Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.290
Filtrar
2.
Am J Nurs ; 121(9): 25, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34438427

RESUMO

Dapagliflozin (Farxiga) is now approved to reduce the risk of declining kidney function, kidney failure, cardiovascular death, and hospitalization for heart failure in adults with chronic kidney disease with or without type 2 diabetes.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Complicações do Diabetes/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/uso terapêutico , Insuficiência Cardíaca/prevenção & controle , Hipoglicemiantes/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Insuficiência Cardíaca/complicações , Humanos , Nefropatias , Fatores de Tempo
4.
Chem Biol Interact ; 347: 109617, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34391751

RESUMO

PURPOSE: This study was designed to investigate the mechanism of Dapagliflozin (Dapa) cardioprotection against diabetic cardiomyopathy (DCM). Structural and functional changes in the heart as well as decrease of erythropoietin (EPO) levels were reported in DCM. EPO simultaneously activates three pathways: the Janus-activated kinase-signal transducer and activator of transcription (JAK2/STAT5), phosphatidylinositol-3-kinase-Akt (PI3K/Akt), and extracellular signal-related kinase (ERK/MAPK) cascades, that result in proliferation and differentiation of cardiac cells. METHODS AND RESULTS: DCM was induced by a high fat diet for 10 weeks followed by administration of streptozotocin. After confirmation of diabetes, rats were divided randomly to 5 groups: Group 1; normal control group, Group 2; untreated diabetic group and Groups (3-5); diabetic groups received Dapa daily (0.75 mg, 1.5 or 3 mg/Kg, p.o) respectively for a month. At the end of the experiment, full anaesthesia was induced in all rats using ether inhalation and ECG was recorded. Blood samples were collected then rats were sacrificed and their heart were dissected out and processed for biochemical and histopathological studies. Untreated diabetic rats showed abnormal ECG pattern, elevation of serum cardiac enzymes, decrease EPO levels, downregulation of P-Akt, P-JAK2 and pMAPK pathways, abnormal histological structure of the heart and increase immunostaining intensity of P53 and TNF α in the cardiomyocytes. Dapa in a dose dependent manner attenuated the alterations in the previously mentioned parameters. CONCLUSION: The cardioprotective effect of Dapa could be mediated by increasing EPO levels and activation of P-Akt, P-JAK2 and pMAPK signalling cascades which in turn decrease apoptosis.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Cardiotônicos/uso terapêutico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Cardiomiopatias Diabéticas/tratamento farmacológico , Glucosídeos/uso terapêutico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/complicações , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/patologia , Eletrocardiografia/efeitos dos fármacos , Eritropoetina/sangue , Eritropoetina/metabolismo , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , Ratos Wistar , Estreptozocina
5.
Int J Mol Sci ; 22(12)2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199317

RESUMO

Empagliflozin, an established treatment for type 2 diabetes (T2DM), has shown beneficial effects on liver steatosis and fibrosis in animals and in humans with T2DM, non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH). However, little is known about the effects of empagliflozin on liver function in advanced NASH with liver fibrosis and without diabetes. This study aimed to assess the effects of empagliflozin on hepatic and metabolic outcomes in a diet-induced obese (DIO) and insulin-resistant but non-diabetic biopsy-confirmed mouse model of advanced NASH. Male C57BL/6JRj mice with a biopsy-confirmed steatosis and fibrosis on AMLN diet (high fat, fructose and cholesterol) for 36-weeks were randomized to receive for 12 weeks: (a) Empagliflozin (10 mg/kg/d p.o.), or (b) vehicle. Metabolic outcomes, liver pathology, markers of Kupffer and stellate cell activation and lipidomics were assessed at the treatment completion. Empagliflozin did not affect the body weight, body composition or insulin sensitivity (assessed by intraperitoneal insulin tolerance test), but significantly improved glucose homeostasis as assessed by oral glucose tolerance test in DIO-NASH mice. Empagliflozin improved modestly the NAFLD activity score compared with the vehicle, mainly by improving inflammation and without affecting steatosis, the fibrosis stage and markers of Kupffer and stellate cell activation. Empagliflozin reduced the hepatic concentrations of pro-inflammatory lactosylceramides and increased the concentrations of anti-inflammatory polyunsaturated triglycerides. Empagliflozin exerts beneficial metabolic and hepatic (mainly anti-inflammatory) effects in non-diabetic DIO-NASH mice and thus may be effective against NASH even in non-diabetic conditions.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Glucosídeos/uso terapêutico , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Antígenos CD/metabolismo , Compostos Benzidrílicos/farmacologia , Biópsia , Composição Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Glucose/metabolismo , Glucosídeos/farmacologia , Homeostase/efeitos dos fármacos , Resistência à Insulina , Lactosilceramidas/metabolismo , Lipidômica , Fígado/efeitos dos fármacos , Fígado/patologia , Camundongos Endogâmicos C57BL , Camundongos Obesos , Hepatopatia Gordurosa não Alcoólica/patologia , Triglicerídeos/metabolismo
6.
Geriatr Psychol Neuropsychiatr Vieil ; 19(2): 137-147, 2021 Jun 01.
Artigo em Francês | MEDLINE | ID: mdl-34165436

