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Diabetes Mellitus Tipo 2 , Hipoglucemiantes , Metformina , Vildagliptina , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Metformina/uso terapéutico , Metformina/farmacología , Vildagliptina/farmacología , Vildagliptina/uso terapéutico , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/farmacología , Glucósidos/uso terapéutico , Glucósidos/farmacología , Glucósidos/efectos adversos , Pirrolidinas/uso terapéutico , Pirrolidinas/farmacología , Pirrolidinas/efectos adversos , Quimioterapia Combinada/métodos , Nitrilos/uso terapéutico , Nitrilos/efectos adversos , Adamantano/análogos & derivados , Adamantano/uso terapéutico , Adamantano/efectos adversos , Compuestos de Bencidrilo/uso terapéutico , Compuestos de Bencidrilo/efectos adversos , Compuestos de Bencidrilo/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Inhibidores de la Dipeptidil-Peptidasa IV/farmacologíaRESUMEN
BACKGROUND: Medical therapy for aortic stenosis (AS) remains an elusive goal. OBJECTIVES: This study sought to establish whether evogliptin, a dipeptidyl peptidase-4 inhibitor, could reduce AS progression. METHODS: A total of 228 patients (age 67 ± 11 years; 33% women) with AS were randomly assigned to receive placebo (n = 75), evogliptin 5 mg (n = 77), or evogliptin 10 mg (n = 76). The primary endpoint was the 96-week change in aortic valve calcium volume (AVCV) on computed tomography. Secondary endpoints included the 48-week change in active calcification volume measured using 18F-sodium fluoride positron emission tomography (18F-NaF PET). RESULTS: There were no significant differences in the 96-week changes in AVCV between evogliptin 5 mg and placebo (-5.27; 95% CI: -55.36 to 44.82; P = 0.84) or evogliptin 10 mg and placebo (-18.83; 95% CI: -32.43 to 70.10; P = 0.47). In the placebo group, the increase in AVCV between 48 weeks and 96 weeks was higher than that between baseline and 48 weeks (136 mm3; 95% CI: 108-163 vs 102 mm3; 95% CI: 75-129; P = 0.0485). This increasing trend in the second half of the study was suppressed in both evogliptin groups. The 48-week change in active calcification volume on 18F-NaF PET was significantly lower in both the evogliptin 5 mg (-1,325.6; 95% CI: -2,285.9 to -365.4; P = 0.008) and 10-mg groups (-1,582.2; 95% CI: -2,610.8 to -553.5; P = 0.0038) compared with the placebo group. CONCLUSIONS: This exploratory study did not demonstrate the protective effect of evogliptin on AV calcification. Favorable 18F-NaF PET results and possible suppression of aortic valve calcification with longer medication use in the evogliptin groups suggest the need for larger confirmatory trials. (A Multicenter, Double-blind, Placebo-controlled, Stratified-randomized, Parallel, Therapeutic Exploratory Clinical Study to Evaluate the Efficacy and Safety of DA-1229 in Patients With Calcific Aortic Valve Disease; NCT04055883).
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Estenosis de la Válvula Aórtica , Válvula Aórtica , Calcinosis , Progresión de la Enfermedad , Humanos , Femenino , Masculino , Anciano , Calcinosis/tratamiento farmacológico , Calcinosis/diagnóstico por imagen , Estenosis de la Válvula Aórtica/tratamiento farmacológico , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Persona de Mediana Edad , Válvula Aórtica/diagnóstico por imagen , Válvula Aórtica/patología , Método Doble Ciego , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Tomografía de Emisión de Positrones/métodos , Resultado del Tratamiento , Tomografía Computarizada por Rayos X , PiperazinasAsunto(s)
Diabetes Mellitus Tipo 2 , Inhibidores de la Dipeptidil-Peptidasa IV , Linagliptina , Penfigoide Ampolloso , Humanos , Linagliptina/efectos adversos , Linagliptina/uso terapéutico , Penfigoide Ampolloso/mortalidad , Penfigoide Ampolloso/tratamiento farmacológico , Penfigoide Ampolloso/diagnóstico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/mortalidad , Diabetes Mellitus Tipo 2/complicaciones , Femenino , Masculino , Anciano , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Inhibidores de la Dipeptidil-Peptidasa IV/efectos adversos , Anciano de 80 o más Años , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/efectos adversos , Factores de Riesgo , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM). However, their effectiveness relative to each other and other second-line antihyperglycemic agents is unknown, without any major ongoing head-to-head clinical trials. OBJECTIVES: The aim of this study was to compare the cardiovascular effectiveness of SGLT2is, GLP-1 RAs, dipeptidyl peptidase-4 inhibitors (DPP4is), and clinical sulfonylureas (SUs) as second-line antihyperglycemic agents in T2DM. METHODS: Across the LEGEND-T2DM (Large-Scale Evidence Generation and Evaluation Across a Network of Databases for Type 2 Diabetes Mellitus) network, 10 federated international data sources were included, spanning 1992 to 2021. In total, 1,492,855 patients with T2DM and cardiovascular disease (CVD) on metformin monotherapy were identified who initiated 1 of 4 second-line agents (SGLT2is, GLP-1 RAs, DPP4is, or SUs). Large-scale propensity score models were used to conduct an active-comparator target trial emulation for pairwise comparisons. After evaluating empirical equipoise and population generalizability, on-treatment Cox proportional hazards models were fit for 3-point MACE (myocardial infarction, stroke, and death) and 4-point MACE (3-point MACE plus heart failure hospitalization) risk and HR estimates were combined using random-effects meta-analysis. RESULTS: Over 5.2 million patient-years of follow-up and 489 million patient-days of time at risk, patients experienced 25,982 3-point MACE and 41,447 4-point MACE. SGLT2is and GLP-1 RAs were associated with lower 3-point MACE risk than DPP4is (HR: 0.89 [95% CI: 0.79-1.00] and 0.83 [95% CI: 0.70-0.98]) and SUs (HR: 0.76 [95% CI: 0.65-0.89] and 0.72 [95% CI: 0.58-0.88]). DPP4is were associated with lower 3-point MACE risk than SUs (HR: 0.87; 95% CI: 0.79-0.95). The pattern for 3-point MACE was also observed for the 4-point MACE outcome. There were no significant differences between SGLT2is and GLP-1 RAs for 3-point or 4-point MACE (HR: 1.06 [95% CI: 0.96-1.17] and 1.05 [95% CI: 0.97-1.13]). CONCLUSIONS: In patients with T2DM and CVD, comparable cardiovascular risk reduction was found with SGLT2is and GLP-1 RAs, with both agents more effective than DPP4is, which in turn were more effective than SUs. These findings suggest that the use of SGLT2is and GLP-1 RAs should be prioritized as second-line agents in those with established CVD.
