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Background: Antidiabetic drugs are widely used in clinical practice as essential drugs for the treatment of diabetes. The effect of hypoglycemic drugs on erectile dysfunction has not been fully proven due to the presence of multiple confounding factors. Methods: Two-sample Mendelian randomization (TSMR) was used to examine the causal effect of antidiabetic drugs (including metformin, insulin and gliclazide) on erectile dysfunction. We used five robust analytic methods, of which the inverse variance weighting (IVW) method was the primary method, and also assessed factors such as sensitivity, pleiotropy, and heterogeneity. Effect statistics for exposures and outcomes were downloaded from publicly available data sets, including open Genome-Wide Association Studies (GWAS) and the UK Biobank (UKB). Results: In some of the hypoglycemic drug use, there was a significant causal relationship between metformin use and erectile dysfunction [Beta: 4.9386; OR:1.396E+02 (95% CI:9.13-2135); p-value: 0.0004), suggesting that metformin increased the risk of erectile dysfunction development. Also, we saw that gliclazide use also increased the risk of erectile dysfunction [Beta: 11.7187; OR:0.0125 (95% CI:12.44-1.21E+09); P value: 0.0125). There was no significant causal relationship between insulin use and erectile dysfunction [Beta: 3.0730; OR:21.6071 (95% CI:0.24-1942.38); p-value: 0.1806).Leave-one-out, MR-Egger, and MR-PRESSO analyses produced consistent results. Conclusion: The use of metformin and gliclazide have the potential to increase the risk of erectile dysfunction. There is no causal relationship between the use of insulin and erectile dysfunction.
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Disfunción Eréctil , Hipoglucemiantes , Análisis de la Aleatorización Mendeliana , Metformina , Humanos , Masculino , Disfunción Eréctil/inducido químicamente , Disfunción Eréctil/epidemiología , Hipoglucemiantes/efectos adversos , Metformina/efectos adversos , Metformina/uso terapéutico , Estudio de Asociación del Genoma Completo , Insulina/efectos adversos , Gliclazida/efectos adversos , Gliclazida/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/genéticaRESUMEN
BACKGROUND: Pre-diabetes is an important risk factor for the development of type 2 diabetes and is common in Nigeria. Effective intervention can reverse the underlying pathogenesis of insulin resistance in pre-diabetes. This study aimed to determine and compare the impact of moderate exercise and metformin interventions on insulin resistance among participants with pre-diabetes. MATERIALS AND METHODS: Using a randomised placebo-controlled design, 54 Nigerians with pre-diabetes were selected using simple random sampling. They were offered metformin, moderate exercise or placebo treatment and followed up for 12 weeks. Insulin resistance was assessed before and after the interventions and the outcome was compared. RESULTS: Forty-nine participants with pre-diabetes completed the study. Participants in both the exercise and metformin groups had significantly decreased insulin resistance compared to placebo after 12 weeks of intervention. However, there was a decrease in insulin resistance by 77.3% (homeostasis model assessment-insulin resistance [HOMA-IR]) and an increase in insulin sensitivity by 81.2% (quantitative insulin sensitivity check index [QUICKI]) in the exercise group. In comparison, participants in the metformin group had a decrease in insulin resistance by 66.3% (HOMA-IR) and an increase in insulin sensitivity by 76.2% (QUICKI). CONCLUSION: Amongst Nigerians with pre-diabetes, both moderate exercise and metformin have significantly higher efficacy than placebo in improving insulin resistance. However, moderate exercise improved insulin resistance more than the metformin intervention. Participants in this study need to be followed up for a longer period to assess the long-term effects of these interventions.
