RESUMO
AIMS: To explore the effect of renal function on the pharmacokinetic (PK) and pharmacodynamic (PD) profile and safety of enavogliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes mellitus (T2DM). METHODS: An open-label, two-part clinical trial was conducted in T2DM patients, stratified by renal function: Group 1, normal renal function; Group 2, mild renal impairment (RI); Group 3, moderate RI; and Group 4, severe RI. In Part A, Groups 2 and 4 received enavogliflozin 0.5 mg once. In Part B, Groups 1 and 3 received enavogliflozin 0.5 mg once daily for 7 days. Serial blood and timed urine samples were collected to analyse the PK and PD characteristics of enavogliflozin. Pearson's correlation coefficients were calculated to assess the correlations between PK or PD parameters and creatinine clearance (CrCL). RESULTS: A total of 21 patients completed the study as planned. The area under the curve (AUC) for enavogliflozin was not significantly correlated with CrCL, although the maximum concentration slightly decreased as renal function decreased. By contrast, daily urinary glucose excretion (UGE) was positively correlated with CrCL after both single- (r = 0.7866, p < 0.0001) and multiple-dose administration (r = 0.6606, p = 0.0438). CONCLUSIONS: Systemic exposure to oral enavogliflozin 0.5 mg was similar among the patients with T2DM regardless of their renal function levels. However, the glucosuric effect of enavogliflozin decreased with RI. Considering the UGE observed and approved therapeutic use of other SGLT2 inhibitors, the efficacy of enavogliflozin with regard to glycaemic control could be explored in patients with mild and moderate RI (estimated glomerular filtration rate ≥30 or ≥45 mL/min/1.73 m2) in a subsequent larger study.
Assuntos
Diabetes Mellitus Tipo 2 , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Masculino , Inibidores do Transportador 2 de Sódio-Glicose/farmacocinética , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Pessoa de Meia-Idade , Feminino , Idoso , Taxa de Filtração Glomerular/efeitos dos fármacos , Glicemia/efeitos dos fármacos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Glucosídeos/farmacocinética , Glucosídeos/uso terapêutico , Glucosídeos/farmacologia , Glucosídeos/efeitos adversos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/fisiopatologia , Adulto , Nefropatias Diabéticas/tratamento farmacológico , Hemoglobinas Glicadas/análise , Hemoglobinas Glicadas/efeitos dos fármacos , Hemoglobinas Glicadas/metabolismo , Insuficiência Renal/metabolismo , Transportador 2 de Glucose-Sódio , Glicosúria/induzido quimicamente , BenzofuranosRESUMO
SGLT2 inhibitors have been shown to provide pronounced reductions in cardiorenal outcomes, including cardiovascular death, heart failure, and renal failure. The mechanisms underlying these benefits remain uncertain. We hypothesized that the effects could be attributed to the elevated glycosuria induced by these drugs. Urine concentrations of glucose, creatinine, and ketones were measured at baseline and after 1 year of treatment with either placebo or canagliflozin 100 mg/day, in approximately 2,600 individuals from the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial (enrolling patients with type 2 diabetes, chronic kidney disease (CKD), and albuminuria). Associations between glycosuria and the primary composite end point from CREDENCE, and secondary outcomes were assessed using Cox proportional hazards models. Canagliflozin treatment increased fractional urinary glucose excretion (± SD) from 3 ± 9% at baseline to 30 ± 26% at year 1 (vs. 5 ± 19% with placebo; P < 0.001). Patients in the canagliflozin arm and in the top quartile of urine glucose to creatinine ratio at year 1 were significantly protected for the primary end point (hazard ratio [HR] 0.42; 95% CI 0.30-0.61); similar results were seen for cases of hospitalized heart failure (HR 0.45; 95% CI 0.27-0.73) and all-cause death (HR 0.56; 95% CI 0.39-0.80). These associations persisted when adjustments were made for multiple conventional risk factors. Among patients with type 2 diabetes and CKD treated with canagliflozin, individuals with the highest glycosuria levels had the strongest protection against multiple cardiorenal outcomes.
Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Glicosúria , Insuficiência Cardíaca , Insuficiência Renal Crônica , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Canagliflozina/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Creatinina , Doenças Cardiovasculares/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/complicações , Glicosúria/induzido quimicamente , Glicosúria/complicações , Glicosúria/tratamento farmacológico , GlucoseRESUMO
A sporadic occurrence of Fanconi syndrome associated with adefovir dipivoxil (ADV) has been reported, particularly when confirmed by renal biopsy. This study presents the case of a 53-year-old man who had been taking ADV 10 mg daily for 10 years to treat chronic hepatitis B (CHB) and subsequently developed Fanconi syndrome. The clinical manifestations included hypophosphatemic osteomalacia, glucosuria, renal tubular acidosis, low-molecular-weight proteinuria, and renal insufficiency. Renal biopsy revealed significant injury to proximal tubular epithelial cells, including vacuolar degeneration and regeneration of tubular epithelial cells. The ultrastructural pathology indicated severe morphological abnormalities of mitochondria, such as densely packed and enlarged mitochondria, with loss, blunting, and disordered arrangement of cristae. Following discontinuation of ADV and supplementation with oral phosphate, hypophosphatemia, glucosuria, and proteinuria were resolved. These findings support the previous hypothesis that ADV-induced nephrotoxicity may involve mitochondrial injury.
Assuntos
Adenina/análogos & derivados , Síndrome de Fanconi , Glicosúria , Hepatite B Crônica , Hipofosfatemia , Organofosfonatos , Osteomalacia , Insuficiência Renal , Masculino , Humanos , Pessoa de Meia-Idade , Síndrome de Fanconi/induzido quimicamente , Síndrome de Fanconi/diagnóstico , Síndrome de Fanconi/complicações , Hepatite B Crônica/tratamento farmacológico , Rim , Hipofosfatemia/induzido quimicamente , Glicosúria/induzido quimicamente , Proteinúria/tratamento farmacológico , Osteomalacia/etiologia , Antivirais/efeitos adversosRESUMO
CONTEXT: This study addresses the development of a new glucoregulatory mechanism in type 2 diabetes (T2D) patients treated with SGLT-2 inhibitors, which is independent of glucose, insulin and glucagon. The data suggest the presence of a potential trigger factor (s) arising in the kidney that stimulates endogenous glucose production (EGP) during sustained glycosuria. OBJECTIVE: To investigate effects of SGLT-2 inhibitor therapy together with GLP-1 receptor agonist on EGP and glucose kinetics in patients with T2D. Our hypothesis was that increased EGP in response to SGLT2i-induced glycosuria persists for a long period and is not abolished by GLP-1 RA stimulation of insulin secretion and glucagon suppression. METHODS: Seventy-five patients received a 5-hour dual-tracer oral glucose tolerance test (OGTT) (intravenous 3-(3H)-glucose oral (1-14C)-glucose): (1) before/after 1 of dapagliflozin (DAPA); exenatide (EXE), or both, DAPA/EXE (acute study), and (2) after 1 and 4 months of therapy with each drug. RESULTS: In the acute study, during the OGTT plasma glucose (PG) elevation was lower in EXE (Δ = 42 ± 1 mg/dL) than DAPA (Δ = 72 ± 3), and lower in DAPA/EXE (Δ = 11 ± 3) than EXE and DAPA. EGP decrease was lower in DAPA (Δ = -0.65 ± 0.03 mg/kg/min) than EXE (Δ = -0.96 ± 0.07); in DAPA/EXE (Δ = -0.84 ± 0.05) it was lower than EXE, higher than DAPA. At 1 month, similar PG elevations (EXE, Δ = 26 ± 1 mg/dL; DAPA, Δ = 62 ± 2, DAPA/EXE, Δ = 27 ± 1) and EGP decreases (DAPA, Δ = -0.60 ± 0.05 mg/kg/min; EXE, Δ = -0.77 ± 0.04; DAPA/EXE, Δ = -0.72 ± 0.03) were observed. At 4 months, PG elevations (EXE, Δ = 55 ± 2 mg/dL; DAPA, Δ = 65 ± 6; DAPA/EXE, Δ = 46 ± 2) and lower EGP decrease in DAPA (Δ = -0.66 ± 0.04 mg/kg/min) vs EXE (Δ = -0.84 ± 0.05) were also comparable; in DAPA/EXE (Δ = -0.65 ± 0.03) it was equal to DAPA and lower than EXE. Changes in plasma insulin/glucagon could not explain higher EGP in DAPA/EXE vs EXE mg/kg/min. CONCLUSION: Our findings provide strong evidence for the emergence of a new long-lasting, glucose-independent, insulin/glucagon-independent, glucoregulatory mechanism via which SGLT2i-induced glycosuria stimulates EGP in patients with T2D. SGLT2i plus GLP-1 receptor agonist combination therapy is accompanied by superior glycemic control vs monotherapy.