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Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Hipoglucemiantes , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Enfermedades Cardiovasculares/prevención & control , Enfermedades Cardiovasculares/epidemiología , Hipoglucemiantes/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Anciano , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Compuestos de Sulfonilurea/uso terapéutico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Resultado del TratamientoRESUMEN
Repurposing antidiabetic drugs for the treatment of Alzheimer's disease (AD) has emerged as a promising therapeutic strategy. This review examines the potential of repurposing antidiabetic drugs for AD treatment, focusing on preclinical evidence, clinical trials, and observational studies. In addition, the review aims to explore challenges and opportunities in repurposing antidiabetic drugs for AD, emphasizing the importance of well-designed clinical trials that consider patient selection criteria, refined outcome measures, adverse effects, and combination therapies to enhance therapeutic efficacy. Preclinical evidence suggests that glucagon-like peptide-1 (GLP-1) analogs, dipeptidyl peptidase-4 (DPP4) inhibitors, metformin, thiazolidinediones, and sodium-glucose co-transporter-2 (SGLT2) inhibitors exhibit neuroprotective effects in AD preclinical models. In preclinical studies, antidiabetic drugs have demonstrated neuroprotective effects by reducing amyloid beta (Aß) plaques, tau hyperphosphorylation, neuroinflammation, and cognitive impairment. Antidiabetic drug classes, notably GLP-1 analogs and SGLT2 inhibitors, and a reduced risk of dementia in patients with diabetes mellitus. While the evidence for DPP4 inhibitors is mixed, some studies suggest a potential protective effect. On the other hand, alpha-glucosidase inhibitors (AGIs) and sulfonylureas may potentially increase the risk, especially in those experiencing recurrent hypoglycemic events. Repurposing antidiabetic drugs for AD is a promising therapeutic strategy, but challenges such as disease heterogeneity, limited biomarkers, and benefits versus risk evaluation need to be addressed. Ongoing clinical trials in mild cognitive impairment (MCI) and early AD patients without diabetes will be crucial in determining the clinical efficacy and safety of the antidiabetic drugs, paving the way for potential treatments for AD.
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Enfermedad de Alzheimer , Reposicionamiento de Medicamentos , Hipoglucemiantes , Enfermedad de Alzheimer/tratamiento farmacológico , Humanos , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/farmacología , Animales , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/farmacología , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Inhibidores de la Dipeptidil-Peptidasa IV/farmacologíaRESUMEN
Individuals suffering from diabetic polyneuropathy (DPN) experience debilitating symptoms such as pain, paranesthesia, and sensory disturbances, prompting a quest for effective treatments. Dipeptidyl-peptidase (DPP)-4 inhibitors, recognized for their potential in ameliorating DPN, have sparked interest, yet the precise mechanism underlying their neurotrophic impact on the peripheral nerve system (PNS) remains elusive. Our study delves into the neurotrophic effects of DPP-4 inhibitors, including Diprotin A, linagliptin, and sitagliptin, alongside pituitary adenylate cyclase-activating polypeptide (PACAP), Neuropeptide Y (NPY), and Stromal cell-derived factor (SDF)-1a-known DPP-4 substrates with neurotrophic properties. Utilizing primary culture dorsal root ganglia (DRG) neurons, we meticulously evaluated neurite outgrowth in response to these agents. Remarkably, all DPP-4 inhibitors and PACAP demonstrated a significant elongation of neurite length in DRG neurons (PACAP 0.1 µM: 2221 ± 466 µm, control: 1379 ± 420, p < 0.0001), underscoring their potential in nerve regeneration. Conversely, NPY and SDF-1a failed to induce neurite elongation, accentuating the unique neurotrophic properties of DPP-4 inhibition and PACAP. Our findings suggest that the upregulation of PACAP, facilitated by DPP-4 inhibition, plays a pivotal role in promoting neurite elongation within the PNS, presenting a promising avenue for the development of novel DPN therapies with enhanced neurodegenerative capabilities.
