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1.
Braz J Med Biol Res ; 53(1): e8652, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31859911

RESUMO

Glycemic variability (GV) may be linked to the development of diabetic complications by inducing inflammation, oxidative stress, and endothelial dysfunction. Flash glucose monitoring (FGM) provides a novel method of continuously monitoring interstitial glucose levels for up to 14 days. This study randomly assigned poorly controlled type 2 diabetes mellitus patients treated with metformin and multiple daily injections of insulin (n=60) to either continuous subcutaneous insulin infusion (CSII) treatment or CSII in combination with liraglutide (CSII+Lira) treatment for 14 days during hospitalization. GV was assessed using a FGM system; weight and cardiometabolic biomarkers were also evaluated. The coefficient of variation was significantly reduced in the CSII+Lira group (P<0.001), while no significant change was observed in the CSII group. The changes differed significantly between the two groups in mean amplitude of glycemic excursions (P=0.004), standard deviation (P=0.006), and the percentage of time in the target range (4-10 mmol/L, P=0.005 and >10 mmol/L, P=0.028). The changes in mean of daily differences, interquartile range, and percentage of time in hypoglycemia (<3.3 mmol/L) and hyperglycemia (>13.9 mmol/L) identified by FGM showed no difference. Treatment with liraglutide increased serum adiponectin [33.5 (3.5, 47.7) pg/mL, P=0.003] and heme oxygenase-1 levels [0.4 (-0.0, 1.8) ng/mL, P=0.001] and reduced serum leptin levels [-2.8 (3.9) pg/mL, P<0.001]. Adding the glucagon-like peptide-1 analog liraglutide improved GV, weight, and some cardiometabolic risk markers. The FGM system is, therefore, shown to be a novel and useful method for glucose monitoring.


Assuntos
Automonitorização da Glicemia/métodos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Sistemas de Infusão de Insulina , Insulina/administração & dosagem , Liraglutida/administração & dosagem , Adulto , Diabetes Mellitus Tipo 2/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto
2.
Endocrinol. diabetes nutr. (Ed. impr.) ; 66(6): 376-384, jun.-jul. 2019. graf, tab
Artigo em Inglês | IBECS | ID: ibc-182854

RESUMO

Introduction and objectives: The worldwide prevalence of type 2 diabetes mellitus increases in parallel to that of obesity. Liraglutide (LRG), a glucagon-like peptide-1 receptor agonist, can reduce body weight. This study assessed the metabolic efficacy of LRG in real-world clinical practice. Methods: An observational, retrospective cohort study including patients treated with LRG for at least one year (187 patients). Anthropometric and metabolic variables, a composite endpoint, factors predicting response to LRG, and cardiovascular risk over time were assessed. A linear mixed-effects model with a bivariate structure was constructed to investigate the time-dependent relationship between weight and HbA1c values. Results: HbA1c levels and weight significantly decreased in the first 12 weeks, and the decrease persisted at 12 and 24 months in all subgroups studied. Mean weight and HbA1c decreases after 24 months were 8.5kg and 1.7% respectively. HbA1c values <7% were achieved by 42% of patients at 12 months and by 40% at 24 months. Treatment with LRG allowed for reduction in insulin dose. No serious adverse events were noted. Cardiovascular risk decreased from high to moderate-low. Conclusions: Under standard clinical practice conditions, LRG achieved a better metabolic response than seen in clinical trials. Efficacy at 12 weeks of treatment is a good predictor of response. LRG allows for delaying or reducing insulin dose by improving both weight and glucose control. Cardiovascular risk improved


Introducción y objetivos: La prevalencia mundial de diabetes mellitus tipo 2 aumenta junto a la de la obesidad. Liraglutida (LRG), un agonista del receptor del péptido similar al GLP1, es un fármaco antidiabético capaz de reducir peso. Evaluamos en práctica clínica de vida real su eficacia metabólica. Método: Estudio de cohorte observacional retrospectivo. Se incluyeron los pacientes tratados al menos durante un año con LRG (187 pacientes). Evaluamos variables antropométricas, metabólicas, objetivos combinados, factores predictivos de respuesta y evolución del riesgo cardiovascular. Se construyó un modelo de efectos mixtos lineales de estructura bivariante para investigar la relación tiempo-dependiente entre el peso y los valores de HbA1c. Resultados: Descenso significativo de los valores de HbA1c y peso en las primeras 12 semanas de tratamiento, mantenido a los 12 y 24 meses, en todos los subgrupos estudiados. Reducción media de peso y HbA1c tras 24 meses de tratamiento de 8,5 kg y 1,7%. El valor de HbA1c fue <7% en 42% de pacientes a los 12 meses, 40% a los 24 meses. El tratamiento con LRG permitió reducir la dosis de insulina. No registramos eventos adversos graves. El riesgo cardiovascular mejoró. Conclusiones: Bajo condiciones de práctica clínica habitual la respuesta metabólica a LRG resultó mejor que la observada en ensayos clínicos. La eficacia a las 12 semanas de tratamiento es un buen predictor de respuesta. LRG permite retrasar o reducir la insulinoterapia. Los pacientes mejoraron su riesgo cardiovascular


Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Liraglutida/administração & dosagem , Doenças Cardiovasculares/prevenção & controle , Sistema Cardiovascular/efeitos dos fármacos , Perda de Peso/efeitos dos fármacos , Liraglutida/metabolismo , Estudos Retrospectivos , Estudos de Coortes , Antropometria , Insulina/uso terapêutico
3.
Clin Obes ; 9(4): e12323, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31183988

