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1.
J Environ Pathol Toxicol Oncol ; 38(2): 133-141, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31679276

RESUMO

The current study is a review of the literature on patients with diabetes who are diagnosed with colorectal cancer (CRC), encompassing recent research on CRC and the molecular level changes occurring in these patients on the basis of varying environmental as well as non-environmental factors. It has been noted that nearly 50% of all patients undergo the systemic treatment module; however, most of them exhibit drug resistance. In addition, targeted gene therapy has also been used in treatment but has been found to be effective only in patients with a specified molecular profile (or else this might lead to an increased risk of developing resistant mutations). This has led to increasing interest among researchers in finding innovative treatment options. Metformin, a biguanide, has been widely used in treating diabetes. The drug has been reportedly used in cases of hypothesis-generating retrospective population studies of diabetic patients showing reduced incidence of cancer. Metformin helps in reduction of excess insulin levels that possess various effects on cell signaling and metabolism. Nonetheless, there is need for an in-depth study on its molecular mechanism to fill any existing research gaps.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Neoplasias Colorretais/complicações , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Insulina/efeitos adversos , Transdução de Sinais/efeitos dos fármacos
2.
Rev Assoc Med Bras (1992) ; 65(9): 1144-1150, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31618328

RESUMO

OBJECTIVE: In view of the high incidence of polycystic ovary syndrome (PCOS) and the unsatisfactory therapeutic effects of dimethyldiguanide or clomifene citrate alone, our study aimed to investigate the therapeutic effects of dimethyldiguanide combined with clomifene citrate in the treatment of PCOS. METHODS: A total of 79 patients with POCS and 35 healthy females were included, and endometrial biopsies were obtained. The sterol regulatory element-binding protein-1 (SREBP1) expression in endometrial tissues was detected by qRT-PCR. POC patients were randomly divided into group A (n=40) and group B (n=39). Patients in group A were treated with dimethyldiguanide combined with clomifene citrate, while patients in group B were treated with clomifene citrate alone. The number of mature follicles and cervical mucus score, follicular development rate and single follicle ovulation rate, cycle pregnancy rate, early miscarriage rate, ovulation rate, endometrial thickness, positive rate of three lines sign, follicle stimulating hormone level and luteinizing hormone level were compared between the two groups. RESULTS: The expression level of SREBP1 was higher in PCOS patients than that in the healthy control. SREBP1 expression was inhibited after treatment, while the inhibitory effects of combined treatment were stronger than those of clomifene citrate alone. Compared with clomifene citrate alone, the combined treatment improved cervical mucus score, follicle development rate, single follicle ovulation rate, endometrial thickness, positive rate of three lines sign, and follicle-stimulating hormone level. CONCLUSION: The therapeutic effect of combined treatment is better than clomifene citrate alone in the treatment of PCOS.


Assuntos
Clomifeno/uso terapêutico , Fármacos para a Fertilidade Feminina/uso terapêutico , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Síndrome do Ovário Policístico/tratamento farmacológico , Adulto , Muco do Colo Uterino/efeitos dos fármacos , Clomifeno/farmacologia , Quimioterapia Combinada , Endométrio/fisiopatologia , Feminino , Fármacos para a Fertilidade Feminina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hipoglicemiantes/farmacologia , Metformina/farmacologia , Folículo Ovariano/efeitos dos fármacos , Indução da Ovulação , Proteína de Ligação a Elemento Regulador de Esterol 1/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Adulto Jovem
3.
Adv Gerontol ; 32(3): 431-438, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31512431