Assuntos
Diabetes Mellitus Tipo 2 , Glicosúria , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Exenatida , Glucagon , Hipoglicemiantes/uso terapêutico , Controle Glicêmico , Agonistas do Receptor do Peptídeo 1 Semelhante ao Glucagon , Glicemia , Insulina , Glucose , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Glicosúria/induzido quimicamenteRESUMO
AIMS: This prespecified exploratory analyses from VERTIS CV (NCT01986881) aimed to assess the effects of the sodium-glucose cotransporter-2 (SGLT2) inhibitor ertugliflozin on glucosuria-related (glycated haemoglobin [HbA1c], uric acid, body weight) and natriuresis-related (blood pressure, haemoglobin, haematocrit, serum albumin) biomarkers according to kidney function risk category. MATERIALS AND METHODS: Patients with type 2 diabetes and atherosclerotic cardiovascular disease were randomized to placebo, ertugliflozin 5 mg, or ertugliflozin 15 mg (1:1:1). Analyses compared placebo (n = 2747) versus ertugliflozin (pooled; n = 5499) on glucosuria- and natriuresis-related biomarkers according to baseline estimated glomerular filtration rate (eGFR) subgroup and Kidney Disease: Improving Global Outcomes in Chronic Kidney Disease (KDIGO CKD) risk category. RESULTS: Patients were classified according to KDIGO CKD low- (49%), moderate- (32%) and high-/very-high-risk categories (19%), and eGFR groups 1 (25%), 2 (53%) and 3 (19%). At Week 18, the high-/very-high-risk category had a smaller placebo-subtracted least squares mean (LSM) change from baseline (95% confidence interval) in HbA1c (-0.34 [-0.43, -0.25]) compared with the low- and moderate-risk categories (-0.54 [-0.60, -0.49] and - 0.47 [-0.54, -0.40], respectively). This pattern was maintained throughout the study (Pinteraction = 0.0001). Similar patterns based on baseline eGFR G stage were observed. Placebo-subtracted LSM changes from baseline in uric acid were lowest in the high-/very-high-risk category at Weeks 6 and 18, but the pattern was not maintained after Week 156 (Pinteraction = 0.15). Effects of ertugliflozin on body weight and natriuresis-related biomarkers did not differ across KDIGO CKD categories. CONCLUSIONS: In VERTIS CV, ertugliflozin was associated with physiologically favourable changes in glucosuria- and natriuresis-related biomarkers. Glycaemic efficacy of ertugliflozin was attenuated in patients with higher chronic kidney disease (CKD) risk. Effects on other biomarkers were consistent, regardless of CKD risk stage.