RESUMO

To assess the effectiveness of liraglutide 3.0 mg in post-bariatric surgery patients, and to determine whether this would differ based on the type of bariatric surgery. One hundred seventeen post-bariatric surgery patients from the Wharton Medical Clinic were analysed. Changes in weight while taking liraglutide 3.0 mg were examined for all patients, and by three types of bariatric surgery-Roux-en-Y gastric bypass, gastric banding and gastric sleeve. Patients primarily underwent Roux-en-Y gastric bypass (n = 53, 45.3%) or gastric banding (n = 50, 42.7%). Over 7.6 ± 7.1 months taking liraglutide 3.0 mg, patients lost a statistically significant amount of weight (-6.3 ± 7.7 kg, P < .05) regardless of the type of surgery they had (P > .05). This decrease in weight remained significant after 1-year of taking liraglutide 3.0 mg (P < .05). Nausea was the most prevalent side effect, reported by 29.1% patients. While options for excess weight management in post-bariatric surgery patients are limited, results of this study suggest that post-bariatric surgery patients can lose a significant amount of weight while taking liraglutide 3.0 mg regardless of the type of surgery they had. Further, similar to non-surgical populations, post-bariatric surgery patients taking liraglutide 3.0 mg may experience gastrointestinal side effects such as nausea and can continue to lose weight up to 1 year.


Assuntos
Liraglutida/administração & dosagem , Obesidade Mórbida/tratamento farmacológico , Obesidade Mórbida/cirurgia , Perda de Peso/efeitos dos fármacos , Adulto , Cirurgia Bariátrica , Índice de Massa Corporal , Terapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade Mórbida/fisiopatologia
4.
Lancet ; 394(10192): 39-50, 2019 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-31186120

RESUMO

BACKGROUND: Glucagon-like peptide-1 (GLP-1) receptor agonists are effective treatments for type 2 diabetes, lowering glycated haemoglobin (HbA1c) and weight, but are currently only approved for use as subcutaneous injections. Oral semaglutide, a novel GLP-1 agonist, was compared with subcutaneous liraglutide and placebo in patients with type 2 diabetes. METHODS: In this randomised, double-blind, double-dummy, phase 3a trial, we recruited patients with type 2 diabetes from 100 sites in 12 countries. Eligible patients were aged 18 years or older, with HbA1c of 7·0-9·5% (53-80·3 mmol/mol), on a stable dose of metformin (≥1500 mg or maximum tolerated) with or without a sodium-glucose co-transporter-2 inhibitor. Participants were randomly assigned (2:2:1) with an interactive web-response system and stratified by background glucose-lowering medication and country of origin, to once-daily oral semaglutide (dose escalated to 14 mg), once-daily subcutaneous liraglutide (dose escalated to 1·8 mg), or placebo for 52 weeks. Two estimands were defined: treatment policy (regardless of study drug discontinuation or rescue medication) and trial product (assumed all participants were on study drug without rescue medication) in all participants who were randomly assigned. The treatment policy estimand was the primary estimand. The primary endpoint was change from baseline to week 26 in HbA1c (oral semaglutide superiority vs placebo and non-inferiority [margin: 0·4%] and superiority vs subcutaneous liraglutide) and the confirmatory secondary endpoint was change from baseline to week 26 in bodyweight (oral semaglutide superiority vs placebo and liraglutide). Safety was assessed in all participants who received at least one dose of study drug. This trial is registered on Clinicaltrials.gov, number NCT02863419, and the European Clinical Trials registry, number EudraCT 2015-005210-30. FINDINGS: Between Aug 10, 2016, and Feb 7, 2017, 950 patients were screened, of whom 711 were eligible and randomly assigned to oral semaglutide (n=285), subcutaneous liraglutide (n=284), or placebo (n=142). 341 (48%) of 711 participants were female and the mean age was 56 years (SD 10). All participants were given at least one dose of study drug, and 277 (97%) participants in the oral semaglutide group, 274 (96%) in the liraglutide group, and 134 (94%) in the placebo group completed the 52-week trial period. Mean change from baseline in HbA1c at week 26 was -1·2% (SE 0·1) with oral semaglutide, -1·1% (SE 0·1) with subcutaneous liraglutide, and -0·2% (SE 0·1) with placebo. Oral semaglutide was non-inferior to subcutaneous liraglutide in decreasing HbA1c (estimated treatment difference [ETD] -0·1%, 95% CI -0·3 to 0·0; p<0·0001) and superior to placebo (ETD -1·1%, -1·2 to -0·9; p<0·0001) by use of the treatment policy estimand. By use of the trial product estimand, oral semaglutide had significantly greater decreases in HbA1c than both subcutaneous liraglutide (ETD -0·2%, 95% CI -0·3 to -0·1; p=0·0056) and placebo (ETD -1·2%, -1·4 to -1·0; p<0·0001) at week 26. Oral semaglutide resulted in superior weight loss (-4·4 kg [SE 0·2]) compared with liraglutide (-3·1 kg [SE 0·2]; ETD -1·2 kg, 95% CI -1·9 to -0·6; p=0·0003) and placebo (-0·5 kg [SE 0·3]; ETD -3·8 kg, -4·7 to -3·0; p<0·0001) at week 26 (treatment policy). By use of the trial product estimand, weight loss at week 26 was significantly greater with oral semaglutide than with subcutaneous liraglutide (-1·5 kg, 95% CI -2·2 to -0·9; p<0·0001) and placebo (ETD -4·0 kg, -4·8 to -3·2; p<0·0001). Adverse events were more frequent with oral semaglutide (n=229 [80%]) and subcutaneous liraglutide (n=211 [74%]) than with placebo (n=95 [67%]). INTERPRETATION: Oral semaglutide was non-inferior to subcutaneous liraglutide and superior to placebo in decreasing HbA1c, and superior in decreasing bodyweight compared with both liraglutide and placebo at week 26. Safety and tolerability of oral semaglutide were similar to subcutaneous liraglutide. Use of oral semaglutide could potentially lead to earlier initiation of GLP-1 receptor agonist therapy in the diabetes treatment continuum of care. FUNDING: Novo Nordisk A/S.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Liraglutida/administração & dosagem , Metformina/administração & dosagem , Administração Oral , Idoso , Peso Corporal/efeitos dos fármacos , Método Duplo-Cego , Feminino , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Humanos , Injeções Subcutâneas , Liraglutida/uso terapêutico , Masculino , Metformina/uso terapêutico , Pessoa de Meia-Idade , Resultado do Tratamento
5.
Pharm Res ; 36(7): 99, 2019 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-31087188