RESUMO

In recent years, the effectiveness of high-dose metformin (MF) to treat the endocrine and oncological diseases has been shown. However, the use of high-dose MF may be associated with the lactic acidosis and the liver dysfunctions. The aim of the work was to study the effect of long-term (10 days) oral administration of a relatively high dose of MF (600 mg/kg per day) into yellow C57Bl/6J (Ay/a) Agouti line mice with the melanocortin type obesity on the liver function, which was evaluated by the morphology of hepatocytes and the severity of steatosis, the expression of the inflammatory and apoptotic factors of and the activity of aminotransferases, as well as on the plasma lactate level in the animals. In Agouti line mice, MF (600 mg/kg per day) caused a decrease in the body and fat weight, led to the reduced hyperglycemia, hyperinsulinemia and hyperleptinemia, and restored the sensitivity to glucose and insulin. At the same time, in the liver of Agouti line mice treated with MF, the small-drop and large-drop fatty degeneration and the hydropic degeneration were attenuated, and the expression of pro-inflammatory IL-1ß and pro-apoptotic Bax protein and the Bax/Bcl-2 ratio did not differ from the control C57Bl/6J (a/a) mice. In the blood of Agouti line mice treated with MF, the activity of alanine aminotransferase was normalized, and the lactate levels was increased, but to a moderate degree. It was concluded that the high-dose MF did not induce the lactic acidosis in Agouti line mice, and at the same time it restored the liver functions impaired in the melanocortin obesity. This allows us to consider the use of the high doses of MF as one of the possible ways to treat obesity and metabolic disorders that are associated with the hepatic steatosis.


Assuntos
Fígado , Melanocortinas , Metformina , Obesidade , Animais , Dasyproctidae , Fígado/efeitos dos fármacos , Melanocortinas/metabolismo , Metformina/farmacologia , Metformina/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Obesidade/fisiopatologia
4.
Rev Med Liege ; 74(9): 443-450, 2019 Sep.
Artigo em Francês | MEDLINE | ID: mdl-31486312

RESUMO

Type 2 diabetes (T2D) is an evolving disease that requires therapeutic adjustments to maintain adequate glucose control in the long run. An increasing number of patients with T2D are treated with a metformin plus gliptin (DPP-4 Inhibitor) combination, especially those for whom a sulfonylurea is avoided because of a risk of hypoglycaemia. When this dual metformin-gliptin therapy becomes insufficient to reach or maintain adequate glucose control, three solutions may be considered : the addition of a gliflozin (SGLT2 inhibitor), the replacement of the gliptin by a glucagon-like peptide-1 receptor agonist or the addition of a basal insulin whose posology should be progressively up-titrated according to fasting glycaemia. This article describes the pro and contra arguments of these three therapeutic regimens. According to the recent data of the literature, the triple oral therapy combining metformin, a gliptin and a gliflozin appears to offer a favourable alternative in terms of efficacy, tolerance, ease of use, patient adherence and cost.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Metformina , Inibidores do Transportador 2 de Sódio-Glicose , Glicemia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Quimioterapia Combinada , Humanos , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
5.
Orv Hetil ; 160(34): 1346-1352, 2019 Aug.
Artigo em Húngaro | MEDLINE | ID: mdl-31423831

RESUMO

Introduction: Some meta-analyses suggested a positive effect of metformin therapy on lipid parameters, but the potential beneficial effect of metformin on cardiovascular risk in type 2 diabetes is not entirely clear. Aim: We investigated the effect of metformin therapy on lipid parameters and cardiovascular risk in patients with type 2 diabetes. Method: In a cross-sectional, monocentric study, 102 patients with type 2 diabetes without lipid-lowering medication were analysed for lipid profile and cardiovascular risk (United Kingdom Prospective Diabetes Study Risk Calculator) depending on metformin therapy. The patients were divided into two subgroups regarding with (n = 52) or without metformin therapy (n = 50). Results: Patients with metformin therapy had significantly lower total cholesterol and LDL cholesterol levels than patients without metformin (p<0.01 and p<0.05). This effect was independent from glucose control. No intrinsic effect of metformin could be found on systolic blood pressure, HDL cholesterol, triglycerides, and long-term cardiovascular risk using a multivariable risk assessment score. Conclusion: Metformin therapy has beneficial effects on cholesterol levels without improving cardiovascular risk in patients with type 2 diabetes. Orv Hetil. 2019; 160(34): 1346-1352.