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Hipoglucemiantes , Resistencia a la Insulina , Metformina , Estado Prediabético , Humanos , Metformina/uso terapéutico , Femenino , Masculino , Estado Prediabético/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/farmacología , Nigeria , Adulto , Persona de Mediana Edad , Ejercicio Físico/fisiología , Glucemia/metabolismo , Glucemia/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Terapia por Ejercicio/métodos , Resultado del Tratamiento , Pueblo de África OccidentalRESUMEN
Objective: To determine the prevalence of non-alcoholic fatty liver disease, and the effect of oral hypoglycaemic drugs and lifestyle modifications in reducing fatty liver changes and liver enzymes in these patients. METHODS: The comparative, observational study was conducted at the Department of Pharmacology, Sohail University, Karachi, from October 2022 to October 2023, and comprised patients of either gender having elevated liver enzymes and ultrasound finding of fatty liver changes along with raised glycated haemoglobin, transaminases, total cholesterol and triglycerides. The participants were prescribed oral hypoglycaemic agents by endocrinologists. Those given empaglifazolin + metformin were in group A, empaglifazolin + linglaptin in group B, sitaglaptin + metformin in group C, metformin alone in group D and sitaglaptin alone in group E. Lifestyle modifications were advised in all the treatment groups, while control group F was only advised lifestyle modifications. The intervention lasted 3 months. Investigations included B-mode ultrasound liver, liver enzymes and glycated haemoglobin, which were done at baseline and after the intervention. Data was analysed using SPSS 25. RESULTS: Of 200 patients, 40 were males and 160 were females in ratio of 1:4. The overall mean age was 48±16 years. There were 154(77%) patients who had non-alcoholic fatty liver disease with type 2 diabetes mellitus, while 46(23%) had only fatty liver changes. There were 50(25%) patients in group A, 30(15%) in group B, 30(15%) in group C, 40(20%) in group D, 10(5%) in group E and 40(20%) in group F. Post-intervention improvement was noted in 48(24%) patients, with 20(41.7%) of them being in group A. Conclusion: The prevalence of non-alcoholic fatty liver disease with type 2 diabetes was high. Combination of empagliflozin + metformin along with lifestyle modifications was highly effective in reducing fatty changes and the level of liver enzymes.
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Diabetes Mellitus Tipo 2 , Hipoglucemiantes , Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Masculino , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Femenino , Persona de Mediana Edad , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/administración & dosificación , Adulto , Metformina/uso terapéutico , Metformina/administración & dosificación , Hemoglobina Glucada/metabolismo , Ultrasonografía , Hígado/diagnóstico por imagen , Hígado/efectos de los fármacos , Administración Oral , Pakistán/epidemiologíaAsunto(s)
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
OBJECTIVE: Aim: This study aims to evaluate how various factors affect various aspects of glycemic control in individuals with type 2 diabetes who are undergoing metformin treatment. PATIENTS AND METHODS: Materials and Methods: A cross-sectional study involved 150 participants who met specific criteria, including being aged between 30 and 70, having a type 2 diabetes diagnosis, and using 1000 mg of metformin as the monotherapy for at least three months. Collected data encompassed various measures, such as levels of glycated hemoglobin (HbA1c), fasting blood glucose concentrations, fasting serum insulin levels, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), and insulin sensitivity. RESULTS: Results: Our research reveals that when it comes to factors such as several socio-demographic variables, there is no statistically significant difference (p-value ≥ 0.05) between patients who exhibit a positive response to metformin and those who do not. Nevertheless, distinctions were noted in patients' previous history and the duration of their illness, which did influence their treatment response. CONCLUSION: Conclusions: Glycemic parameters in individuals with type 2 diabetes can be impacted by a range of factors, such as age, gender, and occupation also it's important to note that these outcomes influenced by additional variables like the adherence for medication, and the existence of diabetes-related complications.
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Diabetes Mellitus Tipo 2 , Hipoglucemiantes , Metformina , Humanos , Metformina/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Femenino , Masculino , Persona de Mediana Edad , Estudios Transversales , Hipoglucemiantes/uso terapéutico , Adulto , Anciano , Hemoglobina Glucada/análisis , Factores Sexuales , Glucemia/metabolismo , Glucemia/análisis , Factores de Edad , Resistencia a la InsulinaRESUMEN
OBJECTIVE: Aim: To assess the impact of BMI and diet control on variation in response to metformin monotherapy in Iraqi people with type 2 DM. PATIENTS AND METHODS: Materials and Methods: a cross-sectional study included 150 patients who met specific criteria, such as being between 30 and 70 years old, diagnosed with type 2 diabetes, and on a daily dose of 1000 mg metformin as a monotherapy for at least three months. Data collected included body mass index (BMI) and glycemic control parameters such as: glycated hemoglobin (HbA1c) levels, fasting blood glucose levels, fasting serum insulin levels, HOMA-IR, and insulin sensitivity. The patients according to their metformin response classified into two groups based on HbA1c as following: poor (HbA1c≥6.5% and good (HbA1c≤6.5%) responder's patients. RESULTS: Results: The statistical analysis suggests that there is no meaningful distinction in glycemic control parameters when comparing good and poor responders within specific BMI subgroups and among individuals practicing diet control. However, in a broader context, it is evident that glycemic control parameters tend to be lower in patients with lower BMI and those who are following a controlled diet. CONCLUSION: Conclusions: The correlation between diet control and BMI with glycemic control in diabetic patients, underscoring the significance of lifestyle adjustments in the management of diabetes.
