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1.
Medicine (Baltimore) ; 98(46): e17918, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31725641

RESUMO

BACKGROUND: Metformin can cause serum vitamin B12 deficiency, but studies on the influence of its duration and dose are lacking. We investigated vitamin B12 deficiency in patients with type 2 diabetes using metformin, in conjunction with other related factors. METHOD: This cross-sectional study included 1111 patients with type 2 diabetes who took metformin for at least 6 months. Serum vitamin B12 levels were quantified using a competitive-binding immunoenzymatic assay, and vitamin B12 deficiency was defined as serum B12 <300 pg/mL. Information on metformin use and confounding variables were collected from records or questionnaires and interviews. RESULT: Serum vitamin B12 deficiency occurred in 22.2% of patients (n = 247). After adjusting for confounders, a 1 mg increase in daily metformin dose was associated with a 0.142 pg/mL decrease in vitamin B12 (P < .001). Compared with a daily dose of <1000 mg, the adjusted odds ratios for 1000 to 1500, 1500 to 2000, and ≥2000 mg metformin were 1.72 (P = .080), 3.34 (P < .001), and 8.67 (P < .001), respectively. Vitamin B12 deficiency occurred less often in patients taking multivitamins (odds ratio 0.23; P < .001). After adjusting for confounding factors, there was no correlation between B12 deficiency and duration of metformin use. Serum homocysteine levels showed significant negative correlation with vitamin B12. CONCLUSION: Metformin at ≥1500 mg/d could be a major factor related to vitamin B12 deficiency, whereas concurrent supplementation of multivitamins may potentially protect against the deficiency. Serum homocysteine levels were negatively correlated with vitamin B12 levels, suggesting that B12 deficiency due to metformin use may occur at the tissue level. However, this hypothesis will require further study.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Deficiência de Vitamina B 12/induzido quimicamente , Fatores Etários , Idoso , Consumo de Bebidas Alcoólicas/epidemiologia , Anemia/epidemiologia , Estudos Transversais , Diabetes Mellitus Tipo 2/epidemiologia , Relação Dose-Resposta a Droga , Feminino , Ácido Fólico/sangue , Homocisteína/sangue , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Masculino , Metformina/administração & dosagem , Metformina/efeitos adversos , Pessoa de Meia-Idade , Razão de Chances , República da Coreia , Fatores de Tempo , Vitamina B 12/sangue , Vitaminas
4.
Lancet ; 394(10208): 1519-1529, 2019 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-31542292

RESUMO

BACKGROUND: Early treatment intensification leading to sustained good glycaemic control is essential to delay diabetic complications. Although initial combination therapy has been suggested to offer more opportunities than a traditional stepwise approach, its validity remains to be determined. METHODS: Vildagliptin Efficacy in combination with metfoRmIn For earlY treatment of type 2 diabetes (VERIFY) was a randomised, double-blind, parallel-group study of newly diagnosed patients with type 2 diabetes conducted in 254 centres across 34 countries. The study consisted of a 2-week screening visit, a 3-week metformin-alone run-in period, and a 5-year treatment period, which was further split into study periods 1, 2, and 3. Patients aged 18-70 years were included if they had type 2 diabetes diagnosed within 2 years prior to enrolment, and centrally confirmed glycated haemoglobin A1c (HbA1c) of 48-58 mmol/mol (6·5-7·5%) and a body-mass index of 22-40 kg/m2. Patients were randomly assigned in a 1:1 ratio either to the early combination treatment group or to the initial metformin monotherapy group, with the help of an interactive response technology system and simple randomisation without stratification. Patients, investigators, clinical staff performing the assessments, and data analysts were masked to treatment allocation. In study period 1, patients received either the early combination treatment with metformin (stable daily dose of 1000 mg, 1500 mg, or 2000 mg) and vildagliptin 50 mg twice daily, or standard-of-care initial metformin monotherapy (stable daily dose of 1000 mg, 1500 mg, or 2000 mg) and placebo twice daily. If the initial treatment did not maintain HbA1c below 53 mmol/mol (7·0%), confirmed at two consecutive scheduled visits which were 13 weeks apart, patients in the metformin monotherapy group received vildagliptin 50 mg twice daily in place of the placebo and entered study period 2, during which all patients received the combination therapy. The primary efficacy endpoint was the time from randomisation to initial treatment failure, defined as HbA1c measurement of at least 53 mmol/mol (7·0%) at two consecutive scheduled visits, 13 weeks apart from randomisation through period 1. The full analysis set included patients who received at least one randomised study medication and had at least one post-randomisation efficacy parameter assessed. The safety analysis set included all patients who received at least one dose of randomised study medication. This study is registered with ClinicalTrials.gov, NCT01528254. FINDINGS: Trial enrolment began on March 30, 2012, and was completed on April 10, 2014. Of the 4524 participants screened, 2001 eligible participants were randomly assigned to either the early combination treatment group (n=998) or the initial metformin monotherapy group (n=1003). A total of 1598 (79·9%) patients completed the 5-year study: 811 (81·3%) in the early combination therapy group and 787 (78·5%) in the monotherapy group. The incidence of initial treatment failure during period 1 was 429 (43·6%) patients in the combination treatment group and 614 (62·1%) patients in the monotherapy group. The median observed time to treatment failure in the monotherapy group was 36·1 (IQR 15·3-not reached [NR]) months, while the median time to treatment failure time for those receiving early combination therapy could only be estimated to be beyond the study duration at 61·9 (29·9-NR) months. A significant reduction in the relative risk for time to initial treatment failure was observed in the early combination treatment group compared with the monotherapy group over the 5-year study duration (hazard ratio 0·51 [95% CI 0·45-0·58]; p<0·0001). Both treatment approaches were safe and well tolerated, with no unexpected or new safety findings, and no deaths related to study treatment. INTERPRETATION: Early intervention with a combination therapy of vildagliptin plus metformin provides greater and durable long-term benefits compared with the current standard-of-care initial metformin monotherapy for patients with newly diagnosed type 2 diabetes. FUNDING: Novartis.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Metformina/administração & dosagem , Vildagliptina/administração & dosagem , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Hemoglobina A Glicada/análise , Humanos , Hipoglicemiantes/efeitos adversos , Masculino , Metformina/efeitos adversos , Pessoa de Meia-Idade , Resultado do Tratamento , Vildagliptina/efeitos adversos
5.
Biochemistry (Mosc) ; 84(8): 829-850, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31522667

