Metformin use and risk of ischemic stroke in patients with type 2 diabetes: A cohort study / 北京大学学报(医学版)

OBJECTIVE@#To explore the association between the use of metformin and the risk of ischemic stroke in patients with type 2 diabetes.@*METHODS@#A prospective cohort study was designed from the Fangshan family cohort in Beijing. According to metformin use at baseline, 2 625 patients with type 2 diabetes in Fangshan, Beijing were divided into metformin group or non-metformin group and the incidence of ischemic stroke between the different groups during follow-up was estimated and compared by Cox proportional hazard regression model. The participants with metformin were first compared with all the parti-cipants who did not use metformin, and then were further compared with those who did not use hypoglycemic agents and those who used other hypoglycemic agents.@*RESULTS@#The patients with type 2 diabetes were with an average age of (59.5±8.7) years, and 41.9% of them were male. The median follow-up time was 4.5 years. A total of 84 patients developed ischemic stroke during follow-up, with a crude incidence of 6.4 (95%CI: 5.0-7.7) per 1 000 person-years. Among all the participants, 1 149 (43.8%) took metformin, 1 476 (56.2%) were metformin non-users, including 593 (22.6%) used other hypoglycemic agents, and 883 (33.6%) did not use any hypoglycemic agents. Compared with metformin non-users, the Hazard ratio (HR) for ischemic stroke in metformin users was 0.58 (95%CI: 0.36-0.93; P = 0.024). Compared with other hypoglycemic agents, HR was 0.48 (95%CI: 0.28-0.84; P < 0.01); Compared with the group without hypoglycemic agents, HR was 0.65 (95%CI: 0.37-1.13; P=0.13). The association between metformin and ischemic stroke was statistically significant in the patients ≥ 60 years old compared with all the metformin non-users and those who used other hypoglycemic agents (HR: 0.48, 95%CI: 0.25-0.92; P < 0.05). Metformin use was associated with a lower incidence of ischemic stroke in the patients with good glycemic control (0.32, 95%CI: 0.13-0.77; P < 0.05). In the patients with poor glycemic control, and the association was not statistically significant (HR: 0.97, 95%CI: 0.53-1.79; P>0.05). There was an interaction between glycemic control and metformin use on incidence of ischemic stroke (Pinteraction < 0.05). The results of the sensitivity analysis were consistent with the results in the main analysis.@*CONCLUSION@#Among patients with type 2 diabetic in rural areas of northern China, metformin use was associated with lower incidence of ischemic stroke, especially in patients older than 60 years. There was an interaction between glycemic control and metformin use in the incidence of ischemic stroke.

The effects of metformin, acetylsalicylic acid and ibuprofen on telomerase enzyme activity: inhibitory effect of ibuprofen

Abstract Telomerase enzyme is necessary for the elongation of telomeres while telomerase being critical for aging and cancer. Metformin, ibuprofen, and acetylsalicylic acid used in this research are drugs that millions of people already use and that many are likely to use in future. In this study, the effects of these drugs on telomerase activity of Mus musculus swiss albino mice in liver tissue were investigated and the telomerase activity was measured with a PCR-ELISA based kit. In the study a possible connection between telomerase enzyme activity and activities of antioxidant enzymes was also investigated by determining the activity of superoxide dismutase (SOD) and catalase enzymes. The data obtained show that metformin slightly decreased telomerase enzyme activity in low dose application; however, this change was not statistically significant. In ibuprofen application, there was a significant inhibitory effect when high doses were used; whereas, there was a slight inhibitory effect at low doses. In acetylsalicylic acid application, a slight activator effect was detected; it was not statistically significant, though. Metformin was observed to increase catalase and SOD activities in general while low and high doses of acetyl salicylic acid showed different effects. In addition, ibuprofen caused a statistically significant increase in liver SOD values. It is important to note that this study demonstrated a significant inhibitory effect of ibuprofen on telomerase enzyme activity in animal models..