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Índice de Masa Corporal , Diabetes Mellitus Tipo 2 , Hipoglucemiantes , Metformina , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/sangre , Metformina/uso terapéutico , Metformina/administración & dosificación , Persona de Mediana Edad , Masculino , Femenino , Estudios Transversales , Anciano , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/administración & dosificación , Adulto , Glucemia/metabolismo , Hemoglobina Glucada/análisis , Irak , Control GlucémicoRESUMEN
The goal of our study was to identify and assess the functionally significant SNPs with potentially important roles in the development of type 2 diabetes mellitus (T2DM) and/or their effect on individual response to antihyperglycemic medication with metformin. We applied a bioinformatics approach to identify the regulatory SNPs (rSNPs) associated with allele-asymmetric binding and expression events in our paired ChIP-seq and RNA-seq data for peripheral blood mononuclear cells (PBMCs) of nine healthy individuals. The rSNP outcomes were analyzed using public data from the GWAS (Genome-Wide Association Studies) and Genotype-Tissue Expression (GTEx). The differentially expressed genes (DEGs) between healthy and T2DM individuals (GSE221521), including metformin responders and non-responders (GSE153315), were searched for in GEO RNA-seq data. The DEGs harboring rSNPs were analyzed using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). We identified 14,796 rSNPs in the promoters of 5132 genes of human PBMCs. We found 4280 rSNPs to associate with both phenotypic traits (GWAS) and expression quantitative trait loci (eQTLs) from GTEx. Between T2DM patients and controls, 3810 rSNPs were detected in the promoters of 1284 DEGs. Based on the protein-protein interaction (PPI) network, we identified 31 upregulated hub genes, including the genes involved in inflammation, obesity, and insulin resistance. The top-ranked 10 enriched KEGG pathways for these hubs included insulin, AMPK, and FoxO signaling pathways. Between metformin responders and non-responders, 367 rSNPs were found in the promoters of 131 DEGs. Genes encoding transcription factors and transcription regulators were the most widely represented group and many were shown to be involved in the T2DM pathogenesis. We have formed a list of human rSNPs that add functional interpretation to the T2DM-association signals identified in GWAS. The results suggest candidate causal regulatory variants for T2DM, with strong enrichment in the pathways related to glucose metabolism, inflammation, and the effects of metformin.
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Diabetes Mellitus Tipo 2 , Estudio de Asociación del Genoma Completo , Metformina , Polimorfismo de Nucleótido Simple , Humanos , Metformina/farmacología , Metformina/uso terapéutico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/farmacología , Sitios de Carácter Cuantitativo , Biología Computacional/métodos , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Regiones Promotoras Genéticas , MultiómicaRESUMEN
As the most common and aggressive primary malignant brain tumor, glioblastoma is still lacking a satisfactory curative approach. The standard management consisting of gross total resection followed by radiotherapy and chemotherapy with temozolomide only prolongs patients' life moderately. In recent years, many therapeutics have failed to give a breakthrough in GBM treatment. In the search for new treatment solutions, we became interested in the repurposing of existing medicines, which have established safety profiles. We focused on the possible implementation of well-known drugs, metformin, and arginine. Metformin is widely used in diabetes treatment, but arginine is mainly a cardiovascular protective drug. We evaluated the effects of metformin and arginine on total DNA methylation, as well as the oxidative stress evoked by treatment with those agents. In glioblastoma cell lines, a decrease in 5-methylcytosine contents was observed with increasing drug concentration. When combined with temozolomide, both guanidines parallelly increased DNA methylation and decreased 8-oxo-deoxyguanosine contents. These effects can be explained by specific interactions of the guanidine group with m5CpG dinucleotide. We showed that metformin and arginine act on the epigenetic level, influencing the foreground and potent DNA regulatory mechanisms. Therefore, they can be used separately or in combination with temozolomide, in various stages of disease, depending on desired treatment effects.