RESUMO

Thiamine (vitamin B1) is a precursor of the well-known coenzyme of central metabolic pathways thiamine diphosphate (ThDP). Highly intense glucose oxidation in the brain requires ThDP-dependent enzymes, which determines the critical significance of thiamine for neuronal functions. However, thiamine can also act through the non-coenzyme mechanisms. The well-known facilitation of acetylcholinergic neurotransmission upon the thiamine and acetylcholine co-release into the synaptic cleft has been supported by the discovery of thiamine triphosphate (ThTP)-dependent phosphorylation of the acetylcholine receptor-associated protein rapsyn, and thiamine interaction with the TAS2R1 receptor, resulting in the activation of synaptic ion currents. The non-coenzyme regulatory binding of thiamine compounds has been demonstrated for the transcriptional regulator p53, poly(ADP-ribose) polymerase, prion protein PRNP, and a number of key metabolic enzymes that do not use ThDP as a coenzyme. The accumulated data indicate that the molecular mechanisms of the neurotropic action of thiamine are far broader than it has been originally believed, and closely linked to the metabolism of thiamine and its derivatives in animals. The significance of this topic has been illustrated by the recently established competition between thiamine and the antidiabetic drug metformin for common transporters, which can be the reason for the thiamine deficiency underlying metformin side effects. Here, we also discuss the medical implications of the research on thiamine, including the role of thiaminases in thiamine reutilization and biosynthesis of thiamine antagonists; molecular mechanisms of action of natural and synthetic thiamine antagonists, and biotransformation of pharmacological forms of thiamine. Given the wide medical application of thiamine and its synthetic forms, these aspects are of high importance for medicine and pharmacology, including the therapy of neurodegenerative diseases.


Assuntos
Hipoglicemiantes/metabolismo , Metformina/metabolismo , Tiamina/análogos & derivados , Tiamina/metabolismo , Complexo Vitamínico B/metabolismo , Animais , Encéfalo/metabolismo , Coenzimas , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Metformina/administração & dosagem , Metformina/efeitos adversos , Camundongos , Fosforilação , Transporte Proteico/fisiologia , Ratos , Tiamina/efeitos adversos , Tiamina/farmacologia , Deficiência de Tiamina/etiologia , Deficiência de Tiamina/prevenção & controle , Tiamina Pirofosfato/metabolismo , Complexo Vitamínico B/efeitos adversos , Complexo Vitamínico B/farmacologia
7.
Postgrad Med ; 131(8): 578-588, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31414934

