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1.
Presse Med ; 48(12): 1489-1495, 2019 Dec.
Artigo em Francês | MEDLINE | ID: mdl-31757735

RESUMO

Lifestyle modifications, especially weight loss, are efficient on NASH liver injury, however rarely followed in clinical practice. The target population of pharmacologic treatments is represented by patients with NASH and fibrosis. Out of histological improvement, efficacy of treatments should be assessed through liver morbi-mortality benefit, but also on extrahepatic events, such as cardiovascular. Among anti-diabetic treatments, glitazones et GLP-1 agonists have shown efficacy on histological liver injury. Vitamin E is efficient on liver injury but at the cost of prostate cancer and stroke over risk. About 60 new molecules are under investigation in NASH and have 4 different types of mechanism of action: metabolic, oxidative stress/apoptosis, anti inflammatory and anti fibrotic. A phase 3 trial evaluating obeticholic acid have shown a 72 weeks duration treatment improved significantly fibrosis.


Assuntos
Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Antioxidantes/uso terapêutico , Chalconas/uso terapêutico , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/uso terapêutico , Citoproteção/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/agonistas , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Humanos , Imidazóis/uso terapêutico , Resistência à Insulina/fisiologia , Metformina/uso terapêutico , Seleção de Pacientes , Preparações Farmacêuticas/classificação , Propionatos/uso terapêutico , Tiazolidinedionas/uso terapêutico
3.
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
4.
Int J Mol Sci ; 20(13)2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31261624

RESUMO

Diabetes Mellitus (DM) is a leading cause of both Cardiovascular Disease (CVD) and End-stage Renal Disease (ESRD). After 2008, there has been much evidence presented, and recently the guidelines for sugar control have changed to focus on being more disease orientated. GLP-1 Receptor Agonists (GLP-1R) and sodium glucose cotransporter-2 inhibitors are suggested as the first line towards fighting all DM, CVD and ESRD. However, the benefits of GLP-1R in organ transplantation recipients remain very limited. No clinical trials have been designed for this particular population. GLP-1R, a gastrointestinal hormone of the incretin family, possesses antidiabetic, antihypertensive, anti-inflammatory, anti-apoptotic and immunomodulatory actions. There are few drug-drug interactions, with delayed gastric emptying being the major concern. The trough level of tacrolimus may not be significant but should still be closely monitored. There are some reasons which support GLP-1R in recipients seeking glycemic control. Post-transplant DM is due to an impaired ß-cell function and glucose-induced glucagon suppression during hyperglycemia, which can be reversed by GLP-1R. GLP-1R infusion tends to relieve immunosuppressant related toxicity. Until now, in some cases, glycemic control and body weight reduction can be anticipated with GLP-1R. Additional renal benefits have also been reported. Side effects of hypoglycemia and gastrointestinal discomfort were rarely reported. In conclusion, GLP-1R could be implemented for recipients while closely monitoring their tacrolimus levels and any potential side effects. Any added benefits, in addition to sugar level control, still require more well-designed studies to prove their existence.


Assuntos
Diabetes Mellitus/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Hipoglicemiantes/uso terapêutico , Transplante de Rim/efeitos adversos , Síndrome Metabólica/tratamento farmacológico , Diabetes Mellitus/etiologia , Nefropatias Diabéticas/cirurgia , Peptídeo 1 Semelhante ao Glucagon/administração & dosagem , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Humanos , Hipoglicemiantes/administração & dosagem
5.
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
6.
Rev Med Suisse ; 15(653): 1117-1123, 2019 May 29.
Artigo em Francês | MEDLINE | ID: mdl-31148423

RESUMO

GLP-1 analogues are a well-established treatment for type 2 diabetes. They act by improving glycemic control through several mechanisms. They also have the advantage of inducing weight loss without the risk of associated hypoglycemia. This class of molecules has also shown a benefit in cardiovascular events such as cardiovascular mortality, stroke and myocardial infarction, and albuminuria. These favorable effects place them, like SGLT-2 inhibitors, as a second option in the case of unsatisfactory glycemic control after metformin and dietary and lifestyle measures. This article provides an overview of the current knowledge of GLP-1 analogue therapy in patients with type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2 , Peptídeo 1 Semelhante ao Glucagon , Hipoglicemiantes , Metformina , Glicemia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Humanos , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico
7.
Diabetes Res Clin Pract ; 152: 125-134, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31004676