RESUMO

PURPOSE: To design and stabilize Liraglutide loaded poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) proper for oral administration. METHODS: PLGA NPs were prepared by means of double emulsion solvent evaporation method and optimized by applying 7-factor 2-level Plackett-Burman screening design. RESULTS: Spherical shaped NPs with homogeneous distribution, 188.95 nm particle size and 51.81% encapsulation efficiency were obtained. Liraglutide was successfully entrapped in the NPs while maintaining its native amorphous nature, and its structural integrity as well. CONCLUSION: Lira-PLGA NPs with the required Critical Quality Attributes (CQAs) were successfully designed by implementing a 7-factor 8-run Plackett Burman design into the extended Quality by Design (QbD) model, to elucidate the effect of formulation and process variables on the particle size, size-distribution, encapsulation efficiency and surface charge. As the developed nanoparticles maintained the native structure of the active pharmaceutical ingredient (API), they are promising compositions for the further development for the oral delivery of Lira. Graphical Abstract.


Assuntos
Portadores de Fármacos/química , Hipoglicemiantes/química , Liraglutida/química , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Administração Oral , Liberação Controlada de Fármacos , Emulsões , Hipoglicemiantes/administração & dosagem , Liraglutida/administração & dosagem , Tamanho da Partícula
6.
Bioanalysis ; 11(9): 887-898, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31094209

RESUMO

Aim: An ultrasensitive UPLC-MS/MS assay for liraglutide was developed and validated according to US FDA and EMA guidelines and applied to the quantification of plasma concentrations after intravenous, nasal and oral administration of liraglutide to beagle dogs. Results: Liraglutide isolation was performed with a combined protein precipitation and solid-phase extraction protocol. The calibrated concentration range of 0.1-200 ng/ml was linear with correlation coefficients >0.998. Precise analysis was achieved through the utilization of an isotopically labeled internal standard. Absolute bioavailability of liraglutide after nasal and oral administration of liraglutide to beagle dogs was 0.03 and 0.006%, respectively. Conclusion: The assay matches the performance in sensitivity of the previously applied immunoassay and optimally covers the therapeutic range of liraglutide.


Assuntos
Análise Química do Sangue/métodos , Liraglutida/sangue , Liraglutida/farmacocinética , Administração Intranasal , Administração Oral , Animais , Disponibilidade Biológica , Precipitação Química , Cromatografia Líquida de Alta Pressão , Cães , Limite de Detecção , Liraglutida/administração & dosagem , Liraglutida/isolamento & purificação , Espectrometria de Massas em Tandem
7.
N Engl J Med ; 381(7): 637-646, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31034184

RESUMO

BACKGROUND: Metformin is the regulatory-approved treatment of choice for most youth with type 2 diabetes early in the disease. However, early loss of glycemic control has been observed with metformin monotherapy. Whether liraglutide added to metformin (with or without basal insulin treatment) is safe and effective in youth with type 2 diabetes is unknown. METHODS: Patients who were 10 to less than 17 years of age were randomly assigned, in a 1:1 ratio, to receive subcutaneous liraglutide (up to 1.8 mg per day) or placebo for a 26-week double-blind period, followed by a 26-week open-label extension period. Inclusion criteria were a body-mass index greater than the 85th percentile and a glycated hemoglobin level between 7.0 and 11.0% if the patients were being treated with diet and exercise alone or between 6.5 and 11.0% if they were being treated with metformin (with or without insulin). All the patients received metformin during the trial. The primary end point was the change from baseline in the glycated hemoglobin level after 26 weeks. Secondary end points included the change in fasting plasma glucose level. Safety was assessed throughout the course of the trial. RESULTS: Of 135 patients who underwent randomization, 134 received at least one dose of liraglutide (66 patients) or placebo (68 patients). Demographic characteristics were similar in the two groups (mean age, 14.6 years). At the 26-week analysis of the primary efficacy end point, the mean glycated hemoglobin level had decreased by 0.64 percentage points with liraglutide and increased by 0.42 percentage points with placebo, for an estimated treatment difference of -1.06 percentage points (P<0.001); the difference increased to -1.30 percentage points by 52 weeks. The fasting plasma glucose level had decreased at both time points in the liraglutide group but had increased in the placebo group. The number of patients who reported adverse events was similar in the two groups (56 [84.8%] with liraglutide and 55 [80.9%] with placebo), but the overall rates of adverse events and gastrointestinal adverse events were higher with liraglutide. CONCLUSIONS: In children and adolescents with type 2 diabetes, liraglutide, at a dose of up to 1.8 mg per day (added to metformin, with or without basal insulin), was efficacious in improving glycemic control over 52 weeks. This efficacy came at the cost of an increased frequency of gastrointestinal adverse events. (Funded by Novo Nordisk; Ellipse ClinicalTrials.gov number, NCT01541215.).