RESUMO

Objectives: To evaluate the efficacy and safety of ipragliflozin as add-on therapy to metformin in patients with type 2 diabetes mellitus.Methods: Systematic literature searches were performed in several databases across PubMed, the Cochrane Central Register of Controlled Trials, Embase, Medline, ClinicalTrials.gov, PsycINFO, and Web of Science from inception to 12 March 2019. After the extraction of data from eligible studies, randomized controlled trials (RCTs) were assessed for quality and analyzed statistically. Standardized mean difference (SMD) and risk ratio (RR) with 95% CIs were used to evaluate efficacy and safety end-points. Sensitivity analyses and subgroup analyses based on intervention times were also performed.Results: Five RCTs with 847 patients were included. Compared to metformin alone, ipragliflozin as an adjuvant to metformin reduced glycated hemoglobin (HbA1c) in 12 weeks and 24 weeks, respectively [12 w: SMD -0.30, 95% CI -0.51 to -0.10%, p = 0.004; 24 w: SMD -0.88, 95% CI -1.04 to -0.72%, p < 0.00001; Total: SMD -0.66, 95% CI -0.79 to -0.53%, p < 0.00001]. In addition, ipragliflozin as adjuvant therapy to metformin body weight (Total: SMD -1.47, 95% CI [-1.80,-1.14], p < 0.00001), waist circumference (Total: SMD -1.09, 95% CI [-1.62,-0.56], p < 0.00001), and blood pressure (SBP Total: SMD -3.36, 95% CI [-5.11.-1.61], p = 0.0002; DBP Total: SMD -2.18, 95% CI [-3.63,-0.74], p = 0.003). Compared to metformin alone, ipragliflozin as an adjuvant to metformin showed significant risks in the skin and subcutaneous tissue disorders and constipation.Conclusion: Compared to metformin alone, ipragliflozin plus metformin significantly improved glycemic control, reduced body weight, and lowered blood pressure; however, further high-quality trials are required to determine their long-term efficacy and safety.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/uso terapêutico , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Tiofenos/uso terapêutico , Glicemia , Pressão Sanguínea , Peso Corporal , Método Duplo-Cego , Quimioterapia Combinada , Glucosídeos/administração & dosagem , Glucosídeos/efeitos adversos , Hemoglobina A Glicada , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Metformina/administração & dosagem , Metformina/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Tiofenos/administração & dosagem , Tiofenos/efeitos adversos
8.
PLoS Med ; 16(8): e1002848, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31386659

RESUMO

BACKGROUND: Metformin is increasingly offered as an acceptable and economic alternative to insulin for treatment of gestational diabetes mellitus (GDM) in many countries. However, the impact of maternal metformin treatment on the trajectory of fetal, infant, and childhood growth is unknown. METHODS AND FINDINGS: PubMed, Ovid Embase, Medline, Web of Science, ClinicalTrials.gov, and the Cochrane database were systematically searched (from database inception to 26 February 2019). Outcomes of GDM-affected pregnancies randomised to treatment with metformin versus insulin were included (randomised controlled trials and prospective randomised controlled studies) from cohorts including European, American, Asian, Australian, and African women. Studies including pregnant women with pre-existing diabetes or non-diabetic women were excluded, as were trials comparing metformin treatment with oral glucose-lowering agents other than insulin. Two reviewers independently assessed articles for eligibility and risk of bias, and conflicts were resolved by a third reviewer. Outcome measures were parameters of fetal, infant, and childhood growth, including weight, height, BMI, and body composition. In total, 28 studies (n = 3,976 participants) met eligibility criteria and were included in the meta-analysis. No studies reported fetal growth parameters; 19 studies (n = 3,723 neonates) reported measures of neonatal growth. Neonates born to metformin-treated mothers had lower birth weights (mean difference -107.7 g, 95% CI -182.3 to -32.7, I2 = 83%, p = 0.005) and lower ponderal indices (mean difference -0.13 kg/m3, 95% CI -0.26 to 0.00, I2 = 0%, p = 0.04) than neonates of insulin-treated mothers. The odds of macrosomia (odds ratio [OR] 0.59, 95% CI 0.46 to 0.77, p < 0.001) and large for gestational age (OR 0.78, 95% CI 0.62 to 0.99, p = 0.04) were lower following maternal treatment with metformin compared to insulin. There was no difference in neonatal height or incidence of small for gestational age between groups. Two studies (n = 411 infants) reported measures of infant growth (18-24 months of age). In contrast to the neonatal phase, metformin-exposed infants were significantly heavier than those in the insulin-exposed group (mean difference 440 g, 95% CI 50 to 830, I2 = 4%, p = 0.03). Three studies (n = 520 children) reported mid-childhood growth parameters (5-9 years). In mid-childhood, BMI was significantly higher (mean difference 0.78 kg/m2, 95% CI 0.23 to 1.33, I2 = 7%, p = 0.005) following metformin exposure than following insulin exposure, although the difference in absolute weights between the groups was not significantly different (p = 0.09). Limited evidence (1 study with data treated as 2 cohorts) suggested that adiposity indices (abdominal [p = 0.02] and visceral [p = 0.03] fat volumes) may be higher in children born to metformin-treated compared to insulin-treated mothers. Study limitations include heterogeneity in metformin dosing, heterogeneity in diagnostic criteria for GDM, and the scarcity of reporting of childhood outcomes. CONCLUSIONS: Following intrauterine exposure to metformin for treatment of maternal GDM, neonates are significantly smaller than neonates whose mothers were treated with insulin during pregnancy. Despite lower average birth weight, metformin-exposed children appear to experience accelerated postnatal growth, resulting in heavier infants and higher BMI by mid-childhood compared to children whose mothers were treated with insulin. Such patterns of low birth weight and postnatal catch-up growth have been reported to be associated with adverse long-term cardio-metabolic outcomes. This suggests a need for further studies examining longitudinal perinatal and childhood outcomes following intrauterine metformin exposure. This review protocol was registered with PROSPERO under registration number CRD42018117503.


