Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 514
Filtrar
1.
J Biochem Mol Toxicol ; 34(1): e22415, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31682045

RESUMO

The aim of this study was to assess the therapeutic potential of oxytocin and liraglutide (LIR), a GLP-1 analogue, in a rat model of vincristine-induced neuropathy. Rats were injected with vincristine (VCR) at a dose of 4 mg/kg twice a week for 5 weeks. The VCR-administered rats were divided into three groups and received saline, oxytocin, or liraglutide simultaneously with VCR. After the treatment period, electrophysiological, biochemical, histological, and immunohistochemical investigations were performed. Electromyography (EMG) recordings demonstrated significant alterations in the VCR + saline group (p < .001). Also, motor performance was decreased in the VCR + saline group (p < .05). Histologically, the axonal diameter was decreased in all groups. VCR + saline group showed significantly increased lipid peroxidation and decreased nerve growth factor (NGF) expression. However, the administration of oxytocin and liraglutide significantly prevented the EMG alterations, lipid peroxidation, and reduction in neuronal NGF expression. On the basis of these findings, oxytocin and liraglutide may be considered as potential agents for the prevention of VCR-induced neuropathy.


Assuntos
Antineoplásicos Fitogênicos/toxicidade , Liraglutida/uso terapêutico , Doenças do Sistema Nervoso/tratamento farmacológico , Ocitocina/uso terapêutico , Vincristina/toxicidade , Animais , Liraglutida/administração & dosagem , Masculino , Doenças do Sistema Nervoso/induzido quimicamente , Ocitocina/administração & dosagem , Ratos , Ratos Sprague-Dawley
2.
Expert Opin Pharmacother ; 21(3): 275-285, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31790314

RESUMO

Introduction: The prevalence of obesity is increasing worldwide and associated conditions, particularly type 2 diabetes mellitus (T2DM), also show increasing prevalence. Lifestyle intervention should be the first line of management for obesity but additional pharmacotherapy is often required and bariatric surgery is appropriate in more severe cases. Drugs acting as glucagon-like peptide-1 receptor agonists (GLP-1RAs) developed for the management of T2DM reduce body weight and liraglutide is the first GLP-1RA to be approved for the treatment of obesity in patients with and without T2DM.Areas covered: In this review of relevant published material, the authors summarize the pharmacokinetics, pharmacodynamics, clinical efficacy and safety of liraglutide for the treatment of obesity.Expert opinion: Liraglutide effectively reduces body weight and body fat through mechanisms involving reduced appetite and lowered energy intake, independent of its glucose-lowering effects. Like most of the other medications currently available for obesity, liraglutide has some common adverse effects, although generally not serious ones. Liraglutide has additional benefits in reducing cardiovascular events in patients with T2DM but the cost and the need for daily injections may limit its use in obesity. Newer GLP-1RAs, such as semaglutide, or other drugs in development for obesity may have advantages over liraglutide.


Assuntos
Hipoglicemiantes/uso terapêutico , Liraglutida/uso terapêutico , Obesidade/tratamento farmacológico , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Humanos
3.
Medicine (Baltimore) ; 98(46): e17860, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31725627

RESUMO

BACKGROUND: Liraglutide is a novel, long-acting glucagon-like peptide-1 (GLP-1) analogue used to treat type 2 diabetes mellitus. However, the cardiovascular safety and benefits of liraglutide treatment on type 2 diabetes patients remain in debate. In this study, we aimed to examine the overall cardiovascular outcomes of liraglutide in patients with type 2 diabetes. METHODS: In this systematic review and meta-analysis, we searched the PubMed, Embase, and Web of Knowledge databases up to September 1st, 2017 for randomized trials in which type 2 diabetes patients were assigned to liraglutide and placebo or other comparators groups. RESULTS: Eight studies fulfilled the eligibility criteria for inclusion and 14,608 patients were analyzed in this systematic review and meta-analysis. We found patients in the liraglutide group had a lower risk of major cardiovascular events (MACE) (RR = 0.89, 95% CI: 0.82-0.96, P = .002), acute myocardial infarction (AMI) (RR = 0.85, 95% CI: 0.74-0.99, P = .036), all-cause death (RR = 0.84, 95% CI: 0.74-0.96, P = .009), and cardiovascular death (RR = 0.77, 95% CI: 0.65-0.91, P = .002) than all comparator groups. However, liraglutide treatment did not decrease incidence of stroke (RR = 0.86, 95% CI: 0.70-1.04, P = .124). But among the MACE subgroups analysis, a significant reduction of MACE with liraglutide was only observed in placebo-controlled trials (RR = 0.89, 95% CI: 0.83-0.96, P = .004) but not in studies concerning other comparators (RR = 0.58, 95% CI: 0.29-1.16, P = .122). CONCLUSIONS: In conclusion, our results suggest that liraglutide treatment decreases the risk of MACE, AMI, all-cause death and cardiovascular death among patients with type 2 diabetes.