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Arginina , Metilación de ADN , Reposicionamiento de Medicamentos , Glioblastoma , Metformina , Temozolomida , Metformina/farmacología , Metformina/uso terapéutico , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Humanos , Arginina/metabolismo , Reposicionamiento de Medicamentos/métodos , Metilación de ADN/efectos de los fármacos , Línea Celular Tumoral , Temozolomida/uso terapéutico , Temozolomida/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Estrés Oxidativo/efectos de los fármacos , Epigénesis Genética/efectos de los fármacos , 5-Metilcitosina/metabolismo , 5-Metilcitosina/análogos & derivadosRESUMEN
Background and aims: To analyze the effect of oral metformin on changes in gut microbiota characteristics and metabolite composition in normal weight type 2 diabetic patients. Methods: T2DM patients in the cross-sectional study were given metformin for 12 weeks. Patients with unmedicated T2DM were used as a control group to observe the metrics of T2DM patients treated with metformin regimen. 16S rDNA high-throughput gene sequencing of fecal gut microbiota of the study subjects was performed by llumina NovaSeq6000 platform. Targeted macro-metabolomics was performed on 14 cases of each of the gut microbiota metabolites of the study subjects using UPLC-MS/MS technology. Correlations between the characteristics of the gut microbiota and its metabolites, basic human parameters, glycolipid metabolism indicators, and inflammatory factors were analyzed using spearman analysis. Results: Glycolipid metabolism indexes and inflammatory factors were higher in normal-weight T2DM patients than in the healthy population (P<0.05), but body weight, BMI, waist circumference, and inflammatory factor concentrations were lower in normal-weight T2DM patients than in obese T2DM patients (P<0.05). Treatment with metformin in T2DM patients improved glycolipid metabolism, but the recovery of glycolipid metabolism was more pronounced in obese T2DM patients. None of the differences in α-diversity indexes were statistically significant (P>0.05), and the differences in ß-diversity were statistically significant (P <0.05). Community diversity and species richness recovered after metformin intervention compared to before, and were closer to the healthy population. We found that Anaerostipes/Xylose/Ribulose/Xylulose may play an important role in the treatment of normal-weight T2DM with metformin by improving glycemic lipids and reducing inflammation. And Metformin may play a role in obese T2DM through Romboutsia, medium-chain fatty acids (octanoic acid, decanoic acid, and dodecanoic acid). Conclusion: Gut microbial dysbiosis and metabolic disorders were closely related to glucose-lipid metabolism and systemic inflammatory response in normal-weight T2DM patients. Metformin treatment improved glucose metabolism levels, systemic inflammation levels in T2DM patients, closer to the state of healthy population. This effect may be mediated by influencing the gut microbiota and microbial host co-metabolites, mainly associated with Anaerostipes and xylose/Ribulose/Xylulose. Metformin may exert its effects through different pathways in normal-weight versus obese T2DM patients.
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Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Hipoglucemiantes , Metformina , Humanos , Metformina/uso terapéutico , Metformina/farmacología , Metformina/administración & dosificación , Microbioma Gastrointestinal/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/microbiología , Masculino , Femenino , Persona de Mediana Edad , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/farmacología , Estudios Transversales , Adulto , Administración Oral , Heces/microbiología , Heces/químicaRESUMEN
Recently, a health-care database study showed that persons with type 2 diabetes taking GLP-1 receptor agonists (GLP-1 RA) had a significantly lower risk of 10 out of 13 obesity-related cancers than patients taking insulin (Wang L, et al. JAMA Netw Open. 2024 7: e2421305). For some cancers, hazard ratios <0.5 were reported. This is reminiscent of studies published >10 years ago showing that people with type 2 diabetes taking metformin had a lower risk of many types of cancer than those not taking metformin. In some studies, also risk reductions of >50 % were reported. The strong effects observed in the metformin studies were explained by time-related biases, in particular, immortal time bias. In the current GLP-1 RA study, it was striking that the curves for the cumulative incidence of several cancers in GLP-1 RA and insulin users diverged immediately after therapy onset. This indicates that there is most likely a time-related bias: insulin is given at much later stages of type 2 diabetes than GLP-1 RA. The current study suggests that one should be sceptical about database results when spectacular risk reductions are reported. Time-related bias should always be considered as an alternative explanation.
