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2.
Mol Immunol ; 116: 73-79, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31630078

RESUMO

Atherosclerosis is a common comorbidity of type II diabetes and a leading cause of death worldwide. The presence of oxidized low-density lipoprotein (ox-LDL) drives atherogenesis by inducing oxidative stress, mitochondrial dysfunction, expression of proinflammatory cytokines and chemokines including interleukin (IL)-1ß, IL-6, and monocyte chemoattractant protein 1 (MCP-1), adhesion molecules including vascular cellular adhesion molecule 1 (VCAM-1) and E-selectin, and downregulating expression of the Krüppel-like factor 2 (KLF2) transcription factor. Importantly, ox-LDL induced the attachment of THP-1 monocytes to endothelial cells. In the present study, we demonstrate for the first time that the specific glucagon-like peptide 1 receptor (GLP-1R) agonist dulaglutide may prevent these atherosclerotic effects of ox-LDL by preventing suppression of KLF2 by p53 protein in human aortic endothelial cells. KLF2 has been shown to play a major role in protecting vascular endothelial cells from damage induced by ox-LDL and oscillatory shear, and therefore, therapies capable of mediating KLF2 signaling may be an attractive treatment option for preventing the development and progression of atherosclerosis.


Assuntos
Aterosclerose/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Fragmentos Fc das Imunoglobulinas/farmacologia , Lipoproteínas LDL/metabolismo , Monócitos/efeitos dos fármacos , Proteínas Recombinantes de Fusão/farmacologia , Aterosclerose/metabolismo , Adesão Celular , Células Cultivadas , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Células Endoteliais , Regulação da Expressão Gênica/efeitos dos fármacos , Peptídeos Semelhantes ao Glucagon/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Fatores de Transcrição Kruppel-Like/metabolismo , Monócitos/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Molécula 1 de Adesão de Célula Vascular/metabolismo
3.
Int Immunopharmacol ; 74: 105649, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31185450

RESUMO

Rheumatoid arthritis is a common autoimmune disease primarily characterized by chronic inflammation, the formation of an invasive pannus, and destruction of the joints. In the present study, we employed real-time PCR and western blot analysis to investigate the role of dulaglutide in human fibroblast-like synoviocytes (FLS). The results of our study show that dulaglutide exerted a powerful protective effect by rescuing mitochondrial membrane potential, inhibiting the production of NOX-4, and abrogating TNF-α-induced downregulation of the antioxidant GSH. Our findings demonstrate that dulaglutide significantly ameliorated the expression of proinflammatory cytokines and chemokines including IL-1ß, IL-6, MCP-1, and HMGB-1. Matrix metalloproteinases mediate cartilage destruction, thereby aiding in pannus formation. Our findings indicate that dulaglutide treatment significantly downregulated the expression of MMP-3 and MMP-13, two crucial degradative enzymes. Importantly, the results of our study demonstrate that the beneficial effects of dulaglutide are mediated through the JNK/NF-κB signaling pathway, which has been suggested as a potential treatment target against RA. Taken together, the results of this study show that dulaglutide may exert significant protective effects against the progression of RA induced by TNF-α.


Assuntos
Anti-Inflamatórios/farmacologia , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Fragmentos Fc das Imunoglobulinas/farmacologia , Proteínas Recombinantes de Fusão/farmacologia , Sinoviócitos/efeitos dos fármacos , Citocinas/genética , Citocinas/metabolismo , Fibroblastos , Peptídeos Semelhantes ao Glucagon/farmacologia , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/fisiologia , NADPH Oxidase 4/genética , NADPH Oxidase 4/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Sinoviócitos/metabolismo
4.
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
5.
Int J Mol Sci ; 20(7)2019 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-30934882