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Liraglutida/uso terapêutico , Metformina/uso terapêutico , Adolescente , Glicemia/análise , Criança , Diabetes Mellitus Tipo 2/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Gastroenteropatias/induzido quimicamente , Hemoglobina A Glicada/análise , Humanos , Hipoglicemiantes/efeitos adversos , Insulina/uso terapêutico , Liraglutida/administração & dosagem , Liraglutida/efeitos adversos , Masculino , Metformina/efeitos adversos
8.
Endocrinol. diabetes nutr. (Ed. impr.) ; 66(3): 140-149, mar. 2019. tab
Artigo em Espanhol | IBECS | ID: ibc-182613

RESUMO

La prevalencia de la obesidad se ha incrementado mundialmente en las últimas décadas. La obesidad se asocia a múltiples comorbilidades, como la diabetes tipo 2, que generan un gran impacto en la salud y en la economía. La pérdida de peso en este colectivo favorece el control glucémico, por lo que es uno objetivo a lograr. Los cambios en el estilo de vida son poco efectivos por sí solos, y en los últimos años se han desarrollado otras opciones terapéuticas como la cirugía bariátrica/metabólica, así como fármacos para la diabetes tipo 2 y fármacos para reducir peso en la obesidad. El objetivo de la revisión es la comparación de los resultados en reducción de peso y control glucémico de los distintos tipos de fármacos con los resultados de la cirugía bariátrica/metabólica en diabetes tipo 2


The prevalence of obesity has increased worldwide over the past decades. Obesity is associated with multiple comorbidities, such as type 2 diabetes, that generates a great impact on health and economy. Weight loss in these patients leads to glycemic control so it is a target to achieve. Lifestyle changes are not effective enough and recently other treatments have been developed such as bariatric/metabolic surgery, as well as drugs for type 2 diabetes and antiobesity drugs. The aim of this review is to compare the results in weight reduction and glycemic control of the different kinds of drugs with bariatric / metabolic surgery's results in type 2 diabetes


Assuntos
Humanos , Diabetes Mellitus Tipo 2/terapia , Obesidade/epidemiologia , Perda de Peso , Índice Glicêmico , Terapia Combinada/tendências , Cirurgia Bariátrica , Obesidade/tratamento farmacológico , Simportadores/administração & dosagem , Orlistate/administração & dosagem , Liraglutida/administração & dosagem , Naltrexona/administração & dosagem , Obesidade/fisiopatologia
9.
Int J Cardiol ; 283: 28-34, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30773266

RESUMO

BACKGROUND: Coronary microvascular dysfunction (CMD) is associated with adverse cardiovascular outcomes and CMD is a hallmark of type 2 diabetes. Liraglutide improves cardiovascular prognosis through partly unknown mechanisms. We hypothesized that treatment with liraglutide improves CMD and symptoms through weight loss, in non-diabetic overweight patients with angina and no obstructive coronary artery disease (CAD). METHODS: We included 33 non-diabetic overweight women (BMI > 25) with CMD (Coronary flow velocity reserve (CFVR) ≤2.5), angina symptoms and no obstructive CAD, in an open-label proof-of-concept study. The protocol included a control period of 5 weeks followed by an intervention period with liraglutide aiming at 3 mg daily for 12 weeks. Participants were investigated before and after the control period and again 1-2 weeks after last liraglutide dose. Primary outcomes were change in CFVR and change in angina symptoms measured by the Seattle Angina Questionnaire (SAQ) in the intervention period compared with the control period. (clinicaltrials.gov, NCT02602600, and ethically approved). RESULTS: Twenty-nine participants completed the study. Liraglutide treatment led to a significant weight loss (mean 6.03 kg (95%CI: 5.22;6.84)) and decrease in systolic blood pressure (mean 10.95 mm Hg (95%CI: 4.60;17.30)). Baseline median CFVR was 2.30 (IQR 1.91;2.51) and remained unchanged after liraglutide treatment (mean change 0.07 (95%CI: -0.07;0.21)). There were no effects on symptoms measured by SAQ or parameters of left ventricular systolic as well as diastolic function. CONCLUSIONS: Treatment with liraglutide led to significant weight loss and lowering of blood pressure with no concomitant symptoms alleviation during treatment and no improvement in coronary microvascular function.


Assuntos
Angina Pectoris/fisiopatologia , Peso Corporal/efeitos dos fármacos , Circulação Coronária/efeitos dos fármacos , Vasos Coronários/fisiopatologia , Liraglutida/administração & dosagem , Microcirculação/efeitos dos fármacos , Sobrepeso/tratamento farmacológico , Idoso , Angina Pectoris/diagnóstico , Angina Pectoris/tratamento farmacológico , Vasos Coronários/diagnóstico por imagem , Relação Dose-Resposta a Droga , Ecocardiografia , Feminino , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/fisiopatologia , Humanos , Hipoglicemiantes/administração & dosagem , Pessoa de Meia-Idade , Sobrepeso/complicações , Sobrepeso/fisiopatologia , Resultado do Tratamento , Função Ventricular Esquerda/efeitos dos fármacos
10.
Adv Ther ; 36(2): 265-277, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30610613