RESUMO

AIMS: Compare the efficacy and safety of albiglutide from a ready-to-use, single-dose, auto-injector system with the lyophilized product in patients with type 2 diabetes mellitus (T2DM). METHODS: In this phase 3 study, 308 patients between 18 and 80 years with T2DM and experiencing inadequate glycemic control on their current regimen of diet/exercise alone or in combination with metformin were randomized 1:1 to weekly injections for 26 weeks with an active albiglutide auto-injector and placebo lyophilized dual-chamber cartridge (DCC) pen injector (n = 154) or active albiglutide lyophilized DCC pen injector and placebo liquid auto-injector (n = 154). Participants received liquid or lyophilized albiglutide 30 mg for 4 weeks, and then 50 mg for the remaining 22 weeks. Change in HbA1c and fasting plasma glucose (FPG), pharmacokinetics, and safety were assessed. RESULTS: In the albiglutide liquid and lyophilized drug product groups, 55.6% (85/153) and 45.5% of patients (70/154) had a baseline HbA1c ≥ 8.0%, respectively. The model-adjusted least squares (LS) mean change in HbA1c from baseline at week 26 was -1.1% (95% CI: -1.3, -1.0) and -1.2% (95% CI: -1.3, -1.0; noninferiority P = 0.0002) in the albiglutide liquid and lyophilized product groups, respectively. Similarly, the model-adjusted LS mean change in FPG from baseline at week 26 in the albiglutide liquid and lyophilized product groups was -2.2 (95% CI: -2.6, -1.8) mmol/L and -1.9 (95% CI: -2.3, -1.5) mmol/L, respectively. No new safety concerns were identified. CONCLUSION: Change from baseline in HbA1c for albiglutide liquid was noninferior to lyophilized drug product in patients with T2DM.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Composição de Medicamentos , Feminino , Liofilização , Peptídeo 1 Semelhante ao Glucagon/administração & dosagem , Peptídeo 1 Semelhante ao Glucagon/efeitos adversos , Hemoglobina A Glicada/análise , Hemoglobina A Glicada/efeitos dos fármacos , Hemoglobina A Glicada/metabolismo , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Masculino , Metformina/administração & dosagem , Metformina/efeitos adversos , Pessoa de Meia-Idade , Soluções , Resultado do Tratamento , Adulto Jovem
8.
Endocr Pract ; 25(7): 698-716, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30865522

RESUMO

Objective: Albiglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), reduces glycated hemoglobin with a low risk of hypoglycemia in patients with type 2 diabetes. The relationship between GLP-1RAs and risk of pancreatitis is unresolved. This independent, rigorous, expert review of the albiglutide HARMONY Phase III clinical program examined suspected cases of acute pancreatitis. Methods: An independent pancreatitis adjudication committee (PAC), composed of physicians with expertise in gastroenterology and pancreatic disease, was prospectively established to review cases of suspected acute pancreatitis in the HARMONY studies. Results: Patients treated in Phase III trials with albiglutide (n = 2,365), or active or placebo comparators (n = 2,530), averaged 56 years of age with a mean 8.3-year diabetes duration. Across the 8 studies, the PAC reviewed potential cases of treatment-emergent acute pancreatitis in 43 patients. Definite or probable acute pancreatitis was adjudicated for 11 patients (8 albiglutide; 3 active comparators). Most of these were considered by the PAC to be at least possibly related to study treatment (6 of 8 albiglutide cases and 2 of 3 active comparator cases). Both cases in the active comparator group adjudicated as definite or probable pancreatitis with at least a possible relationship to study treatment were in patients treated with a GLP-1RA. The frequency of pancreatitis was higher among patients treated with albiglutide (6/2,365, 0.3%) than with placebo (0/486, 0%) or active comparators (2/2,062, 0.08%). Conclusion: In the HARMONY Phase III program, adjudicated cases of acute pancreatitis were uncommon. However, within the limitations of available data, the incidence of acute pancreatitis with albiglutide appears to be within the range described for other studies of GLP-1RAs. Abbreviations: AE = adverse event; CI = confidence interval; DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1; GLP-1RA = glucagon-like peptide-1 receptor agonist; MH-OR = Mantel-Haenszel odds ratio; OR = odds ratio; PAC = pancreatitis adjudication committee; SAE = serious adverse event; ULN = upper limit of normal.