RESUMO

GLP-1 (glucagon-like peptide-1) has been reported to play a vital role in neuroprotection. Experimental autoimmune encephalomyelitis (EAE) is a well-established animal model widely used to study human multiple sclerosis, a chronic demyelination disease in the central nervous system (CNS). Recently, important studies have designated that the signaling axis of GLP-1 and its receptor controls the clinical manifestations and pathogenesis of EAE. However, it is elusive whether GLP-1 receptor signaling regulates the phenotype of autoreactive T cells in the CNS. We administered dulaglutide, a well-established GLP-1 receptor agonist (GLP-1 RA), to treat EAE mice prophylactically or semi-therapeutically and subsequently analyzed the mononuclear cells of the CNS. In this study, dulaglutide treatment significantly alleviates the clinical manifestations and histopathological outcomes of EAE. Dulaglutide decreases incidences of encephalitogenic Th1/Th17 cells and Th1 granulocyte-macrophage-colony-stimulating factor (GM-CSF) expression in the CNS. Administration of dulaglutide failed to control the chemotactic abilities of encephalitogenic Th1 and Th17 cells; however, prophylactic treatment considerably decreased the populations of dendritic cells and macrophages in the CNS parenchyma. These results obtained indicate that dulaglutide modulates the differentiation of encephalitogenic Th1/Th17 and the pathogenicity of Th1 cells by influencing antigen presenting cells quantities, providing mechanism insight on T cells regulation in ameliorating EAE by GLP-1.


Assuntos
Sistema Nervoso Central/patologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/imunologia , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Células Th1/imunologia , Células Th17/imunologia , Animais , Quimiotaxia/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Progressão da Doença , Regulação para Baixo/efeitos dos fármacos , Encefalomielite Autoimune Experimental/patologia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/farmacologia , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Imunização , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Fragmentos Fc das Imunoglobulinas/farmacologia , Subpopulações de Linfócitos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/farmacologia , Células Th1/efeitos dos fármacos , Células Th17/efeitos dos fármacos
6.
Drug Des Devel Ther ; 13: 731-738, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30863012

RESUMO

Type 2 diabetes mellitus (T2DM) has become one of the leading causes of morbidity and mortality in developed countries. Low efficacy, weight gain, and hypoglycemia are the main pitfalls of previous treatments for T2DM. New therapies have been designed with the aim of improving the results in efficacy and quality of life. Glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1 RA) increase glucose-dependent insulin secretion, decrease gastric emptying, and reduce postprandial glucagon secretion. The last GLP-1 RA approved by the US Food and Drug Administration and European Medicines Agency was semaglutide. This review describes its pharmacology, core clinical data coming from the randomized controlled trials included in the development program, proven cardiovascular benefits, safety issues, and precautions for the use of semaglutide in special populations. Additionally, an overview of the positioning of semaglutide in T2DM therapy and practical issues regarding semaglutide initiation are offered.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Peptídeos Semelhantes ao Glucagon/farmacologia , Hipoglicemiantes/farmacologia , Peptídeos Semelhantes ao Glucagon/síntese química , Peptídeos Semelhantes ao Glucagon/química , Humanos , Hipoglicemiantes/química
8.
Psychopharmacology (Berl) ; 236(6): 1717-1728, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30607480