Assuntos
Desenvolvimento Infantil/efeitos dos fármacos , Diabetes Gestacional/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Metformina/uso terapêutico , Pré-Escolar , Feminino , Humanos , Hipoglicemiantes/efeitos adversos , Lactente , Recém-Nascido , Insulina/efeitos adversos , Metformina/efeitos adversos , Gravidez
9.
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
10.
Mayo Clin Proc ; 94(8): 1444-1456, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31378227

RESUMO

OBJECTIVE: To compare incident dementia risk among patients who initiated treatment with metformin or sulfonylurea in Veterans Health Affairs (VHA) patients with replication in Kaiser Permanente Washington (KPW) patients to determine whether first-choice antidiabetic medications are associated with reduced risk of dementia. PATIENTS AND METHODS: Cohorts contained 75,187 VHA patients and 10,866 KPW patients, 50 years and older, who initiated monotherapy with metformin or sulfonylurea. Patients were free of dementia diagnoses and any diabetes treatment for 2 years before cohort entry. Variables were extracted from electronic health data from VHA (1999-2015) and KPW (1996-2015), which included diagnosis codes, pharmacy data, laboratory values, and demographic characteristics. Propensity scores and inverse probability of treatment weighting controlled for confounding. RESULTS: Veterans Health Affairs patients were 60.8±6.8 years of age on average, and KPW patients were 63.1±9.5 years of age. In the VHA sample, 72,769 (96.8%) were male; and in the KPW sample, 5480 (50.4%). After adjusting for confounding, metformin initiation was associated with a significantly (P=.02) lower risk of dementia in VHA (hazard ratio, 0.9; 95% CI, 0.9-1.0), with a similar point estimate in KPW (hazard ratio, 0.9; 95% CI, 0.7-1.1). Metformin was not associated with dementia risk in patients 75 years and older. CONCLUSION: Existing epidemiological studies of metformin and incident dementia have been inconsistent. Using a similar study design in 2 patient populations that differed in clinical and demographic characteristics, our results provide robust evidence that metformin use is associated with a modestly lower risk of incident dementia.


Assuntos
Demência/induzido quimicamente , Demência/epidemiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Metformina/efeitos adversos , Compostos de Sulfonilureia/efeitos adversos , Fatores Etários , Idoso , Bases de Dados Factuais , Demência/fisiopatologia , Diabetes Mellitus Tipo 2/diagnóstico , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Hospitais de Veteranos , Humanos , Incidência , Masculino , Metformina/uso terapêutico , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Fatores Sexuais , Compostos de Sulfonilureia/uso terapêutico , Estados Unidos
11.
J Clin Pharm Ther ; 44(4): 588-594, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31293011