Polineuropatia diabética assintomática induzida pelo uso crônico de metformina e correlação com vitamina B12 / Asymptomatic diabetic polyneuropathy induced by chronic metformin use and correlation with vitamin B12

Introdução: Diabetes Mellitus é doença metabólica, caracterizada pela deficiência absoluta ou relativa de insulina, que acomete cerca de 382 milhões de pessoas em todo mundo, tendo uma das complicações mais comuns a polineuropatia. A Metformina, medicamento amplamente utilizado como tratamento do Diabetes, foi descrita como responsável, em algumas literaturas, por causar ou agravar deficiência de vitamina B12, que está similarmente relacionada ao desenvolvimento de polineuropatia.Métodos: Nesse sentido, foi conduzido um estudo no município de Soledade ­ RS, com objetivo de verificar se essa relação é condizente com a realidade da localidade. Foram escolhidos 58 pacientes, dos quais 30 responderam questionários adaptados baseados na literatura e na Classificação de Neuropatia de Michigan (MNSS-Brasil), então colhidos 5 ml de sangue venoso da fossa antecubital, preparado soro do qual uma alíquota foi separada para determinação bioquímica da vitamina B12.Resultados: Analisando os resultados, a maioria dos pacientes analisados apresentou sintomas de polineuropatia, e 10% deste, deficiência vitamínica.Conclusão: nenhuma variável explicou a correlação do uso crônico da Metformina, dose e gênero com a deficiência da vitamina B12, o que indica que não há evidências fortes o suficiente que sustentem esse fato, de acordo com as particularidades da localidade analisada.

Introduction: Diabetes Mellitus is a metabolic disease, characterized by absolute or relative insulin deficiency, which affects about 382 million people, with polyneuropathy being one of the most common complications. Metformin, a drug widely used as a treatment for diabetes, has been described as responsible, in some literature, for causing or aggravating vitamin B12 deficiency, which is similarly related to the development of polyneuropathy.Methods: In this sense, a study was conducted in Soledade ­ RS, in order to verify whether this relationship is consistent with the reality of the locality. Fifty-eight patients were selected, of which 30 answered adapted questionnaires based on the literature and on the Michigan Neuropathy Classification (MNSS-Brazil), then 5 ml of venous blood was collected from the antecubital fossa, serum prepared from which an aliquot was separated for biochemical determination of the vitamin B12.Results: Analyzing the results, most of these patients presented symptoms of polyneuropathy and, 10% of them, vitamin deficiency.Conclusion: no variable explained the correlation of chronic use of Metformin, dose and gender with vitamin B12 deficiency, which indicates that there is not enough evidence to support this fact, according to the particularities of the analyzed locality.

Efeitos da nanopartícula de ácido poli lático-co-glicólico (PLGA) associada ao cloridrato de metformina na doença periodontal em ratos diabéticos / Effects of polylactic-co-glycolic acid (PLGA) nanoparticle associated with metformin hydrochloride on periodontal disease in diabetic rats

Existe uma associação entre diabetes e a periodontite, e a Metformina (MET) além de controlar os níveis glicêmicos, tem apresentado efeitos antiinflamatórios e na diminuição da perda óssea periodontal. Ao se veicular a MET a um sistema de nanopartículas pode-se apresentar a vantagem de aumento da eficácia terapêutica. Objetivos: esse estudo consistiu na avaliação dos efeitos antiinflamatórios, perda óssea e disponibilidade in vitro/in vivo de uma nanopartícula de ácido poli lático-co-glicólico (PLGA) associada à MET em um modelo de periodontite induzida por ligadura. Materiais e métodos: o PLGA carreado com diferentes doses da MET foi caracterizado pelo seu diâmetro médio, tamanho da partícula, índice de polidispensão e eficiência de aprisionamento. Foram utilizados ratos machos da linhagem Wistar, divididos aleatoriamente, em grupos controles e experimentais com diferentes doses de MET associadas ou não ao PLGA, os quais receberam diferentes tratamentos. Amostras de maxilas e tecidos gengivais foram utilizadas para avaliação de perda óssea e inflamação, por meio da microtomografia computadorizada, histopatológico, imunohistoquímica, análise de citocinas inflamatórias e expressão gênica de proteínas por RT-PCR quantitativo. Para o ensaio de liberação in vitro, utilizou-se o dispositivo de células de difusão vertical de Franz estáticas. Para a disponibilidade in vivo, as amostras de sangue foram coletadas em diferentes intervalos de tempo e analisadas por cromatografia líquida de alta eficiência acoplado a espectrometria de massas (HPLC-MS/MS). Resultados: o diâmetro médio das nanopartículas de PLGA carreadas com MET estava em um intervalo de 457,1 ± 48,9 nm (p <0,05) com um índice de polidispersidade de 0,285 (p <0,05), potencial Z de 8,16 ± 1,1 mV (p <0,01) e eficiência de aprisionamento (EE) de 66,7 ± 3,73. O tratamento com a MET 10 mg / kg + PLGA mostrou uma baixa concentração de células inflamatórias, fraca imunomarcação para RANKL, Catepsina K, OPG e osteocalcina. Diminuição dos níveis de IL-1ß e TNF-α (p <0,05), aumento da expressão gênica do AMPK (p <0,05) e diminuição do NF-κB p65, HMGB1 e TAK-1 (p <0,05). O 10 mg/kg MET + PLGA foi liberado no ensaio in vitro sugerindo um modelo cinético de difusão parabólica com um perfil de liberação que atinge 50% de seu conteúdo em 2h e permanece em liberação constante em torno de 60% até o final de 6h. O ensaio in vivo mostrou o volume aparente de distribuição Vz/F (10 mg/kg MET + PLGA, 46,31 mL/kg vs. 100 mg/kg MET + PLGA, 28,8 mL/kg) e o tempo médio de residência MRTinf (PLGA + MET 10 mg /kg, 37,66h vs. MET 100 mg/kg, 3,34h). Conclusão: o PLGA carreado com MET diminuiu a inflamação e a perda óssea na periodontite em ratos diabéticos. O 10 mg/kg MET + PLGA teve uma taxa de eliminação mais lenta em comparação com o MET 100 mg/kg. A formulação modifica os parâmetros farmacocinéticos, como volume de distribuição aparente e tempo médio de residência (AU).