RESUMO

RATIONALE: Glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are gut derived hormones. GLP-1 and GLP-2 were shown to have pleiotropic effects in intestinal and pancreatic diseases. OBJECTIVE: We aimed to investigate the activities of GLP-1 and GLP-2 on nociception and inflammation in mice, involving their actions on serotonergic, nitrergic, and opioidergic systems. METHODS: Antinociceptive and anti-inflammatory activities of intraperitoneally injected GLPs were evaluated in hotplate latency test, formalin-induced behavioral, and paw edema tests. Ondansetron, a selective 5-HT3 receptor antagonist; L-NAME, a NOS inhibitor; and naloxone, an opioid antagonist were injected to determine the mechanisms of antinociception and anti-inflammation. We also measured blood glucose levels and performed rotarod test in order to evaluate whether the hypoglycemic effect of GLP compounds or alterations in locomotor activity may affect the latency in hotplate test and activity in formalin test. RESULTS: GLP-1 (0.2 mg/kg) and GLP-2 (0.05, 0.2 mg/kg) significantly increased pain threshold. GLP-1 (0.2 mg/kg) and GLP-2 (0.05, 0.1, 0.2 mg/kg) significantly decreased formalin-induced licking and shaking behaviors. GLP-1 or GLP-2 showed no significant inhibitory action on formalin-induced swelling in paws of mice. Antinociceptive actions of GLP-1 and GLP-2 were significantly decreased with ondansetron and naloxone, and paw shaking behavior significantly increased with naloxone. GLP-1 and GLP-2 did not impair rotarod performance, and did not cause a significant hypoglycemic effect in our normoglycemic mice after rotarod test. CONCLUSION: These finding indicated that the antinociceptive and anti-inflammatory effect of GLP-1 was related to opioidergic system. Antinociceptive effect of GLP-2 was partially related to 5-HT3 serotonergic or opioidergic system in hotplate test. However, the anti-inflammatory effect of GLP-2 was not directly related to 5-HT3, NO or opioids.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Peptídeos Semelhantes ao Glucagon/farmacologia , Antagonistas de Entorpecentes/farmacologia , Óxido Nítrico/metabolismo , Receptores 5-HT3 de Serotonina/metabolismo , Analgésicos/uso terapêutico , Animais , Anti-Inflamatórios/uso terapêutico , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Edema/sangue , Edema/tratamento farmacológico , Edema/patologia , Feminino , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Naloxona/farmacologia , Nociceptividade/efeitos dos fármacos , Nociceptividade/fisiologia , Dor/sangue , Dor/tratamento farmacológico , Dor/patologia , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Extratos Vegetais/farmacologia , Teste de Desempenho do Rota-Rod/métodos , Antagonistas do Receptor 5-HT3 de Serotonina/farmacologia
9.
Diabetes Obes Metab ; 21(1): 43-51, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30047216

RESUMO

AIMS: Semaglutide is a glucagon-like peptide-1 (GLP-1) analogue approved for the treatment of type 2 diabetes. The impact of switching treatment from another GLP-1 receptor agonist (GLP-1RA) to semaglutide was investigated by analyses of exposure-response models. METHODS: HbA1c and body weight time-course models were developed, using up to 30 weeks of observations from four trials in the semaglutide phase 3 programme. Given the recommended dosing for each GLP-1RA, pharmacokinetic profiles were simulated based on published population pharmacokinetic models and exposure was adjusted by the relative potencies to ensure that model predictions matched the effects observed in clinical trials. After 26 weeks of simulated treatment with liraglutide, dulaglutide or exenatide extended-release, simulated semaglutide treatment was initiated 1 day after the last once-daily dose of liraglutide and 1 week after the last once-weekly doses of dulaglutide or exenatide extended-release. RESULTS: The potency-adjusted total effective GLP-1RA concentration increased after switching from another GLP-1RA to semaglutide and was associated with reductions ranging from ~0.3% to ~0.8%-points for HbA1c and from ~2% to ~4% for body weight with semaglutide 1.0 mg. Temporary slight deteriorations in HbA1c were observed after switching to semaglutide 0.25 mg from liraglutide 1.2/1.8 mg or dulaglutide 1.5 mg. CONCLUSIONS: Exposure-response modelling suggests that switching to semaglutide from liraglutide, dulaglutide or exenatide extended-release results in further reductions in HbA1c and body weight. Initial slight deterioration in outcome values when switching to semaglutide 0.25 mg could be avoided by initiating semaglutide treatment at a higher dose.


Assuntos
Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon , Hemoglobina A Glicada/análise , Hipoglicemiantes , Adulto , Idoso , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/farmacologia , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos
10.
J Clin Endocrinol Metab ; 104(1): 202-208, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30272170