RESUMO

Glucose and sodium tubular reabsorption inhibitors, or gliflozins, are a new therapeutic class. Their novel mechanism of action involves inhibition of a glucose and Na+ reabsorption co-transporter in the renal proximal tubule. They reduce blood glucose levels by reducing renal glucose reabsorption. They therefore cause glycosuria, which constitutes an energy loss and ultimately leads to a weight loss of around 2 to 3 kg. They reduce the sodium load and lower blood pressure. This class improves HbA1c by about 0.7%. Empagliflozin has been shown to reduce all-cause mortality in type 2 diabetic patients at high cardiovascular risk and to reduce episodes of cardiac decompensation and is nephroprotective in diabetic and non-diabetic subjects. Empagliflozin, like other gliflozins, does not induce hypoglycaemia as it does not directly stimulate insulin secretion. Due to the high prevalence of type 2 diabetes, heart failure and renal failure in the elderly, gliflozins will become part of geriatric prescriptions. Their advantages and use must be known, especially as their place will be extended to numerous indications in the field of chronic diseases.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Glucosídeos/uso terapêutico , Hipoglicemiantes/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Idoso , Compostos Benzidrílicos/efeitos adversos , Compostos Benzidrílicos/farmacologia , Glucosídeos/efeitos adversos , Glucosídeos/farmacologia , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos
7.
J Ayub Med Coll Abbottabad ; 33(2): 188-191, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34137526

RESUMO

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a progressive disease due to multiple pathophysiological defects. Monotherapy alone cannot achieve adequate glycemic control and can lead to treatment failure. Empagliflozin, a sodium-glucose cotransporter2 (SGLT2) inhibitor improves glycemic control in patients with T2DM. There were limited studies to determine efficacy and safety profile of empagliflozin with conventional oral antidiabetic drugs (OADs) in Pakistan. So we investigated the efficacy and safety profile of empagliflozin as add-on therapy to metformin and sitagliptin in T2DM patients. METHODS: In this comparative randomized placebo-controlled trial, 240 obese type 2 diabetic patients with inadequate glycaemic control (i.e, HbA1c ≥7%) with metformin and sitagliptin were allocated in to two groups. Patients in group B were given tab empagliflozin 10mg twice a day while patients in group A were given tab placebo for a period of 24 weeks. Changes in body weight, HbA1c, blood pressure were analysed pre and post treatment by using SPSS v23. RESULTS: Empagliflozin caused a significant reduction in body weight -6.9±2.4 kg as compared to placebo -3.1±0.8 kg with p-value <0.001. This body weight reduction was further accompanied by reduction in systolic blood pressure -10.1±2.6 mmHg in empagliflozin group versus -5.3±2.5 mmHg in placebo group with p-value <0.001, and HbA1c -1.68±0.45 in empagliflozin group versus -0.1±0.06 in placebo group with p-value <0.001. There were 28.3% patients in empagliflozin group in whom HbA1c levels reduced <7% as compared to only 13.3% patients in placebo group (p-value 0.04). However no significant adverse effects were recorded in both study groups. CONCLUSIONS: Empagliflozin as a combination therapy has good efficacy and safety profile in obese type 2 diabetic patients.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/uso terapêutico , Hipoglicemiantes/uso terapêutico , Obesidade/complicações , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Adulto , Compostos Benzidrílicos/administração & dosagem , Compostos Benzidrílicos/farmacologia , Glicemia/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Tipo 2/complicações , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Glucosídeos/administração & dosagem , Glucosídeos/farmacologia , Hemoglobina A Glicada/análise , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacologia , Masculino , Pessoa de Meia-Idade , Placebos , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Resultado do Tratamento , Perda de Peso/efeitos dos fármacos
8.
Diabetes Obes Metab ; 23(8): 1886-1891, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33950573