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Observational clinical studies of metformin for prevention and treatment of several cancer types have reported mixed findings. Although preclinical studies have suggested metformin may reduce head and neck cancer (HNC) proliferation, clinical evidence is limited. The objective of this large population-based study was to evaluate the relationship between metformin exposure following HNC diagnosis and all-cause mortality. METHODS: We conducted a retrospective cohort study using the Italian Emilia-Romagna Regional administrative healthcare database, which includes demographic, hospital and outpatient prescription information for ~4.5 million residents. Included patients were followed from the first hospital discharge (index) during the study period (01/2003-12/2012) with a diagnosis of HNC. Metformin exposure and select covariates were operationalized in a time-dependent manner during follow-up. Cox proportional hazards models estimated the covariate-adjusted time-dependent association between metformin exposure and all-cause mortality. RESULTS AND DISCUSSION: Among 7872 patients diagnosed with HNC, 708 (9.0%) were exposed to metformin after HNC diagnosis, and 3626 (46.1%) died during follow-up (median follow-up: 35.2 months). In the covariate-adjusted model, the all-cause mortality rate appeared lower (HR: 0.81, 95% CI: 0.61-1.09) among metformin exposed patients during the 2 years post-diagnosis, while the all-cause mortality rate appeared higher (HR: 1.20, 95% CI: 0.94-1.53) among exposed patients after 2 years post-diagnosis. Metformin was protective among patients ≤60 years of age (HR for the period of 0-2 years post-diagnosis: 0.22, 95% CI 0.09-0.56; HR for the period ≥2 years post-diagnosis: 0.56, 95% CI 0.26-1.22) but not in those >60 years. WHAT IS NEW AND CONCLUSION: In this population-based study of metformin in HNC, we found a modest protective association between metformin exposure and all-cause mortality in the 2-year post-diagnosis period. Age appeared to modify the association between metformin and HNC survival.


Assuntos
Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/mortalidade , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Metformina/efeitos adversos , Metformina/uso terapêutico , Idoso , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos
12.
Pak J Pharm Sci ; 32(3): 1107-1110, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31278727

RESUMO

One of the most common endocrinological disorder affecting women in adolescence is Polycystic Ovarian Syndrome (PCOS). Women suffering from PCOS diagnosed with follicles in ovaries show enlarged reproductive organs with small filled follicles. Unusual bleeding, prolonged menstruation, unwanted hair growth, accumulation of fat and acne are the most common problems experienced by adolescents with PCOS. Nowadays, PCOS is treated successfully with the oral antidiabetic drug, metformin and hormone replacement therapy. Its off-label use is still controversial with unknown mechanisms due to patient risk versus benefit hypothesis by practitioners as they successfully treat PCOS in adolescents with metformin. But in few reported cases metformin has potential to induce back pain and swollen joints less frequently with rare cases of behavior alteration. Penicillin belongs to the beta-lactam antibiotics and is most commonly used to treat rheumatic fever although it has potential to cause allergic reactions affecting 10% of patients who exhibit IgE-mediated immunological reactions. Here, we present a case of a female diagnosed with PCOS who after treatment with metformin for more than two years, reported with hyperuricemia, migraine, neurological pain, severe joint and knee pains on shoulders and legs, and rheumatic fever. After treatment with benzathine benzyl penicillin for rheumatic fever, the patient also exhibited Type IV delayed hypersensitivity reaction.


Assuntos
Artralgia/induzido quimicamente , Metformina/efeitos adversos , Penicilina G Benzatina/efeitos adversos , Síndrome do Ovário Policístico/tratamento farmacológico , Febre Reumática/tratamento farmacológico , Analgésicos/uso terapêutico , Artralgia/tratamento farmacológico , Artralgia/etiologia , Hipersensibilidade a Drogas/etiologia , Feminino , Humanos , Hiperuricemia/induzido quimicamente , Metformina/uso terapêutico , Transtornos de Enxaqueca/induzido quimicamente , Penicilina G Benzatina/uso terapêutico , Síndrome do Ovário Policístico/diagnóstico por imagem , Febre Reumática/induzido quimicamente , Febre Reumática/microbiologia , Infecções Estreptocócicas/tratamento farmacológico , Infecções Estreptocócicas/etiologia , Streptococcus pyogenes/patogenicidade , Adulto Jovem
13.
J Diabetes Res ; 2019: 9484717, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31192264

RESUMO

Objectives: Type 2 diabetes mellitus (T2DM) is associated with coronary artery calcification (CAC) which is an independent risk factor for cardiovascular events. Metformin is the first-line antidiabetic medication. We aimed to investigate the association between metformin use and CAC. Methods: We included 369 patients with T2DM in this cross-sectional study. CAC scores, clinical characteristics, and antidiabetic drug prescription information of the patients were acquired. Baseline parameters were balanced for metformin and nonmetformin users using the propensity score matching (PSM) strategy. Results: Among the 369 subjects who met our inclusion criteria, 288 subjects were included for further analysis after PSM. Metformin prescription rather than other antidiabetic medications was related to lower CAC scores (OR [95% CI] = 0.55 [0.34-0.90]; P = 0.018). Further multivariable logistic regression analysis demonstrated that metformin was negatively associated with CAC severity (OR [95% CI] = 0.58 [0.34-0.99]; P = 0.048), which was independent of age, BMI, eGFR, gender, cigarette smoking, duration of diabetes, hypertension, statin prescription, and number of nonmetformin antidiabetic agents. A subgroup analysis revealed a significant association between metformin and CAC scores in smokers (OR [95% CI] = 0.38 [0.16-0.93]; P = 0.035), but the association was not observed in never-smokers (OR [95% CI] = 0.72 [0.34-1.51]; P = 0.383). Conclusions: Metformin usage was independently associated with lower CAC scores in T2DM patients. The negative correlation between CAC scores and metformin was most prominent in patients with a history of cigarette smoking.