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Neuropatías Diabéticas , Inhibidores de la Dipeptidil-Peptidasa IV , Ganglios Espinales , Proyección Neuronal , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa , Animales , Ganglios Espinales/metabolismo , Ganglios Espinales/efectos de los fármacos , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/farmacología , Proyección Neuronal/efectos de los fármacos , Neuropatías Diabéticas/tratamiento farmacológico , Neuropatías Diabéticas/metabolismo , Ratones , Neuropéptido Y/metabolismo , Neuropéptido Y/farmacología , Quimiocina CXCL12/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Linagliptina/farmacología , Dipeptidil Peptidasa 4/metabolismo , Fosfato de Sitagliptina/farmacología , Células Cultivadas , Neuritas/efectos de los fármacos , Neuritas/metabolismo , OligopéptidosRESUMEN
OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
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Diabetes Mellitus Tipo 2 , Hemoglobina Glucada , Linagliptina , Aprendizaje Automático , Vildagliptina , Vildagliptina/uso terapéutico , Humanos , Linagliptina/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/sangre , Femenino , Persona de Mediana Edad , Masculino , Hemoglobina Glucada/análisis , Hemoglobina Glucada/metabolismo , Anciano , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Control Glucémico/métodos , Hipoglucemiantes/uso terapéutico , Glucemia/análisis , Glucemia/metabolismo , Resultado del Tratamiento , Pirrolidinas/uso terapéutico , Nitrilos/uso terapéuticoRESUMEN
The inhibition of dipeptidyl peptidase-IV (DPP-IV) is a promising approach for regulating the blood glucose levels in patients with type 2 diabetes (T2D). Oysters, rich in functional peptides, contain peptides capable of inhibiting DPP-IV activity. This study aims to identify the hypoglycemic peptides from oysters and investigate their potential anti-T2D targets and mechanisms. This research utilized virtual screening for the peptide selection, followed by in vitro DPP-IV activity assays to validate the chosen peptide. Network pharmacology was employed to identify the potential targets, GO terms, and KEGG pathways. Molecular docking and molecular dynamics simulations were used to provide virtual confirmation. The virtual screening identified LRGFGNPPT as the most promising peptide among the screened oyster peptides. The in vitro studies confirmed its inhibitory effect on DPP-IV activity. Network pharmacology revealed that LRGFGNPPT exerts an anti-T2D effect through multiple targets and signaling pathways. The key hub targets are AKT1, ACE, and REN. Additionally, the molecular docking results showed that LRGFGNPPT exhibited a strong binding affinity with targets like AKT1, ACE, and REN, which was further confirmed by the molecular dynamics simulations showcasing a stable peptide-target interaction. This study highlights the potential of LRGFGNPPT as a natural anti-T2D peptide, providing valuable insights for potential future pharmaceutical or dietary interventions in T2D management.
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Diabetes Mellitus Tipo 2 , Dipeptidil Peptidasa 4 , Inhibidores de la Dipeptidil-Peptidasa IV , Simulación del Acoplamiento Molecular , Péptidos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Inhibidores de la Dipeptidil-Peptidasa IV/química , Inhibidores de la Dipeptidil-Peptidasa IV/aislamiento & purificación , Animales , Dipeptidil Peptidasa 4/metabolismo , Dipeptidil Peptidasa 4/química , Péptidos/farmacología , Péptidos/química , Péptidos/aislamiento & purificación , Humanos , Simulación de Dinámica Molecular , Hipoglucemiantes/farmacología , Hipoglucemiantes/química , Ostreidae/química , Farmacología en Red , Descubrimiento de DrogasRESUMEN
In this study, we aimed to explore the hypoglycemic effects of a hydrolysate on Takifugu bimaculatus skin (TBSH). The effect of the dipeptidyl peptidase-IV (DPP-IV) inhibitory activities from different TBSH fractions was investigated on basic indexes, gut hormones, blood lipid indexes, viscera, and the gut microbiota and its metabolites in rats with type 2 diabetes mellitus (T2DM). The results showed that the <1 kDa peptide fraction from TBSH (TBP) exhibited a more potent DPP-IV inhibitory effect (IC50 = 0.45 ± 0.01 mg/mL). T2DM rats were induced with streptozocin, followed by the administration of TBP. The 200 mg/kg TBP mitigated weight loss, lowered fasting blood glucose levels, and increased insulin secretion by 20.47%, 25.23%, and 34.55%, respectively, rectified irregular hormonal fluctuations, lipid metabolism, and tissue injuries, and effectively remedied gut microbiota imbalance. In conclusion, TBP exerts a hypoglycemic effect in rats with T2DM. This study offers the potential to develop nutritional supplements to treat T2DM and further promote the high-value utilization of processing byproducts from T. bimaculatus. It will provide information for developing nutritional supplements to treat T2DM and further promote the high-value utilization of processing byproducts from T. bimaculatus.