RESUMO

AIM: To investigate whether the cardiorenal benefits of the sodium-glucose co-transporter-2 inhibitor empagliflozin are affected by body mass index (BMI) in type 2 diabetes patients with established cardiovascular (CV) disease, including Asians. METHODS: In this exploratory analysis of the EMPA-REG OUTCOME trial, we used Cox regression to evaluate the effects of empagliflozin on all-cause mortality, hospitalization for heart failure (HHF) or CV death, and incident or worsening nephropathy by baseline BMI category. RESULTS: Of the 7020 participants (1517 Asians [21.6%]), 934 (13.3%), 2465 (35.1%) and 3621 (51.6%) had a BMI of less than 25, 25 to less than 30, and 30 kg/m2 or higher, respectively. Overall, hazard ratios for empagliflozin versus placebo for all-cause mortality, HHF or CV death, and incident or worsening nephropathy were 0.68 (95% CI 0.57, 0.82), 0.66 (0.55, 0.79) and 0.61 (0.53, 0.70), respectively, and were consistent across BMI categories (P values for interaction between treatment and BMI were .6772, .3087 and .6265, respectively). Results were similar in Asians using these BMI categories and categories of less than 24, 24 to less than 28, and 28 kg/m2 or higher. CONCLUSION: Empagliflozin reduced cardiorenal and mortality risk regardless of BMI at baseline, including in Asians with a lower BMI.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Ásia/epidemiologia , Compostos Benzidrílicos/uso terapêutico , Índice de Massa Corporal , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/uso terapêutico , Humanos , Hipoglicemiantes
9.
Diabetes Res Clin Pract ; 175: 108843, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33933498

RESUMO

AIM: To assess the efficacy and tolerability of adjunct therapy with a sodium-glucose cotransporter-2 inhibitor, dapagliflozin, compared with insulin escalation for patients with uncontrolled type 2 diabetes on current insulin therapy. METHODS: A 12-month retrospective case-control study of patients with glycated hemoglobin (HbA1c) > 7% on insulin therapy. The study group received add-on therapy with dapagliflozin (10 mg once daily); the control group received titrated increases of their existing insulin dose by a mean of 21.6% from baseline. The primary endpoint was the change in HbA1c after 12 months. Secondary outcomes included changes in fasting plasma glucose, postprandial 2-h glucose levels, insulin requirements, and body weight. RESULTS: After 12 months, the reduction in HbA1c was significantly greater in the dapagliflozin group than in the control group (from 8.9 ±â€¯1.2% to 8.0 ±â€¯1.0% vs 9.1 ±â€¯1.2% to 8.7 ±â€¯1.5%, respectively). Results for fasting plasma glucose and postprandial 2-h glucose were similar. Dapagliflozin therapy decreased systolic blood pressure (-4.7 mmHg) and body weight (-1.4 kg) significantly, whereas body weight increased by 0.6 kg in the control group. The dapagliflozin group showed significantly fewer hypoglycemic events than the control group (18.5% vs 32.6%, respectively). Daily insulin dose increased by 5.4 ±â€¯6.1 U (21.6%) in the control group but decreased by 1.9 ±â€¯5.3 U (-4.5%) in the dapagliflozin group (p < 0.001). CONCLUSION: As an adjunct to insulin therapy, dapagliflozin therapy significantly improved glycemic control, with the clinical advantages of weight loss, insulin sparing, and less hypoglycemia.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Quimioterapia Combinada/métodos , Glucosídeos/uso terapêutico , Insulina/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Compostos Benzidrílicos/farmacologia , Estudos de Casos e Controles , Feminino , Glucosídeos/farmacologia , Humanos , Insulina/fisiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
10.
Life Sci ; 278: 119638, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34051216