Assuntos
Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Liraglutida/uso terapêutico , Doenças Cardiovasculares/mortalidade , Diabetes Mellitus Tipo 2/mortalidade , Humanos , Hipoglicemiantes/uso terapêutico , Infarto do Miocárdio/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Acidente Vascular Cerebral/epidemiologia
4.
Endocrinology ; 160(12): 2787-2799, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31593246

RESUMO

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and ovulatory dysfunction. Women with PCOS have an elevated prevalence of cardiometabolic risk factors that worsen after menopause. Liraglutide (Lira), a glucagon-like peptide-1 receptor agonist, has shown beneficial metabolic effects in small clinic trials in reproductive-age women with PCOS. We have shown that chronic hyperandrogenemia in an experimental model of postmenopausal PCOS is associated with an adverse cardiometabolic profile and upregulation of the intrarenal renin-angiotensin system (RAS). We analyzed the effect of Lira in the cardiometabolic profile, intrarenal RAS, and blood pressure (BP) in postmenopausal PCOS. Four-week-old female Sprague Dawley rats were treated with DHT or placebo for 17 months. Lira administration during the last 3 weeks caused a bigger reduction in food intake, body weight, fat mass, and homeostasis model assessment of insulin resistance index in PCOS than in control rats. Moreover, Lira improved dyslipidemia and elevated leptin levels in PCOS. In contrast, Lira decreased intrarenal expression of RAS components only in the control group. Lira transiently increased heart rate and decreased BP in control rats. However, Lira did not modify BP but increased heart rate in PCOS. The angiotensin-converting-enzyme inhibitor enalapril abolished the BP differences between PCOS and control rats. However, Lira coadministration with enalapril further reduced BP only in control rats. In summary, Lira has beneficial effects for several cardiometabolic risk factors in postmenopausal PCOS. However, hyperandrogenemia blunted the BP-lowering effect of Lira in postmenopausal PCOS. Androgen-induced activation of intrarenal RAS may play a major role mediating increases in BP in postmenopausal PCOS.


Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hiperandrogenismo/complicações , Liraglutida/uso terapêutico , Síndrome Metabólica/prevenção & controle , Síndrome do Ovário Policístico/complicações , Animais , Pressão Sanguínea/efeitos dos fármacos , Composição Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Frequência Cardíaca/efeitos dos fármacos , Resistência à Insulina , Leptina/sangue , Lipídeos/sangue , Liraglutida/farmacologia , Síndrome Metabólica/etiologia , Pós-Menopausa , Distribuição Aleatória , Ratos Sprague-Dawley , Sistema Renina-Angiotensina/efeitos dos fármacos
5.
J Diabetes Res ; 2019: 1534365, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31396537

RESUMO

Background: Glucagon-like peptide-1 (GLP-1) receptor agonists are effective glucose-lowering drugs, but there is concern that they may increase the risk of malignant neoplasia. The present meta-analysis examined the safety of GLP-1 receptor agonists with regard to malignant neoplasia. Methods: We analyzed data from randomized controlled trials with a minimum duration of 24 weeks that assessed the incidence of neoplasms in type 2 diabetes patients receiving GLP-1 receptor agonists compared with placebo or other hypoglycemic drugs. We searched the MEDLINE, Embase, and Cochrane databases with a language restriction of English through October 1, 2018, and carried out a meta-analysis of the available trial data using a fixed effects model to calculate odds ratios (ORs) for neoplasia. Results: Thirty-four relevant articles, providing data for 50452 patients, were included in the meta-analysis. Compared with the incidence of malignant neoplasia with placebo or other interventions, no increase in malignant neoplasm formation was observed with the use of GLP-1 receptor agonists (OR 1.04, 95% confidence interval (CI) 0.94-1.15; p = 0.46), liraglutide (OR 1.08, 95% CI 0.91-1.27; p = 0.38), exenatide (OR 1.00, 95% CI 0.86-1.16; p = 1.00), semaglutide (OR 0.89, 95% CI 0.35-2.22; p = 0.80), or albiglutide (OR 1.07, 95% CI 0.23-4.88; p = 0.93). A subanalysis of trials lasting longer than 3 years also showed no increase in the neoplasia risk with GLP-1 receptor agonist use (OR 1.03, 95% CI 0.92-1.15; p = 0.60). Between-trial statistical heterogeneity was low for all comparisons. Conclusion: GLP-1 receptor agonists can be used without safety concerns related to malignant neoplasia in patients with type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hipoglicemiantes/uso terapêutico , Neoplasias/epidemiologia , Exenatida/uso terapêutico , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Humanos , Incidência , Liraglutida/uso terapêutico , Neoplasias/induzido quimicamente , Fatores de Risco
6.
Int J Clin Pract ; 73(11): e13399, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31397946