Assuntos
Diabetes Mellitus Tipo 2 , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Peptídeo 1 Semelhante ao Glucagon/efeitos adversos , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1 , Humanos , Hipoglicemiantes , Pessoa de Meia-Idade , Pâncreas
9.
Acta Biochim Biophys Sin (Shanghai) ; 51(3): 293-300, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30883649

RESUMO

Diabetic cardiomyopathy is an important contributor to morbidity and mortality of diabetic patients by causing heart failure. Interstitial and perivascular fibrosis plays a crucial role in diabetic cardiomyopathy. However, there is a lack of effective specific treatments available for diabetic cardiomyopathy. In the present study, we aim to explore the effects of Liraglutide, a GLP-1 analogue, on diabetic cardiomyopathy in STZ-induced diabetic rats fed with high-fat diet. A total of 60 male Wistar rats were randomly assigned to three groups, i.e. normal group, model group, and Liraglutide group, with 20 rats in each group. Serum levels of TC, TG, LDL-C, NEFA, and hydroxyproline were measured using commercial kits. Cardiac function was evaluated by QRS waves, LVEDd, LVESd, and LVEF. Myocardial fibrosis was measured by immunohistochemistry. Our results demonstrated that chronic administration of Liraglutide decreased the level of blood glucose and significantly alleviated lipid metabolic disturbance compared with the model group. Furthermore, Liraglutide was found to improve the damaged cardiac function. In line with this, we also found that the alleviation of cardiac dysfunction was associated with the decreased fibrosis in diabetic myocardial tissues, which was reflected by the decreased expressions of P4hα-1, COL-1, COL-3, MMP-1, and MMP-9. Our results thus suggest that Liraglutide might have a myocardial protective effect by inhibiting P4hα-1-mediated myocardial fibrosis.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Cardiomiopatias Diabéticas/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Liraglutida/uso terapêutico , Miocárdio/patologia , Pró-Colágeno-Prolina Dioxigenase/antagonistas & inibidores , Animais , Glicemia/análise , Diabetes Mellitus Experimental/complicações , Fibrose , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Estreptozocina
10.
Biomed Pharmacother ; 111: 926-933, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30841472

RESUMO

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a prevalent disease that is highly associated with the metabolic syndrome and type II diabetes. The development of in vivo models that reflect all nuances of the human NASH pathology is essential for drug discovery and development. We aimed to further characterise a dietary induced model of NASH both biochemically and histologically. In addition, we also investigated whether pioglitazone and liraglutide, drugs that have both been investigated as potential NASH treatments, could modulate the pathological changes induced by the NASH diet. Furthermore, to aid the translation of data from pre-clinical in vivo models, we aimed to adapt the NASH Clinical Research Network (CRN) histological score system for use in rodent studies. METHODS: Sprague Dawley rats were fed a high-fat diet (HFD) for 9 weeks, after which they were switched to a high fat, high cholesterol and cholate diet (HFCC) for 12 weeks. The rats were divided into treatment groups, receiving either 30 mg/kg pioglitazone p.o. SID or liraglutide s.c. 200 µg/kg BID or the respective vehicles. Serum levels of triglycerides (TG), cholesterol (Chol), LDL, HDL, AST and ALT, as well as body weight were assessed in all subjects. Upon termination, the liver was weighed and evaluated histologically using modified NASH-CRN criteria. RESULTS: HFCC feeding induced severe hepatic injury and hepatomegaly as indicated by significant increases in AST, ALT and an increased liver weight. Additionally, HFCC feeding induced dyslipidaemia, significant increases in circulating cholesterol and LDL were observed. No obesogenic effect of the HFCC diet was observed, though the diet did induce insulin resistance. Histological analysis showed that the HFCC diet induced several NASH like features, though it did not induce the development of severe fibrosis. However, microgranulomas were often prevalent in addition to lobular inflammatory foci. Pioglitazone showed little efficacy upon both biochemical and histological features. However, liraglutide induced weight loss, improved glycaemic control, reduced ALT and AST and showed some beneficial effects upon steatosis and lobular inflammation. CONCLUSION: Similar to previous reports we have shown that the atherogenic diet, HFCC, induces a phenotype akin to that seen in human NASH patients. Despite inducing all histological features of NASH, HFCC feeding does not promote the development of significant fibrosis within rodents. Pioglitazone and liraglutide have been investigated as potential NASH treatments. Within this model of NASH we have shown that pioglitazone has little efficacy, whereas liraglutide reduced the levels of circulating aminotransferases and had some beneficial effects upon NASH histological parameters.