RESUMO

The progressive nature of type 2 diabetes (T2D) means that many patients will require basal insulin therapy at some point in the course of the disease due to ß-cell failure. As basal insulin primarily targets fasting plasma glucose, patients may still experience considerable postprandial glucose excursions and therefore require an additional agent to achieve good glycemic control. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) provide an alternative to prandial insulin, with the benefits of fewer daily injections, and a lower risk of hypoglycemia and weight gain. Two fixed-ratio combinations (FRCs) of basal insulin and a GLP-1 RA are now available in the USA and the EU: insulin glargine + lixisenatide (iGlarLixi) and insulin degludec + liraglutide (IDegLira). Titratable FRCs are suitable for most patients with T2D and can help to simplify treatment regimens into one daily injection, potentially aiding in patient adherence. The complementary modes of action of the two components target seven of the many known pathophysiologic defects in T2D. FRCs have demonstrated enhanced glycemic control compared with their constituent components alone, comparable risk of hypoglycemia compared with basal insulin alone, and better tolerability compared with the GLP-1RA component alone due to the slower titration. In this article, we discuss the advantages of FRCs over multiple daily injections, present case studies of typical patients who could benefit from FRC therapy, and outline practical considerations for the initiation of FRC therapy in clinical practice.Funding Sanofi.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hipoglicemiantes/uso terapêutico , Insulina de Ação Prolongada/uso terapêutico , Insulina/uso terapêutico , Terapia Combinada , Combinação de Medicamentos , Peptídeo 1 Semelhante ao Glucagon/administração & dosagem , Hemoglobina A Glicada/análise , Humanos , Liraglutida/administração & dosagem , Cooperação do Paciente , Período Pós-Prandial , Ganho de Peso
11.
Biomed Pharmacother ; 109: 429-439, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30399578

RESUMO

Kindling is a model for studying epileptogenesis and associated neuropsychiatric conditions. The antiepileptic drug levetiracetam (LEV) presents anti-kindling properties, but some severe neuropsychiatric events, especially depression, have been associated with its use in epileptic patients. The positive modulation of glucagon-like peptide-1 (GLP-1) receptors emerged as a potential target for the treatment of epilepsy and other neurological disorders. Here, we investigated behavioral and neurochemical effects of liraglutide (LIRA), a GLP-1 receptor agonist, alone or combined with LEV in mice subjected to PTZ-induced kindling. Male mice received PTZ on alternate days for 21 days. Before PTZ, the animals received LIRA, LEV (alone or in combination with LIRA) or saline. After seizures staging according to Racine's scale, behavioral evaluations were performed to verify anxiety-, depressive-like and cognitive performance. Brain oxidative alterations and BDNF levels were also measured. LEV showed anti-kindling properties, but aggravated depressive-like behavior in PTZ-kindling. In control conditions, LEV induced a pro-depressant effect and impaired avoidance memory retention. LIRA delayed but did not prevent the full kindling development. LIRA prevented the depressive-like behavior induced by PTZ kindling and PTZ + LEV. LEV + LIRA protected against PTZ-induced anxiety-like alterations and impairments in locomotion and cognition. Furthermore, LEV + LIRA reduced nitrite levels and lipid peroxidation in the hippocampus and prefrontal cortex, while it increased reduced glutathione levels in all evaluated brain areas. LIRA or LEV + LIRA increased hippocampal BDNF levels. In conclusion, our results showed that LIRA can be a promising adjunctive therapy for epilepsy-related neuropsychiatric comorbidities and to improve the management of antiepileptic drug associated behavioral adverse effects.


Assuntos
Antioxidantes/metabolismo , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Encéfalo/metabolismo , Peptídeo 1 Semelhante ao Glucagon/agonistas , Excitação Neurológica/metabolismo , Levetiracetam/administração & dosagem , Liraglutida/administração & dosagem , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Encéfalo/efeitos dos fármacos , Comorbidade , Quimioterapia Combinada , Excitação Neurológica/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Pentilenotetrazol/toxicidade , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologia
12.
J Pharm Pract ; 32(4): 447-449, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30270723

RESUMO

The US Food and Drug Administration recently approved 2 combination products containing a basal insulin and a glucagon-like peptide 1 receptor agonist: insulin glargine/lixisenatide and insulin degludec/liraglutide. These agents were shown to be noninferior in lowering hemoglobin A1c compared to basal insulin and are indicated for patients inadequately controlled on basal insulin or glucagon-like peptide 1 receptor agonists alone. The clinical implications of these agents are unclear due to limitations in the clinical trials and limited recommendations in current guidelines. While these agents may provide financial and adherence benefits, their role is likely limited to the outpatient setting. With the availability of these agents, concerns with transitions of care arise due to multiple vulnerabilities in reconciling these agents throughout the inpatient admission and discharge process. Provider awareness of the availability and dosing of insulin glargine/lixisenatide and insulin degludec/liraglutide is essential to reduce errors in the medication reconciliation process.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hipoglicemiantes/administração & dosagem , Aprovação de Drogas , Combinação de Medicamentos , Hemoglobina A Glicada/efeitos dos fármacos , Humanos , Hipoglicemiantes/farmacologia , Insulina Glargina/administração & dosagem , Insulina de Ação Prolongada/administração & dosagem , Liraglutida/administração & dosagem , Adesão à Medicação , Peptídeos/administração & dosagem , Guias de Prática Clínica como Assunto
13.
Diabetes Obes Metab ; 21(2): 293-302, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30187620