Assuntos
Doenças Cardiovasculares/prevenção & controle , HDL-Colesterol/efeitos dos fármacos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/efeitos adversos , Metformina/efeitos adversos , Doenças Cardiovasculares/epidemiologia , Colesterol/sangue , HDL-Colesterol/sangue , Estudos Transversais , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Humanos , Hipoglicemiantes/uso terapêutico , Lipídeos/sangue , Metformina/uso terapêutico , Estudos Prospectivos , Fatores de Risco , Reino Unido
6.
BMC Public Health ; 19(1): 1063, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31391021

RESUMO

BACKGROUND: At present, only a few studies have focused on the risk factors for depression in elderly diabetic patients, and there is little evidence for the effect of metformin in depressed elderly patients with diabetes than on its effect on blood glucose. The aim of the current work was to study the risk factors for depression in elderly diabetic patients and to ascertain the effects of metformin on the depressive state. METHODS: We initiated a 1:4 matched case-control study. The case group comprised 110 elderly diabetic patients with depression from nine communities in Shenyang in 2017. The control group comprised 440 non-depressed elderly diabetic patients from the same communities, which were matched by gender and age (± 2 years of age) with the case group. Depression was measured using the Geriatric Depression Scale-15, and we performed matched univariate and multivariate logistic regression analyses. RESULTS: In the multivariate analysis, overweight status, poor physical capabilities and low activity level, and the presence of more than two additional illnesses were risk factors for depression in elderly patients with diabetes. For these risk factors, the adjusted ORs (all P < 0.05) were as follows: an adjusted OR of 2.031 and 95% CI of 1.180-3.495; an adjusted OR of 2.342 and 95% CI of 1.465-3.743; and an adjusted OR of 5.350 and 95% CI of 2.222-12.883, respectively. Patients taking metformin had a lower risk of depression than those taking no medication, with an adjusted OR of 0.567 and 95% CI of 0.323-0.997 (P < 0.05). CONCLUSIONS: Overweight status, poor physical capabilities and low activity level, and the presence of more than two additional illnesses were risk factors for depression in elderly diabetic patients, and metformin was a protective factor against depression in elderly diabetic patients.


Assuntos
Depressão/epidemiologia , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/psicologia , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
8.
Orv Hetil ; 160(31): 1207-1215, 2019 Aug.
Artigo em Húngaro | MEDLINE | ID: mdl-31352807

RESUMO

Type 2 diabetes - due to its natural course - should be considered as a progressive chronic disease. Owing to this fact, antihyperglycemic treatment should be continuously increased stepwise in order to achieve proper glycemic control. Lifestyle modification should be initiated immediately after manifestation, shortly followed by metformin monotherapy, and later, dual or triple combinations and, finally, injectable derivatives - only insulin in the past - should be used for appropriate glycemic control. Guidelines about treatment approach of patients with type 2 diabetes unequivocally emphasize and describe in detail the need of treatment intensification, in other words, stepwise escalation in clinical practice. In the last couple of years, evidences provided that step down therapy, simplification of complex treatment regimens should also be considered in certain cases. This approach was generally called de-escalation in antihyperglycemic treatment which should be considered in patients with type 2 diabetes 1) after bariatric (metabolic) surgery; 2) with significant weight reduction irrespective of its origin; 3) with complex insulin regimens where re-evaluation of this treatment was missed; 4) with continuously decreasing renal function; 5) among elderly patients with comorbidities; 6) in social deprivation. In this article, data about therapeutic de-escalation of antihyperglycemic treatment in patients with type 2 diabetes and first experiences with this treatment approach are summarized. Orv Hetil. 2019; 160(31): 1207-1215.


Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Idoso , Hemoglobina A Glicada/metabolismo , Humanos , Hipoglicemiantes/administração & dosagem , Insulina/farmacologia , Conduta do Tratamento Medicamentoso , Metformina/administração & dosagem , Resultado do Tratamento
9.
Nat Commun ; 10(1): 2987, 2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31278260

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a fatal disease in which the intricate alveolar network of the lung is progressively replaced by fibrotic scars. Myofibroblasts are the effector cells that excessively deposit extracellular matrix proteins thus compromising lung structure and function. Emerging literature suggests a correlation between fibrosis and metabolic alterations in IPF. In this study, we show that the first-line antidiabetic drug metformin exerts potent antifibrotic effects in the lung by modulating metabolic pathways, inhibiting TGFß1 action, suppressing collagen formation, activating PPARγ signaling and inducing lipogenic differentiation in lung fibroblasts derived from IPF patients. Using genetic lineage tracing in a murine model of lung fibrosis, we show that metformin alters the fate of myofibroblasts and accelerates fibrosis resolution by inducing myofibroblast-to-lipofibroblast transdifferentiation. Detailed pathway analysis revealed a two-arm mechanism by which metformin accelerates fibrosis resolution. Our data report an antifibrotic role for metformin in the lung, thus warranting further therapeutic evaluation.