Assuntos
Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Liraglutida/farmacologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , PPAR gama/agonistas , Pioglitazona/farmacologia , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Glicemia/efeitos dos fármacos , Colesterol/sangue , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Fígado Gorduroso/sangue , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/metabolismo , Inflamação/sangue , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/metabolismo , Ratos , Ratos Sprague-Dawley , Roedores/sangue , Roedores/metabolismo , Triglicerídeos/sangue
11.
Diabetes Res Clin Pract ; 150: 167-173, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30844468

RESUMO

BACKGROUND: It has been reported that GLP-1 analogue can improve the skin lesions of psoriasis. However further research is needed to confirm that finding. OBJECTIVE: The study can provide further data regarding the efficacy and safety of GLP-1 analogue liraglutide in the treatment of psoriasis patients with type 2 diabetes. METHODS: We recruit 7 psoriasis patients with type 2 diabetes, and use hypodermic injection with liraglutide1.8 mg. In 12 weeks of treatment, we estimate the difference of before and after respectively, likeBMI, waist circumference, fasting blood glucose, fasting C-peptide, HbA1c, blood lipid levels, CRP, PASI, DLQI, skin tissue and pathological analysis of psoriasis. RESULTS: After 12 weeks of treatment, the mean value of PASI decreased from 15.7 ±â€¯11.8 to 2.2 ±â€¯3.0 (P = 0.03), while the DLQI decreased from 21.8 ±â€¯6 to 4.1 ±â€¯3.9 (P = 0.001). HbA1c was significantly improved after 12 weeks of treatment, decreased to 6.4 ±â€¯0.8% (P = 0.04), the BMI decreased to 21 ±â€¯3 kg m-2 (P < 0.01), and the waist circumference was also significantly improved to 83 ±â€¯1 cm (P < 0.05). And 12 weeks after, the fasting C-peptide levels increased to 1.9 ±â€¯0.5 ng/ml (P = 0.006), HOMA - IR fell to 1.6 ±â€¯0.6 (P = 0.03). Histological analysis showed a reduction in epidermal thickness after treatment. The mean PASI decreased from 15.7 (1.5-31.3) to 2.0 (0.3-8.7) (P = 0.03), the DLQI decreased from 22 (8-27) to 4 (0-10) (P = 0.001). CONCLUSION: GLP-1 analogueliraglutide can improve the skin lesions of psoriasis patients with type 2 diabetes effectively, especially for extremely severe psoriasis patients. Its therapeutic effect may be related to anti-inflammatory, hypoglycemic and reducing weight.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Hipoglicemiantes/uso terapêutico , Liraglutida/uso terapêutico , Psoríase/tratamento farmacológico , Idoso , Glicemia/análise , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Psoríase/etiologia , Psoríase/patologia
12.
Nat Commun ; 10(1): 924, 2019 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-30804332

RESUMO

Peptides have gained so much attention in the last decade that they are now part of the main strategies, with small molecules and biologics, for developing new medicines. Despite substantial progress, the successful development of peptides as drugs still requires a number of limitations to be addressed, including short in vivo half-lives and poor membrane permeability. Here, we describe the use of oligourea foldamers as tool to improve the pharmaceutical properties of GLP-1, a 31 amino acid peptide hormone involved in metabolism and glycemic control. Our strategy consists in replacing four consecutive amino acids of GLP-1 by three consecutive ureido residues by capitalizing on the structural resemblance of oligourea and α-peptide helices. The efficacy of the approach is demonstrated with three GLP-1-oligourea hybrids showing prolonged activity in vivo. Our findings should enable the use of oligoureas in other peptides to improve their pharmaceutical properties and may provide new therapeutic applications.