RESUMO

AIMS: To evaluate in a real-world setting the effectiveness of two drugs, orlistat and liraglutide, in patients with overweight or obesity and insufficient weight loss (WL) after a lifestyle modification programme. METHODS: Retrospective, observational cohort study comparing clinical outcomes of orlistat 120 mg three times a day and liraglutide (up to 3 mg daily) in adult patients with BMI ≥30 kg/m2 or ≥27 kg/m2 with at least a weight-related comorbidity who had failed to lose at least 5% of their weight after 6 months of lifestyle modification. The co-primary end-points, assessed at 3-6 months and at the end of the follow-up, were weight change from baseline, proportion of patients who lost at least 5% of their baseline weight and adjusted differences in WL between both drugs. RESULTS: Five hundred patients, 400 in the group of orlistat (age 47.0, weight 107.8 kg) and 100 in the group of liraglutide (age 51.9 years, weight 105.1 kg), were included. Treatment with both drugs significantly reduced weight, fasting plasma glucose, systolic BP, low-density lipoprotein-cholesterol and alanine transaminase over a median follow-up period of 7 months. WL with liraglutide (-7.7 kg) was significantly greater than that observed with orlistat (-3.3 kg), and more individuals lost at least 5% of their baseline weight with liraglutide (64.7%) than with orlistat (27.4%). Rates of prediabetes significantly decreased with liraglutide in comparison to orlistat. CONCLUSIONS: In this real-world study, liraglutide showed a greater effectiveness in WL compared with orlistat and improved several obesity-associated metabolic and cardiovascular risk factors.


Assuntos
Fármacos Antiobesidade/uso terapêutico , Liraglutida/uso terapêutico , Obesidade/tratamento farmacológico , Orlistate/uso terapêutico , Adulto , Estudos de Coortes , Feminino , Humanos , Lactonas/uso terapêutico , Estilo de Vida , Liraglutida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Orlistate/efeitos adversos , Sobrepeso/tratamento farmacológico , Estudos Retrospectivos , Perda de Peso/efeitos dos fármacos
7.
Diabetes Metab Syndr ; 13(4): 2489-2494, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31405666

RESUMO

AIMS: GLP-1 analogues decrease food intake and have great promise for the fight against obesity. Little is known about their effects on food hedonic sensations and taste perception in poor controlled patients with type 2 diabetes (T2D). MATERIALS AND METHODS: Eighteen T2D patients with BMI ≥25 kg/m2 and poor controlled glycemia were studied before and after 3 months of treatment with Liraglutide. Detection thresholds for salty, sweet and bitter tastes, optimal preferences, olfactory liking, wanting and recalled liking for several food items were assessed. Subjects also answered questionnaires to measure their attitudes to food. RESULTS: T2D patients had a significant decrease in bodyweight and HbA1c after treatment with Liraglutide. Liraglutide improved gustative detection threshold of sweet flavors, and decreased wanting for sweet foods and recalled liking for fatty foods. It also led to a decrease in feelings of hunger. CONCLUSIONS: Liraglutide increases sensitivity to sweet tastes and decreases pleasure responses for fatty foods in poor controlled T2D patients, and is of particular interest in the understanding of the mechanisms of weight loss. CLINICAL TRIAL: NCT02674893.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Ingestão de Alimentos/psicologia , Comportamento Alimentar/psicologia , Preferências Alimentares/psicologia , Peptídeo 1 Semelhante ao Glucagon/agonistas , Liraglutida/uso terapêutico , Rememoração Mental , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/análise , Comportamento de Escolha , Diabetes Mellitus Tipo 2/psicologia , Feminino , Seguimentos , Humanos , Fome/fisiologia , Hipoglicemiantes/uso terapêutico , Masculino , Pessoa de Meia-Idade , Obesidade/prevenção & controle , Prognóstico , Paladar/fisiologia , Adulto Jovem
8.
Eur J Pharmacol ; 861: 172594, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31412267