Assuntos
Fibrose Pulmonar Idiopática/tratamento farmacológico , Lipogênese/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Metformina/farmacologia , Miofibroblastos/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 2/metabolismo , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Colágeno/biossíntese , Modelos Animais de Doenças , Humanos , Fibrose Pulmonar Idiopática/etiologia , Fibrose Pulmonar Idiopática/patologia , Pulmão/citologia , Pulmão/patologia , Masculino , Metformina/uso terapêutico , Camundongos , Miofibroblastos/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Cultura Primária de Células , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Resultado do Tratamento , Regulação para Cima/efeitos dos fármacos
10.
Artigo em Português | LILACS | ID: biblio-1022942

RESUMO

Já é bem conhecida a importância da terapêutica para os pacientes com diabetes mellitus (DM) no que diz respeito à redução dos eventos cardiovasculares e, por isso, existe interesse em comprovar a segurança cardiovascular das diferentes terapias anti-hiperglicêmicas disponíveis no mercado. O objetivo desta revisão consiste em discutir três grandes estudos publicados recentemente, LEADER, CANVAS e DECLARE ­ TIME 58, que avaliaram o efeito sobre morbidade e mortalidade cardiovascular das medicações em questão em comparação com placebo


The importance of therapy for patients with diabetes mellitus (DM) in reducing cardiovascular events is well-known and, therefore, there is interest in confirming the cardiovascular safety of the different antihyperglycemic therapies available on the market. The objective of this review is to discuss three large recently-published studies, LEADER, CANVAS and DECLARE ­ TIME 58, which evaluated the effect of the medications in question on morbidity and cardiovascular mortality as compared to a placebo


Assuntos
Humanos , Masculino , Feminino , Doenças Cardiovasculares , Diabetes Mellitus/terapia , Prática Clínica Baseada em Evidências , Placebos , Fatores de Risco , Resultado do Tratamento , Doença Arterial Periférica , Canagliflozina/uso terapêutico , Metformina/uso terapêutico
11.
Cancer Sci ; 110(9): 2834-2845, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31278880

RESUMO

Recurrence and chemoresistance in colorectal cancer remain important issues for patients treated with conventional therapeutics. Metformin and phenformin, previously used in the treatment of diabetes, have been shown to have anticancer effects in various cancers, including breast, lung and prostate cancers. However, their molecular mechanisms are still unclear. In this study, we examined the effects of these drugs in chemoresistant rectal cancer cell lines. We found that SW837 and SW1463 rectal cancer cells were more resistant to ionizing radiation and 5-fluorouracil than HCT116 and LS513 colon cancer cells. In addition, metformin and phenformin increased the sensitivity of these cell lines by inhibiting cell proliferation, suppressing clonogenic ability and increasing apoptotic cell death in rectal cancer cells. Signal transducer and activator of transcription 3 and transforming growth factor-ß/Smad signaling pathways were more activated in rectal cancer cells, and inhibition of signal transducer and activator of transcription 3 expression using an inhibitor or siRNA sensitized rectal cancer cells to chemoresistant by inhibition of the expression of antiapoptotic proteins, such as X-linked inhibitor of apoptosis, survivin and cellular inhibitor of apoptosis protein 1. Moreover, metformin and phenformin inhibited cell migration and invasion by suppression of transforming growth factor ß receptor 2-mediated Snail and Twist expression in rectal cancer cells. Therefore, metformin and phenformin may represent a novel strategy for the treatment of chemoresistant rectal cancer by targeting signal transducer and activator of transcription 3 and transforming growth factor-ß/Smad signaling.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Metformina/farmacologia , Fenformin/farmacologia , Neoplasias Retais/terapia , Transdução de Sinais/efeitos dos fármacos , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/efeitos da radiação , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Quimiorradioterapia/métodos , Colo/patologia , Neoplasias do Colo/patologia , Neoplasias do Colo/terapia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos da radiação , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Humanos , Masculino , Metformina/uso terapêutico , Camundongos , Camundongos Nus , Recidiva Local de Neoplasia , Fenformin/uso terapêutico , Neoplasias Retais/patologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos da radiação , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Yonsei Med J ; 60(7): 679-686, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31250582