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Diabetes Mellitus Tipo 2 , Receptor del Péptido 1 Similar al Glucagón , Hipoglucemiantes , Metformina , Neoplasias , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/complicaciones , Receptor del Péptido 1 Similar al Glucagón/agonistas , Metformina/uso terapéutico , Hipoglucemiantes/uso terapéutico , Neoplasias/epidemiología , Insulina/uso terapéutico , Incidencia , Sesgo , Agonistas Receptor de Péptidos Similares al GlucagónRESUMEN
BACKGROUND: Antidiabetic therapies are effective, but could indirectly modify the inflammatory response in the ocular microenvironment; therefore, a study was developed to evaluate the inflammatory cytokine profile in the vitreous humor of diabetic patients with retinopathy under treatment with antidiabetic drugs. METHODS: Observational, comparative, retrospective, cross-sectional study. Interleukins 1ß, 6, 8, 10, and tumor necrosis factor-alpha (TNFα) were evaluated in the vitreous humor obtained from patients with type 2 diabetes mellitus, proliferative diabetic retinopathy, and concomitant retinal detachment or vitreous hemorrhage, and who were already on antidiabetic treatment with insulin or metformin + glibenclamide. The quantification analysis of each cytokine was performed by the cytometric bead array (CBA) technique; medians and interquartile ranges were obtained, and the results were compared between groups using the Mann-Whitney U test, where a p-value < 0.05 was considered significant. RESULTS: Thirty-eight samples; quantification of TNFα concentrations was higher in the group of patients administered insulin, while interleukin-8 was lower; in the metformin + glibenclamide combination therapy group, it occurred inversely. In the stratified analysis, the highest concentrations of interleukin-8 and TNFα occurred in patients with vitreous hemorrhage; however, the only statistical difference existed in patients with retinal detachment, whose TNFα concentration in the combined therapy group was the lowest value found (53.50 (33.03-86.66), p = 0.03). Interleukins 1ß, 6, and 10 were not detected. CONCLUSION: Interleukin-8 and TNFα concentrations are opposite between treatment groups; this change is more accentuated in patients with proliferative diabetic retinopathy and vitreous hemorrhage, where the highest concentrations of both cytokines are found, although only TNFα have statistical difference.
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Diabetes Mellitus Tipo 2 , Retinopatía Diabética , Hipoglucemiantes , Interleucina-8 , Factor de Necrosis Tumoral alfa , Cuerpo Vítreo , Humanos , Retinopatía Diabética/tratamiento farmacológico , Retinopatía Diabética/metabolismo , Masculino , Cuerpo Vítreo/metabolismo , Femenino , Persona de Mediana Edad , Estudios Transversales , Factor de Necrosis Tumoral alfa/metabolismo , Estudios Retrospectivos , Hipoglucemiantes/uso terapéutico , Anciano , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Interleucina-8/metabolismo , Insulina/uso terapéutico , Metformina/uso terapéutico , Gliburida/uso terapéutico , Quimioterapia CombinadaRESUMEN
Recently, in Hepatocellular carcinoma (HCC) setting, the use of metformin has been associated to a trend toward worse response rate, overall survival and progression free survival in patients who received immunotherapy. The study population included individuals from both Eastern and Western regions with a confirmed diagnosis of HCC and receiving first line treatment with Atezolizumab plus bevacizumab or Lenvatinib. Univariate and multivariate analyses were performed by Cox proportional. For the analysis, patients were stratified based on their use of concomitant medication or not. At the time of database lock, 319 deaths were observed: 209 in the Lenvatinib cohort, 110 in the Atezolizumab plus bevacizumab cohort. In the Atezolizumab plus Bevacizumab arm, 50 (16.5%) patients were on chronic metformin use. At the univariate analysis for OS, patients who used metformin showed significantly shorter OS compared to patients who did not use metformin (HR 1.9, 95% CI 1.1-3.2). Multivariate analysis confirmed that patients in metformin group had significantly shorter OS compared to patients in no-metformin group (HR 1.9; 95% CI 1.1-3.1). At the univariate analysis for PFS, patients in metformin group had significantly shorter PFS compared to patients in no-metformin group (HR 1.6, 95% CI 1.0-2.6). Multivariate analysis confirmed that patients in metformin group had significantly shorter PFS compared to patients in no-metformin group (HR 1.7; 95% CI 1.1-2.7; p = 0.0147). No differences were reported in terms of ORR and DCR between patients in metformin group and those in no-metformin group. In the Lenvatinib cohort, 65 (15%) patients were recorded to chronically use metformin. No statistically significant differences in terms of both OS and PFS were found between patients in metformin group and patients in no-metformin group. This analysis unveils a negative prognostic role associated with metformin use specifically within the Atezolizumab plus Bevacizumab group.