RESUMO

Glucagon like peptide-1 (GLP-1) promotes postprandial insulin secretion. Liraglutide, a full agonist of the GLP-1 receptor, reduces body weight, improve insulin sensitivity, and alleviate Non Alcoholic Fatty Liver Disease (NAFLD). However, the underlying mechanisms remain unclear. This study aims to explore the underlying mechanisms and cell signaling pathways involved in the anti-obesity and anti-inflammatory effects of liraglutide. Mice were fed a high fat high sucrose diet to induce diabetes, diabetic mice were divided into two groups and injected with liraglutide or vehicle for 14 days. Liraglutide treatment improved insulin sensitivity, accompanied with reduced expression of the phosphorylated Acetyl-CoA carboxylase-2 (ACC2) and upregulation of long chain acyl CoA dehydrogenase (LCAD) in insulin sensitive tissues. Furthermore, liraglutide induced adenosine monophosphate-activated protein kinase-α (AMPK-α) and Sirtuin-1(Sirt-1) protein expression in liver and perigonadal fat. Liraglutide induced elevation of fatty acid oxidation in these tissues may be mediated through the AMPK-Sirt-1 cell signaling pathway. In addition, liraglutide induced brown adipocyte differentiation in skeletal muscle, including induction of uncoupling protein-1 (UCP-1) and PR-domain-containing-16 (PRDM-16) protein in association with induction of SIRT-1. Importantly, liraglutide displayed anti-inflammation effect. Specifically, liraglutide led to a significant reduction in circulating interleukin-1 ß (IL-1 ß) and interleukin-6 (IL-6) as well as hepatic IL-1 ß and IL-6 content. The expression of inducible nitric oxide synthase (iNOS-1) and cyclooxygenase-2 (COX-2) in insulin sensitive tissues was also reduced following liraglutide treatment. In conclusion, liraglutide improves insulin sensitivity through multiple pathways resulting in reduction of inflammation, elevation of fatty acid oxidation, and induction of adaptive thermogenesis.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Dieta Hiperlipídica/efeitos adversos , Resistência à Insulina , Liraglutida/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Adipócitos/patologia , Adipogenia/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/patologia , Ingestão de Alimentos/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Ácidos Graxos/metabolismo , Liraglutida/uso terapêutico , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Oxirredução/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismo
9.
J Pharmacol Exp Ther ; 370(3): 447-458, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31270216

RESUMO

We have shown that the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide (Lir) inhibits development of early atherosclerosis in vivo by modulating immune cell function. We hypothesized that Lir could attenuate pre-established disease by modulating monocyte or macrophage phenotype to induce atheroprotective responses. Human atherosclerotic plaques obtained postendarterectomy and human peripheral blood macrophages were treated ex vivo with Lir. In parallel, apolipoprotein E-deficient (ApoE-/-) mice received a high-fat, high-cholesterol diet to induce atherosclerosis for 8 weeks, after which ApoE-/- mice received 300 µg/kg of Lir daily or vehicle control for a further 4 weeks to investigate the attenuation of atherosclerosis. Lir inhibited proinflammatory monocyte chemoattractant protein-1 secretion from human endarterectomy samples and monocyte chemoattractant protein-1, tumor necrosis factor-α, and interleukin (IL)-1ß secretion from human macrophages after ex vivo treatment. An increase in CD206 mRNA and IL-10 secretion was also detected, which implies resolution of inflammation. Importantly, Lir significantly attenuated pre-established atherosclerosis in ApoE-/- mice in the whole aorta and aortic root. Proteomic analysis of ApoE-/- bone marrow cells showed that Lir upregulated the proinflammatory cathepsin protein family, which was abolished in differentiated macrophages. In addition, flow cytometry analysis of bone marrow cells induced a shift toward reduced proinflammatory and increased anti-inflammatory macrophages. We concluded that Lir attenuates pre-established atherosclerosis in vivo by altering proinflammatory mediators. This is the first study to describe a mechanism through which Lir attenuates atherosclerosis by increasing bone marrow proinflammatory protein expression, which is lost in differentiated bone marrow-derived macrophages. This study contributes to our understanding of the anti-inflammatory and cardioprotective role of GLP-1RAs. SIGNIFICANCE STATEMENT: It is critical to understand the mechanisms through which liraglutide (Lir) mediates a cardioprotective effect as many type 2 diabetic medications increase the risk of myocardial infarction and stroke. We have identified that Lir reduces proinflammatory immune cell populations and mediators from plaque-burdened murine aortas in vivo and augments proresolving bone marrow-derived macrophages in attenuation of atherosclerotic disease, which provides further insight into the atheroprotective effect of Lir.