RESUMO

AIMS: To evaluate if glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce antipsychotic-associated body weight gain in patients with schizophrenia, when compared to controls. MATERIALS AND METHODS: We systematically searched PubMed/EMBASE/PsycINFO/Cochrane using the search terms '(antipsychotic and GLP-1RA)'. Individual participant data from studies randomizing patients to GLP-1RA or control were meta-analysed. The primary outcome was difference in body weight between GLP-1RA and control; secondary outcomes included cardio-metabolic variables and adverse drug reactions (ADRs). Multiple linear regression was conducted including sex, age, psychosis severity, metabolic variable, ADRs, and GLP-1RA agent. RESULTS: Three studies (exenatide once-weekly = 2; liraglutide once-daily = 1) provided participant-level data (n = 164, age = 40.0 ± 11.1 years, body weight = 105.8 ± 20.8 kg). After 16.2 ± 4.0 weeks of treatment, body weight loss was 3.71 kg (95% CI = 2.44-4.99 kg) greater for GLP-1RA versus control (p < 0.001), number-needed-to-treat ≥5% body weight loss = 3.8 (95% CI = 2.6-7.2). Waist circumference, body mass index, HbA1c, fasting glucose and visceral adiposity were each significantly lower with GLP-1RA. Sex, age, psychosis severity, nausea, any ADR, and GLP-1RA agent did not significantly impact outcomes. Body weight loss with GLP-1RAs was greater for clozapine/olanzapine-treated patients (n = 141) than other antipsychotics (n = 27) (4.70 kg, 95% CI = 3.13-6.27 vs. 1.5 kg, 95% CI = -1.47-4.47) (p < 0.001). Nausea was more common with GLP-1RAs than control (53.6% vs. 27.5%, p = 0.002, number-needed-to-harm = 3.8). CONCLUSION: GLP-1RAs are effective and tolerable for antipsychotic-associated body weight gain, particularly clozapine/olanzapine-treated patients. With few included patients, further studies are required before making routine use recommendations for GLP-1RAs.


Assuntos
Antipsicóticos/efeitos adversos , Doenças Cardiovasculares/prevenção & controle , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hipoglicemiantes/uso terapêutico , Doenças Metabólicas/prevenção & controle , Ganho de Peso/efeitos dos fármacos , Adolescente , Adulto , Idoso , Peso Corporal/efeitos dos fármacos , Doenças Cardiovasculares/induzido quimicamente , Esquema de Medicação , Exenatida/administração & dosagem , Exenatida/uso terapêutico , Feminino , Humanos , Hipoglicemiantes/administração & dosagem , Liraglutida/administração & dosagem , Liraglutida/uso terapêutico , Masculino , Doenças Metabólicas/induzido quimicamente , Pessoa de Meia-Idade , Obesidade/induzido quimicamente , Obesidade/prevenção & controle , Fatores de Risco , Esquizofrenia/tratamento farmacológico , Adulto Jovem
14.
BMJ Case Rep ; 11(1)2018 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-30567126

RESUMO

Older patients with type 2 diabetes are prone to developing adverse events with aggressive antihyperglycaemic therapy. Metformin-associated lactic acidosis (MALA) is one such rare, life-threatening adverse drug effect. We report the case of a 70-year-old man with a glycated haemoglobin of 7.9% who was on a stable, maximally tolerated dose of metformin for managing his type 2 diabetes. He was initiated on liraglutide injections with hopes to achieve better glycaemic control, but developed unrelenting nausea and vomiting during the third week of treatment. He presented to the hospital with these symptoms and was noted to have severe MALA. He sustained an in-hospital cardiac arrest requiring emergent resuscitation along with vasopressor and mechanical ventilator support. He underwent continuous venovenous haemodiafiltration to remove metformin and correct the acidosis, following which he stabilised and supportive therapy was weaned off. He was discharged from the hospital on insulin therapy with incomplete renal recovery.


Assuntos
Acidose Láctica/induzido quimicamente , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/efeitos adversos , Liraglutida/efeitos adversos , Acidose Láctica/diagnóstico , Idoso , Glicemia/efeitos dos fármacos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Hemoglobina A Glicada/análise , Parada Cardíaca/induzido quimicamente , Hemodiafiltração/métodos , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/uso terapêutico , Doença Iatrogênica , Insulina/uso terapêutico , Liraglutida/administração & dosagem , Liraglutida/uso terapêutico , Masculino , Metformina/efeitos adversos , Resultado do Tratamento
15.
Biosci Rep ; 38(6)2018 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-30473540

RESUMO

Type 2 diabetes mellitus (T2DM) complicated with non-alcoholic fatty liver disease (NAFLD) is difficult to treat. The present study explored the efficacy of (liraglutide) Lira in treating T2DM complicated with NAFLD. A total of 127 patients suffering from T2DM complicated with NAFLD were enrolled in the present study, and randomly assigned to a Lira group (liraglutide injection: 0.6-1.2 mg/day, 12 weeks, n=52) or a Metformin (Met) group (oral metformin: 1000-1500 mg/day, 12 weeks, n=75). During the treatment phase, the values for fasting plasma glucose (FPG), 2 h plasma glucose (2hPG), glycated hemoglobin (HbA1c), aspartate aminotransferase (AST)/alanine aminotransferase (ALT), and adiponectin (APN) decreased in both the Lira and Met groups, and the levels of Δ2hPG, ΔAST/ALT, and ΔAPN in the Lira group were significantly lower than those in the Met group. The values for total cholesterol (TC), triglycerides (TG), low-and high-density lipoproteins (LDL and HDL), ALT, AST, weight, body mass index (BMI), waist to hip ratio (WHR), and C-reactive protein were markedly increased in both groups, and levels of ΔAST, ΔALT, Δweight, ΔBMI, ΔWHR, and ΔCRP (C-reactive protein) in the Lira group were significantly higher than those in the Met group. An analysis of treatment efficacy showed that liraglutide was better than metformin in its ability to significantly decrease the ALT levels in patients with combined T2DM and NAFLD. Furthermore, liraglutide was more effective than metformin at ameliorating the severity of T2DM complicated with NAFLD, and produced its effects by alleviating liver inflammation and improving liver function.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Liraglutida/administração & dosagem , Metformina/administração & dosagem , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Adiponectina/sangue , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Glicemia , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/patologia , Triglicerídeos/sangue , Relação Cintura-Quadril
16.
ACS Appl Mater Interfaces ; 10(43): 36693-36702, 2018 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-30298718