RESUMO

Context: Recent findings from animal and human studies indicate that glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) modulate stress response by activating the hypothalamic-pituitary-adrenal (HPA) axis, which may have relevant clinical implications. Objective: To investigate the influence of GLP-1 RA treatment on HPA axis activity compared with placebo in healthy volunteers. Design: Double-blind, randomized, crossover study. Setting: University Hospital Basel, Switzerland. Participants: Twenty healthy volunteers. Intervention: Dulaglutide (Trulicity®) 1.5 mg and placebo (0.9% sodium chloride) were given subcutaneously once weekly for 3 weeks. Main Outcome Measures: Twenty-four-hour urinary free cortisol, circadian rhythm of serum and salivary cortisol, cortisol after 1 mg dexamethasone suppression test, and cortisol levels before and after stimulation with ACTH. Results: Urinary free cortisol levels were similar under dulaglutide [median (interquartile range) 240 nmol/L (164, 324)] vs placebo [188 nmol/L (133, 338), P = 0.131]. The circadian rhythm of serum and salivary cortisol were comparable in both groups as were cortisol levels after dexamethasone [dulaglutide 28 nmol/L (22, 47.5) vs placebo 26.5 nmol/L (15.8, 45.5), P = 0.4]. Serum cortisol levels in dulaglutide and placebo treated participants were 522 nmol (388, 710) and 530 nmol/L (394, 747), before (P = 0.6), and 658 nmol/L (604, 810) and 636 nmol/L (512, 910) after ACTH stimulation (P = 0.87). Conclusion: Our results suggest that there is no activation of the HPA axis by long-term GLP-1 RA exposure, particularly dulaglutide, at the medically approved dosage of 1.5 mg once weekly.


Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hipoglicemiantes/farmacologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Fragmentos Fc das Imunoglobulinas/farmacologia , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Proteínas Recombinantes de Fusão/farmacologia , Hormônio Adrenocorticotrópico/farmacologia , Adulto , Ritmo Circadiano , Estudos Cross-Over , Dexametasona/farmacologia , Método Duplo-Cego , Feminino , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Peptídeos Semelhantes ao Glucagon/farmacologia , Voluntários Saudáveis , Humanos , Hidrocortisona/metabolismo , Hidrocortisona/urina , Hipoglicemiantes/administração & dosagem , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Masculino , Proteínas Recombinantes de Fusão/efeitos adversos , Estimulação Química , Adulto Jovem
11.
Sci Transl Med ; 10(472)2018 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-30567927

RESUMO

Glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) has been identified in multiple genome-wide association studies (GWAS) as a contributor to obesity, and GIPR knockout mice are protected against diet-induced obesity (DIO). On the basis of this genetic evidence, we developed anti-GIPR antagonistic antibodies as a potential therapeutic strategy for the treatment of obesity and observed that a mouse anti-murine GIPR antibody (muGIPR-Ab) protected against body weight gain, improved multiple metabolic parameters, and was associated with reduced food intake and resting respiratory exchange ratio (RER) in DIO mice. We replicated these results in obese nonhuman primates (NHPs) using an anti-human GIPR antibody (hGIPR-Ab) and found that weight loss was more pronounced than in mice. In addition, we observed enhanced weight loss in DIO mice and NHPs when anti-GIPR antibodies were codosed with glucagon-like peptide-1 receptor (GLP-1R) agonists. Mechanistic and crystallographic studies demonstrated that hGIPR-Ab displaced GIP and bound to GIPR using the same conserved hydrophobic residues as GIP. Further, using a conditional knockout mouse model, we excluded the role of GIPR in pancreatic ß-cells in the regulation of body weight and response to GIPR antagonism. In conclusion, these data provide preclinical validation of a therapeutic approach to treat obesity with anti-GIPR antibodies.


Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Obesidade/tratamento farmacológico , Receptores dos Hormônios Gastrointestinais/antagonistas & inibidores , Adipócitos/metabolismo , Animais , Anticorpos/farmacologia , Anticorpos/uso terapêutico , Dieta , Quimioterapia Combinada , Comportamento Alimentar , Polipeptídeo Inibidor Gástrico/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Peptídeos Semelhantes ao Glucagon/farmacologia , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Humanos , Fragmentos Fc das Imunoglobulinas/farmacologia , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Liraglutida/farmacologia , Liraglutida/uso terapêutico , Camundongos Obesos , Obesidade/patologia , Primatas , Receptores dos Hormônios Gastrointestinais/metabolismo , Proteínas Recombinantes de Fusão/farmacologia , Proteínas Recombinantes de Fusão/uso terapêutico , Respiração , Ganho de Peso/efeitos dos fármacos , Perda de Peso/efeitos dos fármacos
12.
Sci Transl Med ; 10(467)2018 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-30429357