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Glucemia , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Hiperglucemia , Hipoglucemiantes , Péptidos , Piel , Takifugu , Animales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Ratas , Masculino , Microbioma Gastrointestinal/efectos de los fármacos , Hipoglucemiantes/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Piel/efectos de los fármacos , Piel/metabolismo , Hiperglucemia/tratamiento farmacológico , Glucemia/efectos de los fármacos , Péptidos/farmacología , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Metaboloma/efectos de los fármacos , Ratas Sprague-Dawley , Insulina/metabolismo , Insulina/sangreRESUMEN
Diabetes mellitus (DM) is a rapidly prevailing disease throughout the world that poses boundless risk factors linked to several health problems. Vildagliptin is the standard dipeptidyl peptidase-4 (DPP-4) inhibitor type of medication that is used for the treatment of diabetes anti-hyperglycemic agent (anti-diabetic drug). The current study aimed to synthesize vildagliptin-loaded ZnO NPs for enhanced efficacy in terms of increased retention time minimizing side effects and increased hypoglycemic effects. Herein, Zinc Oxide (ZnO) nanoparticles (NPs) were constructed by precipitation method then the drug vildagliptin was loaded and drug loading efficiency was estimated by the HPLC method. X-ray diffraction analysis (XRD), UV-vis spectroscopy, FT-IR, scanning electron microscope (SEM), and EDX analysis were performed for the characterization of synthesized vildagliptin-loaded ZnO NPs. The UV-visible spectrum shows a distinct peak at 363 nm which confirms the creation of ZnO NPs and SEM showed mono-dispersed sphere-shaped NPs. EDX analysis shows the presence of desired elements along with the elemental composition. The physio-sorption studies, which used adsorption isotherms to assess adsorption capabilities, found that the Freundlich isotherm model explains the data very well and fits best. The maximum adsorption efficiency of 58.83% was obtained. Further, In vitro, anti-diabetic activity was evaluated by determining the α-amylase and DPP IV inhibition activity of the product formed. The formulation gave maximum inhibition of 82.06% and 94.73% of α-amylase and DPP IV respectively. While at 1000 µg/ml concentration with IC50 values of 24.11 µg/per ml and 42.94 µg/ml. The inhibition of α-amylase can be ascribed to the interactive effect of ZnO NPs and vildagliptin.
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Hipoglucemiantes , Nanopartículas , Vildagliptina , Óxido de Zinc , Vildagliptina/química , Vildagliptina/farmacología , Óxido de Zinc/química , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Nanopartículas/química , Inhibidores de la Dipeptidil-Peptidasa IV/química , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Difracción de Rayos X , Portadores de Fármacos/química , Espectroscopía Infrarroja por Transformada de Fourier , Nitrilos/química , HumanosRESUMEN
BACKGROUND: Western guidelines often recommend biguanides as the first-line treatment for diabetes. However, dipeptidyl peptidase-4 (DPP-4) inhibitors, alongside biguanides, are increasingly used as the first-line therapy for type 2 diabetes (T2DM) in Japan. However, there have been few studies comparing the effectiveness of biguanides and DPP-4 inhibitors with respect to diabetes-related complications and cardio-cerebrovascular events over the long term, as well as the costs associated. OBJECTIVE: We aimed to compare the outcomes of patients with T2DM who initiate treatment with a biguanide versus a DPP-4 inhibitor and the long-term costs associated. METHODS: We performed a cohort study between 2012 and 2021 using a new-user design and the Shizuoka Kokuho database. Patients were included if they were diagnosed with T2DM. The primary outcome was the incidence of cardio-cerebrovascular events or mortality from the initial month of treatment; and the secondary outcomes were the incidences of related complications (nephropathy, renal failure, retinopathy, and peripheral neuropathy) and the daily cost of the drugs used. Individuals who had experienced prior events during the preceding year were excluded, and events within 6 months of the start of the study period were censored. Propensity score matching was performed to compare between two groups. RESULTS: The matched 1:5 cohort comprised 529 and 2,116 patients who were initially treated with a biguanide or a DPP-4 inhibitor, respectively. Although there were no significant differences in the incidence of cardio-cerebrovascular events or mortality and T2DM-related complications between the two groups (p = 0.139 and p = 0.595), daily biguanide administration was significantly cheaper (mean daily cost for biguanides, 61.1 JPY; for DPP-4 inhibitors, 122.7 JPY; p<0.001). CONCLUSION: In patients with T2DM who initiate pharmacotherapy, there were no differences in the long-term incidences of cardio-cerebrovascular events or complications associated with biguanide or DPP-4 use, but the former was less costly.