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Anticuerpos Monoclonales Humanizados , Aspirina , Bevacizumab , Carcinoma Hepatocelular , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Insulina , Neoplasias Hepáticas , Metformina , Compuestos de Fenilurea , Quinolinas , Humanos , Metformina/uso terapéutico , Metformina/administración & dosificación , Masculino , Femenino , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Bevacizumab/uso terapéutico , Bevacizumab/administración & dosificación , Quinolinas/uso terapéutico , Quinolinas/administración & dosificación , Anciano , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/mortalidad , Persona de Mediana Edad , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/mortalidad , Pronóstico , Insulina/uso terapéutico , Compuestos de Fenilurea/uso terapéutico , Compuestos de Fenilurea/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Aspirina/uso terapéutico , Aspirina/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Estudios Retrospectivos , Anciano de 80 o más AñosAsunto(s)
Síndrome del Cromosoma X Frágil , Metformina , Metformina/uso terapéutico , Metformina/farmacología , Síndrome del Cromosoma X Frágil/tratamiento farmacológico , Síndrome del Cromosoma X Frágil/genética , Animales , Ratones , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/farmacología , Modelos Animales de Enfermedad , HumanosRESUMEN
Liver fibrosis is a pathological process that endangers human health, for which effective treatments remain elusive to date. Paeoniflorin (PAE), a pineane-type monoter penoid compound from the traditional Chinese medicine PaeoniaeRubra Radix, and metformin (MET), an oral biguanide hypoglycemic agent, both demonstrate anti-inflammatory and hepatoprotective effects. In current work, we first discovered that the combined treatment of PAE and MET synergistically inhibited the progression of liver fibrosis in two different animal models: therapeutic and preventive. This therapeutic effect is evidenced by a reduction in the expression levels of liver fibrosis markers and an improvement in histopathological characteristics. Mechanistic exploration further revealed that this combination therapy downregulated the expression of TGF-ß1 and p-Smad2, while upregulating Smad7 expression in both models. Importantly, we also found that this combinatorial approach significantly reduced hepatotoxicity and nephrotoxicity in both models. Our findings suggest an effective combination therapy for liver fibrosis and provide the possibility of therapeutic improvement for patients with liver fibrosis.