There is an association between diabetes and periodontitis, and Metformin (MET) in addition to controlling glycemic levels, has shown anti-inflammatory effects and decreased periodontal bone loss. By transferring MET to a nanoparticle system, the advantage of increasing therapeutic efficacy can be presented. Objectives: this study consisted of evaluating the antiinflammatory effects, bone loss and in vitro/in vivo availability of a polylactic-co-glycolic acid (PLGA) nanoparticle associated with MET in a ligature-induced periodontitis model. Materials and methods: PLGA loaded with different doses of MET was characterized by its mean diameter, particle size, polydispension index and entrapment efficiency. Male Wistar rats were used, randomly divided into control and experimental groups with different doses of MET associated or not with PLGA, which received different treatments. Samples of jaws and gingival tissues were used to assess bone loss and inflammation, using computed microtomography, histopathology, immunohistochemistry, analysis of inflammatory cytokines and gene expression of proteins by quantitative RT-PCR. For the in vitro release assay, the static Franz vertical diffusion cell device was used. For in vivo availability, blood samples were collected at different time intervals and analyzed by high performance liquid chromatography coupled with mass spectrometry (HPLC-MS/MS). Results: the mean diameter of MET-loaded PLGA nanoparticles was in the range of 457.1 ± 48.9 nm (p <0.05) with a polydispersity index of 0.285 (p <0.05), Z potential of 8.16 ± 1.1 mV (p <0.01) and trapping efficiency (EE) of 66.7 ± 3.73. Treatment with MET 10 mg/kg + PLGA showed a low concentration of inflammatory cells, weak immunostaining for RANKL, Cathepsin K, OPG and osteocalcin. Decreased IL-1ß and TNF-α levels (p <0.05), increased AMPK gene expression (p <0.05) and decreased NF-κB p65, HMGB1 and TAK-1 (p <0. 05). The 10 mg/kg MET + PLGA was released in the in vitro assay suggesting a kinetic model of parabolic diffusion with a release profile that reaches 50% of its content in 2h and remains in constant release around 60% until the end of 6h . The in vivo assay showed the apparent volume of distribution Vz/F (10 mg/kg MET + PLGA, 46.31 mL/kg vs. 100 mg/kg MET + PLGA, 28.8 mL/kg) and the mean MRTinf residency (PLGA + MET 10 mg/kg, 37.66h vs. MET 100 mg/kg, 3.34h). Conclusion: MET-loaded PLGA decreased inflammation and bone loss in periodontitis in diabetic rats. 10 mg/kg MET + PLGA had a slower rate of elimination compared to 100 mg/kg MET. The formulation modifies pharmacokinetic parameters such as apparent volume of distribution and mean residence time (AU).