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Biguanidas , Diabetes Mellitus Tipo 2 , Retinopatía Diabética , Inhibidores de la Dipeptidil-Peptidasa IV , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Biguanidas/efectos adversos , Biguanidas/economía , Biguanidas/uso terapéutico , Enfermedades Cardiovasculares/economía , Enfermedades Cardiovasculares/tratamiento farmacológico , Estudios de Cohortes , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/economía , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/economía , Neuropatías Diabéticas/tratamiento farmacológico , Neuropatías Diabéticas/economía , Retinopatía Diabética/tratamiento farmacológico , Retinopatía Diabética/economía , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Inhibidores de la Dipeptidil-Peptidasa IV/economía , Inhibidores de la Dipeptidil-Peptidasa IV/efectos adversos , Hipoglucemiantes/economía , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/efectos adversos , Japón , Resultado del TratamientoRESUMEN
BACKGRUOUND: Dipeptidyl peptidase-4 (DPP4) inhibitors are frequently prescribed for patients with type 2 diabetes; however, their cost can pose a significant barrier for those with impaired kidney function. This study aimed to estimate the economic benefits of substituting non-renal dose-adjusted (NRDA) DPP4 inhibitors with renal dose-adjusted (RDA) DPP4 inhibitors in patients with both impaired kidney function and type 2 diabetes. METHODS: This retrospective cohort study was conducted from January 1, 2012 to December 31, 2018, using data obtained from common data models of five medical centers in Korea. Model 1 applied the prescription pattern of participants with preserved kidney function to those with impaired kidney function. In contrast, model 2 replaced all NRDA DPP4 inhibitors with RDA DPP4 inhibitors, adjusting the doses of RDA DPP4 inhibitors based on individual kidney function. The primary outcome was the cost difference between the two models. RESULTS: In total, 67,964,996 prescription records were analyzed. NRDA DPP4 inhibitors were more frequently prescribed to patients with impaired kidney function than in those with preserved kidney function (25.7%, 51.3%, 64.3%, and 71.6% in patients with estimated glomerular filtration rates [eGFRs] of ≥60, <60, <45, and <30 mL/min/1.73 m2, respectively). When model 1 was applied, the cost savings per year were 7.6% for eGFR <60 mL/min/1.73 m2 and 30.4% for eGFR <30 mL/min/1.73 m2. According to model 2, 15.4% to 51.2% per year could be saved depending on kidney impairment severity. CONCLUSION: Adjusting the doses of RDA DPP4 inhibitors based on individual kidney function could alleviate the economic burden associated with medical expenses.
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Diabetes Mellitus Tipo 2 , Inhibidores de la Dipeptidil-Peptidasa IV , Insuficiencia Renal Crónica , Humanos , Inhibidores de la Dipeptidil-Peptidasa IV/economía , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/economía , Diabetes Mellitus Tipo 2/complicaciones , Estudios Retrospectivos , Masculino , Insuficiencia Renal Crónica/economía , Femenino , Persona de Mediana Edad , Anciano , Análisis Costo-Beneficio , República de Corea , Tasa de Filtración GlomerularRESUMEN
DPP-IV inhibitors, which are close to the natural hypoglycemic pathway of human physiology and have few side effects, have been extensively employed in the management of type 2 diabetes mellitus (T2DM). However, there are currently no specific blood indicators that can indicate or predict a patient's suitability for DPP-IV inhibitors. In this study, based on the self-developed high-specificity fluorescent substrate glycyl-prolyl-N-butyl-4-amino-1, 8-naphthimide (GP-BAN), a detection method of human serum DPP-IV activity was established and optimized. The method demonstrates a favorable lower limit of detection (LOD) at 0.32â¯ng/mL and a satisfactory lower limit of quantification (LOQ) of 1.12â¯ng/mL, and can be used for the detection of DPP-IV activity in trace serum (2⯵L). In addition, Vitalliptin and Sitagliptin showed similar IC50 values when human recombinant DPP-IV and human serum were used as enzyme sources, and the intra-day and inter-day precision obtained by the microplate analyzer were less than 15â¯%. These results indicate that the microplate reader based detection technique has good accuracy, repeatability and reproducibility. A total of 700 volunteers were recruited, and 646 serum samples were tested for DPP-IV activity. The results showed that serum DPP-IV activity was higher in patients with T2DM than in controls (P < 0.01). However, the statistical data of family history of diabetes, gender and age of diabetic patients showed no statistical significance, and there was no contrast difference. The DPP-IV activity of serum in T2DM patients ranged from 2.4 µmol/min/L to 78.6 µmol/min/L, with a huge difference of up to 32-fold. These results suggest that it is necessary to test DPP-IV activity in patients with T2DM when taking DPP-IV inhibitors to determine the applicability of DPP-IV inhibitors in T2DM patients. These results suggest that it is necessary to detect the activity of DPP-IV in blood before taking DPP-IV inhibitors in patients with T2DM to judge the applicability of DPP-IV inhibitors in patients with T2DM.
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Diabetes Mellitus Tipo 2 , Dipeptidil Peptidasa 4 , Inhibidores de la Dipeptidil-Peptidasa IV , Límite de Detección , Fosfato de Sitagliptina , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/sangre , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Dipeptidil Peptidasa 4/sangre , Reproducibilidad de los Resultados , Masculino , Persona de Mediana Edad , Femenino , Espectrometría de Fluorescencia/métodos , Fluorescencia , Anciano , Adulto , Hipoglucemiantes/sangre , Hipoglucemiantes/uso terapéuticoRESUMEN
INTRODUCTION: Gliptins are a relatively recent class of oral antidiabetic agents used in the treatment of type 2 diabetes. The aim of this study is to identify the adverse effects of gliptins in patients with type 2 diabetes, compare the tolerability of these drugs with data from the literature, and determine patients' behavior in the face of these adverse effects with a view to optimizing their management. METHODS: Our study is cross-sectional, descriptive, and analytical, involving 100 patients aged over 20 years, followed at the Endocrinology Department of the Military Hospital Mohammed V. RESULTS: The average age of the patients was 63 years, with a sex ratio F/H of 1.13. The median age of diabetes in the patients was 13 years, with an average blood glucose level of 1.64 and an average hemoglobin A1c of 8.26. The comorbidities were 30% cardiovascular disease, 25% hypertension, and 14% dyslipidemia, and 30% of patients had no comorbidities. Forth-six percent of patients reported adverse events and 54% did not report any adverse event. Twenty-eight percent of the adverse events were gastrointestinal, 18% skin disorders, 14% urinary tract infections, 12% hypoglycemia, 12% nervous system disorders, 8% airway infections, and 8% general disorders. CONCLUSION: This study shows that gliptins remain a safe option as the side effects seem fairly well tolerated by patients. Adverse events may impact patient compliance and pose a problem of adherence to treatment. Thus, it would be advantageous to develop therapeutic education for diabetic patients to detect and manage adverse effects.