Assuntos
Diabetes Mellitus/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Peptídeo 1 Semelhante ao Glucagon/farmacocinética , Peptídeos/química , Peptídeos/farmacocinética , Sequência de Aminoácidos , Animais , Peptídeo 1 Semelhante ao Glucagon/sangue , Humanos , Cinética , Masculino , Camundongos Endogâmicos C57BL , Modelos Moleculares , Dados de Sequência Molecular , Peptídeos/sangue
13.
Diabetes Metab Res Rev ; 35(1): e3070, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30156747

RESUMO

Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are an important class of drugs with a well-established efficacy and safety profile in patients with type 2 diabetes mellitus. Agents in this class are derived from either exendin-4 (a compound present in Gila monster venom) or modifications of human GLP-1 active fragment. Differences among these drugs in duration of action (ie, short-acting vs long-acting), effects on glycaemic control and weight loss, immunogenicity, tolerability profiles, and administration routes offer physicians several options when selecting the most appropriate agent for individual patients. Patient preference is also an important consideration. The aim of this review is to discuss the differences between and similarities of GLP-1 RAs currently approved for clinical use, focusing particularly on the properties characterising the single short-acting and long-acting GLP-1 RAs rather than on their individual efficacy and safety profiles. The primary pharmacodynamic difference between short-acting (ie, exenatide twice daily and lixisenatide) and long-acting (ie, albiglutide, dulaglutide, exenatide once weekly, liraglutide, and semaglutide) GLP-1 RAs is that short-acting agents primarily delay gastric emptying (lowering postprandial glucose) and long-acting agents affect both fasting glucose (via enhanced glucose-dependent insulin secretion and reduced glucagon secretion in the fasting state) and postprandial glucose (via enhanced postprandial insulin secretion and inhibition of glucagon secretion). Other advantages of long-acting GLP-1 RAs include smaller fluctuations in plasma drug concentrations, improved gastrointestinal tolerability profiles, and simpler, more convenient administration schedules (once daily for liraglutide and once weekly for albiglutide, dulaglutide, the long-acting exenatide formulation, and semaglutide), which might improve treatment adherence and persistence.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hipoglicemiantes/uso terapêutico , Exenatida/uso terapêutico , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Humanos , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Resultado do Tratamento
14.
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
16.
Lancet ; 392(10157): 1519-1529, 2018 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-30291013

RESUMO

BACKGROUND: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. METHODS: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30-50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. FINDINGS: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68-0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. INTERPRETATION: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. FUNDING: GlaxoSmithKline.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Hipoglicemiantes/uso terapêutico , Adulto , Idoso , Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 2/complicações , Método Duplo-Cego , Esquema de Medicação , Feminino , Peptídeo 1 Semelhante ao Glucagon/administração & dosagem , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Humanos , Hipoglicemiantes/administração & dosagem , Injeções Subcutâneas , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/prevenção & controle , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle , Resultado do Tratamento
17.
Pharmacol Res ; 137: 219-229, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30359962

RESUMO

Accumulating experimental and clinical evidences over the last decade indicate that GLP-1 analogues have a series of central nervous system and peripheral target tissues actions which are able to significantly influence the liver metabolism. GLP-1 analogues pleiotropic effects proved to be efficacious in T2DM subjects not only reducing liver steatosis and ameliorating NAFLD and NASH, but also in lowering plasma glucose and liver inflammation, improving cardiac function and protecting from kidney dysfunction. While the experimental and clinical data are robust, the precise mechanisms of action potentially involved in these protective multi-target effects need further investigation. Here we present a systematic review of the most recent literature data on the multi-target effects of GLP-1 analogues on the liver, on adipose and muscular tissue and on the nervous system, all capable of influencing significant aspects of the fatty liver disease physiopathology. From this analysis, we can conclude that the multi-target beneficial action of the GLP-1 analogues could explain the positive effects observed in animal and human models on progression of NAFLD to NASH.


Assuntos
Peptídeo 1 Semelhante ao Glucagon , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Humanos
18.
Praxis (Bern 1994) ; 107(19): 1031-1037, 2018 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-30227796

RESUMO

Technological Innovations in Diabetes Therapy Abstract. In the last few years a whole array of technical innovations has dramatically increased treatment options for patients with diabetes mellitus. Capillary blood glucose measurements are increasingly replaced by continuous glucose monitoring. More and more insulin pump systems are linked up to continuous glucose monitoring, which thereby become ever more self-regulating. Novel ultra-long and ultra-short acting insulins have become available. There will soon be oral alternatives for several anti-diabetic treatments, which hitherto needed to be injected.