RESUMO

PURPOSE: Statins, metformin, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) have been suggested for treating age-related macular degeneration (AMD) due to their pleiotropic effects. Therefore, we investigated whether these drugs prevent AMD. MATERIALS AND METHODS: We conducted a nested case-control study using the Korean National Health Insurance Service database. Using risk-set sampling of age, sex, cohort entry date, and follow-up duration, we identified incident patients with AMD and 10 matching controls in cohorts with diabetes mellitus or cardiovascular diseases. Exposure was assessed within one year before the index date using patient prescription records. We conducted conditional logistic regression to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) to evaluate the association between cardiovascular medications and AMD. RESULTS: Our study included 2330 cases and 23278 controls from a cohort of 231274 patients. The ORs (95% CI) for AMD occurrence in users prescribed with statins, metformin, ACE inhibitors, and ARBs were 1.12 (0.94-1.32), 1.15 (0.91-1.45), 0.90 (0.61-1.34), and 1.21 (1.05-1.39), respectively. A duration-response was not observed. CONCLUSION: Statins, metformin, ACE inhibitors, and ARBs did not inhibit AMD in elderly patients. The absence of a duration-response supports the lack of a causal relationship.


Assuntos
Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Degeneração Macular/tratamento farmacológico , Metformina/farmacologia , Idoso , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Modelos Logísticos , Masculino , Metformina/uso terapêutico
13.
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
14.
Medicine (Baltimore) ; 98(25): e16038, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31232936

RESUMO

INTRODUCTION: The purpose of this protocol is to provide a network meta-analysis methodology that compares the effects of metformin and physical exercise in the prevention and treatment of gestational diabetes mellitus (GDM) and its associated fetal and maternal morbidity. METHODS AND ANALYSIS: This protocol conforms to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) and the recommendations of the Cochrane Collaboration Handbook. An electronic search will be conducted in MEDLINE, EMBASE, Web of Science and the Cochrane Library, from the inception until July 2019. There will be no language restrictions. The Cochrane Collaboration tool for assessing risk of bias (RoB2) and the quality assessment tool for quantitative studies will be used. The Grading of Recommendations, Assessment, Development and Evaluation scale will be used to evaluate the strength of the evidence. A Bayesian network meta-analysis will be carried out, which allows direct and indirect comparison of the interventions, for the risk of GDM, prematurity, caesarean section, macrosomia, hypertensive disorders, insulin requirement, and differences in basal glucose, maternal weight, and weight of the newborn. DISCUSSION: With this protocol, a methodology is established that resolves the limitations of previous meta-analysis. It will be possible to determine the difference of effect between physical exercise and metformin in the main outcomes of the GDM, as well as the type and intensity of the exercise, and the dose of metformin, more effective. ETHICS AND DISSEMINATION: The data included in the network meta-analysis will be obtained from trials that meet accepted ethical standards and the Declaration of Helsinki. The results will be published in a peer-reviewed journal. The evidence obtained could be included in the guidelines of clinical practice in pregnancy. STRENGTHS AND LIMITATIONS: A comprehensive methodology is established for the analysis, through network meta-analysis, of the comparative efficacy of metformin and physical exercise in gestational diabetes mellitus. The results obtained could help medical professionals by establishing the best evidence-based interventions which may be recommended for these population groups. REGISTRATION NUMBER: PROSPERO CRD42019121715.