RESUMO

Delivering drugs and agents to the brain is a huge challenge, especially for chronic neurodegenerative disorders, such as Alzheimer's disease (AD). For this, prolonged and sustained release methods to increase brain uptake represent an impacting concept. The bioresorbable polymer poly-lactic acid (PLA) has high potential for medical implants; at the same time, glucagon-like peptide-1 (GLP-1) analogues have considerable neuroprotective attributes and represent a therapeutic strategy for AD. Here, a biodevice is produced by electrospinning PLA with a GLP-1 analogue (liraglutide, LG), coated with a thin layer of gelatin. The biodevice is subcutaneously implanted in a transgenic mouse model of AD and LG is released for 14 days in mice serum. After 4 weeks of implantation, crucial hallmarks of the AD are highly diminished: hippocampal senile amyloid ß plaque load and neuroinflammatory markers. Furthermore, neurogenesis is enhanced in the subventricular zone, an important neurogenic niche in the brain. The designed biodevice holds great promise for being an affordable candidate to act as a prolonged drug provider, promoting LG mission through increasing its lifetime, constituting a relevant approach for old and impaired brain.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Liraglutida/administração & dosagem , Peptídeos beta-Amiloides/metabolismo , Animais , Linhagem Celular Tumoral , Dano ao DNA , Feminino , Gelatina/química , Humanos , Inflamação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células-Tronco Neurais/citologia , Placa Amiloide , Poliésteres/química , Próteses e Implantes , Tecidos Suporte
17.
High Blood Press Cardiovasc Prev ; 25(4): 369-378, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30203268

RESUMO

INTRODUCTION: Glucagon-like peptide 1-receptor agonists (incretin mimetics) and dipeptidyl peptidase-4 inhibitors (incretin enhancers) have been recently introduced in the treatment of diabetes mellitus. In particular, incretin mimetics seems to have ancillary antioxidant/antinflammatory properties that might be involved in endothelial protection. AIM: To investigate the effect of incretin mimetic therapy (liraglutide, exenatide) given to 11 patients with type 2 diabetes mellitus, on circulating endothelial progenitor cells (EPCs) (bone marrow-derived cells possibly participating in neovascularization and endothelial protection and repair) and capillary density. METHODS: Four diabetic patients were treated with exenatide (5 µg twice daily for 4 weeks and then 10 µg twice daily for 3 weeks) and 7 with liraglutide (0.6 mg per day for 1 week and then 1.2 mg per day for 3 weeks). Peripheral venous blood samples were obtained before treatment (basal) and after 4 week in patients treated with liraglutide, and after 4 and 7 weeks in patients treated with exenatide, since drug titration is usually longer. EPCs were evaluated by flow cytometry as CD34+/KDR+ cells. Capillary density was evaluated by videomicroscopy, before and after venous congestion, in the dorsum of the 4th finger. RESULTS: Patients treated with liraglutide (6 males 1 female, age 54 ± 12 years) showed a decrease in body mass index and blood pressure during treatment, while patients treated with exenatide (3 males 1 female, age 57 ± 6 years) did not show any relevant change. EPCs were significantly increased after treatment with exenatide, but not after treatment with liraglutide. Capillary density was slightly increased only after 4 weeks of treatment with exenatide, however the increase was no longer present at the final evaluation. CONCLUSIONS: Treatment with exenatide, but not with liraglutide, was able to increase the number of circulating EPCs, possibly through an antioxidative/antiinflammatory effect.


Assuntos
Capilares/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Células Progenitoras Endoteliais/efeitos dos fármacos , Exenatida/administração & dosagem , Hipoglicemiantes/administração & dosagem , Incretinas/administração & dosagem , Liraglutida/administração & dosagem , Pele/irrigação sanguínea , Adulto , Idoso , Biomarcadores/sangue , Capilares/patologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/patologia , Células Progenitoras Endoteliais/metabolismo , Células Progenitoras Endoteliais/patologia , Exenatida/efeitos adversos , Feminino , Humanos , Hipoglicemiantes/efeitos adversos , Incretinas/efeitos adversos , Liraglutida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento
18.
ESC Heart Fail ; 5(6): 1035-1043, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30120812

RESUMO

AIMS: Obesity is present in up to 45% of patients with heart failure (HF). Liraglutide, a glucagon-like peptide-1 (GLP-1) receptor antagonist, facilitates weight loss in obese patients. The efficacy of liraglutide as a weight loss agent among patients with HF and reduced ejection fraction (HFrEF) and a recent acute HF hospitalization remains unknown. METHODS AND RESULTS: The Functional Impact of GLP-1 for Heart Failure Treatment study randomized 300 patients with HFrEF (ejection fraction ≤ 40%), both with and without diabetes and a recent HF hospitalization to liraglutide or placebo. The primary outcome for this post hoc analysis was the change in weight from baseline to last study visit. We conducted an 'on-treatment' analysis of patients with at least one follow-up visit on study drug (123 on liraglutide and 124 on placebo). The median age was 61 years, 21% were female, and 69% of patients had New York Heart Association functional Class III or IV symptoms. The median ejection fraction was 25% (25th, 75th percentile 19-32%). Liraglutide use was associated with a significant weight reduction [liraglutide -1.00 lbs vs. placebo 2.00 lbs; treatment difference -4.10 lbs; 95% confidence interval (CI) -7.94, -0.25; P = 0.0367; percentage treatment difference -2.07%, 95% CI -3.86, -0.28; P = 0.0237]. Similar results were seen after multivariable adjustments. Liraglutide also significantly reduced triglyceride levels (liraglutide 7.5 mg/dL vs. placebo 12.0 mg/dL; treatment difference -33.1 mg/dL; 95% CI -60.7, -5.6; P = 0.019). CONCLUSIONS: Liraglutide is an efficacious weight loss agent in patients with HFrEF. These findings will require further exploration in a well-powered cardiovascular outcomes trial.


Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Liraglutida/administração & dosagem , Obesidade/complicações , Volume Sistólico/fisiologia , Perda de Peso/efeitos dos fármacos , Idoso , Peso Corporal , Método Duplo-Cego , Esquema de Medicação , Feminino , Seguimentos , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipoglicemiantes/administração & dosagem , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Obesidade/tratamento farmacológico , Obesidade/fisiopatologia , Resultado do Tratamento
19.
Medicina (B Aires) ; 78(4): 225-233, 2018.
Artigo em Espanhol | MEDLINE | ID: mdl-30125249

RESUMO

Diabetes mellitus is a true pandemic; type 2 diabetes in particular, with its progressive nature, constitutes a serious health problem. Despite advances and innovations in treatment, it continues to generate high morbidity and mortality. Many patients do not achieve their metabolic control objectives, due to clinical inertia, fear of hypoglycaemia, weight gain, the complexity of the treatment and the lack of adherence to it. Recently, the clinical results of the combined use of basal insulin and agonist receptor of the glucagon-like peptide type 1 (AR-GLP1) have been successfully evaluated. Therefore, the combined use of a basal insulin (insulin degludec) with an AR-GLP1 (liraglutide), in a single device (IdegLira), is proposed as an effective and safe therapeutic alternative for the treatment intensification in people with type 2 diabetes. IdegLira has shown greater reductions in HbA1c compared to its individual components, with a low risk of hypoglycaemia and weight loss, both in insulin naïve patients and in those previously insulinized. In this review we describe the pharmacology, the rational of the combination and the most relevant clinical evidence on IdegLira safety and efficacy.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Insulina de Ação Prolongada/administração & dosagem , Liraglutida/administração & dosagem , Ensaios Clínicos como Assunto , Combinação de Medicamentos , Quimioterapia Combinada , Humanos
20.
Lancet ; 392(10148): 637-649, 2018 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-30122305

RESUMO

BACKGROUND: Obesity is a major public health issue, and new pharmaceuticals for weight management are needed. Therefore, we evaluated the efficacy and safety of the glucagon-like peptide-1 (GLP-1) analogue semaglutide in comparison with liraglutide and a placebo in promoting weight loss. METHODS: We did a randomised, double-blind, placebo and active controlled, multicentre, dose-ranging, phase 2 trial. The study was done in eight countries involving 71 clinical sites. Eligible participants were adults (≥18 years) without diabetes and with a body-mass index (BMI) of 30 kg/m2 or more. We randomly assigned participants (6:1) to each active treatment group (ie, semaglutide [0·05 mg, 0·1 mg, 0·2 mg, 0·3 mg, or 0·4 mg; initiated at 0·05 mg per day and incrementally escalated every 4 weeks] or liraglutide [3·0 mg; initiated at 0·6 mg per day and escalated by 0·6 mg per week]) or matching placebo group (equal injection volume and escalation schedule to active treatment group) using a block size of 56. All treatment doses were delivered once-daily via subcutaneous injections. Participants and investigators were masked to the assigned study treatment but not the target dose. The primary endpoint was percentage weight loss at week 52. The primary analysis was done using intention-to-treat ANCOVA estimation with missing data derived from the placebo pool. This study is registered with ClinicalTrials.gov, number NCT02453711. FINDINGS: Between Oct 1, 2015, and Feb 11, 2016, 957 individuals were randomly assigned (102-103 participants per active treatment group and 136 in the pooled placebo group). Mean baseline characteristics included age 47 years, bodyweight 111·5 kg, and BMI 39·3 kg/m2. Bodyweight data were available for 891 (93%) of 957 participants at week 52. Estimated mean weight loss was -2·3% for the placebo group versus -6·0% (0·05 mg), -8·6% (0·1 mg), -11·6% (0·2 mg), -11·2% (0·3 mg), and -13·8% (0·4 mg) for the semaglutide groups. All semaglutide groups versus placebo were significant (unadjusted p≤0·0010), and remained significant after adjustment for multiple testing (p≤0·0055). Mean bodyweight reductions for 0·2 mg or more of semaglutide versus liraglutide were all significant (-13·8% to -11·2% vs -7·8%). Estimated weight loss of 10% or more occurred in 10% of participants receiving placebo compared with 37-65% receiving 0·1 mg or more of semaglutide (p<0·0001 vs placebo). All semaglutide doses were generally well tolerated, with no new safety concerns. The most common adverse events were dose-related gastrointestinal symptoms, primarily nausea, as seen previously with GLP-1 receptor agonists. INTERPRETATION: In combination with dietary and physical activity counselling, semaglutide was well tolerated over 52 weeks and showed clinically relevant weight loss compared with placebo at all doses. FUNDING: Novo Nordisk A/S.


Assuntos
Peptídeos Semelhantes ao Glucagon/farmacologia , Liraglutida/farmacologia , Obesidade/tratamento farmacológico , Perda de Peso/efeitos dos fármacos , Adulto , Glicemia/efeitos dos fármacos , Índice de Massa Corporal , Método Duplo-Cego , Feminino , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Hemoglobina A Glicada/análise , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacologia , Injeções Subcutâneas/métodos , Liraglutida/administração & dosagem , Liraglutida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Obesidade/epidemiologia , Placebos , Resultado do Tratamento
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