Assuntos
Diabetes Mellitus Tipo 2 , Glicosúria , Insuficiência Renal Crônica , Inibidores do Transportador 2 de Sódio-Glicose , Biomarcadores , Peso Corporal , Compostos Bicíclicos Heterocíclicos com Pontes , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Hemoglobinas Glicadas , Glicosúria/induzido quimicamente , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Natriurese , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Ácido ÚricoRESUMO
Shiga toxin-producing Escherichia coli (STEC) causes proximal tubular defects in the kidney. However, factors altered by Shiga toxin (Stx) within the proximal tubules are yet to be shown. We determined Stx receptor Gb3 in murine and human kidneys and confirmed the receptor expression in the proximal tubules. Stx2-injected mouse kidney tissues and Stx2-treated human primary renal proximal tubular epithelial cell (RPTEC) were collected and microarray analysis was performed. We compared murine kidney and RPTEC arrays and selected common 58 genes that are differentially expressed vs. control (0 h, no toxin-treated). We found that the most highly expressed gene was GDF15, which may be involved in Stx2-induced weight loss. Genes associated with previously reported Stx2 activities such as src kinase Yes phosphorylation pathway activation, unfolded protein response (UPR) and ribotoxic stress response (RSR) showed differential expressions. Moreover, circadian clock genes were differentially expressed, suggesting Stx2-induced renal circadian rhythm disturbance. Circadian rhythm-regulated proximal tubular Na+-glucose transporter SGLT1 (SLC5A1) was down-regulated, indicating proximal tubular functional deterioration, and mice developed glucosuria confirming proximal tubular dysfunction. Stx2 alters gene expression in murine and human proximal tubules through known activities and newly investigated circadian rhythm disturbance, which may result in proximal tubular dysfunctions.
Assuntos
Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/metabolismo , Ritmo Circadiano , Regulação da Expressão Gênica/efeitos dos fármacos , Túbulos Renais Proximais/efeitos dos fármacos , Toxina Shiga II/toxicidade , Animais , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/genética , Células Epiteliais/efeitos dos fármacos , Glicosúria/induzido quimicamente , Humanos , Túbulos Renais Proximais/citologia , Lipopolissacarídeos/toxicidade , Camundongos , Análise Serial de ProteínasRESUMO
Although sodium-glucose cotransporter 2 (SGLT2) inhibitors lower serum uric acid, their long-term effect on uric acid metabolism is not well understood. We analyzed pooled data from studies wherein patients with type 2 diabetes mellitus received luseogliflozin, an SGLT2 inhibitor. Upon stratifying patients by baseline glycated hemoglobin (HbA1c ) or serum uric acid, lower HbA1c or higher serum uric acid level was associated with a greater reduction in serum uric acid after treatment. At week 12 of treatment, significant increases in urinary glucose/creatinine (Cr) ratio and urinary uric acid clearance/Cr clearance ratio (CUA /CCr ratio) and a significant reduction in serum uric acid were observed. Comparison of the subgroups of patients with a reduction or an increase in serum uric acid showed that the increase subgroup had a higher estimated glomerular filtration rate (eGFR) at baseline, and the eGFR was significantly reduced, associated with a significant reduction in the CUA /CCr ratio. Multiple regression analysis showed that the reduction in serum uric acid in the luseogliflozin group was strongly associated with baseline high serum uric acid, low HbA1c levels, and an increase in eGFR. Luseogliflozin was shown to reduce serum uric acid by enhancing urinary uric acid excretion in association with increased urinary glucose. Treatment with luseogliflozin resulted in increased serum uric acid in some patients, which may be due to reduced glomerular filtration of uric acid via the tubuloglomerular feedback. SGLT2 inhibitors reduced serum uric acid desirably in patients with type 2 diabetes mellitus with low HbA1c and high serum uric acid.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Sorbitol/análogos & derivados , Ácido Úrico/sangue , Idoso , Creatinina/urina , Método Duplo-Cego , Feminino , Taxa de Filtração Glomerular , Hemoglobinas Glicadas , Glicosúria/induzido quimicamente , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Sorbitol/farmacologia , Sorbitol/uso terapêuticoRESUMO
We herein present the case of a 45-year-old diabetic woman who developed diabetic ketoacidosis following the administration of dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor. The patient had been diagnosed with diabetes three years previously and was being treated with multiple daily injections of insulin. Metformin hydrochloride and dapagliflozin were added seven months and 11 months later, respectively. Her clinical course was uneventful until the onset of influenza. She then discontinued insulin and oral medications voluntarily. On arrival at the hospital, she was found to be in a state of ketoacidosis, and promptly received insulin and saline infusion. In retrospect, the initial amount of glucose infused was insufficient, and the hypoglycemia was thought to have been prolonged. This phenomenon may also have affected her long-term urinary glucose excretion. Her urinary L-type fatty acid-binding protein (L-FABP) level was found to be markedly elevated (48.8 µg/g·Cr, reference value < 8.4 µg/g·Cr) as was her urinary ß2-microglobulin level (9,230 µg/L, reference value < 230 µg/L). Patients with SGLT-2 inhibitor-associated diabetic ketoacidosis often exhibit protracted hyperglycosuria, in which acute proximal renal tubular dysfunction is considered to be etiologically implicated.