Assuntos
Diabetes Gestacional/terapia , Exercício , Hipoglicemiantes/uso terapêutico , Metanálise como Assunto , Metformina/uso terapêutico , Revisão Sistemática como Assunto , Feminino , Macrossomia Fetal , Humanos , Meta-Análise em Rede , Gravidez , Resultado da Gravidez , Cuidado Pré-Natal
15.
Vasc Endovascular Surg ; 53(6): 452-457, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31170884

RESUMO

BACKGROUND: Metformin is the most commonly used drug for type 2 diabetes. Research has shown that metformin also has a protective effect on endothelium by decreasing endothelial vascular reactivity. We hypothesize that metformin will decrease restenosis/reintervention rates in patients receiving lower extremity non-drug-eluting stents (nDESs) in the superficial femoral artery(SFA) and/or popliteal artery. MATERIALS/METHODS: Retrospective study was performed on 187 patients from October 2012 to December 2015 who received an nDES in the SFA and/or popliteal artery. Patients were divided into 3 groups (Table 1) and compared against for duplex based restenosis (>60%) rates, limb loss rates, and reintervention rates. Each patient's Trans-Atlantic-Inter-Society-Consensus II (TASC-II) class was collected. Postoperative duplex was performed 1 week after the procedure, then every 3 months for the first year, then, every 6 months to check for patency. IBM-SPSS-22 was used for all analyses. RESULTS: Average age of the patients was 64.65 ± 73.4 years. 101 patients had 101 procedures performed on the left lower extremity; 86 patients had 86 procedures performed on the right lower extremity; 123 patients were male and 64 were female. Average length of follow-up was 13.1±9.7 months. Most common indication for intervention was claudication, followed by critical limb threatening ischemia. Restenosis and reintervention by groups can be seen in Table 1. No patients experienced limb loss. There were no statistically significant differences between any of the 3 groups and their limb loss, restenosis, or reintervention rates. CONCLUSIONS: Despite having multiple proven effects in improving certain clinical outcomes and a proven protective effect on endothelium by decreasing endothelial vascular reactivity, metformin does not appear to reduce restenosis or reintervention rates in patients receiving lower extremity nDESs in the SFA and/or popliteal artery.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Procedimentos Endovasculares/instrumentação , Artéria Femoral/cirurgia , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Doença Arterial Periférica/cirurgia , Artéria Poplítea/cirurgia , Stents , Grau de Desobstrução Vascular/efeitos dos fármacos , Idoso , Constrição Patológica , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Procedimentos Endovasculares/efeitos adversos , Feminino , Artéria Femoral/diagnóstico por imagem , Artéria Femoral/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/complicações , Doença Arterial Periférica/diagnóstico por imagem , Doença Arterial Periférica/fisiopatologia , Artéria Poplítea/diagnóstico por imagem , Artéria Poplítea/fisiopatologia , Recidiva , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Ultrassonografia Doppler Dupla
16.
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
18.
World J Gastroenterol ; 25(15): 1797-1816, 2019 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-31057295

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease with no efficacious treatment options. PDAC incidence is projected to increase, which may be caused at least partially by the obesity epidemic. Significantly enhanced efforts to prevent or intercept this cancer are clearly warranted. Oncogenic KRAS mutations are recognized initiating events in PDAC development, however, they are not entirely sufficient for the development of fully invasive PDAC. Additional genetic alterations and/or environmental, nutritional, and metabolic signals, as present in obesity, type-2 diabetes mellitus, and inflammation, are required for full PDAC formation. We hypothesize that oncogenic KRAS increases the intensity and duration of the growth-promoting signaling network. Recent exciting studies from different laboratories indicate that the activity of the transcriptional co-activators Yes-associated protein (YAP) and WW-domain-containing transcriptional co-activator with PDZ-binding motif (TAZ) play a critical role in the promotion and maintenance of PDAC operating as key downstream target of KRAS signaling. While initially thought to be primarily an effector of the tumor-suppressive Hippo pathway, more recent studies revealed that YAP/TAZ subcellular localization and co-transcriptional activity is regulated by multiple upstream signals. Overall, YAP has emerged as a central node of transcriptional convergence in growth-promoting signaling in PDAC cells. Indeed, YAP expression is an independent unfavorable prognostic marker for overall survival of PDAC. In what follows, we will review studies implicating YAP/TAZ in pancreatic cancer development and consider different approaches to target these transcriptional regulators.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Carcinoma Ductal Pancreático/genética , Regulação Neoplásica da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Pancreáticas/genética , Fosfoproteínas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Animais , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinogênese/patologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Reposicionamento de Medicamentos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Metformina/farmacologia , Metformina/uso terapêutico , Terapia de Alvo Molecular/métodos , Mutação , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Fosfoproteínas/antagonistas & inibidores , Prognóstico , Proteínas Proto-Oncogênicas p21(ras)/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transcrição Genética/efeitos dos fármacos , Transcrição Genética/genética
19.
Clin Drug Investig ; 39(8): 757-763, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31124014