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Sinergismo Farmacológico , Glucósidos , Cirrosis Hepática , Metformina , Monoterpenos , Animales , Monoterpenos/farmacología , Monoterpenos/uso terapéutico , Monoterpenos/administración & dosificación , Glucósidos/farmacología , Glucósidos/uso terapéutico , Glucósidos/administración & dosificación , Metformina/farmacología , Metformina/uso terapéutico , Metformina/administración & dosificación , Ratones , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/patología , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/metabolismo , Masculino , Progresión de la Enfermedad , Ratones Endogámicos C57BL , Quimioterapia Combinada , Factor de Crecimiento Transformador beta1/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Proteína Smad2/metabolismo , Modelos Animales de EnfermedadRESUMEN
Metformin is a widely employed drug in type 2 diabetes. In addition to warranting good short- and long-term glycemic control, metformin displays many intriguing properties as protection against cardiovascular and neurodegenerative diseases, anti-tumorigenic and longevity promotion. In addition to being a low-cost drug, metformin is generally well tolerated. However, despite the enthusiastic drive to aliment these novel studies, many contradictory results suggest the importance of better elucidating the complexity of metformin action in different tissues/cells to establish its possible employment in neurodegenerative diseases. This review summarises recent data identifying lysosomal-dependent processes and lysosomal targets, such as endosomal Na+/H+ exchangers, presenilin enhancer 2 (PEN2), the lysosomal pathway leading to AMP-activated protein kinase (AMPK) activation, and the transcription factor EB (TFEB), modulated by metformin. Lysosomal dysfunctions resulting in autophagic and lysosomal acidification and biogenesis impairment appear to be hallmarks of many inherited and acquired neurodegenerative diseases. Lysosomes are not yet seen as a sort of cellular dump but are crucial in determining key signalling paths and processes involved in the clearance of aggregated proteins. Thus, the possibility of pharmacologically modulating them deserves great interest. Despite the potentiality of metformin in this context, many additional important issues, such as dosing, should be addressed in the future.
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Reposicionamiento de Medicamentos , Lisosomas , Metformina , Enfermedades Neurodegenerativas , Metformina/farmacología , Metformina/uso terapéutico , Humanos , Lisosomas/metabolismo , Lisosomas/efectos de los fármacos , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/metabolismo , Reposicionamiento de Medicamentos/métodos , Animales , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Autofagia/efectos de los fármacosRESUMEN
OBJECTIVES: To explore parameters that may determine the improvement in C-peptide levels in patients with type 2 diabetes (T2D) receiving continuous subcutaneous insulin infusion (CSII) therapy. METHODS: The trial included a lead-in period for collecting baseline parameters and correcting hyperglycemia, a 4-day CGM period, and a 2-3 weeks treatment period. After screening, patients were hospitalized and randomized to the metformin add-on NovoRapid group or the Prandilin group. Once the glycemic target was reached, all patients underwent a 4-day CGM, with treatments maintained for 2-3 weeks. OGTTs were performed at baseline and endpoint. The primary endpoint was identifying factors contributing to better ß-cell function recovery after CSII therapy. RESULTS: A total of 99 recruited patients were admitted as inpatients and achieved glycemic control within 3.8 ± 1.1 days. Of these, 83 (84 %) patients showed improvement in C-peptide levels, while 16 (16 %) did not show any change in C-peptide levels at the endpoint. Pearson analysis showed a negative correlation between the incremental AUC of glucose concentration (from 0700 to 1000) and the increase in incremental AUC of C-peptide levels (r = -0.199, P < 0.05). CONCLUSIONS: Drug-naïve T2D patients with lower postprandial glucose concentration during CSII therapy exhibit better ß-cell function recovery.
Asunto(s)
Glucemia , Péptido C , Diabetes Mellitus Tipo 2 , Hipoglucemiantes , Células Secretoras de Insulina , Insulina , Periodo Posprandial , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/sangre , Masculino , Femenino , Persona de Mediana Edad , Células Secretoras de Insulina/fisiología , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Glucemia/metabolismo , Glucemia/análisis , Insulina/administración & dosificación , Insulina/uso terapéutico , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/administración & dosificación , Periodo Posprandial/fisiología , Péptido C/sangre , Anciano , Sistemas de Infusión de Insulina , Metformina/uso terapéuticoRESUMEN
AIMS: To evaluate whether treatment with insulin is advantageous compared with oral anti-diabetic drugs (OAD) for patients newly diagnosed with type 2 diabetes with moderate hyperglycemia. METHODS: Patients newly diagnosed with type 2 diabetes with moderate hyperglycemia were recruited and randomized to receive insulin, metformin or sitagliptin treatment. The oral glucose tolerance test (OGTT) was performed before treatment and 6 months thereafter. The primary outcome was the glycohemoglobin (HbA1c) level change. For the secondary efficacy analysis, the ß-cell function and insulin sensitivity were calculated from the OGTT, as was the proportion of subjects who reached the treatment target (HbA1c level < 7.0 % or < 6.5 %) at 6 months. RESULTS: We randomized 50 patients to the three groups and 32 patients who received the allocated treatment were analyzed. The change of HbA1c level in the insulin, metformin, and sitagliptin groups was - 2.06 ± 1.37 %, -0.43 ± 0.32 %, and - 1.62 ± 0.92 %, respectively. This change was smallest in the metformin group. There was no significant difference in the changes or final HbA1c levels between the insulin and sitagliptin groups. The treat-to-target (HbA1c level < 7.0 %) rates in the insulin, metformin and sitagliptin were 75 %, 50 % and 100 %, respectively. The treat-to-target rates were not significantly different among the three groups. The insulin secretion indices, including the Matsuda index and HOMA-IR, indicated that the groups did not differ after 6 months of therapy. CONCLUSION: A 6-month course of basal insulin therapy did not benefit patients newly diagnosed with diabetes with moderate hyperglycemia in terms of insulin sensitivity or insulin secretion.