RESUMO

Hepatotoxicity is the main adverse effect of methotrexate (MTX), which limits its clinical use and effectiveness. Both empagliflozin (EMPA) and neohesperidin dihydrochalcone (NHD) have promising criteria for suppressing oxidative stress, inflammation and apoptosis. In this current study, we suggested that EMPA and NHD exhibit protective effects against MTX-triggered liver injury, considering N-acetylcysteine (NAC) as a reference standard. In order to inspect our suggestion, An experimental rat model comprising 70 male adult rats (7 groups, 10 rats in each) was implemented to investigate the effects of MTX (20 mg/kg, i.p. once), alone or with EMPA (10 and 30 mg/kg/day, p.o.), NHD (40 and 80 mg/kg/day, p.o.), and NAC (150 mg/kg/day, p.o.) compared to the normal control animals (1%CMC, p.o.). Pre-treatment with EMPA and NHD showed significant attenuation in liver function abnormalities, pathological tissue deteriorations, hepatic oxidative stress parameters, and the level of expression of pro-inflammatory cytokines TNF-α and IL-6. Also, EMPA and NHD showed significant decreases in NF-κB/Keap1/HSP70/caspase-3 and increases in Nrf2/PPARγ/HO-1 expression levels. In addition, EMPA and NHD showed a marked enhancement of the anti-tumour activity of MTX against HepG2 and lung (A549) cancer cells. This research reveals that both EMPA and NHD can inhibit oxidation, inflammatory reactions, and apoptosis in the liver tissues of MTX-treated rats, mainly through Nrf2/PPARγ/HO-1 signalling initiation and suppression of NF-κB/Keap1/HSP70/caspase-3 axis, considered a unique class of drugs that attenuates or at least delays the onset of MTX-induced toxicity and serves as an innovative therapeutic target for future clinical application in humans.


Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Compostos Benzidrílicos/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Glucosídeos/uso terapêutico , Hesperidina/análogos & derivados , Metotrexato/efeitos adversos , Substâncias Protetoras/uso terapêutico , Animais , Caspase 3/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Proteínas de Choque Térmico HSP72/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Hesperidina/uso terapêutico , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Transdução de Sinais/efeitos dos fármacos
11.
Am J Cardiol ; 150: 65-68, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34001339

RESUMO

The sodium-glucose cotransporter 2 inhibitors (SGLT2i) empagliflozin, canagliflozin, and dapagliflozin reduce the risk of heart failure (HF) events in patients with diabetes mellitus (DM) at high risk for HF. Differences in HF outcomes between SGLT2i were demonstrated in a recent-published meta-analysis. Nevertheless, comparative cost-effectiveness analyses of SGLT2i provided for this indication have not been published yet. Therefore, we aimed to provide a preceding economic comparison of the costs required for improving HF outcomes by these three SGLT2i. The primary outcome was the cost needed to treat (CNT) to prevent one event of hospitalization for HF or cardiovascular mortality. CNT is calculated by multiplying the annualized number needed to treat to prevent one event by the annual cost of therapy. Clinical outcome data were extracted from pre-specified cohorts of HF-naïve patients in the pivotal randomized controlled trials (RCTs). Costs of interventions were estimated as 75% of the US National Average Drug Acquisition Cost listing. Sensitivity analysis was performed to mitigate differences between the RCT's populations. We figured the CNT for the primary prevention of HF events in DM patients to be $542,328 ($409,044-$905,412) for empagliflozin, $2,347,488 ($1,066,208-∞) for canagliflozin and $2,128,374 ($1,204,740-$48,140,518) for dapagliflozin. Sensitivity analysis confirmed the cost benefit of empagliflozin. Our findings suggest that between the available SGLT2i, the cost of primary prevention of HF in patients with DM at high risk for HF is lowest with empagliflozin. These findings may help choose an SGLT2i until head-to-head RCTs, and comprehensive cost-effective analyses for this indication are available.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Insuficiência Cardíaca/prevenção & controle , Prevenção Primária , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Compostos Benzidrílicos/uso terapêutico , Canagliflozina/uso terapêutico , Feminino , Glucosídeos/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Inibidores do Transportador 2 de Sódio-Glicose/economia
12.
J Cardiovasc Pharmacol ; 78(1): e12-e19, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34001719

RESUMO

ABSTRACT: Epidemiological studies indicate that diabetes is the second most common comorbidity in COVID-19 (coronavirus disease 2019). Dapagliflozin, a sodium-glucose co-transporter 2 inhibitor, exerts direct cardioprotective and nephroprotective effects. DARE-19 (Dapagliflozin in Respiratory Failure in Patients With COVID-19), an ongoing clinical trial, is designed to investigate the impact of dapagliflozin on COVID-19 progression. This article discusses the potential favorable impact of dapagliflozin on COVID-19 and its complications.