Assuntos
Calcinose/etiologia , Doença da Artéria Coronariana/etiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/efeitos adversos , Metformina/efeitos adversos , Idoso , Calcinose/complicações , Doença da Artéria Coronariana/complicações , Vasos Coronários/efeitos dos fármacos , Estudos Transversais , Diabetes Mellitus Tipo 2/complicações , Feminino , Taxa de Filtração Glomerular , Humanos , Hipertensão/complicações , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estresse Oxidativo , Pontuação de Propensão , Fatores de Risco , Fumar , Tomografia Computadorizada por Raios X
14.
J Exp Clin Cancer Res ; 38(1): 210, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31118051

RESUMO

BACKGROUND: Metformin, a biguanide, is one of the most commonly prescribed treatments for type 2 diabetes and has recently been recommended as a potential drug candidate for advanced cancer therapy. Although Metformin has antiproliferative and proapoptotic effects on breast cancer, the heterogenous nature of this disease affects the response to metformin leading to the activation of pro-invasive signalling pathways that are mediated by the focal adhesion kinase PYK2 in pure HER2 phenotype breast cancer. METHODS: The effect of metformin on different breast cancer cell lines, representing the molecular heterogenicity of the disease was investigated using in vitro proliferation and apoptosis assays. The activation of PYK2 by metformin in pure HER2 phenotype (HER2+/ER-/PR-) cell lines was investigated by microarrays, quantitative real time PCR and immunoblotting. Cell migration and invasion PYK2-mediated and in response to metformin were determined by wound healing and invasion assays using HER2+/ER-/PR- PYK2 knockdown cell lines. Proteomic analyses were used to determine the role of PYK2 in HER2+/ER-/PR- proliferative, migratory and invasive cellular pathways and in response to metformin. The association between PYK2 expression and HER2+/ER-/PR- patients' cancer-specific survival was investigated using bioinformatic analysis of PYK2 expression from patient gene expression profiles generated by the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) study. The effect of PYK2 and metformin on tumour initiation and invasion of HER2+/ER-/PR- breast cancer stem-like cells was performed using the in vitro stem cell proliferation and invasion assays. RESULTS: Our study showed for the first time that pure HER2 breast cancer cells are more resistant to metformin treatment when compared with the other breast cancer phenotypes. This drug resistance was associated with the activation of PTK2B/PYK2, a well-known mediator of signalling pathways involved in cell proliferation, migration and invasion. The role of PYK2 in promoting invasion of metformin resistant HER2 breast cancer cells was confirmed through investigating the effect of PYK2 knockdown and metformin on cell invasion and by proteomic analysis of associated cellular pathways. We also reveal a correlation between high level of expression of PYK2 and reduced survival in pure HER2 breast cancer patients. Moreover, we also report a role of PYK2 in tumour initiation and invasion-mediated by pure HER2 breast cancer stem-like cells. This was further confirmed by demonstrating a correlation between reduced survival in pure HER2 breast cancer patients and expression of PYK2 and the stem cell marker CD44. CONCLUSIONS: We provide evidence of a PYK2-driven pro-invasive potential of metformin in pure HER2 cancer therapy and propose that metformin-based therapy should consider the molecular heterogeneity of breast cancer to prevent complications associated with cancer chemoresistance, invasion and recurrence in treated patients.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Quinase 2 de Adesão Focal/genética , Metformina/farmacologia , Receptor ErbB-2/genética , Apoptose/efeitos dos fármacos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células MCF-7 , Metformina/efeitos adversos , Invasividade Neoplásica/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Proteômica , Transdução de Sinais
15.
Biomed Res Int ; 2019: 5308308, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31080822

RESUMO

Development of cirrhosis is two- to threefold greater in patients with diabetes mellitus (DM), and in this setting, the prevalence of cirrhosis is surging worldwide. The present review served to examine clinical ties between DM and liver fibrosis and hepatic cirrhosis and explore related biologic mechanisms. Pathways contributing to various etiologies of cirrhosis in conjunction with DM were key investigative targets.