Assuntos
Apolipoproteínas E/deficiência , Mediadores da Inflamação/metabolismo , Liraglutida/farmacologia , Fenótipo , Placa Aterosclerótica/imunologia , Placa Aterosclerótica/metabolismo , Animais , Quimiocinas/metabolismo , Progressão da Doença , Feminino , Humanos , Liraglutida/uso terapêutico , Masculino , Camundongos , Placa Aterosclerótica/tratamento farmacológico
10.
Cardiol Clin ; 37(3): 335-343, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31279427

RESUMO

Diabetes is a major risk factor for cardiovascular disease, yet until now treatments for diabetes had only a modest impact on cardiovascular events. New interventions for patients with type 2 diabetes mellitus (oral empagliflozin and injectable liraglutide) are associated with unprecedented reductions in composite cardiovascular outcomes that seem disproportionate to the impact on glycated hemoglobin. This review examines in detail the recent trials that arrived at these conclusions, limitations of these studies, and how these outcomes may influence patient management in the future.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/uso terapêutico , Liraglutida/uso terapêutico , Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 2/complicações , Humanos , Hipoglicemiantes/uso terapêutico , Fatores de Risco , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
11.
Mol Med Rep ; 20(1): 701-708, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31180545

RESUMO

The pathogenesis of nonalcoholic fatty liver disease non­alcoholic steatohepatitis (NASH) has not been fully elucidated, and there are currently no effective treatments for NASH. The aim of the present study was to explore the therapeutic effects of the glucagon­like peptide­1 (GLP­1) receptor agonist liraglutide (LRG) on NASH and the underlying mechanisms. C57BL6J mice were fed a high­fat diet (HFD) for 8 weeks to induce hepatic steatosis, and then LRG was injected subcutaneously for 4 weeks. The expression of sterol regulatory element­binding protein 1 (SREBP1) and adenosine monophosphate­activated protein kinase (AMPK) as well as the phosphorylation of mechanistic target of rapamycin (mTOR) and p70 ribosomal S6 kinase (p70S6K) were determined by western blot analysis. The intracellular distribution of SREBP1 was assessed by immunofluorescence staining. The results revealed that LRG treatment ameliorated HFD­induced hepatic lipid accumulation and inhibited body weight gain. In addition, LRG treatment significantly suppressed the expression of hepatic SREBP1 as well as the phosphorylation of mTOR and p70S6K; it also increased the phosphorylation of AMPK and acetyl coenzyme A carboxylase. Furthermore, LRG treatment inhibited the hepatic nuclear translocation of SREBP1. It was suggested that the GLP­1 receptor agonist LRG may have ameliorated hepatic steatosis by activating the AMPK/mTOR/SREBP1 signaling pathway as opposed to inhibiting body weight gain.


Assuntos
Peptídeo 1 Semelhante ao Glucagon/agonistas , Liraglutida/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Masculino , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Serina-Treonina Quinases TOR/metabolismo
12.
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
13.
Chem Biol Interact ; 310: 108688, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31173752