RESUMO

BACKGROUND: Metformin (MET) is used as first-line treatment for type 2 diabetes mellitus but has been shown to have pleiotropic effects that have expanded its use to various conditions. Limited current data exist regarding unconventional use within various patient populations. OBJECTIVE: The aim of this study was to evaluate US FDA-approved and off-label MET utilization in the US from 2000 to 2015. METHODS: We performed a retrospective analysis of outpatient MET prescribing in the US from 2000 to 2015. Data from the Medical Expenditure Panel Survey (MEPS) administered by the Agency of Healthcare Research and Quality were analyzed. Demographic characteristics, including age, sex, socioeconomic status, comorbidities, and region, were analyzed using the MEPS Household Component (HC). Prescription rates were defined as the annual number of MET prescriptions divided by the corresponding population estimate. Population denominators were derived using the MEPS HC. The MEPS estimates US populations based on sampled persons in the target population (civilian, non-institutionalized) for an entire year. MET prescribing is represented by population per 1000 persons. We determined if changes of MET prescribing were uniform across five age groups: < 18 years, 18-29 years, 30-49 years, 50-64 years, and 64 years and older. RESULTS: An estimated 553,291,094 MET prescriptions were dispensed in the US from 2000 to 2015. Prescribing rates steadily increased from 2000 to 2015. FDA-approved MET prescription rates increased from 2.27 per 1000 persons in 2000 to 235 per 1000 persons in 2015, while off-label MET prescription rates increased from 0.74 per 1000 persons in 2000 to 20.3 per 1000 persons in 2015. The top indications for off-label MET use were endocrine disorders (45.8%), cardiovascular disorders (18.2%), female reproductive disorders (12.9%), and metabolic disorders (10.9%). MET prescribing rates for FDA-approved indications increased across all age groups in 2000 and 2015, with the most substantial increase seen in adults aged 50-64 years and > 65 years (1.7 per 1000 persons to 20.6 per 1000 persons, and 2.3 per 1000 persons to 18.7 per 1000 persons, respectively). While off-label MET increased across all age groups from 2000 to 2015, a tenfold increase (< 1.0 to 10.6) was seen in adults aged 30-49 years of age. CONCLUSION: Overall, MET use has substantially increased within the past 15 years, which was mainly driven by older adults. Our study highlights the emerging prevalence of MET use in both FDA-approved and off-label indications.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Revisão de Uso de Medicamentos , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Padrões de Prática Médica/estatística & dados numéricos , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Estados Unidos , Adulto Jovem
20.
Vnitr Lek ; 65(4): 284-288, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31091948

RESUMO

Therapy with GLP1 receptors agonists shows various multiorgans benefits. Possible reasons of preference of this treatment are: efficacy, decrease of weight, CV protectivity, slow down the progression of nephropathy, protection of function of B-cells, safety (low risk of hypoglycemia, small incidence of serious adverse events), decrease of blood pressure, lipids, biomarkers of CV risk, markers of chronic subclinical inflammation. In context of individual approach, therapy with GLP1 receptors agonists should be preferably used in early stages of type 2 diabetes mellitus, as second choice treatment after metformin, mainly in more obese patients with subclinical or clinical manifestations of atherosclerosis, but without symptoms of heart failure.


Assuntos
Diabetes Mellitus Tipo 2 , Hipoglicemiantes , Insulina , Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Metformina/uso terapêutico
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