database. The study population comprised patients with DM, and those who first used SGLT-2is during 2016-2018 were assigned to the study group. Greedy propensity score matching was performed to select patients who first used dipeptidyl peptidase 4 inhibitors (DPP-4is), and these patients were assigned to the control group. A Cox proportional hazards model was used to estimate the adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for cancer risk in the study and control groups; this model was adjusted for demographic characteristics, DM severity, comorbidities and concomitant medication use. RESULTS: After controlling for relevant variables, the SGLT-2i cohort (aHR = 0.90, 95% CI = 0.87-0.93) had a significantly lower risk of developing cancer than the DPP-4i cohort, particularly when the SGLT-2i was dapagliflozin (aHR = 0.91, 95% CI = 0.87-0.95) or empagliflozin (aHR = 0.90, 95% CI = 0.86-0.94). Regarding cancer type, the SGLT-2i cohort's risk of cancer was significantly lower than that of the DPP-4i cohort for leukaemia, oesophageal, colorectal, liver, pancreatic, lung, skin and bladder cancer. CONCLUSIONS: SGLT-2i use was associated with a significantly lower risk of cancer than DPP-4i use.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Neoplasias , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Glucose , Hipoglicemiantes/efeitos adversos , Neoplasias/epidemiologia , Neoplasias/etiologia , Estudos Retrospectivos , Sódio/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos
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