Assuntos
Complicações do Diabetes , Diabetes Mellitus , Cirrose Hepática/epidemiologia , Cirrose Hepática/etiologia , Alcoolismo/epidemiologia , Alcoolismo/etiologia , Complicações do Diabetes/epidemiologia , Glucose/metabolismo , Hepacivirus , Hepatite B/epidemiologia , Hepatite B/etiologia , Vírus da Hepatite B/patogenicidade , Hepatite C/epidemiologia , Hepatite C/etiologia , Humanos , Hipoglicemiantes/efeitos adversos , Metformina/efeitos adversos , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Prevalência , Prognóstico , Fatores de Risco , Tiazolidinedionas/efeitos adversos
16.
Geriatr Gerontol Int ; 19(8): 755-761, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31119857

RESUMO

AIM: We investigated the effects of metformin on cognitive function in a prospective cohort of older adults. METHODS: Participants aged ≥60 years were selected, and their Korean version of the Consortium to Establish a Registry for Alzheimer's Diseases Assessment, including the Mini-Mental State Examination, and activities of daily living were evaluated prospectively. Rapid deterioration of cognitive function was defined as annual change of test scores in the lowest quartile. RESULTS: A total of 732 participants (mean age 76.7 ± 6.6 years) were followed up for 2.9 years (interquartile range 1.0-5.7 years). A linear mixed model showed that diabetes was associated with significant deterioration of Verbal Delayed Free Recall and Recognition scores (P = 0.007 and 0.022, respectively). Among diabetes patients, metformin treatment was not associated with changes of any Korean version of the Consortium to Establish a Registry for Alzheimer's Diseases Assessment component or activities of daily living index. However, rapid deterioration of Mini-Mental State Examination and Verbal Immediate Recall scores was more frequently found in the metformin-taking group, even after adjustment for age, sex, education level, baseline cognitive function, baseline glycated hemoglobin levels, renal and liver function, body mass index, hypertension, dyslipidemia, antidiabetic agents other than metformin, and baseline brain imaging abnormality (odds ratio 4.47, 95% confidence interval 1.24-16.05 and odds ratio 7.37, 95% confidence interval 1.19-45.56). CONCLUSIONS: Metformin treatment was not associated with changes of any of Korean version of the Consortium to Establish a Registry for Alzheimer's Diseases Assessment component scores or activities of daily living index. However, rapid deterioration of Mini-Mental State Examination and Verbal Immediate Recall scores was more frequently found in the metformin-treated group. Geriatr Gerontol Int 2019; 19: 755-761.


Assuntos
Cognição/efeitos dos fármacos , Disfunção Cognitiva , Diabetes Mellitus , Metformina , Atividades Cotidianas , Idoso , Idoso de 80 Anos ou mais , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/etiologia , Correlação de Dados , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/psicologia , Progressão da Doença , Feminino , Avaliação Geriátrica/métodos , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Masculino , Testes de Estado Mental e Demência/estatística & dados numéricos , Metformina/administração & dosagem , Metformina/efeitos adversos , República da Coreia/epidemiologia
17.
Pak J Pharm Sci ; 32(2 (Supplementary)): 859-863, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31103983

RESUMO

To discuss metformin and iv-contrast induced acute renal failure with its reported cases worldwide, associated risk factors and precautions that can be taken to reduce this tragedy & to address this sensitive issue to my technologist family working in clinical situations. As these studies were observational studies and just report contrast induced nephrotoxicity in different countries by analyzing patients data. By Personal experience or by analyzing data available on PACS (Picture archiving and communication system) most commonly available in Hospitals now a days, that is why these studies did not use any scientific procedure. In our study, we collected opinions of Senior Doctors about use of Metformin before and after contrast study. All Doctors were agreed upon investigation of serum creatinine before contrast study. Doctors were not agreed on single opinion but surely they agreed on stop of Metformin before and after procedure. They said its responsibility of imaging technologist or Radiologist to guide patient about this problem. Diabetic patients using Metformin are at high risk of acute renal acidosis if they are undergoing for iodinated contrast study.