Respuesta a metformina en el síndrome de ovario poliquístico (SOP): rol de las variantes genéticas / Response to metformin in polycystic ovary syndrome (PCOS): role of genetic variants

La metformina es un hipoglicemiante ampliamente utilizado en el tratamiento de mujeres con síndrome de ovario poliquístico (SOP) por su acción como sensibilizante a la insulina, demostrando tener múltiples efectos favorables en parámetros clínicos y bioquímicos. Especial interés ha causado la variabilidad interindividual en el tratamiento con metformina, que se manifiesta con una respuesta subóptima en diversos grados o con la presencia de efectos adversos, principalmente gastrointestinales. Hasta ahora, pocos estudios han caracterizado este fenómeno en el SOP, así como los mecanismos que le subyacen. Se ha propuesto que variantes de genes envueltos en el transporte y acción de metformina podrían contribuir a la heterogeneidad de su respuesta. En este sentido, se han identificado polimorfismos de nucleótidos únicos (SNPs) en los transportadores de cationes orgánicos, en las proteínas de extrusión de múltiples fármacos y toxinas, y en proteínas quinasas; cuyas principales acciones son a nivel intestinal, hepático y renal, afectando la absorción, distribución y excreción de metformina, probablemente por modificaciones en su farmacocinética. Hasta ahora los escasos estudios disponibles en el SOP han identificado SNPs que estarían afectando la eficacia del tratamiento, sin embargo, no se ha profundizado en los efectos adversos asociados a las variantes genéticas. Es evidente que dichas variantes tienen relevancia clínica y que debieran ser consideradas al diseñar un tratamiento farmacológico, para optimizar su efectividad y minimizar reacciones adversas. El objetivo de este artículo es revisar la información sobre las variantes genéticas asociadas a la variabilidad en la respuesta del tratamiento con metformina en el SOP.

Metformin is a hypoglycemic agent widely used in the treatment of women with Polycystic Ovary Syndrome (PCOS) due to its action as an insulin sensitizer and its multiple favorable effects on clinical and biochemical parameters. There is great concern regarding the inter-individual variability in the response to metformin treatment, which may manifest as a suboptimal effect to varying degrees or by the presence of adverse effects, mainly gastrointestinal. Until now, scarce studies have characterized this phenomenon in PCOS, as well as the mechanisms that underlie it. It has been proposed that genetic variants involved in metformin transport and action could contribute to the heterogeneity of its response. In this sense, single nucleotide polymorphisms (SNPs) have been identified in organic cation transporters, in multidrug and toxin extrusion proteins, and in protein kinases; whose main actions are at the intestinal, hepatic and renal levels, affecting the absorption, distribution and excretion of metformin, probably due to modifications in the pharmacokinetics of the drug. Until now, the few studies available on PCOS have identified SNPs that may be affecting the efficacy of the treatment. However, the adverse effects associated with genetic variants have not been studied in depth. These variants may have clinical relevance and should be considered when designing a pharmacological treatment, to optimize its effectiveness and minimize adverse reactions. The objective of this article is to review the information on genetic variants associated with variability in the response to metformin treatment in PCOS.

Metformin versus glyburide in treatment and control of gestational diabetes mellitus: a systematic review with meta-analysis

ABSTRACT Objective To compare the major outcomes of use of metformin and glyburide in treatment of gestational diabetes mellitus. Methods Studies published in English, in the last 10 years, in the databases MEDLINE®, SciELO, LILACS and Cochrane Library were analyzed, and randomized controlled trials were selected. Health Sciences Descriptors were used to compose the search phrase, and the keywords "Gestational diabetes", "Glyburide", "Metformin" and their variations were searched in the Medical Subject Headings. PRISMA systematization was used to prepare this review, and a meta-analysis was conducted aiming to mathematically show the results of fasting blood glucose, postprandial blood glucose, birth weight and weight gain during pregnancy after using metformin and glyburide. Results The studies evaluated birth weight, neonatal hypoglycemia, mode of delivery, need for intensive care, Apgar score, macrosomia, fasting glucose, postprandial glucose and weight gain during pregnancy. In 60% of studies, there were no statistically significant differences regarding safety and efficacy of administration of metformin and glyburide. Meta-analysis demonstrated the absence of statistical differences between these drugs in fasting blood glucose (p=0.821), postprandial blood glucose (p=0.217) and birth weight (p=0.194). However, significant differences were shown in weight gain during pregnancy (p=0.036). Conclusion The methods are effective, but the adverse effects of glyburide are more common; therefore, the use of metformin should be recommended, if in monotherapy.