Assuntos
Compostos Benzidrílicos/uso terapêutico , COVID-19/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Compostos Benzidrílicos/efeitos adversos , COVID-19/diagnóstico , COVID-19/mortalidade , Ensaios Clínicos Fase III como Assunto , Comorbidade , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/mortalidade , Progressão da Doença , Glucosídeos/efeitos adversos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Resultado do Tratamento
13.
Int Heart J ; 62(3): 592-600, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34054000

RESUMO

The clinical evidence is accumulating since 2015 that anti-diabetic sodium-glucose cotransporter 2 (SGLT2) inhibitors have the beneficial effect of cardiovascular and, recently, renal protection. Although it is not well analyzed how the transfer of this new evidence into daily practice has expedited, we hypothesize that the recent usage of the drugs is positively associated with several certified cardiologists in each region.The 2016 annual and 2016-2017 increased number of SGLT2 inhibitor tablets, based on the National Database of Health Insurance Claims and Specific Health Checkups of Japan, were divided by the estimated number of patients with type 2 diabetes mellitus for each of the 47 prefectures. Then, regression analyses were performed to investigate the potential association of the number of certified cardiologists with the drug prescription.The 2016 prescription of ipragliflozin, dapagliflozin, luseogliflozin, canagliflozin, and empagliflozin was 2.7- to 4.4-fold different between prefectures. The 2016-2017 increased prescription volume also varied among prefectures by as large as 7.3-fold for ipragliflozin. Regression analysis revealed that the annual and increased prescription volume of all the SGLT2 inhibitors except luseogliflozin were higher in regions with more certified cardiologists (P < 0.05), even after adjusting for regional parameters.In conclusion, the regional number of certified cardiologists was positively associated with a 2016 annual of and 2016-2017 increase in SGLT2 inhibitor prescription amount, implying an early adopter role of clinical experts in healthcare delivery.


Assuntos
Cardiologistas/estatística & dados numéricos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Prescrições/estatística & dados numéricos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Compostos Benzidrílicos/farmacologia , Compostos Benzidrílicos/uso terapêutico , Canagliflozina/farmacologia , Canagliflozina/uso terapêutico , Sistema Cardiovascular/efeitos dos fármacos , Análise de Dados , Feminino , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Humanos , Japão/epidemiologia , Rim/efeitos dos fármacos , Masculino , Análise de Regressão , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Sorbitol/análogos & derivados , Sorbitol/farmacologia , Sorbitol/uso terapêutico , Tiofenos/farmacologia , Tiofenos/uso terapêutico
14.
Biomed Pharmacother ; 140: 111738, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34029949

RESUMO

BACKGROUND: Diabetes and obesity contribute to the pathogenesis of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). However, how diabetes and obesity accelerate liver tumorigenesis remains to be fully understood. Moreover, to verify the therapeutic potential of anti-diabetic drugs, there exists a strong need for appropriate animal models that recapitulate human pathophysiology of NASH and HCC. METHODS: We established a novel murine model of NASH-associated liver tumors using genetically obese melanocortin 4 receptor-deficient mice fed on Western diet in combination with a chemical procarcinogen, and verified the validity of our model in evaluating drug efficacy. FINDINGS: Our model developed multiple liver tumors together with obesity, diabetes, and NASH within a relatively short period (approximately 3 months). In this model, sodium glucose cotransporter 2 inhibitor Tofogliflozin prevented the development of NASH-like liver phenotypes and the progression of liver tumors. Tofogliflozin attenuated p21 expression of hepatocytes in non-tumorous lesions in the liver. INTERPRETATION: Tofogliflozin treatment attenuates cellular senescence of hepatocytes under obese and diabetic conditions. This study provides a unique animal model of NASH-associated liver tumors, which is applicable for assessing drug efficacy to prevent or treat NASH-associated HCC.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Glucosídeos/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Animais , Compostos Benzidrílicos/farmacologia , Glicemia/análise , Senescência Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/patologia , Dieta Ocidental , Modelos Animais de Doenças , Progressão da Doença , Glucosídeos/farmacologia , Hepatócitos/efeitos dos fármacos , Insulina/sangue , Fígado/efeitos dos fármacos , Fígado/patologia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/sangue , Obesidade/complicações , Obesidade/tratamento farmacológico , Obesidade/patologia , Receptor Tipo 4 de Melanocortina/genética , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
16.
Diabetes Obes Metab ; 23(8): 1851-1858, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33908691