RESUMO

Glucagon-like peptide 1 (GLP-1) has neuroprotective properties in Alzheimer's disease (AD). In this study, our aim is to explore the neuroprotective effects of liraglutide, a GLP-1 analogue, on AD-like neurodegeneration induced by H2O2 in human neuroblastoma SH-SY5Y cells. Cytotoxicity was determined by MTT assay and lactate dehydrogenase level was monitored by LDH assay. The level of lipid peroxidation and cell apoptosis rate were measured by malondialdehyde (MDA) assay and Annexin V-FITC/propidium iodide (PI) staining. Western blotting was used to assess the expression of Bcl-2, Bax, caspase-3, tau and the Akt/GSK-3ß. Liraglutide pre-treatment enhanced cell viability with reduced cytotoxicity, lipid peroxidationand and apoptosis. In addition, pre-treatment of liraglutide displayed that increased the expression of the pro-survival Bcl-2 and reduced pro-apoptotic Bax with ameliorated the hyperphosphorylation of tau and Akt/GSK-3ß signaling pathway in H2O2 stressed SH-SY5Y cells. These finding provided evidences that liraglutide protected the H2O2 induced AD-like neurodegeneration through improving Akt/GSK-3ß signaling pathway. These results suggest that liraglutide may have potential values for the treatment for AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Liraglutida/uso terapêutico , Neuroblastoma/metabolismo , Doenças Neurodegenerativas/tratamento farmacológico , Estresse Oxidativo , Linhagem Celular Tumoral , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Peróxido de Hidrogênio/farmacologia , Neuroblastoma/patologia , Doenças Neurodegenerativas/induzido quimicamente , Doenças Neurodegenerativas/etiologia , Fármacos Neuroprotetores/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
14.
Expert Rev Cardiovasc Ther ; 17(5): 377-387, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31055989

RESUMO

Introduction: The GLP-1 receptor agonist (GLP-1 RA) liraglutide has a half-life of approximately 13 h and is suitable for subcutaneous administration once daily. The use of liraglutide in people with type 2 diabetes has become popular because of the efficacy and durability in relation to glycemic control in combination with weight loss in most patients. Areas covered: PubMed searches were completed using the terms 'GLP-1 receptor agonist', 'Liraglutide', 'Liraglutide and CVD', 'Liraglutide and CVD risk factors'. The reference list of articles subsequently identified was searched and articles of interest were selected. Expert commentary: Liraglutide has been found superior to oral antidiabetic drugs and other GLP-1 RAs with greater reductions in both HbA1c and weight except when compared with semaglutide. Liraglutide has beneficial effects on blood pressure, weight, postprandial lipids, low-grade inflammation and on the myocardium. In the cardiovascular endpoint trial LEADER liraglutide reduced the composite endpoint of cardiovascular mortality, nonfatal myocardial infarction, nonfatal stroke as well as cardiovascular and total mortality but had no effect on heart failure. Liraglutide reduces the progression of diabetic kidney disease. In the recent 2018 consensus report from EASD/ADA liraglutide is recommended to patients with established cardiovascular diseases after metformin.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Liraglutida/uso terapêutico , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Peptídeos Semelhantes ao Glucagon/farmacologia , Humanos , Fatores de Risco
15.
Cardiovasc Diabetol ; 18(1): 55, 2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-31039778