Free interstitial levels of metformin in the liver of healthy and diabetic Wistar rats

Abstract In the present study, free interstitial levels reached by metformin in the liver were investigated in control and diabetic rats by microdialysis. Firstly, a bioanalytical method using an HPLC-UV system to determine the drug concentration in microdialysis samples was validated. The blood glucose levels and biochemical parameters were investigated in control and diabetic animals. Following that, both groups received a dose of 50 mg/kg of metformin iv bolus and the free interstitial levels reached in the liver were assessed by microdialysis. The method was validated according to FDA guidelines being suitable to quantify free concentrations of metformin in the liver of control and diabetics rats. Free exposure to metformin was similar in control and diabetic animals: AUC0-∞ 118.50 ± 40.18 vs 112.93 ± 50.25 µg.h/mL, respectively. The half-life in tissue was similar to that described in the literature for plasma. Hence diabetes induced by streptozotocin after administration of nicotinamide in our study did not damage the renal and hepatic function of the animals. The levels reached in the liver were 1.6 times higher than the free plasma concentrations, demonstrating higher liver penetration of metformin. This is the first investigation in liver interstitial concentration of metformin in control and diabetic rats

Tratamento para o diabetes mellitus gestacional: uma revisão de literatura / Treatment for gestational diabetes mellitus: a literature review

O diabetes mellitus gestacional (DMG) é uma complicação que atinge o metabolismo da gestante, resultando em intolerância à glicose e consequente hiperglicemia, originada pela insuficiência de insulina materna. Este estudo tem como objetivo identificar os tratamentos disponíveis e mais utilizados para o DMG. Trata-se de um uma revisão de literatura, feita a partir de 22 referências, acerca dos tratamentos para o DMG. As bases de dados escolhidas foram Google Acadêmico, UpToDate, SciELO e o acervo da Universidade do Planalto Catarinense. Estudos apontam a insulina humana ­ NPH e regular ­ como a principal escolha, quando comparada aos seus análogos, apesar de ainda existirem muitas controvérsias quanto ao início do tratamento, o esquema terapêutico e os ajustes das doses. Pesquisas têm demonstrado bons resultados sobre a eficácia e a segurança dos hipoglicemiantes orais ­ gliburida e metformina ­ no tratamento de gestantes diabéticas, mas é evidente a necessidade de mais estudos para confirmar a efetividade deles e garantir um bom desenvolvimento do concepto. Concluiu-se que o controle dietético e o exercício físico são a primeira opção de tratamento para o DMG. Todavia, caso a euglicemia não seja atingida, opta-se pelo tratamento medicamentoso por meio da insulinoterapia ou hipoglicemiantes orais, o que possibilita a redução da incidência dos efeitos adversos ao binômio materno-fetal.(AU)

Gestational diabetes mellitus (DMG) is a complication that affects the pregnant woman's metabolism, resulting in glucose intolerance and consequent hyperglycemia, caused by insufficient maternal insulin. This study aims to identify the available and most used treatments for DMG. This is a literature review, based on 22 references, about treatments for Gestational Diabetes; the databases chosen were Google Scholar, UpToDate, SciELO and the collection of the Universidade do Planalto Catarinense. Studies point to human insulin ­ NPH and regular ­ as the main choice when compared to its analogues, although there are still many controversies about the beginning of treatment, therapeutic scheme and dose adjustments. Researches have shown good results on the efficacy and safety of oral hypoglycemic agents ­ glyburide and metformin ­ in the treatment of diabetic pregnant women, but it is evident the need for further studies to confirm their effectiveness and to guarantee a good development of the fetus. It was concluded that dietary control and physical exercise are the first treatment option for DGM. However, if euglycemia is not achieved, drug treatment is chosen through insulin therapy or oral hypoglycemic agents, which makes it possible to reduce the incidence of adverse effects to the maternal-fetal binomial.(AU)

Trombolisis endovenosa post reversión de acenocumarol con complejo de protrombina: caso clínico / Intravenous thrombolysis after reversion of acenocoumarol anticoagulation: report of one case

We report an 89-year-old male under oral anticoagulant therapy with a therapeutic international normalized ratio, presenting at the emergency room with right side hemiparesis and aphasia. Neuroimaging was compatible with an acute middle cerebral artery ischemic stroke. Anticoagulation was reverted with the use of four factor prothrombin complex, followed by thrombolysis with alteplase, with a favorable evolution, returning to his basal functional status.