Assuntos
Diabetes Mellitus Tipo 2 , Glicosúria , Hipoglicemia , Cetose , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Glucose , Glicosúria/induzido quimicamente , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Cetose/induzido quimicamente , Pessoa de Meia-Idade , Sódio , Transportador 2 de Glucose-SódioRESUMO
INTRODUCTION: The presence of mercury in the environment is a worldwide concern. Inorganic mercury is present in industrial materials, is employed in medical devices, is widely used in batteries, is a component of fluorescent light bulbs, and it has been associated with human poisoning in gold mining areas. The nephrotoxicity induced by inorganic mercury is a relevant health problem mainly in developing countries. The primary mechanism of mercury toxicity is oxidative stress. Trimetazidine (TMZ) is an anti-ischemic drug, which inhibits cellular oxidative stress, eliminates oxygen-free radicals, and improves lipid metabolism. The aim of this study was to evaluate whether the administration of TMZ protects against mercuric chloride (HgCl2) kidney damage. METHODS: Adult male Wistar rats received only HgCl2 (4 mg/kg bw, sc) (Hg group, n = 5) or TMZ (3 mg/kg bw, ip) 30 min before HgCl2 administration (4 mg/kg bw, sc) (TMZHg group, n = 7). Simultaneously, a control group of rats (n = 4) was studied. After 4 days of HgCl2 injection, urinary flow, urea and creatinine (Cr) plasma levels, Cr clearance, urinary glucose, and sodium-dicarboxylate cotransporter 1 (NaDC1) in urine were determined. Lipid peroxidation (MDA) and glutathione (GSH) levels were measured in kidney homogenates. RESULTS: Rats only treated with HgCl2 showed an increase in urea and Cr plasma levels, urinary flow, fractional excretion of water, glucosuria, and NaDC1 urinary excretion as compared with the control group and a decrease in Cr clearance. TMZHg group showed a decrease in urea and Cr plasma levels, urinary flow, fractional excretion of water, glucosuria, NaDC1 urinary excretion, and an increase in Cr clearance when compared to the Hg group. Moreover, MDA and GSH levels observed in Hg groups were decreased and increased, respectively, by TMZ pretreatment. CONCLUSION: TMZ exerted a renoprotective action against HgCl2-induced renal injury, which might be mediated by the reduction of oxidative stress. Considering the absence of toxicity of TMZ, its clinical application against oxidative damage due to HgCl2-induced renal injury should be considered. The fact that TMZ is commercially available should simplify and accelerate the translation of the present data "from bench to bedside." In this context, TMZ become an interesting new example of drug repurposing.