RESUMO

AIMS: To evaluate the effects of separate and combined use of the sodium-glucose cotransporter-2 (SGLT2) inhibitor dapagliflozin and the glucagon-like peptide-1 receptor agonist (GLP-1RA) exenatide on measures of kidney function. METHODS: In this prespecified secondary analysis of the DECREASE trial, we enrolled 66 obese patients with type 2 diabetes in a 16-week randomized double-blind placebo-controlled clinical trial to investigate the effects of dapagliflozin and exenatide twice daily, alone or in combination, versus placebo on 24-hour urinary albumin:creatinine ratio (UACR), creatinine and cystatin C-estimated glomerular filtration rate (GFR) and kidney injury molecule-1:creatinine ratio (KIM-1:Cr). RESULTS: At week 16, the mean UACR change from baseline was -39.6% (95% confidence interval [CI] -58.6, -11.9; P = 0.001) in the combined exenatide-dapagliflozin group, -18.1% (95% CI -43.1, 18.0; P = 0.278) in the dapagliflozin group, -15.6% (95% CI -41.4, 21.6; P = 0.357) in the exenatide group and - 11.0% (95% CI -39.8, 31.5; P = 0.552) in the placebo group. Compared to placebo, UACR difference at week 16 in the exenatide-dapagliflozin group was -32.2% (95% CI -60.7, 16.9; P = 0.159). Effects were similar in 37 participants who were using angiotensin-converting enzyme inhibitors or angiotensin receptor blockers at baseline. Compared to placebo, in the exenatide-dapagliflozin group, an acute dip in estimated GFR was observed with creatinine-estimated GFR (-4.0 mL/min/1.73 m2 [95% CI -9.3, 1.2]; P = 0.129) and cystatin C-estimated GFR (-10.4 mL/min/1.73 m2 [95% CI -14.9, -5.8]; P < 0.001). The mean KIM-1:Cr difference in the combined treatment arm versus placebo was -43.8% (95% CI -73.5, 18.9; P = 0.129). CONCLUSION: This prespecified secondary analysis suggests that combined therapy with exenatide and dapagliflozin may have synergistic effects on markers of kidney function compared to either therapy alone or placebo in obese patients with type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2 , Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Método Duplo-Cego , Exenatida , Glucosídeos , Humanos , Rim , Obesidade/complicações
17.
Biomed Pharmacother ; 139: 111624, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33915503

RESUMO

Acute kidney injury (AKI) is a sudden insult of the kidney that happens within a short period of time, which is associated with poor prognosis in diabetic patients with myocardial infarction (MI). Subclinical AKI is a condition in which tubular damage biomarkers [Neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1(KIM-1)] are positive even in the absence of elevated serum creatinine. Recent studies reported that SGLT-2 inhibitors could protect against subclinical AKI in diabetic patients by elevating the level of ß-Hydroxybutyric acid (ßOHB). This study aims to examine the reno-protective potential of empagliflozin (EMPA) against MI associated AKI in diabetic rats. Eighty Albino Wistar rats were divided into: (1) nondiabetic sham group (CS), (2) nondiabetic + myocardial infarction group (CM), (3) diabetic + myocardial infarction group (DM) and (4) diabetic + myocardial infarction + empagliflozin group (DME). At the end of the experiment, blood samples and kidneys were collected for biochemical analysis, histopathological, and immunohistochemical studies. After induction of myocardial infarction, there was a significant decrease in serum creatinine and NGAL levels in DME. After EMPA administration, mesangial matrix index and glomerular area were lowered in DME if compared to DM group. As a marker for tubular injury, we used anti-NGAL and anti-KIM-1 immunohistochemistry. Strong positive reaction was noticed in DM group if compared to DME group which showed weak positive reaction. Levels of renal mRNAs [NGAL; KIM-1; Nox-2,4; TLR-2,4; MyD88; TNF- α and IL-1 ß, 18] in DME group were reduced significantly compared to DM group. In conclusion, empagliflozin can protect against subclinical acute kidney injury in diabetic albino Wistar rats after myocardial infarction induction, which could improve the clinical outcome of SGLT-2 inhibitors in diabetic patients.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Glucosídeos/uso terapêutico , Rim/efeitos dos fármacos , Rim/metabolismo , Infarto do Miocárdio/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Injúria Renal Aguda/patologia , Injúria Renal Aguda/prevenção & controle , Animais , Moléculas de Adesão Celular/metabolismo , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/prevenção & controle , Eletrocardiografia , Rim/patologia , Lipocalina-2/metabolismo , Masculino , Infarto do Miocárdio/patologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Ratos , Ratos Wistar
18.
Endocrine ; 73(2): 325-330, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33871793

RESUMO

PURPOSE: Sodium-glucose cotransporter 2 inhibitors increase glucagon secretion by pancreatic alpha cells and the susceptibility to ketoacidosis. On the other hand, growth hormone (GH) stimulates peripheral lipolysis and provides free fatty acids (FFA) for ketogenesis; however, it remains unresolved whether GH directly impacts hepatic ketogenesis. We aimed to investigate the role of physiologic GH levels in promoting ketogenesis in prediabetic or type 2 diabetic patients under empagliflozin treatment. METHODS: Sixteen patients (11 women, 5 men) with prediabetes or type 2 diabetes mellitus, aged 55.6 ± 4.7 years and with a mean BMI of 30.7 ± 4.8 kg/m2 and HbA1c 7.1 ± 1.6% (means ± SD), participated in this study. All of them were submitted to three mixed-meal tests: they received placebo at -60 min (test 1), and empagliflozin 25 mg (test 2, 21st day) and empagliflozin 25 mg plus pegvisomant 30 mg were administered subcutaneously 36 h before (test 3, 28th day). After test 1, all patients were instructed to take empagliflozin 25 mg daily. RESULTS: The empagliflozin treatment decreased the plasma concentrations of glucose by 14% (P < 0.01), FFA by 23% (P < 0.01), and the insulin/glucagon ratio by 26% (P < 0.01), and it increased ß-hydroxybutyrate by 44% (P < 0.05). The GH receptor block by pegvisomant restored the plasma ß-hydroxybutyrate to baseline levels. CONCLUSIONS: We conclude that GH has a direct effect on promoting the ketogenesis environment in patients treated with empagliflozin.


Assuntos
Diabetes Mellitus Tipo 2 , Estado Pré-Diabético , Compostos Benzidrílicos/farmacologia , Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Hormônio do Crescimento , Humanos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Masculino
20.
Kidney Int ; 99(5): 1062-1064, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33892855

RESUMO

Sodium-glucose cotransporter 2 inhibitors offer cardiovascular and renal benefits in patients with chronic kidney disease through not yet clearly defined mechanisms. Juni et al. showed that sodium-glucose cotransporter 2 inhibitor empagliflozin exposure in vitro can restore cardiomyocyte function by counteracting harmful effects of uremic serum on the endothelium-cardiomyocyte crosstalk between endothelial cells and cardiomyocytes. The author's findings improved our understanding of cardiovascular impairment in chronic kidney disease and provided new perspectives for the beneficial effects of sodium-glucose cotransporter 2 inhibitor therapy.


Assuntos
Síndrome Cardiorrenal , Diabetes Mellitus Tipo 2 , Insuficiência Renal Crônica , Inibidores do Transportador 2 de Sódio-Glicose , Compostos Benzidrílicos/uso terapêutico , Síndrome Cardiorrenal/tratamento farmacológico , Células Endoteliais , Endotélio , Glucosídeos , Humanos , Miócitos Cardíacos , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...