RESUMO

Oral administration of therapeutic peptides is hindered by poor absorption across the gastrointestinal barrier and extensive degradation by proteolytic enzymes. Here, we investigated the absorption of orally delivered semaglutide, a glucagon-like peptide-1 analog, coformulated with the absorption enhancer sodium N-[8-(2-hydroxybenzoyl) aminocaprylate] (SNAC) in a tablet. In contrast to intestinal absorption usually seen with small molecules, clinical and preclinical dog studies revealed that absorption of semaglutide takes place in the stomach, is confined to an area in close proximity to the tablet surface, and requires coformulation with SNAC. SNAC protects against enzymatic degradation via local buffering actions and only transiently enhances absorption. The mechanism of absorption is shown to be compound specific, transcellular, and without any evidence of effect on tight junctions. These data have implications for understanding how highly efficacious and specific therapeutic peptides could be transformed from injectable to tablet-based oral therapies.


Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Peptídeos Semelhantes ao Glucagon/farmacologia , Absorção Intestinal , Estômago/fisiologia , Administração Oral , Adolescente , Adulto , Idoso , Animais , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Cães , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/ultraestrutura , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/farmacocinética , Humanos , Concentração de Íons de Hidrogênio , Masculino , Pessoa de Meia-Idade , Ratos , Estômago/efeitos dos fármacos , Fatores de Tempo , Adulto Jovem
13.
Yakugaku Zasshi ; 138(10): 1323-1327, 2018.
Artigo em Japonês | MEDLINE | ID: mdl-30270278

RESUMO

 Incretin-based therapy consists of dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists. Whether switching from DPP-4 inhibitors to one of the GLP-1 receptor agonists, dulaglutide, has greater beneficial effects remains unknown. Therefore, this study aimed to investigate the effectiveness of switching from DPP-4 inhibitors to dulaglutide in four patients with type 2 diabetes. All four patients with hyperglycemia who switched from DPP-4 inhibitors to dulaglutide demonstrated noticeable decreased plasma glucose levels on the next day after switching. Two of the patients observed maintained a decreased plasma glucose level over 14 day after switching. Moreover, all patients demonstrated decreased glycosylated hemoglobin A1c levels during the observation period (1-6 months) after switching and lost weight from 6 to 27 day. Minor and manageable hypoglycemia, nausea, and diarrhea were observed as side effects in one case. The current findings suggest that dulaglutide is a suitable treatment alternative in patients with type 2 diabetes who are not currently achieving adequate glycemic control with DPP-4 inhibitors.


Assuntos
Glicemia/análise , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Substituição de Medicamentos , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hemoglobina A Glicada/análise , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Inibidores da Dipeptidil Peptidase IV/farmacologia , Feminino , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/farmacologia , Humanos , Fragmentos Fc das Imunoglobulinas/farmacologia , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes de Fusão/farmacologia , Resultado do Tratamento
14.
Expert Rev Clin Pharmacol ; 11(11): 1061-1072, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30296182

RESUMO

INTRODUCTION: Semaglutide once-weekly glucagon-like peptide-1 receptor agonist (GLP-1 RA) injection has been approved as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus (T2DM). Areas Covered: The safety and efficacy of the semaglutide once-weekly injection are reviewed using results from preliminary pharmacology studies and later-phase randomized control trials (RCTs) and meta-analyses. Semaglutide once-weekly is compared to placebo and active comparators for T2DM in the SUSTAIN clinical trial series, with outcomes of: glycemic control, weight loss, major adverse cardiovascular events, and adverse effects. Risk for diabetic retinopathy complications (DRCs) is reviewed in detail, due to significantly higher risk for DRCs seen in SUSTAIN 6. SUSTAIN 6 is the first instance of a GLP-1 RA demonstrating significantly increased risk for DRCs. Semaglutide's current regulatory approvals, practice considerations, and cost-effectiveness compared to similar therapies are also considered. Expert Commentary: Semaglutide demonstrates high glycemic efficacy and favorable safety profile, and reduces the risk for cardiovascular events. Mild to moderate gastrointestinal events and retinopathy complications were more common with semaglutide compared to placebo, though serious adverse events were similar to controls and infrequent. Improved clinical efficacy should be carefully weighed against the risk for GI and retinopathy complications.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Hipoglicemiantes/administração & dosagem , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/complicações , Retinopatia Diabética/epidemiologia , Esquema de Medicação , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Peptídeos Semelhantes ao Glucagon/farmacologia , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto
15.
Clin Ther ; 40(8): 1396-1407, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30093131