Assuntos
Nefropatias/prevenção & controle , Intoxicação por Mercúrio/prevenção & controle , Substâncias Protetoras/farmacologia , Trimetazidina/farmacologia , Animais , Creatinina/sangue , Transportadores de Ácidos Dicarboxílicos/urina , Glutationa/metabolismo , Glicosúria/induzido quimicamente , Glicosúria/prevenção & controle , Nefropatias/induzido quimicamente , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Cloreto de Mercúrio/efeitos adversos , Transportadores de Ânions Orgânicos Dependentes de Sódio/urina , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Ratos Wistar , Cloreto de Sódio/urina , Simportadores/urina , Trimetazidina/uso terapêutico , Ureia/sangue , Micção/efeitos dos fármacosRESUMO
Diabetes is considered one of the most important health emergencies worldwide and Egypt has 8.2 million diabetic patients according to the International Diabetes Federation report in 2017. The objective of this study was to monitor the time-course variation in the metabolic profile of diabetic rats to detect urinary metabolic biomarkers using the metabolomics approach. Type 2 diabetes was induced in male Wistar albino rats using a single intraperitoneal injection of 40 mg/kg of streptozotocin following oral administration of 10% fructose in drinking water for 3 weeks. Then, urine was collected for 24 h from rats at three time points (0, 2, and 4 weeks after confirmation of diabetes), and were analyzed by nuclear magnetic resonance (H1 -NMR), followed by multivariate data analysis. The results from H1 -NMR pointed out that d-glucose, taurine, l-carnitine, l-fucose, 1,5-anhydrosorbitol, and d-galactose levels showed consistent significant variation (p < 0.05) between the positive (diabetic) and negative (normal) controls during the whole experimental period. Also, with the disease progression, myoinositol, and l-phenylalanine levels were significantly altered (p < 0.05) after 2 weeks and this alteration was maintained till the end of the 4-week experimental period in the positive control group. From the results of the present study, it could be concluded that we cannot depend only on glucose levels for prognostic purposes since there are other metabolic disturbances in diabetes which need to be tracked for better disease prognosis.
Assuntos
Diabetes Mellitus Experimental/urina , Glicosúria/urina , Metabolômica/métodos , Animais , Biomarcadores/urina , Carnitina/urina , Análise por Conglomerados , Desoxiglucose/urina , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Progressão da Doença , Frutose/administração & dosagem , Fucose/urina , Galactose/urina , Glicosúria/induzido quimicamente , Glicosúria/genética , Glicosúria/patologia , Inositol/urina , Espectroscopia de Ressonância Magnética , Masculino , Metaboloma , Fenilalanina/urina , Ratos , Ratos Wistar , Estreptozocina/administração & dosagem , Taurina/urina , Fatores de TempoRESUMO
BACKGROUND: Sodium-glucose co-transporter 2 (SGLT2) inhibitors are novel hypoglycemic agents which reduce reabsorption of glucose at the renal proximal tubule, resulting in significant glycosuria and increased risk of genital mycotic infections (GMI). These infections are typically not severe as reported in large systematic reviews and meta-analyses of the medications. These reviews have also demonstrated significant cardiovascular benefits through other mechanisms of action, making them attractive options for the management of Type 2 diabetes mellitus (T2DM). We present two cases with underlying abnormalities of the urogenital tract in which the GMI were complicated and necessitated cessation of the SGLT2 inhibitor. CASE PRESENTATIONS: Both cases are patients with T2DM on empagliflozin, an SGLT2 inhibitor. The first case is a 64 year old man with Candida albicans balanitis and candidemia who was found to have an obstructing renal calculus and prostatic abscess requiring operative management. The second case describes a 72 year old man with Candida glabrata candidemia who was found to have prostatomegaly, balanitis xerotica obliterans with significant urethral stricture and bladder diverticulae. His treatment was more complex due to fluconazole resistance and concerns about urinary tract penetration of other antifungals. Both patients recovered following prolonged courses of antifungal therapy and in both cases the SGLT2 inhibitor was ceased. CONCLUSIONS: Despite their cardiovascular benefits, SGLT2 inhibitors can be associated with complicated fungal infections including candidemia and patients with anatomical abnormalities of the urogenital tract may be more susceptible to these infections as demonstrated in these cases. Clinicians should be aware of their mechanism of action and associated risk of infection and prior to prescription, assessment of urogenital anatomical abnormalities should be performed to identify patients who may be at risk of complicated infection.