RESUMO

BACKGROUND: Liraglutide is an antidiabetic agent with cardioprotective effect. The purpose of this study is to test efficacy of liraglutide to improve diabetic cardiomyopathy in patients with diabetes mellitus type 2 (DM2) without cardiovascular disease. METHODS: Patients with DM2 were randomly assigned to receive liraglutide 1.8 mg/day or placebo in this double-blind trial of 26 weeks. Primary outcome measures were LV diastolic function (early (E) and late (A) transmitral peak flow rate, E/A ratio, early deceleration peak (Edec), early peak mitral annular septal tissue velocity (Ea) and estimated LV filling pressure (E/Ea), and systolic function (stroke volume, ejection fraction, cardiac output, cardiac index and peak ejection rate) assessed with CMR. Intention-to-treat analysis of between-group differences was performed using ANCOVA. Mean estimated treatment differences (95% confidence intervals) are reported. RESULTS: 23 patients were randomized to liraglutide and 26 to placebo. As compared with placebo, liraglutide significantly reduced E (- 56 mL/s (- 91 to - 21)), E/A ratio (- 0.17 (- 0.27 to - 0.06)), Edec (- 0.9 mL/s2 * 10-3 (- 1.3 to - 0.2)) and E/Ea (- 1.8 (- 3.0 to - 0.6)), without affecting A (3 mL/s (- 35 to 41)) and Ea (0.4 cm/s (- 0.9 to 1.4)). Liraglutide reduced stroke volume (- 9 mL (- 16 to - 2)) and ejection fraction (- 3% (- 6 to - 0.1)), but did not change cardiac output (- 0.4 L/min (- 0.9 to 0.2)), cardiac index (- 0.1 L/min/m2 (- 0.4 to 0.1)) and peak ejection rate (- 46 mL/s (- 95 to 3)). CONCLUSIONS: Liraglutide reduced early LV diastolic filling and LV filling pressure, thereby unloading the left ventricle. LV systolic function reduced and remained within normal range. Future studies are needed to investigate if liraglutide-induced left ventricular unloading slows progression of diabetic cardiomyopathy into symptomatic stages. Trial registration ClinicalTrials.gov: NCT01761318.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Cardiomiopatias Diabéticas/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Liraglutida/uso terapêutico , Volume Sistólico/efeitos dos fármacos , Disfunção Ventricular Esquerda/tratamento farmacológico , Função Ventricular Esquerda/efeitos dos fármacos , Pressão Ventricular/efeitos dos fármacos , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico por imagem , Diabetes Mellitus Tipo 2/fisiopatologia , Cardiomiopatias Diabéticas/sangue , Cardiomiopatias Diabéticas/diagnóstico por imagem , Cardiomiopatias Diabéticas/fisiopatologia , Método Duplo-Cego , Feminino , Humanos , Hipoglicemiantes/efeitos adversos , Liraglutida/efeitos adversos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Países Baixos , Recuperação de Função Fisiológica , Fatores de Tempo , Resultado do Tratamento , Disfunção Ventricular Esquerda/sangue , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/fisiopatologia , Adulto Jovem
16.
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
17.
Trials ; 20(1): 191, 2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30944040

RESUMO

BACKGROUND: Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue currently approved for type 2 diabetes and obesity. Preclinical evidence in transgenic models of Alzheimer's disease suggests that liraglutide exerts neuroprotective effects by reducing amyloid oligomers, normalising synaptic plasticity and cerebral glucose uptake, and increasing the proliferation of neuronal progenitor cells. The primary objective of the study is to evaluate the change in cerebral glucose metabolic rate after 12 months of treatment with liraglutide in participants with Alzheimer's disease compared to those who are receiving placebo. METHODS/DESIGN: ELAD is a 12-month, multi-centre, randomised, double-blind, placebo-controlled, phase IIb trial of liraglutide in participants with mild Alzheimer's dementia. A total of 206 participants will be randomised to receive either liraglutide or placebo as a daily injection for a year. The primary outcome will be the change in cerebral glucose metabolic rate in the cortical regions (hippocampus, medial temporal lobe, and posterior cingulate) from baseline to follow-up in the treatment group compared with the placebo group. The key secondary outcomes are the change from baseline to 12 months in z scores for clinical and cognitive measures (Alzheimer's Disease Assessment Scale-Cognitive Subscale and Executive domain scores of the Neuropsychological Test Battery, Clinical Dementia Rating Sum of Boxes, and Alzheimer's Disease Cooperative Study-Activities of Daily Living) and the incidence and severity of treatment-emergent adverse events or clinically important changes in safety assessments. Other secondary outcomes are 12-month change in magnetic resonance imaging volume, diffusion tensor imaging parameters, reduction in microglial activation in a subgroup of participants, reduction in tau formation and change in amyloid levels in a subgroup of participants measured by tau and amyloid imaging, and changes in composite scores using support machine vector analysis in the treatment group compared with the placebo group. DISCUSSION: Alzheimer's disease is a leading cause of morbidity worldwide. As available treatments are only symptomatic, the search for disease-modifying therapies is a priority. If the ELAD trial is successful, liraglutide and GLP-1 analogues will represent an important class of compounds to be further evaluated in clinical trials for Alzheimer's treatment. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01843075 . Registration 30 April 2013.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Glucose/metabolismo , Hipoglicemiantes/uso terapêutico , Liraglutida/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Atividades Cotidianas , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/psicologia , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Ensaios Clínicos Fase II como Assunto , Cognição/efeitos dos fármacos , Método Duplo-Cego , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Humanos , Hipoglicemiantes/efeitos adversos , Liraglutida/efeitos adversos , Memória/efeitos dos fármacos , Estudos Multicêntricos como Assunto , Fármacos Neuroprotetores/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Reino Unido
18.
Acta Diabetol ; 56(9): 1051-1060, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30993527