RESUMO

PURPOSE: The aims of this study were to use real-world treatment results to compare changes in estimated glomerular filtration rate (eGFR) and glycosylated hemoglobin (HbA1c) among patients with type 2 diabetes who initiated treatment with dulaglutide or insulin glargine and to determine the proportions of patients with renal impairment who initiate each treatment. METHODS: The study used data from the Practice Fusion electronic health records database from October 2013 through June 2017. Adults with type 2 diabetes who initiated dulaglutide or insulin glargine therapy and had multiple recorded serum creatinine and/or HbA1c laboratory test results were included in the study. The dulaglutide cohort (n = 1222) was matched to the insulin glargine cohort (n = 13,869) using Mahalanobis distance matching with propensity score calipers. Multivariable analyses of the matched cohorts of individuals with serum creatinine results (n = 1183 dulaglutide and 1183 insulin glargine) examined the association between intent-to-treat therapy and changes in eGFR. In addition, multivariable analyses were also conducted on a subset of these patients who also had recorded HbA1c tests (n = 1088 dulaglutide and 1088 insulin glargine) to examine the association between changes in HbA1c during the 1 year postperiod. FINDINGS: Among patients who initiated dulaglutide therapy, only 0.9% of patients had an index eGFR <30 and ≥15 mL/min/1.73 m2 and 0.1% had an index eGFR <15 mL/min/1.73 m2. In contrast, 4.1% of insulin glargine-treated patients had an index eGFR <30 and ≥15 mL/min/1.73 m2 and 1.2% had an index eGFR <15 mL/min/1.73 m2. Compared with patients who initiated therapy with insulin glargine, initiation of dulaglutide therapy was associated with a significantly smaller decrease in eGFR (-0.4 vs -0.9 mL/min/1.73 m2; P = 0.0024), a significantly smaller likelihood of having a 30% or greater reduction in eGFR (3.3% vs 4.1%; P < 0.0001), and a significantly larger reduction in HbA1c (-0.5% vs -0.2%; P < 0.0001). IMPLICATIONS: In clinical practice, the use of dulaglutide was relatively more limited in patients with a higher degree of renal impairment compared with use of insulin glargine. However, initiation of dulaglutide therapy, compared with insulin glargine therapy, was associated with a significantly smaller decrease in eGFR and a larger reduction in HbA1c during the 1 year postperiod.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Taxa de Filtração Glomerular/efeitos dos fármacos , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hipoglicemiantes/farmacologia , Fragmentos Fc das Imunoglobulinas/farmacologia , Insulina Glargina/farmacologia , Proteínas Recombinantes de Fusão/farmacologia , Insuficiência Renal/fisiopatologia , Idoso , Creatinina/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Feminino , Peptídeos Semelhantes ao Glucagon/farmacologia , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Hemoglobina A Glicada/metabolismo , Humanos , Hipoglicemiantes/uso terapêutico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Insulina Glargina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes de Fusão/uso terapêutico , Insuficiência Renal/complicações , Resultado do Tratamento
16.
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
17.
Diabetes Obes Metab ; 20(11): 2565-2573, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29893488