Résumé Introduction:Les gliptines sont une classe relativement récente d'antidiabétiques oraux utilisés dans le traitement du diabète de type 2. Le but de cette étude est d'identifier les effets indésirables des gliptines chez les patients diabétiques de type 2, de comparer la tolérance de ces médicaments avec les données de la littérature et de déterminer le comportement des patients face à ces effets indésirables afin d'optimiser leur prise en charge.Méthodes:Notre étude est transversale, descriptive et analytique, portant sur 100 patients âgés de plus de 20 ans, suivis au service d'endocrinologie de l'hôpital militaire Mohammed V.Résultats:L'âge moyen des patients était de 63 ans, avec un sex-ratio F/H de 1,13. L'âge médian d'apparition du diabète chez les patients était de 13 ans, avec une glycémie moyenne de 1,64 et une hémoglobine A1c moyenne de 8,26%. Les comorbidités étaient les suivantes: 30 % de maladies cardiovasculaires, 25 % d'hypertension et 14 % de dyslipidémie; 30 % des patients n'avaient aucune comorbidité. Quarante-six pour cent des patients ont signalé des effets indésirables et 54 % n'ont signalé aucun effet indésirable. Vingt-huit pour cent des effets indésirables étaient d'ordre gastro-intestinal, 18 % des troubles cutanés, 14 % des infections urinaires, 12 % des hypoglycémies, 12 % des troubles du système nerveux, 8 % des infections des voies respiratoires et 8 % des troubles généraux.Conclusion:Cette étude montre que les gliptines restent une option sûre car les effets secondaires semblent assez bien tolérés par les patients. Les effets indésirables peuvent avoir un impact sur la compliance des patients et poser un problème d'adhésion au traitement. Ainsi, il serait avantageux de développer l'éducation thérapeutique des patients diabétiques pour détecter et gérer les effets indésirables.
Asunto(s)
Diabetes Mellitus Tipo 2 , Hemoglobina Glucada , Hipoglucemiantes , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Masculino , Femenino , Persona de Mediana Edad , Estudios Transversales , Marruecos/epidemiología , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/uso terapéutico , Anciano , Adulto , Glucemia/efectos de los fármacos , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/inducido químicamente , Inhibidores de la Dipeptidil-Peptidasa IV/efectos adversos , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Hipoglucemia/inducido químicamente , Hipoglucemia/epidemiología , Hipertensión/epidemiologíaRESUMEN
AIMS: This systematic review was aimed to assess the association between magnitude of body weight loss (BWL) in type 2 diabetes (T2D) patients and cardiovascular (CV) risk in CV outcome trials (CVOTs). METHODS: We searched electronic databases (PubMed, Cochrane and Scopus) for available CVOTs, observational cohort studies or post hoc analyses of clinical trials of adult T2D patients investigated the association of BWL with CV outcomes and/or all-cause mortality. RESULTS: 19 RCTs of novel glucose-lowering drugs (GLP-1RA, DPP-4i and SGLT2i) and 6 RCT or observational trial of different strategies (intensive treatment or standard care) were included (379.904 T2D patients). Higher BWL during GLP-1RA treatment, in comaprison to lower BWL, was associated with higher decrease in risk of MACE, while DPP-4i had not that effect. With SGLT2i the higher decrease in risk of MACE was associated with lower BWL. In contrast, in other different strategies, higher BWL lead to increase in risk for MACE and all-cause mortality. CONCLUSIONS: In CVOTs, treatment of T2D patients resulted in BWL, which correlated with reduction in risk for CV outcomes, particularly with GLP-1 RAs. However, interventional non-CVOTs are warning that in the absence of structured behavioral intervention and relevant medication, the large BWL might be harmful for CV outcomes.