Asunto(s)
Glucemia , Diabetes Mellitus Tipo 2 , Hemoglobina Glucada , Hiperglucemia , Hipoglucemiantes , Células Secretoras de Insulina , Insulina , Metformina , Fosfato de Sitagliptina , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/sangre , Masculino , Femenino , Persona de Mediana Edad , Hipoglucemiantes/uso terapéutico , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/fisiología , Insulina/uso terapéutico , Metformina/uso terapéutico , Fosfato de Sitagliptina/uso terapéutico , Hemoglobina Glucada/metabolismo , Hemoglobina Glucada/análisis , Glucemia/metabolismo , Glucemia/efectos de los fármacos , Glucemia/análisis , Anciano , Control Glucémico , Prueba de Tolerancia a la GlucosaRESUMEN
Comorbidities in the elderly not only make them more susceptible to kidney disease, but also increase the risk of drug interactions due to polypharmacy. Such patients require regular kidney function tests when treated with renally excreted drugs. We conducted a retrospective study of post-mortem cases over a five- year period. Of 3040 toxicologically investigated cases, 3.8% had a history of renal failure. Thirteen deaths were directly attributable to inadequate drug dosing, 46% of which were related to lactic acidosis due to metformin accumulation. Appropriate dose adjustment could prevent fatal drug toxicity in patients with renal insufficiency.
Asunto(s)
Insuficiencia Renal , Humanos , Estudios Retrospectivos , Anciano , Alemania , Femenino , Masculino , Anciano de 80 o más Años , Persona de Mediana Edad , Metformina/efectos adversos , Metformina/administración & dosificación , Metformina/uso terapéuticoRESUMEN
Well-controlled type 1 diabetes (T1DM) is characterized by inflammation and endothelial dysfunction, thus constituting a suitable model of subclinical cardiovascular disease (CVD). miR-199b-5p overexpression in murine CVD has shown proatherosclerotic effects. We hypothesized that miR-199b-5p would be overexpressed in subclinical CVD yet downregulated following metformin therapy. Inflammatory and vascular markers were measured in 29 individuals with T1DM and 20 matched healthy controls (HCs). miR-199b-5p expression in CFU-Hill's colonies was analyzed from each study group, and correlations with inflammatory/vascular health indices were evaluated. Significant upregulation of miR-199b-5p was observed in T1DM, which was significantly downregulated by metformin. miR-199b-5p correlated positively with vascular endothelial growth factor-D and c-reactive protein (CRP: nonsignificant). ROC analysis determined miR-199b-5p to define subclinical CVD by discriminating between HCs and T1DM individuals. ROC analyses of HbA1c and CRP showed that the upregulation of miR-199b-5p in T1DM individuals defined subclinical CVD at HbA1c > 44.25 mmol and CRP > 4.35 × 106 pg/mL. Ingenuity pathway analysis predicted miR-199b-5p to inhibit the target genes SIRT1, ETS1, and JAG1. Metformin was predicted to downregulate miR-199b-5p via NFATC2 and STAT3 and reverse its downstream effects. This study validated the antiangiogenic properties of miR-199b-5p and substantiated miR-199b-5p overexpression as a biomarker of subclinical CVD. The downregulation of miR-199b-5p by metformin confirmed its cardio-protective effect.