Assuntos
Lesão Renal Aguda/induzido quimicamente , Meios de Contraste/administração & dosagem , Creatinina/sangue , Hipoglicemiantes/uso terapêutico , Iodo/administração & dosagem , Metformina/uso terapêutico , Meios de Contraste/efeitos adversos , Diabetes Mellitus/tratamento farmacológico , Interações de Medicamentos , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Injeções Intravenosas , Iodo/efeitos adversos , Metformina/administração & dosagem , Metformina/efeitos adversos , Paquistão , Médicos , Guias de Prática Clínica como Assunto
18.
J Neurol ; 266(8): 1988-1997, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31093755

RESUMO

OBJECTIVE: Traumatic brain injury (TBI) is a leading cause of morbidity and mortality worldwide. Metformin is reported to have pleiotropic neuroprotective effects through anti-inflammatory, antioxidative, and anti-ischemic activity, and improvements in vascular hemodynamics and endothelial function. The aim of this study is to examine the efficacy and safety of metformin therapy in severe TBI patients. METHODS: This single-blind, parallel-group, randomized controlled trial enrolled adult TBI patients. Of 158 trauma patients assessed, 30 met the eligibility criteria and were randomly allocated in a one-to-one ratio to receive 1 g metformin every 12 h for five consecutive days (intervention group) or to usual management only (control group). For efficacy analysis, temporal profiles of serum levels of S100b, neutrophil to lymphocyte ratio (NLR), and glial fibrillary acidic protein (GFAP) were assessed. For pharmacokinetic analysis, serum concentrations of metformin were evaluated in the intervention group. RESULTS: The two study groups were similar in terms of demographics, baseline clinical characteristics, and on-admission biomarkers' serum levels. Longitudinal analysis of S100b and NLR levels showed statistically significant declines in values toward normal levels in the intervention group (p values of < 0.001 and 0.030, respectively), different from the profiles of the control group (p values of 0.074 and 0.645, respectively). Pharmacokinetic analysis demonstrated that metformin absorption is delayed in TBI patients. No events of hypoglycemia and lactic acidosis occurred. CONCLUSIONS: Metformin could potentially be an effective and safe therapeutic intervention in patients with severe TBI. Large-scale, multicentre studies are needed to confirm our encouraging results.


Assuntos
Lesões Encefálicas Traumáticas/sangue , Lesões Encefálicas Traumáticas/tratamento farmacológico , Metformina/sangue , Metformina/uso terapêutico , Índice de Gravidade de Doença , Adulto , Biomarcadores/sangue , Lesões Encefálicas Traumáticas/diagnóstico , Feminino , Seguimentos , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/sangue , Hipoglicemiantes/uso terapêutico , Estudos Longitudinais , Masculino , Metformina/efeitos adversos , Pessoa de Meia-Idade , Subunidade beta da Proteína Ligante de Cálcio S100/sangue , Método Simples-Cego , Resultado do Tratamento , Adulto Jovem
19.
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
20.
J Pediatr Endocrinol Metab ; 32(5): 461-470, 2019 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-31005950

RESUMO

Background Hyperandrogenism with or without polycystic ovarian syndrome is seen in adolescents with type 1 diabetes (T1D), especially those with suboptimal control. Objective To assess the effect of metformin on hyperandrogenism and ovarian function in adolescents with T1D. Methods This prospective study included 28 T1D females showing signs of hyperandrogenism. History taking (detailed diabetes history and menstrual history) and anthropometric measurements (weight, height, body mass index [BMI], waist and hip circumference) were initially performed, and then the patients were assessed for the manifestations of hyperandrogenism (acne, hirsutism as well as pelvic ultrasound [U/S] for ovarian morphology). Biochemical evaluation for ovulation (progesterone assessment during the luteal phase), sex steroids (estradiol, testosterone, dehydroepiandrosterone sulfate [DHEAS] and androstenedione), prolactin, glycemic control (hemoglobin A1c [HbA1c]) and gonadotropin levels (follicle stimulating hormone [FSH] and luteinizing hormone [LH]) was done. Patients were subjected to 500 mg metformin twice daily orally for 1 year, and then the patients were re-evaluated for clinical and biochemical parameters. Results Metformin therapy resulted in a significant reduction in weight (p = 0.001), BMI (p = 0.002), acne (p = 0.008), hirsutism score (0.007), LH (p = 0.008), testosterone (p < 0.001) and androstenedione levels (p = 0.028) in adolescent girls with T1D. Regarding menstrual irregularities, there was a significant reduction in the number of patients with oligomenorrhea (68%) with a p value of <0.001. However, there were no significant reduction in the daily insulin requirements (p = 0.782) or HbA1c (p = 0.068). Nausea and/or abdominal pain were the commonly reported side effects of metformin (64%). Conclusions Metformin as an insulin sensitizing agent improved the BMI and cycle regularity together with clinical and biochemical hyperandrogenism in T1D adolescent girls. However, it did not improve their glycemic control.


Assuntos
Biomarcadores/análise , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hiperandrogenismo/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Metformina/efeitos adversos , Adolescente , Adulto , Criança , Diabetes Mellitus Tipo 1/patologia , Feminino , Seguimentos , Humanos , Prognóstico , Estudos Prospectivos , Adulto Jovem
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