Metformin and blood cancers

Type 2 diabetes mellitus and cancer are correlated with changes in insulin signaling, a pathway that is frequently upregulated in neoplastic tissue but impaired in tissues that are classically targeted by insulin in type 2 diabetes mellitus. Many antidiabetes treatments, particularly metformin, enhance insulin signaling, but this pathway can be inhibited by specific cancer treatments. The modulation of cancer growth by metformin and of insulin sensitivity by anticancer drugs is so common that this phenomenon is being studied in hundreds of clinical trials on cancer. Many meta-analyses have consistently shown a moderate but direct effect of body mass index on the incidence of multiple myeloma and lymphoma and the elevated risk of leukemia in adults. Moreover, new epidemiological and preclinical studies indicate metformin as a therapeutic agent in patients with leukemia, lymphomas, and multiple myeloma. In this article, we review current findings on the anticancer activities of metformin and the underlying mechanisms from preclinical and ongoing studies in hematologic malignancies.

Use of medications for type 2 diabetes mellitus in the Brazil's family health strategy: gender differences

Introduction: The medications are the main therapeutic inputs in the treatment of type 2 diabetes mellitus. When properly used, they allow disease control and reduction of morbidity and mortality, resulting in improvements in quality of life. Thus, the purpose of this article is to characterize the use of medications for type 2 diabetes mellitus with emphasis on gender differences. Methods: A cross-sectional study performed in Family Health Units in Ribeirão Preto, São Paulo, Brazil, with 100 men and 100 women. Sociodemographic characteristics, clinical data, lifestyle and use of medications were the variables of interest. Results: Mean number of diabetes medications referred by study participants was 1.6 (SD = 0.7) for women and 1.5 (SD = 0.6) for men (p = 0.40). The use of metformin was mentioned by 70% of women and 65% of men, and adverse reactions were reported by 15% of women and 2% of men (p < 0.01). Medications were obtained mainly from public health system pharmacies in both genders. Conclusions: Gender differences in the use of diabetes medications were found in reported adverse reactions, with more cases among women.

Acidosis láctica asociada a metformina: caso clínico / Metformin-associated lactic acidosis: report of one case

Metformin-associated lactic acidosis is a severe and infrequent adverse event. Early diagnosis is essential to start an early treatment, which often has favorable results. We report a 56 years old non-insulin-requiring type 2 diabetic female who developed a severe metabolic acidosis associated with metformin in relation to an acute renal failure secondary to infectious diarrhea. Early treatment with bicarbonate and continuous hemofiltration allowed a quick improvement of the patient. Metformin-associated lactic acidosis has an elevated mortality (50-80%) and has a specific and effective treatment. Therefore, the condition must be born in mind.

Oxidative stress in patients with type 2 diabetes mellitus treated with metformin / Estresse oxidativo em pacientes com diabetes mellitus tipo 2 em tratamento com metformina

AIMS: To evaluate oxidative stress parameters in patients with type 2 diabetes mellitus treated with metformin, relating these values to its side effects, plasma levels, glycemic control, diabetic complications, lipid profile, and the influence of pharmacotherapeutic follow-up. METHODS: Patients with type 2 diabetes mellitus, on metformin and in pharmacotherapeutic follow-up for four months, were evaluated. The pharmacotherapeutic follow-up consisted in providing information and answering patients' questions about medication and disease. In addition, administration times, dosages, and presence or absence of side effects related to the use of metformin were verified. Glycemic and lipid profile, oxidative stress (superoxide dismutase and malondialdehyde) and plasma metformin were evaluated. Pearson's correlation and Spearman's correlation were performed to evaluate the relationship between the variables at the beginning of the study. The independent t-test and Mann-Whitney U test were used to assess the difference between the groups with and without diabetic complications. The range of values between the beginning and end of the study was evaluated using Student's t-test or Wilcoxon U test. The significance level was set at 5%. RESULTS: The initial sample consisted of 49 patients aged 59±9 years with a body mass index of 29.8±5.1 kg/m2 , who have had diabetes for a median time of 36 months (interquartile range of 1-240) and have been on metformin for a median time of 36 months (interquartile range of 1-180). Twenty-five patients left the study between the second and fourth meetings. Malondialdehyde levels differed between before and after pharmacotherapeutic follow-up, being positively correlated with blood glucose, glycohemoglobin, and triglyceride level, and negatively correlated with metformin and superoxide dismutase. Blood glucose, glycohemoglobin, and malondialdehyde levels increased, whereas metformin levels decreased in the group with diabetic complications, and there was a correlation between malondialdehyde and the number of diabetic complications per patient. CONCLUSIONS: In this sample of patients with type 2 diabetes mellitus treated with metformin, oxidative stress was more pronounced in those with poor glycemic control and diabetic complications.