Asunto(s)
Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Hipoglucemiantes , Pérdida de Peso , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Enfermedades Cardiovasculares/prevención & control , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/epidemiología , Hipoglucemiantes/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéuticoRESUMEN
BACKGROUND: Dipeptidyl peptidase IV (DPP4) is a cell surface receptor that possesses numerous substrates implicated in tumor growth and metastasis. Prior studies have suggested an association between DPP4 inhibition and increased progression-free survival (PFS) and overall survival (OS) in colorectal and lung cancers but no benefit in breast or pancreatic cancers. However, no studies to date have explored the impact of DPP4 inhibitors (DPP4i) in patients with metastatic renal cell carcinoma (mRCC). In this study we present a first-time analysis examining the impact of DPP4i use on PFS and OS in patients with mRCC and type 2 diabetes mellitus. METHODS: We performed a retrospective analysis of patients with diabetes and mRCC at the University of Virginia. The study group comprised those whose diabetic regimen included a DPP4i during mRCC treatment. The control group comprised patients whose diabetic regimen did not include a DPP4i during treatment. Cox regression analysis was utilized to determine the hazard ratios of progression and death between groups. RESULTS: Fifty-nine patients were eligible for the study, with 11 in the DPP4i group and 48 in the control group. Cancer progression occurred in 81.8% of patients in the DPP4i group and 66.7% in the control group. No statistically significant differences on PFS (HR: 1.60 [95% CI, 0.75-3.43]) or OS (HR: 0.69 [95% CI, 0.28-1.70]) were found between groups. CONCLUSIONS: This retrospective study explored the effect of DPP4i on outcomes in patients with mRCC and diabetes. DPP4i have been shown to have favorable effects on PFS and OS in some cancers but not in others. The results of this study suggest that DPP4i do not confer clinical benefit in patients with mRCC. Larger studies are warranted to better elucidate the effect of DPP4i in mRCC and the mechanisms underlying differential tumor response to these agents in different malignancies.
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Carcinoma de Células Renales , Diabetes Mellitus Tipo 2 , Inhibidores de la Dipeptidil-Peptidasa IV , Neoplasias Renales , Humanos , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/mortalidad , Masculino , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/mortalidad , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Estudios Retrospectivos , Femenino , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Persona de Mediana Edad , Anciano , Supervivencia sin Progresión , Dipeptidil Peptidasa 4/metabolismo , Resultado del TratamientoRESUMEN
BACKGROUND: How a person's Parkinson disease (PD) risk is affected by dipeptidyl peptidase-4 (DPP-4) inhibitors remains unclear. We evaluated the association of PD risk with use of these inhibitors in individuals diagnosed as having diabetes mellitus (DM). METHODS: Individuals diagnosed as having new-onset DM were enrolled into the case group and comparison group, comprising patients who received a DPP-4 inhibitor and a sulfonylurea, respectively. These groups were matched through propensity score matching on the basis of income level, gender, urbanization level, enrollment year, age, and diabetes complications severity index score. The case group was divided into subgroups on the basis of whether they had a cumulative defined daily dose (cDDD) of <75, 75-150, or >150. The DPP-4 inhibitor-PD risk association was evaluated through a Cox proportional hazards model. The Bonferroni adjustment test was employed to adjust P-values and reduce the false positive rate. RESULTS: Compared with those in the comparison group (treatment with a sulfonylurea), patients with a DPP-4 inhibitor cDDD of >150 had a hazard ratio (HR) of 1.30 for PD development (95% confidence interval [CI]: 0.97-1.73; adjusted P = .263); the HRs for patients with a cDDD of <75 or 75-150 were 0.95 (95% CI: 0.71-1.27; adjusted P = .886) and 1.06 (95% CI: 0.75-1.50; adjusted P = .886), respectively. We noted nonsignificant differences regarding the associations between the use of the various DPP-4 inhibitors (linagliptin, saxagliptin, sitagliptin, and vildagliptin) and PD risk after adjustment for any individual inhibitor (adjusted P > .05). CONCLUSIONS: DPP-4 inhibitors were discovered in this study to not be associated with increased PD risk. This result was confirmed when the analysis was conducted individually for the 4 investigated DPP-4 inhibitors (sitagliptin, saxagliptin, linagliptin, and vildagliptin).
Asunto(s)
Inhibidores de la Dipeptidil-Peptidasa IV , Enfermedad de Parkinson , Humanos , Inhibidores de la Dipeptidil-Peptidasa IV/efectos adversos , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Masculino , Femenino , Estudios Retrospectivos , Anciano , Persona de Mediana Edad , Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Factores de Riesgo , Compuestos de Sulfonilurea/efectos adversos , Compuestos de Sulfonilurea/uso terapéuticoRESUMEN
OBJECTIVE: To compare the risk of dementia associated with sodium-glucose cotransporter-2 (SGLT-2) inhibitors versus dipeptidyl peptidase-4 (DPP-4) inhibitors in adults aged 40-69 years with type 2 diabetes. DESIGN: Population based cohort study. SETTING: Korean National Health Insurance Service data, 2013-21. PARTICIPANTS: 110 885 propensity score matched pairs of adults with type 2 diabetes aged 40-69 years who were initiators of either an SGLT-2 inhibitor or a DPP-4 inhibitor. MAIN OUTCOME MEASURES: The primary outcome was new onset dementia. Secondary outcomes were dementia requiring drug treatment and individual types of dementia, including Alzheimer's disease and vascular dementia. Control outcomes were genital infections (positive), and osteoarthritis related clinical encounters and cataract surgery (negative). Hazard ratios and 95% confidence intervals (CIs) were estimated using Cox models. Follow-up time stratified analyses (>2 years and ≤2 years) and subgroup analyses by age, sex, concomitant use of metformin, and baseline cardiovascular risk were performed. RESULTS: 110 885 propensity score matched pairs of initiators of an SGLT-2 inhibitor or a DPP-4 inhibitor were followed-up for a mean 670 (standard deviation 650) days, generating 1172 people with newly diagnosed dementia: incidence rate 0.22 per 100 person years in initiators of SGLT-2 inhibitors and 0.35 per 100 person years in initiators of DPP-4 inhibitors, with hazard ratios of 0.65 (95% CI 0.58 to 0.73) for dementia, 0.54 (0.46 to 0.63) for dementia requiring drugs, 0.61 (0.53 to 0.69) for Alzheimer's disease, and 0.48 (0.33 to 0.70) for vascular dementia. The hazard ratios for the control outcomes were 2.67 (2.57 to 2.77) for genital infections, 0.97 (0.95 to 0.98) for osteoarthritis related encounters, and 0.92 (0.89 to 0.96) for cataract surgery. When calibrated for residual confounding measured by cataract surgery, the hazard ratio for dementia was 0.70 (0.62 to 0.80). The association was greater for more than two years of treatment (hazard ratio of dementia 0.57, 95% CI 0.46 to 0.70) than for two years or less (0.52, 0.41 to 0.66) and persisted across subgroups. CONCLUSION: SGLT-2 inhibitors might prevent dementia, providing greater benefits with longer treatment. As this study was observational and therefore prone to residual confounding and informative censoring, the effect size could have been overestimated. Randomised controlled trials are needed to confirm these findings.