RESUMO

AIMS: To investigate the effects of semaglutide vs placebo on glucagon and other counterregulatory hormones during hypoglycaemia in type 2 diabetes (T2D). METHODS: In this double-blind, placebo-controlled, single-centre trial, we randomized 38 men and women (treated only with metformin) 1:1 to 2 12-week crossover periods of once-weekly subcutaneous semaglutide or placebo, each followed by a hypoglycaemic clamp procedure. The primary endpoint was change in glucagon concentration from target plasma glucose (PG) level 5.5 mmol/L to nadir (target 2.5 mmol/L). RESULTS: The mean (range) participant age was 54.2 (41-64) years, body mass index 29.4 (23.3-36.1) kg/m2 , glycated haemoglobin 60.8 (44.3-83.6) mmol/mol (7.7 [6.2-9.8]%), and diabetes duration 4.5 (0.3-13.2) years. A total of 35 participants completed the trial and were included in the analyses. During the hypoglycaemic clamp from 5.5 mmol/L PG to nadir, the absolute change in mean glucagon concentration was similar for semaglutide vs placebo: 88.3 vs 83.1 pg/mL (estimated difference 5.2 pg/mL [95% confidence interval -7.7 to 18.1]). Concentrations of other counterregulatory hormones increased with both treatments, with a statistically significantly lower increase for noradrenaline and cortisol with semaglutide vs placebo. The glucose infusion rate to maintain constant clamp levels was similar for each treatment group, suggesting an overall similar counterregulatory response. The mean hypoglycaemic symptom score and proportion of participants recognizing hypoglycaemia during the study were lower for semaglutide vs placebo treatment at nadir, but cognitive function test results were similar. No new safety issues were observed for semaglutide. CONCLUSIONS: Semaglutide treatment did not compromise the counterregulatory glucagon response during experimental hypoglycaemia in people with T2D.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Hipoglicemia/metabolismo , Adulto , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Estudos Cross-Over , Diabetes Mellitus Tipo 2/metabolismo , Método Duplo-Cego , Esquema de Medicação , Feminino , Peptídeos Semelhantes ao Glucagon/farmacologia , Humanos , Hipoglicemia/sangue , Hipoglicemia/induzido quimicamente , Hipoglicemia/epidemiologia , Masculino , Pessoa de Meia-Idade , Placebos
18.
Diabet Med ; 35(10): 1434-1439, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29869810

RESUMO

AIMS: To evaluate the effects of dulaglutide vs placebo on liver and glycaemic/metabolic measurements in a population with Type 2 diabetes and in a subgroup with non-alcoholic fatty liver/non-alcoholic steatohepatitis. METHODS: A total of 1499 participants from AWARD-1, AWARD-5, AWARD-8 and AWARD-9 clinical trials were included in this analysis (dulaglutide 1.5 mg, n=971 and placebo, n=528). Thresholds of alanine aminotransferase levels ≥30 IU/l in men and ≥19 IU/l in women were used to determine the subgroup who had non-alcoholic fatty liver/non-alcoholic steatohepatitis. Objectives included changes from baseline to 6 months in: (1) alanine aminotransferase, aspartate transaminase and gamma-glutamyl transpeptidase levels in the overall population and (2) alanine aminotransferase, aspartate transaminase, gamma-glutamyl transpeptidase and glycaemic/metabolic measurements (e.g. HbA1c , fasting serum glucose, body weight, lipids and homeostatic model assessment) in the non-alcoholic fatty liver/non-alcoholic steatohepatitis subgroup. RESULTS: In the overall population at 6 months, dulaglutide significantly reduced alanine aminotransferase, aspartate transaminase and gamma-glutamyl transpeptidase levels vs placebo [least squares mean treatment differences: -1.7 IU/l (95% CI -2.8, -0.6), P=0.003; -1.1 IU/l (95% CI -2.1, -0.1), P=0.037; -6.6 IU/l (95% CI -12.4, -0.8), P=0.025, respectively]. In the subgroup with non-alcoholic fatty liver/non-alcoholic steatohepatitis (alanine aminotransferase levels greater than or equal to the upper limit of normal), mean baseline liver enzyme values were 38.0 IU/l, 27.8 IU/l and 43.9 IU/l for alanine aminotransferase, aspartate transaminase and gamma-glutamyl transpeptidase, respectively. In this population, more pronounced reductions from baseline in alanine aminotransferase were observed with dulaglutide vs placebo (-8.8 IU/l vs -6.7 IU/l). In the subgroup of people with alanine aminotransferase levels less than the upper limit of normal, changes from baseline in alanine aminotransferase did not significantly differ between treatment groups (0.0 IU/l vs 0.7 IU/l). CONCLUSIONS: Once-weekly dulaglutide improved alanine aminotransferase, aspartate transaminase and gamma-glutamyl transpeptidase levels compared with placebo in a pattern consistent with liver fat reductions. Our results add further weight to the notion that glucagon-like peptide-1 receptor agonists may provide benefit in lowering liver fat in addition to their other metabolic actions.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Fígado/efeitos dos fármacos , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Proteínas Recombinantes de Fusão/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Diabetes Mellitus Tipo 2/complicações , Regulação para Baixo/efeitos dos fármacos , Feminino , Peptídeos Semelhantes ao Glucagon/farmacologia , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Humanos , Fragmentos Fc das Imunoglobulinas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/enzimologia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/sangue , Proteínas Recombinantes de Fusão/farmacologia , Estudos Retrospectivos , Adulto Jovem , gama-Glutamiltransferase/sangue
19.
Hormones (Athens) ; 17(3): 333-350, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29949126