RESUMO

AIMS: Patients with type 2 diabetes (T2D) have an increased risk of cardiovascular disease. Recent cardiovascular outcome trials (CVOTs) with liraglutide, semaglutide, and albiglutide have shown significant reduction in major adverse cardiovascular events. Conversely, the CVOT with exenatide long-acting release (ELAR) confirmed cardiovascular safety of the drug, but did not reached superiority versus placebo. Herein, we systematically evaluated the effect of ELAR versus placebo or active comparators on cardiovascular events and mortality in patients with T2D. METHODS: We screened the literature for randomized controlled trials reporting cardiovascular events and deaths in patients receiving ELAR versus those receiving placebo or any other glucose-lowering medications. Event rates were pooled and compared using the random-effects model. RESULT: We retrieved 16 trials comparing the occurrence of cardiovascular events and mortality in patients treated with ELAR versus placebo or active comparators. The pooled rate ratio for cardiovascular events was similar in the two groups (0.99; 95% CI 0.92-1.06). The rate ratio for all-cause mortality was significantly lower in exenatide group than in comparators (0.87; 95% CI 0.77-0.97). When results of the EXSCEL trial were omitted, the pooled rate ratio for cardiovascular events and mortality was 0.80 (95% CI 0.40-1.63) and 0.75 (95% CI 0.30-1.84), respectively. CONCLUSIONS: Treatment with ELAR does not increase the risk of cardiovascular events and may reduce all-cause mortality.


Assuntos
Preparações de Ação Retardada/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Angiopatias Diabéticas/epidemiologia , Exenatida/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/mortalidade , Sistema Cardiovascular/efeitos dos fármacos , Causas de Morte , Preparações de Ação Retardada/administração & dosagem , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/mortalidade , Angiopatias Diabéticas/tratamento farmacológico , Angiopatias Diabéticas/mortalidade , Exenatida/administração & dosagem , Feminino , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Humanos , Incidência , Liraglutida/uso terapêutico , Masculino , Pessoa de Meia-Idade , Mortalidade
20.
J Coll Physicians Surg Pak ; 29(3): 218-221, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30823945

RESUMO

OBJECTIVE: To investigate the effects of liraglutide combined with insulin on oxidative stress and expression levels of serum monocyte chemoattractant protein-1 (MCP-1) and nuclear factor-kB (NF-kB) in patients with type 2 diabetes. STUDY DESIGN: An experimental study. PLACE AND DURATION OF STUDY: Department of Endocrinology, the Second Hospital Affiliated to Lanzhou University, China, from September 2016 to January 2018. METHODOLOGY: Ninety-two patients with type 2 diabetes were selected as objects of study. They were randomly divided into observation group and control group, with 46 cases in each group. The control group was treated with insulin alone, and the observation group was treated with liraglutide in combination with insulin. The changes of levels of blood glucose, serum MDA, SOD, MCP-1 and NF-kB were compared between the two groups before and after treatment, and the blood glucose target rate after treatment was compared between the two groups. RESULTS: Before treatment, there were no significant differences in fasting blood glucose, 2h postprandial blood glucose, serum MDA, serum SOD, serum MCP-1 and serum NF-kB between the two groups (p=0.885, 0.961, 0.919, 0.990, 0.954 and 0.837, respectively). After treatment, levels of the fasting blood glucose, 2h postprandial blood glucose, serum MDA, serum MCP-1, and serum NF-kB in the observation group were lower than those in the control group (all p<0.001). The serum SOD level and blood glucose target rate were higher in the observation group than those in the control group (p<0.001 and p=0.010, respectively). CONCLUSION: Liraglutide combined with insulin therapy can effectively improve blood glucose levels in type 2 diabetic, reduce oxidative stress status, decrease the expression of serum MCP-1 and NF-kB, and inhibit the internal inflammatory response.


Assuntos
Quimiocina CCL2/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insulina/uso terapêutico , Liraglutida/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Adulto , Idoso , Glicemia/análise , Glicemia/efeitos dos fármacos , China , Diabetes Mellitus Tipo 2/diagnóstico , Quimioterapia Combinada , Ensaio de Imunoadsorção Enzimática , Feminino , Hospitais Universitários , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Pessoa de Meia-Idade , NF-kappa B/sangue , Prognóstico , Valores de Referência , Índice de Gravidade de Doença , Resultado do Tratamento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA