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1.
Medicine (Baltimore) ; 100(6): e24593, 2021 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-33578559

RESUMEN

BACKGROUND: The goals of improving quality of life and increasing longevity are receiving growing amounts of attention. Body weight and lipid metabolism are closely related to various complications of diabetes. The aim of this study was to rank SGLT inhibitors according to their efficacy with regard to weight and evaluate the effect of SGLT inhibitors on lipid metabolism at 24 weeks of treatment. METHODS: The Web of Science, PubMed, Cochrane Library, Embase, and Clinical Trials databases were electronically searched to collect randomized controlled trials involving patients with type 2 diabetes mellitus through June 2020. Two researchers independently screened and evaluated the selected studies and extracted the outcome indexes. ADDIS 1.16.5 and STATA 16 software were used to perform the network meta-analysis and draw the plots. RESULTS: Ultimately, 36 studies were selected and included in this study. We found that all SGLT inhibitors were effective at reducing weight; canagliflozin was the most effective. SGLT inhibitors and placebo were not associated with significantly different serum cholesterol levels. SGLT inhibitors lowered serum triglyceride levels and increased serum high-density and low-density lipoprotein cholesterol levels. SGLT inhibitors also reduced the level of alanine aminotransferase. CONCLUSIONS: SGLT inhibitors can bring about weight loss in patients with T2DM and can also improve lipid metabolism. Therefore, patients with hyperlipidemia who have been unsuccessful at losing weight should consider taking SGLT inhibitors. In addition, SGLT inhibitors are hepatoprotective and appear to be safe for patients with mild to moderate liver dysfunction. TRIAL REGISTRATION: CRD42020198516.


Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Metabolismo de los Lípidos/efectos de los fármacos , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Peso Corporal/efectos de los fármacos , Humanos , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología
2.
Medicine (Baltimore) ; 100(1): e24101, 2021 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-33429775

RESUMEN

BACKGROUND: To evaluate dapagliflozin, canagliflozin, empagliflozin, ertugliflozin, and sotagliflozin according to their effect on the glycated hemoglobin A1c (HbA1c) level in patients with type 2 diabetes mellitus. METHODS: The Web of Science, PubMed, Cochrane Library, EMBASE, and Clinical Trials databases were electronically searched to collect randomized controlled trials of patients with type 2 diabetes mellitus through June 2020. Two researchers independently screened and evaluated the obtained studies and extracted the outcome indexes. RevMan 5.3 software was used to perform the meta-analysis and to create plots. RESULTS: Finally, 27 studies were selected and included in this study. The meta-analysis results showed that sodium-dependent glucose transporter (SGLT) inhibitors significantly reduced the HbA1c level in patients with type 2 diabetes mellitus. However, these results were highly heterogeneous, so we conducted a subgroup analysis. The results of the subgroup analysis suggested that by dividing populations into different subgroups, the heterogeneity of each group could be reduced. CONCLUSIONS: SGLT inhibitors had a good effect on the HbA1c level in patients with type 2 diabetes mellitus, but there might be differences in the efficacy of SGLT inhibitors in different populations. It is hoped that more studies will be conducted to evaluate the efficacy and safety of SGLT inhibitors in different populations. REGISTRATION NUMBER: CRD42020185025.


Asunto(s)
Hemoglobina A Glucada/análisis , Inhibidores del Cotransportador de Sodio-Glucosa 2/normas , Compuestos de Bencidrilo/farmacología , Compuestos de Bencidrilo/normas , Compuestos de Bencidrilo/uso terapéutico , Glucemia/análisis , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/normas , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Canagliflozina/farmacología , Canagliflozina/normas , Canagliflozina/uso terapéutico , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucósidos/farmacología , Glucósidos/normas , Glucósidos/uso terapéutico , Glicósidos/farmacología , Glicósidos/normas , Glicósidos/uso terapéutico , Humanos , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Factores de Tiempo
3.
Nat Commun ; 11(1): 5162, 2020 10 14.
Artículo en Inglés | MEDLINE | ID: mdl-33056984

RESUMEN

Bioactive natural C-glycosides are rare and chemical C-glycosylation faces challenges while enzymatic C-glycosylation catalyzed by C-glycosyltransferases provides an alternative way. However, only a small number of C-glycosyltransferases have been found, and most of the discovered C-glycosyltransferases prefer to glycosylate phenols with an acyl side chain. Here, a promiscuous C-glycosyltransferase, AbCGT, which is capable of C-glycosylating scaffolds lacking acyl groups, is identified from Aloe barbadensis. Based on the substrate promiscuity of AbCGT, 16 C-glycosides with inhibitory activity against sodium-dependent glucose transporters 2 are chemo-enzymatically synthesized. The C-glycoside 46a shows hypoglycemic activity in diabetic mice and is biosynthesized with a cumulative yield on the 3.95 g L‒1 scale. In addition, the key residues involved in the catalytic selectivity of AbCGT are explored. These findings suggest that AbCGT is a powerful tool in the synthesis of lead compounds for drug discovery and an example for engineering the catalytic selectivity of C-glycosyltransferases.


Asunto(s)
Aloe/enzimología , Glicósidos/biosíntesis , Glicosiltransferasas/metabolismo , Proteínas de Plantas/metabolismo , Inhibidores del Cotransportador de Sodio-Glucosa 2/metabolismo , Aloxano/toxicidad , Aloe/genética , Animales , Biocatálisis , Glucemia/análisis , Glucemia/efectos de los fármacos , Clonación Molecular , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/inducido químicamente , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Descubrimiento de Drogas/métodos , Femenino , Glicósidos/farmacología , Glicósidos/uso terapéutico , Glicosilación , Glicosiltransferasas/genética , Glicosiltransferasas/aislamiento & purificación , Humanos , Masculino , Ratones , Proteínas de Plantas/genética , Proteínas de Plantas/aislamiento & purificación , Proteínas Recombinantes/genética , Proteínas Recombinantes/aislamiento & purificación , Proteínas Recombinantes/metabolismo , Transportador 2 de Sodio-Glucosa/metabolismo , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Especificidad por Sustrato
4.
Am J Physiol Renal Physiol ; 319(4): F712-F728, 2020 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-32893663

RESUMEN

Inhibitors of proximal tubular Na+-glucose cotransporter 2 (SGLT2) are natriuretic, and they lower blood pressure. There are reports that the activities of SGLT2 and Na+-H+ exchanger 3 (NHE3) are coordinated. If so, then part of the natriuretic response to an SGLT2 inhibitor is mediated by suppressing NHE3. To examine this further, we compared the effects of an SGLT2 inhibitor, empagliflozin, on urine composition and systolic blood pressure (SBP) in nondiabetic mice with tubule-specific NHE3 knockdown (NHE3-ko) and wild-type (WT) littermates. A single dose of empagliflozin, titrated to cause minimal glucosuria, increased urinary excretion of Na+ and bicarbonate and raised urine pH in WT mice but not in NHE3-ko mice. Chronic empagliflozin treatment tended to lower SBP despite higher renal renin mRNA expression and lowered the ratio of SBP to renin mRNA, indicating volume loss. This effect of empagliflozin depended on tubular NHE3. In diabetic Akita mice, chronic empagliflozin enhanced phosphorylation of NHE3 (S552/S605), changes previously linked to lesser NHE3-mediated reabsorption. Chronic empagliflozin also increased expression of genes involved with renal gluconeogenesis, bicarbonate regeneration, and ammonium formation. While this could reflect compensatory responses to acidification of proximal tubular cells resulting from reduced NHE3 activity, these effects were at least in part independent of tubular NHE3 and potentially indicated metabolic adaptations to urinary glucose loss. Moreover, empagliflozin increased luminal α-ketoglutarate, which may serve to stimulate compensatory distal NaCl reabsorption, while cogenerated and excreted ammonium balances urine losses of this "potential bicarbonate." The data implicate NHE3 as a determinant of the natriuretic effect of empagliflozin.


Asunto(s)
Compuestos de Bencidrilo/farmacología , Diabetes Mellitus/tratamiento farmacológico , Glucósidos/farmacología , Túbulos Renales Proximales/efectos de los fármacos , Natriuresis/efectos de los fármacos , Natriuréticos/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Transportador 2 de Sodio-Glucosa/metabolismo , Intercambiador 3 de Sodio-Hidrógeno/metabolismo , Equilibrio Ácido-Base/efectos de los fármacos , Animales , Glucemia/metabolismo , Presión Sanguínea/efectos de los fármacos , Diabetes Mellitus/metabolismo , Diabetes Mellitus/fisiopatología , Modelos Animales de Enfermedad , Glucosuria/metabolismo , Glucosuria/fisiopatología , Túbulos Renales Proximales/metabolismo , Túbulos Renales Proximales/fisiopatología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Fosforilación , Intercambiador 3 de Sodio-Hidrógeno/deficiencia , Intercambiador 3 de Sodio-Hidrógeno/genética
5.
N Engl J Med ; 383(15): 1436-1446, 2020 10 08.
Artículo en Inglés | MEDLINE | ID: mdl-32970396

RESUMEN

BACKGROUND: Patients with chronic kidney disease have a high risk of adverse kidney and cardiovascular outcomes. The effect of dapagliflozin in patients with chronic kidney disease, with or without type 2 diabetes, is not known. METHODS: We randomly assigned 4304 participants with an estimated glomerular filtration rate (GFR) of 25 to 75 ml per minute per 1.73 m2 of body-surface area and a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of 200 to 5000 to receive dapagliflozin (10 mg once daily) or placebo. The primary outcome was a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes. RESULTS: The independent data monitoring committee recommended stopping the trial because of efficacy. Over a median of 2.4 years, a primary outcome event occurred in 197 of 2152 participants (9.2%) in the dapagliflozin group and 312 of 2152 participants (14.5%) in the placebo group (hazard ratio, 0.61; 95% confidence interval [CI], 0.51 to 0.72; P<0.001; number needed to treat to prevent one primary outcome event, 19 [95% CI, 15 to 27]). The hazard ratio for the composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes was 0.56 (95% CI, 0.45 to 0.68; P<0.001), and the hazard ratio for the composite of death from cardiovascular causes or hospitalization for heart failure was 0.71 (95% CI, 0.55 to 0.92; P = 0.009). Death occurred in 101 participants (4.7%) in the dapagliflozin group and 146 participants (6.8%) in the placebo group (hazard ratio, 0.69; 95% CI, 0.53 to 0.88; P = 0.004). The effects of dapagliflozin were similar in participants with type 2 diabetes and in those without type 2 diabetes. The known safety profile of dapagliflozin was confirmed. CONCLUSIONS: Among patients with chronic kidney disease, regardless of the presence or absence of diabetes, the risk of a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes was significantly lower with dapagliflozin than with placebo. (Funded by AstraZeneca; DAPA-CKD ClinicalTrials.gov number, NCT03036150.).


Asunto(s)
Compuestos de Bencidrilo/uso terapéutico , Tasa de Filtración Glomerular/efectos de los fármacos , Glucósidos/uso terapéutico , Insuficiencia Renal Crónica/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Anciano , Compuestos de Bencidrilo/efectos adversos , Compuestos de Bencidrilo/farmacología , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/prevención & control , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Nefropatías Diabéticas/tratamiento farmacológico , Femenino , Glucósidos/efectos adversos , Glucósidos/farmacología , Humanos , Estimación de Kaplan-Meier , Fallo Renal Crónico/mortalidad , Masculino , Persona de Mediana Edad , Análisis de Regresión , Insuficiencia Renal Crónica/complicaciones , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología
6.
Nat Rev Endocrinol ; 16(10): 556-577, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32855502

RESUMEN

The management of type 2 diabetes mellitus (T2DM) is becoming increasingly complex. Sodium-glucose cotransporter type 2 inhibitors (SGLT2is) are the newest antidiabetic agents for T2DM. By targeting the kidney, they have a unique mechanism of action, which results in enhanced glucosuria, osmotic diuresis and natriuresis, thereby improving glucose control with a limited risk of hypoglycaemia and exerting additional positive effects such as weight loss and the lowering of blood pressure. Several outcome studies with canagliflozin, dapagliflozin or empagliflozin reported a statistically significant reduction in major cardiovascular events, hospitalization for heart failure and progression to advanced renal disease in patients with T2DM who have established atherosclerotic cardiovascular disease, several cardiovascular risk factors, albuminuric mild to moderate chronic kidney disease or heart failure. Current guidelines proposed a new paradigm in the management of T2DM, with a preferential place for SGLT2is, after metformin, in patients with atherosclerotic cardiovascular disease, heart failure and progressive kidney disease. Ongoing trials might extend the therapeutic potential of SGLT2is in patients with, but also without, T2DM. This Review provides an update of the current knowledge on SGLT2is, moving from their use as glucose-lowering medications to their new positioning as cardiovascular and renal protective agents.


Asunto(s)
Enfermedades Cardiovasculares/prevención & control , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Insuficiencia Renal Crónica/prevención & control , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Cardiotónicos/farmacología , Cardiotónicos/uso terapéutico , Enfermedades Cardiovasculares/etiología , Ensayos Clínicos como Asunto , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Hipoglucemiantes/farmacología , Insuficiencia Renal Crónica/etiología , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Resultado del Tratamiento
7.
Medicine (Baltimore) ; 99(30): e21409, 2020 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-32791755

RESUMEN

BACKGROUND: This study aim at evaluating the efficacy and safety of dapagliflozin plus saxagliptin vs monotherapy as added to metformin in patients with type 2 diabetes mellitus (T2DM). METHOD: PubMed, Cochrane library, Embase, CNKI and Wanfang databases were searched up to 31 December 2019. Randomized controlled trials (RCTs) applicable in dapagliflozin plus saxagliptin vs monotherapy as added to metformin in the treatment of T2DM were included. The outcomes included changes in HbA1c, FPG, body weight, SBP, DBP and adverse reactions. Fixed or random effects model were used to assess these outcomes. RESULTS: In this study, 8 RCTs involved 7346 patients were included. Compared with dapagliflozin plus metformin(DM) group, patients treated with dapagliflozin plus saxagliptin add on to metformin(DSM) could significantly increase the adjusted mean change levels of HbA1c, FPG, SBP and DBP(P < .00001, SMD = -4.88, 95%CI = -6.93∼-2.83; P < .00001, SMD = -6.50, 95%CI = -8.55∼-4.45; P < .00001, SMD = -0.97, 95%CI = -1.15∼-0.78; P < .00001, SMD = -2.00, 95%CI = -2.20∼-1.80), but no major difference in body weight loss showed(P = .12, SMD = 0.92, 95%CI = -0.22∼2.06). Furthermore, DSM therapy displayed better effects than saxagliptin plus metformin(SM) in the adjusted mean change levels of HbA1c, FPG, body weight and SBP(P < .00001, SMD = -7.75, 95%CI = -8.84∼-6.66; P < .00001, SMD = -7.75, 95%CI = -8.84∼-6.66; P = .04, SMD = -3.40, 95%CI = -6.64∼-0.17; P = .04, SMD = -7.75, 95%CI = -8.84∼-6.66), whereas no obvious difference in lowering DBP(P = .18, SMD = -16.35, 95%CI = -40.12∼7.41). Additionally, compared with DM and SM groups, there were no remarkable difference in the incidence of nausea, influenza, headache, diarrhea, urinary tract infection and renal failure for patients taking DSM, but the incidence of genital infection and hypoglycemia were higher in DSM group. CONCLUSIONS: Patients taking the DSM therapy had better effects in reducing the level of HbA1c, FPG, body weight, SBP and DBP than the DM and SM therapy. However, patients treated with DSM therapy are more likely to have hypoglycemia and genital infection. Dapagliflozin plus saxagliptin may be a suitable therapy strategy for patients with T2DM inadequately controlled with metformin, and this will provide a clinical reference for the treatment of T2DM.


Asunto(s)
Adamantano/análogos & derivados , Compuestos de Bencidrilo/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dipéptidos/uso terapéutico , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Glucósidos/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Adamantano/farmacología , Adamantano/uso terapéutico , Glucemia/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Diabetes Mellitus Tipo 2/sangre , Dipéptidos/farmacología , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Quimioterapia Combinada , Humanos , Hipoglucemiantes/uso terapéutico , Metformina/farmacología , Metformina/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología
9.
Life Sci ; 257: 118076, 2020 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-32659371

RESUMEN

AIMS: Huntington's disease is a rare neurodegenerative disorder which is associated with defected glucose metabolism with consequent behavioral disturbance including memory and locomotion. 3-nitropropionic acid (3-NP) can cause, in high single dose, an acute striatal injury/Huntington's disease. Dapagliflozin, which is one of the longest duration of action of SGLTIs family, may be able to diminish that injury and its resultant behavioral disturbances. MATERIAL AND METHODS: Forty rats were divided into four groups (n = 10 in each group): normal control group (CTRL), dapagliflozin (CTRL + DAPA) group, 3-nitropropionic acid (3-NP) group, and dapagliflozin plus 3-nitropropionic acid (DAPA + 3-NP) group. Behavioral tests (beam walking test, hanging wire test, limb withdrawal test, Y-maze spontaneous alteration, elevated plus maze) were performed with evaluating neurological scoring. In striatum, neurotransmitters (glutamate, aspartate, GABA, ACh and AChE activity) were measured. In addition, apoptosis and glycolysis markers (NF-κB, Cyt-c, lactate, HK-II activity, P53, calpain, PEA15 and TIGAR) were determined. Inflammation (IL-1ß, IL-6, IL-8 and TNF-α) and autophagy (beclin-1, LC3 and DRAM) indicators were measured. Additionally, histopathological screening was conducted. KEY FINDINGS: 3-Nitropropionic acid had the ability to perturb the neurotransmission which was reflected in impaired behavioral outcome. All of glycolysis, apoptosis and inflammation markers were elevated after 3-NP acute intoxication but autophagy parameters, except DRAM, were reduced. However, DAPA markedly reversed the abovementioned parameters. SIGNIFICANCE: Dapagliflozin demonstrated anti-glycolytic, anti-apoptotic, anti-inflammatory and autophagic effects on 3-NP-damaged striatal cells and promoted the behavioral outcome.


Asunto(s)
Apoptosis/efectos de los fármacos , Compuestos de Bencidrilo/farmacología , Glucósidos/farmacología , Glucólisis/efectos de los fármacos , Enfermedad de Huntington/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Animales , Autofagia/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Enfermedad de Huntington/fisiopatología , Inflamación/tratamiento farmacológico , Inflamación/patología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratas , Ratas Wistar
10.
Medicine (Baltimore) ; 99(29): e20735, 2020 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-32702819

RESUMEN

BACKGROUND: Type 2 diabetes mellitus is one of the most common chronic diseases, which endangers peoples health and life qualities. Sodium-Glucose Transporter 2 (SGLT2) inhibitors have been widely recognized since their clinical application in blood glucose control. While, dyslipidemia caused by SGLT2 inhibitors has been identified that affected the prognosis of this disease. METHODS: We will retrieve 8 databases including English and Chinese. After multiple screening, all randomized controlled trials (RCTs) related to SGLT2 inhibitors will be included by the 2 authors and data will be extracted. After completion of the risk of bias assessment, we will use these effect values including risk ratio (RR), weighted mean difference (WMD) and 95% confidence interval (CI) to conduct data analysis. Chi-Squared test and I test will be used to assess heterogeneity between studies. The robustness of meta-analysis results will be determined by sensitivity analysis. It will be assessed that evidence quality of the outcomes on the GRADE. RESULTS: The results of our research will be published in a peer-reviewed journal. CONCLUSION: The purpose of this systematic review and meta-analysis is to evaluate the association and degree of association between different doses of SGLT2 inhibitors and changes on blood lipid levels in patients with type 2 diabetes mellitus, in order to provide a reliable basis for clinical medication. INPLASY REGISTRATION NUMBER: INPLASY202040201.


Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Metabolismo de los Lípidos/efectos de los fármacos , Lípidos/sangre , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Glucemia/efectos de los fármacos , Estudios de Casos y Controles , Protocolos Clínicos/normas , Femenino , Humanos , Masculino , Placebos/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico
11.
Cardiovasc Diabetol ; 19(1): 91, 2020 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-32539724

RESUMEN

BACKGROUND: A sodium-glucose co-transporter 2 (SGLT-2) inhibitor had favorable impact on the attenuation of hyperglycemia together with the severity of heart failure. However, the effects of acute dapagliflozin administration at the time of cardiac ischemia/reperfusion (I/R) injury are not established. METHODS: The effects of dapagliflozin on cardiac function were investigated by treating cardiac I/R injury at different time points. Cardiac I/R was instigated in forty-eight Wistar rats. These rats were then split into 4 interventional groups: control, dapagliflozin (SGLT2 inhibitor, 1 mg/kg) given pre-ischemia, at the time of ischemia and at the beginning of reperfusion. Left ventricular (LV) function and arrhythmia score were evaluated. The hearts were used to evaluate size of myocardial infarction, cardiomyocyte apoptosis, cardiac mitochondrial dynamics and function. RESULTS: Dapagliflozin given pre-ischemia conferred the maximum level of cardioprotection quantified through the decrease in arrhythmia, attenuated infarct size, decreased cardiac apoptosis and improved cardiac mitochondrial function, biogenesis and dynamics, leading to LV function improvement during cardiac I/R injury. Dapagliflozin given during ischemia also showed cardioprotection, but at a lower level of efficacy. CONCLUSIONS: Acute dapagliflozin administration during cardiac I/R injury exerted cardioprotective effects by attenuating cardiac infarct size, increasing LV function and reducing arrhythmias. These benefits indicate its potential clinical usefulness.


Asunto(s)
Compuestos de Bencidrilo/farmacología , Glucósidos/farmacología , Infarto del Miocardio/prevención & control , Daño por Reperfusión Miocárdica/prevención & control , Miocitos Cardíacos/efectos de los fármacos , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Disfunción Ventricular Izquierda/prevención & control , Función Ventricular Izquierda/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/patología , Arritmias Cardíacas/fisiopatología , Arritmias Cardíacas/prevención & control , Modelos Animales de Enfermedad , Metabolismo Energético/efectos de los fármacos , Masculino , Mitocondrias Cardíacas/efectos de los fármacos , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/patología , Dinámicas Mitocondriales/efectos de los fármacos , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/fisiopatología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Ratas Wistar , Disfunción Ventricular Izquierda/metabolismo , Disfunción Ventricular Izquierda/patología , Disfunción Ventricular Izquierda/fisiopatología
12.
Cardiovasc Diabetol ; 19(1): 66, 2020 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-32414364

RESUMEN

BACKGROUND: Empagliflozin showed efficacy in controlling glycaemia, leading to reductions in HbA1c levels, weight loss and blood pressure, compared to standard treatment. Moreover, the EMPA-REG OUTCOME trial demonstrated a 14% reduction of major adverse cardiovascular events (MACE), a 38% reduction in cardiovascular (CV) death and a 35% reduction in the hospitalization rate for heart failure (HF). These beneficial effect on HF were apparently independent from glucose control. However, no mechanistic in vivo studies are available to explain these results, yet. We aimed to determine the effect of empagliflozin on left ventricular (LV) function in a mouse model of doxorubicin-induced cardiomyopathy (DOX-HF). METHODS: Male C57Bl/6 mice were randomly assigned to the following groups: controls (CTRL, n = 7), doxorubicin (DOX, n = 14), DOX plus empagliflozin (DOX + EMPA, n = 14), or DOX plus furosemide (DOX + FURO group, n = 7). DOX was injected intraperitoneally. LV function was evaluated at baseline and after 6 weeks of treatment using high-resolution echocardiography with 2D speckle tracking (Vevo 2100). Histological assessment was obtained using Haematoxylin and Eosin and Masson's Goldner staining. RESULTS: A significant decrease in both systolic and diastolic LV function was observed after 6 weeks of treatment with doxorubicin. EF dropped by 32% (p = 0.002), while the LS was reduced by 42% (p < 0.001) and the CS by 50% (p < 0.001). However, LV function was significantly better in the DOX + EMPA group, both in terms of EF (61.30 ± 11% vs. 49.24 ± 8%, p = 0.007), LS (- 17.52 ± 3% vs. - 13.93 ± 5%, p = 0.04) and CS (- 25.75 ± 6% vs. - 15.91 ± 6%, p < 0.001). Those results were not duplicated in the DOX + FURO group. Hearts from the DOX + EMPA group showed a 50% lower degree of myocardial fibrosis, compared to DOX mice (p = 0.03). No significant differences were found between the DOX + FURO and the DOX group (p = 0.103). CONCLUSION: Empagliflozin attenuates the cardiotoxic effects exerted by doxorubicin on LV function and remodelling in nondiabetic mice, independently of glycaemic control. These findings support the design of clinical studies to assess their relevance in a clinical setting.


Asunto(s)
Compuestos de Bencidrilo/farmacología , Cardiomiopatías/prevención & control , Doxorrubicina , Glucósidos/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Disfunción Ventricular Izquierda/prevención & control , Función Ventricular Izquierda/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacos , Animales , Cardiomiopatías/inducido químicamente , Cardiomiopatías/metabolismo , Cardiomiopatías/fisiopatología , Cardiotoxicidad , Diástole , Modelos Animales de Enfermedad , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Fibrosis , Masculino , Ratones Endogámicos C57BL , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Sístole , Disfunción Ventricular Izquierda/inducido químicamente , Disfunción Ventricular Izquierda/metabolismo , Disfunción Ventricular Izquierda/fisiopatología
13.
Obesity (Silver Spring) ; 28(6): 1068-1074, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32352644

RESUMEN

OBJECTIVE: Epicardial adipose tissue (EAT) thickness is a marker of visceral fat and an emerging therapeutic target. Dapagliflozin, a selective sodium-glucose cotransporter 2 inhibitor, improves glucose control and induces moderate weight loss in patients with type 2 diabetes mellitus. Dapagliflozin has recently been shown to reduce cardiovascular risk. Nevertheless, whether dapagliflozin could reduce EAT thickness is unknown. METHODS: This hypothesis was tested in a 24-week, randomized, double-blind, placebo-controlled clinical trial in 100 patients with type 2 diabetes mellitus with BMI ≥ 27 kg/m2 and a hemoglobin A1c level ≤ 8% on metformin monotherapy. Individuals were randomly assigned to 2 groups to receive additional dapagliflozin up to 10 mg once daily or to remain on metformin up to 1,000 mg twice daily. Ultrasound-measured EAT thickness was measured at baseline, 12 weeks, and 24 weeks. RESULTS: In the dapagliflozin group, EAT decreased by 20% from baseline to 24 weeks, by 15% after 12 weeks, and by 7% between 12 and 24 weeks, respectively (P < 0.01 for all), whereas in the metformin group, there was a significant but smaller EAT reduction. There was no statistically significant correlation between EAT and body weight changes. CONCLUSIONS: Dapagliflozin causes a rapid and significant EAT reduction that could be independent of weight loss.


Asunto(s)
Tejido Adiposo/efectos de los fármacos , Compuestos de Bencidrilo/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucósidos/uso terapéutico , Hipoglucemiantes/uso terapéutico , Obesidad/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Compuestos de Bencidrilo/farmacología , Método Doble Ciego , Femenino , Glucósidos/farmacología , Humanos , Hipoglucemiantes/farmacología , Masculino , Persona de Mediana Edad , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología
14.
PLoS One ; 15(4): e0232283, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32343721

RESUMEN

AIM: Metabolic reprograming is crucial in the proliferation of hepatocellular carcinoma (HCC). Canagliflozin (CANA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, affects various metabolisms. We investigated the effects of CANA on proliferation and metabolic reprograming of HCC cell lines using multi-omics analysis of metabolomics and absolute quantification proteomics (iMPAQT). METHODS: The cells were counted 72 hours after treatment with CANA (10 µM; n = 5) or dimethyl sulfoxide (control [CON]; n = 5) in Hep3B and Huh7 cells. In Hep3B cells, metabolomics and iMPAQT were used to evaluate the levels of metabolites and metabolic enzymes in the CANA and CON groups (each n = 5) 48 hours after treatment. RESULTS: Seventy-two hours after treatment, the number of cells in the CANA group was significantly decreased compared to that in the CON group in Hep3B and Huh7 cells. On multi-omics analysis, there was a significant difference in the levels of 85 metabolites and 68 metabolic enzymes between the CANA and CON groups. For instance, CANA significantly downregulated ATP synthase F1 subunit alpha, a mitochondrial electron transport system protein (CON 297.28±20.63 vs. CANA 251.83±22.83 fmol/10 µg protein; P = 0.0183). CANA also significantly upregulated 3-hydroxybutyrate, a beta-oxidation metabolite (CON 530±14 vs. CANA 854±68 arbitrary units; P<0.001). Moreover, CANA significantly downregulated nucleoside diphosphate kinase 1 (CON 110.30±11.37 vs. CANA 89.14±8.39 fmol/10 µg protein; P = 0.0172). CONCLUSIONS: We found that CANA suppressed the proliferation of HCC cells through alterations in mitochondrial oxidative phosphorylation metabolism, fatty acid metabolism, and purine and pyrimidine metabolism. Thus, CANA may suppress the proliferation of HCC by regulating metabolic reprograming.


Asunto(s)
Canagliflozina/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ácidos Grasos/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Metabolómica , Modelos Biológicos , Fosforilación Oxidativa/efectos de los fármacos , Proteómica , Transportador 2 de Sodio-Glucosa/metabolismo
15.
Cardiovasc Drugs Ther ; 34(4): 443-461, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32335797

RESUMEN

PURPOSE: Ticagrelor, a P2Y12 receptor antagonist, and dapagliflozin, a sodium-glucose-cotransporter-2 inhibitor, suppress the activation of the NLRP3 inflammasome. The anti-inflammatory effects of dapagliflozin depend on AMPK activation. Also, ticagrelor can activate AMPK. We assessed whether dapagliflozin and ticagrelor have additive effects in attenuating the progression of diabetic cardiomyopathy in T2DM mice. METHODS: Eight-week-old BTBR and wild-type mice received no drug, dapagliflozin (1.5 mg/kg/day), ticagrelor (100 mg/kg/day), or their combination for 12 weeks. Heart function was evaluated by echocardiography and heart tissue samples were assessed for fibrosis, apoptosis, qRT-PCR, and immunoblotting. RESULTS: Both drugs attenuated the progression of diabetic cardiomyopathy as evident by improvements in left ventricular end-systolic and end-diastolic volumes and left ventricular ejection fraction, which were further improved by the combination. Both drugs attenuated the activation of the NOD-like receptor 3 (NLRP3) inflammasome and fibrosis. The effect of the combination was significantly greater than each drug alone on myocardial tissue necrotic factorα (TNFα) and interleukin-6 (IL-6) levels, suggesting additive effects. The combination had also a greater effect on ASC, collagen-1, and collagen-3 mRNA levels than each drug alone. While both drugs activated adenosine mono-phosphate kinase (AMPK), only dapagliflozin activated mTOR and increased RICTOR levels. Moreover, only dapagliflozin decreased myocardial BNP and Caspase-1 mRNA levels, and the effects of dapagliflozin on NLRP3 and collagen-3 mRNA levels were significantly greater than those of ticagrelor. CONCLUSIONS: Both dapagliflozin and ticagrelor attenuated the progression of diabetic cardiomyopathy, the activation of the NLRP3 inflammasome, and fibrosis in BTBR mice with additive effects of the combination. While both dapagliflozin and ticagrelor activated AMPK, only dapagliflozin activated mTOR complex 2 (mTORC2) in hearts of BTBR mice.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Compuestos de Bencidrilo/farmacología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Cardiomiopatías Diabéticas/prevención & control , Glucósidos/farmacología , Inflamasomas/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Antagonistas del Receptor Purinérgico P2Y/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Ticagrelor/farmacología , Animales , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/enzimología , Cardiomiopatías Diabéticas/enzimología , Cardiomiopatías Diabéticas/etiología , Cardiomiopatías Diabéticas/fisiopatología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Activación Enzimática , Fibrosis , Masculino , Diana Mecanicista del Complejo 2 de la Rapamicina/metabolismo , Ratones Endogámicos C57BL , Miocitos Cardíacos/enzimología , Transducción de Señal , Volumen Sistólico/efectos de los fármacos , Función Ventricular Izquierda/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacos
16.
Diabetes Res Clin Pract ; 162: 108127, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32224163

RESUMEN

SGLT-2 inhibitors are known to increase hematocrit. We present two cases with marked asymptomatic erythrocytosis developing after taking SGLT-2 inhibitors. No other predisposing or causative factor was found and SGLT-2 inhibitor drug was the most likely cause in both cases. Both patients underwent phlebotomy and haematocrit came down after withdrawing the offending drug.


Asunto(s)
Diabetes Mellitus Tipo 2/complicaciones , Hipoglucemiantes/efectos adversos , Policitemia/etiología , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Humanos , Hipoglucemiantes/farmacología , Masculino , Persona de Mediana Edad , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología
18.
Diabetes Res Clin Pract ; 162: 108131, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32234505

RESUMEN

Type 1 diabetes mellitus (T1DM) prevalence is increasing and despite all available modern treatment options, an overall small but noticeable increase of mean HbA1c was recently observed in various registries. Authorized adjunctive pharmacological treatment options to insulin therapy are still scarce for T1DM. In February 2019, the European Medicines Agency (EMA) approved dapagliflozin as first in class sodium/glucose co-transporter 2 inhibitor (SGLT-2i) adjunctive therapy to insulin in patients with T1DM, which is currently still not approved by the FDA in the United States. SGLT-2is have shown significant improvement in HbA1c, reducing body weight and increasing time-in-range by reducing glycaemic variability, as well as reductions in total daily insulin dose in the trials in persons with T1DM. The cases presented here translate some of the observations gained from clinical trials into a real-world environment. They demonstrate that even highly practised and educated patients can benefit from the addition of a SGLT-2i as adjunctive treatment to insulin in T1DM. In summary, these cases demonstrate that a variety of patients with T1DM in a real-world setting may benefit from SGLT-2i treatment, as they have the potential to improve HbA1c, excess of body weight and increasing TiR among other things.


Asunto(s)
Diabetes Mellitus Tipo 1/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Adulto , Humanos , Hipoglucemiantes/farmacología , Masculino , Persona de Mediana Edad , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología
19.
Expert Opin Pharmacother ; 21(10): 1157-1166, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32301361

RESUMEN

INTRODUCTION: Sodium-glucose cotransporter 2 (SGLT2) inhibitors such as Empagliflozin are novel antihyperglycemic drugs approved for the treatment of type 2 diabetes (T2D). In addition to its glucose-lowering effects, Empagliflozin promotes weight loss, blood pressure reduction, and other beneficial metabolic benefits. AREAS COVERED: This review outlines the pharmacokinetics, pharmacodynamics, safety, and tolerability of Empagliflozin and discusses its role in diabetes-associated hypertension. EXPERT OPINION: Empagliflozin was the first in class to not only demonstrate safety of SGLT2 inhibition but also cardio- and reno-protective effects in an adequately powered cardiovascular outcome trial. The EMPA-REG study showed significant reductions in mortality from cardiovascular causes, hospitalization for heart failure, and progression of diabetic kidney disease. These benefits cannot be attributed to glycemic control alone, suggesting the involvement of other SGLT2 inhibition-mediated mechanisms. Recent data suggests the potential utility of SGLT2 inhibition in other conditions including type 1 diabetes (T1D) and non-diabetic heart failure patients with clinical trials currently being conducted. In concert with ongoing pre-clinical investigations to unravel the mechanisms contributing to cardiorenal protection, the full therapeutic potential of SGLT2 inhibition will become apparent over the next few years and promises to be one of the major success stories in clinical medicine. ABBREVIATIONS: T1D: type 1 diabetes; T2D: type 2 diabetes; SGLT2: sodium-glucose cotransporter 2; CVD: cardiovascular disease; SBP: systolic blood pressure; DBP: diastolic blood pressure; SNS: sympathetic nervous system; BP: blood pressure; CV: cardiovascular; ZDF: Zucker diabetic fatty; CKD: chronic kidney disease; FDA: Food and Drug Administration.


Asunto(s)
Compuestos de Bencidrilo/uso terapéutico , Glucósidos/uso terapéutico , Hipertensión/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Compuestos de Bencidrilo/farmacología , Glucósidos/farmacología , Humanos , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología
20.
Cardiovasc Diabetol ; 19(1): 46, 2020 04 07.
Artículo en Inglés | MEDLINE | ID: mdl-32264868

RESUMEN

BACKGROUND: The clear evidence of cardiovascular benefits in cardiovascular outcome trials of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in type 2 diabetes might suggest an effect on atherosclerotic plaque vulnerability and/or thrombosis, in which myeloid angiogenic cells (MAC) and platelets (PLT) are implicated. We tested the effects of SGLT2i on inflammation and oxidant stress in a model of stearic acid (SA)-induced lipotoxicity in MAC and on PLT activation. The possible involvement of the Na+/H+ exchanger (NHE) was also explored. METHOD: MAC and PLT were isolated from peripheral blood of healthy subjects and incubated with/without SGLT2i [empagliflozin (EMPA) and dapagliflozin (DAPA) 1-100 µM] to assess their effects on SA (100 µM)-induced readouts of inflammation, oxidant stress and apoptosis in MAC and on expression of PLT activation markers by flow-cytometry after ADP-stimulation. Potential NHE involvement was tested with amiloride (aspecific NHE inhibitor) or cariporide (NHE1 inhibitor). Differences among culture conditions were identified using one-way ANOVA or Friedman test. RESULTS: NHE isoforms (1,5-9), but not SGLT2 expression, were expressed in MAC and PLT. EMPA and DAPA (100 µM) significantly reduced SA-induced inflammation (IL1ß, TNFα, MCP1), oxidant stress (SOD2, TXN, HO1), but not apoptosis in MAC. EMPA and DAPA (both 1 µM) reduced PLT activation (CD62p and PAC1 expression). SGLT2i effects were mimicked by amiloride, and only partially by cariporide, in MAC, and by both inhibitors in PLT. CONCLUSIONS: EMPA and DAPA ameliorated lipotoxic damage in stearate-treated MAC, and reduced ADP-stimulated PLT activation, potentially via NHE-inhibition, thereby pointing to plaque stabilization and/or thrombosis inhibition as potential mechanism(s) involved in SGLT2i-mediated cardiovascular protection.


Asunto(s)
Adenosina Difosfato/farmacología , Compuestos de Bencidrilo/farmacología , Plaquetas/efectos de los fármacos , Células Progenitoras Endoteliales/efectos de los fármacos , Glucósidos/farmacología , Activación Plaquetaria/efectos de los fármacos , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Transportador 2 de Sodio-Glucosa/metabolismo , Ácidos Esteáricos/toxicidad , Apoptosis/efectos de los fármacos , Plaquetas/metabolismo , Plaquetas/patología , Células Cultivadas , Células Progenitoras Endoteliales/metabolismo , Células Progenitoras Endoteliales/patología , Humanos , Mediadores de Inflamación/metabolismo , Estrés Oxidativo/efectos de los fármacos , Transducción de Señal , Intercambiadores de Sodio-Hidrógeno/metabolismo
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