RESUMO

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are an important asset in the armamentarium for the treatment of type 2 diabetes mellitus (type 2 DM). Incretin failure is a critical etiopathogenetic feature of type 2 DM, which, if reversed, results in improved glycaemic control. GLP-1 RAs are injectable peptides that resemble the structure and function of endogenous incretin GLP-1, but as they are not deactivated by the dipeptidyl peptidase-4 (DPP-4), their half-life is prolonged compared with native GLP-1. Based on their ability to activate GLP-1 receptor, GLP-1 RAs are classified as short-acting (exenatide twice-daily and lixisenatide once-daily), and long-acting (liraglutide once-daily and the once-weekly formulations of exenatide extended-release, dulaglutide, and albiglutide). Semaglutide, another long-acting, once-weekly GLP-1 RA, was recently approved by the FDA and EMA. Although all of these agents potently reduce haemoglobin A1C (HbA1c), there are unique features and fundamental differences among them related to fasting and postprandial hyperglycaemia reduction, weight loss potency, cardiovascular protection efficacy, and adverse events profile. It is imperative that current evidence be integrated and applied in the context of an individualised patient-centred approach. This should include not only glucose management but also targeting as many as possible of the pathophysiologic mechanisms responsible for type 2 DM development and progression.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hipoglicemiantes/farmacologia , Fragmentos Fc das Imunoglobulinas/farmacologia , Liraglutida/farmacologia , Proteínas Recombinantes de Fusão/farmacologia , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/farmacocinética , Peptídeos Semelhantes ao Glucagon/farmacologia , Humanos , Hipoglicemiantes/administração & dosagem , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Liraglutida/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem
20.
Biochim Biophys Acta Mol Basis Dis ; 1864(9 Pt B): 2814-2821, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29778663

RESUMO

Type 2 diabetes mellitus (T2DM) is a metabolic condition with an elevated impact on cardiovascular (CV) risk. The innovative therapeutic approaches for T2DM - incretin-based therapies (IBTs), including glucagon-like peptide 1 (GLP-1) receptor agonists, have become popular and more widely used in recent years. The available scientific data from clinical studies and clinical practice highlights their beyond glucose-lowering effects, which is achieved without any increase in hypoglycaemia. The former effects include reduction in body weight, lipids, blood pressure, inflammatory markers, oxidative stress, endothelial dysfunction, and subclinical atherosclerosis, thus reducing and potentially preventing CV events. In fact, the introduction of IBTs is one of the key moments in the history of diabetes research and treatment. Such therapeutic strategies allow customization of antidiabetic treatment to each patient's need and therefore obtain better metabolic control with reduced CV risk. The aim of the present paper is to provide a comprehensive overview of the effects of GLP-1RA on various cardiometabolic markers and overall CV risk, with particular attention on recent CV outcome studies and potential mechanisms. In particular, the effects of liraglutide on formation and progression of atherosclerotic plaque and mechanisms explaining its cardioprotective effects are highlighted.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Incretinas/farmacologia , Placa Aterosclerótica/tratamento farmacológico , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Peptídeos Semelhantes ao Glucagon/farmacologia , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Humanos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Incretinas/uso terapêutico , Liraglutida/farmacologia , Liraglutida/uso terapêutico , Placa Aterosclerótica/sangue , Placa Aterosclerótica/etiologia , Placa Aterosclerótica/metabolismo
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