OBJETIVOS: Avaliar parâmetros de estresse oxidativo em pacientes com diabetes mellitus tipo 2 em uso de metformina, relacionando estes valores a seus efeitos adversos, níveis plasmáticos, controle glicêmico, complicações diabéticas, perfil lipídico, e a influência do acompanhamento farmacoterapêutico. MÉTODOS: Foram avaliados pacientes com diabetes mellitus tipo 2, em uso de metformina, em acompanhamento farmacoterapêutico por quatro meses. O acompanhamento farmacoterapêutico consistiu na prestação de informações e no esclarecimento de dúvidas dos pacientes sobre a medicação e a doença. Além disto, foram verificados os horários, as doses e a presença ou não de efeitos adversos relacionados ao uso de metformina. Foram avaliados perfil glicêmico e lipídico, estresse oxidativo (superóxido dismutase e malondialdeído) e metformina plasmática. Foram realizados os testes de correlação de Pearson e de Spearman para avaliar as relações entre as variáveis no início do estudo. Para testar a diferença entre os grupos com e sem complicações diabéticas, foram utilizados o t-teste independente ou o teste U de MannWhitney. A gama de valores entre o início e o final do estudo foi avaliada utilizando o teste t de Student ou o teste de Wilcoxon U. Foi adotado um nível de significância de 5%. RESULTADOS: A amostra inicial foi composta por 49 pacientes com idade de 59±9 anos e índice de massa corporal de 29,8±5,1 kg/m2 , com diabetes por uma mediana de tempo de 36 (intervalo interquartil 1-240) meses e em uso de metformina há uma mediana de 36 (intervalo interquartil 1-180) meses. Vinte e cinco pacientes deixaram o estudo entre a segunda e a quarta reunião. Os níveis de malondialdeído diferiram entre antes e após o acompanhamento farmacoterapêutico, correlacionando-se positivamente com glicemia, glicohemoglobina e triglicerídeos e negativamente com metformina e superóxido dismutase. Encontrou-se elevação da glicemia, glicohemoglobina e malondialdeído, e diminuição da metformina no grupo com complicações diabéticas, e foi identificada correlação entre malondialdeído e o número de complicações diabéticas por paciente. CONCLUSÕES: Nesta amostra de pacientes com diabetes mellitus tipo 2 em tratamento com metformina, o estresse oxidativo foi mais pronunciado nos que apresentavam pior controle glicêmico e complicações diabéticas.

Effect of metformin on semen quality

ABSTRACT Various studies have linked metformin, a universally antidiabetic drug, with semen quality; however, such a direct link has not been established. This review systematically addresses and summarizes the effect of metformin on semen quality, particularly sperm function. We searched the MEDLINE electronic database for English articles and abstracts containing the key words 'metformin' and 'sperm', and relevant articles were reviewed. In summary, metformin appears to have improved and provided positive impact on sperm quality. This effect may be due to the ability of metformin to reduce oxidative stress and lipid peroxidation, enhance 5'-AMP activated protein kinase activity, and restore the normal levels of pituitary-gonadal hormones. However, further clinical research is still necessary to confirm such effect.

La metformina como una alternativa en la prevención y tratamiento del cáncer / Metformin as an alternative for the prevention and treatment of cancer

Antecedentes: la metformina, fármaco económico y seguro, ha demostrado mejorar el pronóstico de varios tipos de cánceres. Objetivo: revisar los aspectos más relevantes de la relación entre la diabetes mellitus, la metformina y el cáncer. Desarrollo: la diabetes mellitus, en especial la tipo 2, se relaciona con algunos cánceres (mama, hígado, páncreas, ginecológico, vejiga, colon y recto), y en el sexo masculino, aumenta su recurrencia y la mortalidad. Los mecanismos responsables de esta relación no están del todo esclarecidos. La insulina y el factor de crecimiento similar a la insulina en un estado de hiperinsulinismo e insulinorresistencia, pudieran desempeñar un papel fundamental en el desarrollo de cáncer, así como otros factores de riesgo comunes a la diabetes mellitus y al cáncer (alimentación no saludable, sedentarismo, adicciones, edad, sexo, etnia y raza). La proteína liver kinase B1 se ha identificado como una proteína supresora tumoral, y al unirse con la metformina interrumpe el complejo 1 de la cadena respiratoria mitocondrial, y conduce a la disminución de la síntesis de trifosfato de adenosin, y al aumento del cociente proteína activada por mitógenos-trifosfato de adenosin en el espacio intracelular. Los quimioterápicos, esteroides y antiandrógenos, pueden afectar negativamente el metabolismo hidrocarbonado. Algunas drogas antihiperglucemiantes se han relacionado a cánceres específicos, aunque las evidencias son pobres, indirectas y controversiales. Conclusiones: la metformina pudiera utilizarse en la prevención y el tratamiento de algunos cánceres, y reducir su recurrencia y la mortalidad. Parece existir una relación entre cáncer y la diabetes mellitus, aunque muchos aspectos quedan por dilucidar, como el papel desempeñado por los fármacos anticancerígenos y antihiperglucemiantes utilizados en ambas entidades(AU)