Asunto(s)
Demencia , Diabetes Mellitus Tipo 2 , Inhibidores de la Dipeptidil-Peptidasa IV , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/epidemiología , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Inhibidores de la Dipeptidil-Peptidasa IV/efectos adversos , Persona de Mediana Edad , Femenino , Masculino , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Demencia/epidemiología , Anciano , Adulto , República de Corea/epidemiología , Estudios de Cohortes , Puntaje de Propensión , Factores de Riesgo , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/efectos adversos , Incidencia , Modelos de Riesgos ProporcionalesRESUMEN
In this study, double enzyme hydrolysis significantly enhanced the DPP-IV inhibition rate compared to single enzyme. The α + K enzymes exhibited the highest inhibition rate. Ultrasonic pretreatment for 30 min improved the hydrolysis efficiency and DPP-IV inhibition rate, potentially due to the structural changes in hydrolysates, such as the increased surface hydrophobicity, and reduced particle size, α-helix and ß-turn. Six peptides were screened and verified in vitro. QPY, WPEYL, and YPPQVM displayed competitive inhibition, while LPAAP and IPAPSFPRL displayed mixed competitive/non-competitive inhibition. The interactions between these six peptides and DPP-IV primarily occurred through hydrogen bonds, electrostatic and hydrophobic interactions. Network pharmacological analysis indicated that LPAAP might inhibit DPP-IV activity trough interactions with diabetes-related targets such as CASP3, HSP90AA1, MMP9, and MMP9. These results uncover the potential mechanism of regulating blood glucose by camel milk hydrolysates, establishing camel milk peptide as a source of DPP-IV inhibitory peptide.
Asunto(s)
Camelus , Dipeptidil Peptidasa 4 , Inhibidores de la Dipeptidil-Peptidasa IV , Leche , Péptidos , Animales , Dipeptidil Peptidasa 4/química , Dipeptidil Peptidasa 4/metabolismo , Leche/química , Inhibidores de la Dipeptidil-Peptidasa IV/química , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Péptidos/química , Péptidos/farmacología , Hidrólisis , Interacciones Hidrofóbicas e Hidrofílicas , Secuencia de Aminoácidos , HumanosRESUMEN
OBJECTIVE: To assess the risk of all-cause mortality and major adverse cardiovascular events (MACE) in patients with immune-mediated inflammatory diseases (IMIDs) and type 2 diabetes newly initiating glucagon-like peptide-1 receptor agonists (GLP-1-RAs) versus dipeptidyl peptidase-4 inhibitors (DPP-4is). METHODS: We performed a population-based cohort study using administrative health data from British Columbia. Patients with an IMID (i.e., rheumatoid arthritis, psoriatic disease, ankylosing spondylitis, inflammatory bowel disease, or a systemic autoimmune rheumatic disease) and type 2 diabetes who newly initiated a GLP-1-RA or DPP-4i between January 1, 2010, and December 31, 2021 were identified using ICD-9/10 codes. The primary outcome was all-cause mortality. Secondary outcomes included MACE and its components (i.e., cardiovascular death, myocardial infarction, and ischemic stroke). Cox proportional hazard regressions were used with propensity score overlap weighting. The analysis was repeated in age- and sex-matched adults without IMIDs. RESULTS: We identified 10,855 adults with IMIDs and type 2 diabetes who newly initiated a GLP-1-RA or DPP-4i. All-cause mortality rate was lower among initiators of GLP-1-RAs compared to initiators of DPP-4is, with a weighted hazard ratio (HR) of 0.48 (95% confidence interval [CI], 0.31-0.75) and rate difference (RD) of -9.4 (95% CI, -16.0 to -2.7) per 1000 person-years. Rate of MACE was also lower with GLP-1-RA exposure (HR 0.66 [0.50-0.88], RD -10.5 [-20.4 to -0.8]). Effect sizes were similar in adults without IMIDs. CONCLUSION: In patients with IMIDs and type 2 diabetes, GLP-1-RA exposure is associated with a lower risk of all-cause mortality and MACE compared to a cardioneutral active comparator.