Assuntos
Automonitorização da Glicemia/instrumentação , Diabetes Mellitus/terapia , Invenções , Pâncreas Artificial , Administração Oral , Ensaios Clínicos Fase III como Assunto , Diabetes Mellitus/diagnóstico , Glucagon/administração & dosagem , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Humanos , Insulina/administração & dosagem , Sistemas de Infusão de Insulina
19.
Curr Cardiol Rep ; 20(11): 113, 2018 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-30259238

RESUMO

PURPOSE OF REVIEW: Mimetics and analogs that extend the half-life of native glucagon-like peptide-1 (GLP-1), i.e., glucagon-like peptide-1 receptor agonists (GLP-1 RAs), at therapeutic doses, are indicated as adjuncts to diet and exercise, to improve glycemic control in adults with type 2 diabetes mellitus (T2DM). In patients with T2DM, GLP-1 RAs not only affect improvements in impaired beta cell and alpha cell function, suppress appetite, and induce weight loss but also possess multiple cardiovascular protective properties that potentially have a beneficial impact on atherosclerotic cardiovascular disease (ASCVD) morbidity and mortality. RECENT FINDINGS: Required to demonstrate CV safety, compared to standard-of-care antidiabetic therapies, GLP-1 RAs have revealed statistically significant non-inferiority (p < 0.001), among CV outcome trials (CVOTs) thus far completed. Once-daily liraglutide and once-weekly semaglutide demonstrated significant superiority (p = 0.01 and p = 0.02, respectively), reducing 3-point composite major adverse cardiovascular events (MACE) in extreme risk secondary prevention adults with T2DM. Once-weekly exenatide demonstrated only a non-significant (p = 0.06) favorable trend for CV superiority, possibly due to in-trial mishaps, including placebo drop-ins with other CV protective medications. The short half-life lixisenatide was neutral (p = 0.81) in reducing MACE, most likely due to ineffective once-daily dosing. Structural differences among GLP-1 mimetics and analogs may explain potency differences in both A1C reduction and weight loss that may parallel important cardiovascular protective properties of the GLP-1 RA class. Significant superiority in reducing 3-point composite MACE in adults with T2DM with GLP-1 RAs has been limited to liraglutide and semaglutide. Careful attention to within-trial drop-in of cardioprotective antidiabetic agents assuring equipoise between placebo and investigational product groups might demonstrate significant MACE risk reduction with once-weekly exenatide. Maintenance of 24-h circulating levels, by an alternative administration method, may resurrect lixisenatide as a cardioprotective agent. Before a GLP-1 RA bioequivalence "class effect" claim for composite MACE risk reduction superiority can be fully discussed, we are obliged to wait for the pending results of CVOTs with other GLP-1 RAs, particularly albiglutide and dulaglutide, where steric hindrance may potentially inhibit full mimicry of pharmacologic GLP-1.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hipoglicemiantes/administração & dosagem , Esquema de Medicação , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Comportamento de Redução do Risco
20.
Bull Exp Biol Med ; 165(5): 644-648, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30225696

RESUMO

The effects of the pegylated form of glucagon-like peptide 1 (pegGLP-1) on oligopotent ß cell precursors (CD45-TER119-CD133+CD49flow) in the pancreas were studied in C57Bl/6 mice. Under conditions of streptozotocin-induced type 1 diabetes mellitus, intraperitoneal injection of pegGLP1 increased the content of ß cell precursors and dithizone-stained cells in the pancreas. ß Cell precursors of mice with diabetes demonstrated high self-maintenance potential. In contrast to pegGLP-1, native GLP-1 did not affect ß cell precursors in diabetic animals. Treatment of a culture of ß cell precursors from mice with diabetes induced the yield of dithizone-stained mononuclears. In conditioned mediums of dithizone-positive cells obtained as a result of differentiation of ß cell precursors from mice with diabetes, insulin was detected after administration of pegGLP-1 (10-7 M) and glucose (3 mmol/liter); the level of insulin increased with increasing glucose concentration (to 20 mmol/liter). The in vitro effect of pegGLP-1 did not differ from the effect of GLP-1 (10-7 M).


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Incretinas/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Insulina/agonistas , Polietilenoglicóis/química , Animais , Antígenos CD/metabolismo , Biomarcadores/metabolismo , Diferenciação Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Incretinas/química , Injeções Intraperitoneais , Insulina/biossíntese , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Regeneração , Estreptozocina
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