Background: metformin, a safe inexpensive drug, has proved to improve the prognosis of several types of cancer. Objective: to review the most relevant aspects of the relationship among diabetes mellitus, metformin and cancer. Development: diabetes mellitus, particularly type 2, is related to some kinds of cancer (breast, liver, pancreas, gynecological, gallbladder, colon and rectum), and its recurrence and mortality increase in men. The mechanism behind this relationship is not fully clarified. Insulin and insulin-like growth factor under hyperinsulinism and insulin resistance conditions may play a fundamental role in developing cancer as well as other common risk factors for diabetes mellitus and cancer (unhealthy feeding, sedentary lifestyle, addictions, age, sex, ethnic group and race). Liver kinase B1 protein has been identified as tumor suppressor protein which binds the metformin to impair the mitochondrial respiratory chain complex I and leads to reduction of adenosine triphosphate synthesis and to the increase of mytogen-activated protein-adenosine triphosphate quotient in the intracellular space. Chemotherapeutic, steroid and anti-androgen drugs may negatively affect the hydrocarbon metabolism. Some antihyperglycemic drugs have been related to specific cancers, although the evidence is still poor, indirect and controversial. Conclusions: metformin may be used to prevent and treat some types of cancer and to reduce recurrence and mortality. There seems to be some relationship between cancer and diabetes mellitus, even when many aspects remain to be ascertained such as the role played by anticancer and antihyperglycemic drugs intended to treat both diseases(AU)

Nuevas evidencias del uso de la metformina en el tratamiento del cáncer / New evidence of the use of metformin in the treatment of cancer

La metformina es una biguanida ampliamente usada en el tratamiento de la diabetes mellitus tipo 2. Evidencias recientes proponen nuevos usos para esta vieja droga. El cáncer, que constituye un problema de salud mundial, se desarrolla con más frecuencia y peor pronóstico en los pacientes con diabetes tipo 2. Sin embargo, se ha comprobado que cuando estos son tratados con metformina presentan menor incidencia, complicaciones y mortalidad por cáncer. Por tal motivo, durante casi una década, se llevaron a cabo numerosas investigaciones epidemiológicas, básicas, preclínicas y ensayos clínicos, para fundamentar las evidencias del efecto protector y antitumoral de este medicamento. En tal sentido, se encontró que posee efectos antineoplásicos, por mecanismos sensibilizadores de la insulina, y otros, como que son pro-apoptóticos, que alteran el desarrollo de la célula madre cancerosa e interfieren con la carcinogénesis. Esto ha abierto una amplia gama de aplicaciones de la metformina en la terapéutica del cáncer, que abarcan desde los efectos preventivos, hasta las coadyuvantes de los tratamientos estándares(AU)

Metformin is a widely used biguanide in the treatment of type 2 diabetes mellitus. Recent evidence indicates new uses for this old drug. Cancer is a worldwide health problem that develops more frequently in type 2 diabetic people with worse prognosis. However, it has been demonstrated that when they are treated with metformin, the incidence, complications and mortality rates are lower. For these reasons, a number of epidemiological, basic, preclinical research studies as well as clinical assays have been conducted for almost a decade in order to substantiate evidence from the protective and antitumor effect of this drug. It was found that it has some antineoplastic effects due to insulin sensitizing mechanisms and other pro-apoptotic ones that impair the cancer stem cell development and interfere in carcinogenesis. This has shown a wide range of applications of metformin in the treatment of cancer including the preventive and coadjuvant effects of the conventional treatments(AU)