Assuntos
Compostos Benzidrílicos/efeitos adversos , Candidíase/complicações , Glicosúria/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Idoso , Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/efeitos adversos , Glicosúria/tratamento farmacológico , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Pessoa de Meia-Idade , Preparações Farmacêuticas , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêuticoRESUMO
The present report describes two surgical cases involving the development of sudden glycosuria after isoflurane anaesthesia, despite the dogs having normal blood glucose levels and renal glucose reabsorption. The glycosuria manifested 1 day after surgery and resolved spontaneously within 2 days in both cases. Considering that the surgeries (subcutaneous mandibular mass removal and fracture repair) were unrelated to the kidneys, and there were no remarkable events during anaesthesia, the glycosuria may have been associated with the isoflurane anaesthesia. There have been several previous reports of glycosuria in human patients following transient proximal tubule dysfunction due to volatile anaesthetics. This case report suggests the possibility of transient renal dysfunction following isoflurane anaesthesia in these two clinically healthy dogs. However, considering the observational nature of this report, it can not be excluded that any other procedure performed in these animals was responsible of the observed glycosuria.
Assuntos
Anestesia , Doenças do Cão , Glicosúria , Isoflurano , Anestesia/veterinária , Animais , Doenças do Cão/induzido quimicamente , Cães , Glucose , Glicosúria/induzido quimicamente , Glicosúria/veterinária , Humanos , Isoflurano/efeitos adversos , RimRESUMO
BACKGROUND: Type 2 diabetes mellitus (T2DM) in postmenopausal women is associated with a high incidence of urogenital infections, which negatively impact the quality of life and increase morbidity, mortality, and health-care costs. Glucosuria is a known risk factor for these infections; therefore, it is of interest to determine if increased glucosuria secondary to sodium-glucose cotransporter-2 inhibitors (SGLT2in) impacts the incidence and severity of urogenital infections in postmenopausal women with T2DM. METHODS: The study was conducted at Gaffrée Guinle University Hospital on two groups of postmenopausal women with T2DM: with and without SGLT2in therapy (n = 80 in each group). Medical records and laboratory parameters (urinary dipstick test and culture; blood glucose, glycosylated hemoglobin, and creatinine; cervical cytologic study) of all subjects were carefully assessed at baseline and thrice during the 12-month study period. RESULTS: We observed a significant incidence of vulvovaginitis (relative risk [RR], 2.37; 95% confidence interval [CI], 1.10-5.10; P = 0.03) and asymptomatic bacteriuria (RR, 2.47; 95% CI, 1.09-5.60; P = 0.03), but not of urinary tract infections (RR, 2.08; 95% CI, 0.74-5.81; P = 0.16), secondary to SGLT2in therapy. Genital infection was severe enough to warrant treatment discontinuation in 57.89% of patients in group 1. All urinary tract infections were of mild intensity with a good response to antibiotic therapy. CONCLUSION: Glucosuria induced by SGLT2in therapy may lead to a high incidence of urogenital infections in postmenopausal women with T2DM and can be considered a risk factor for these infections.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Glicosúria/induzido quimicamente , Glicosúria/complicações , Pós-Menopausa , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Infecções Urinárias/etiologia , Idoso , Antibacterianos/uso terapêutico , Bacteriúria/etiologia , Glicemia , Estudos de Casos e Controles , Creatinina/sangue , Feminino , Hemoglobinas Glicadas , Humanos , Incidência , Estudos Longitudinais , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Índice de Gravidade de Doença , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Infecções Urinárias/tratamento farmacológico , Vulvovaginite/etiologiaRESUMO
BACKGROUND: The nucleotide reverse transcriptase inhibitor Tenofovir Alafenamide (TAF) is a novel pro-drug of tenofovir (TFV) and possesses a superior renal safety profile compared with tenofovir disoproxil fumerate (TDF). Due to unique pharmacokinetic characteristics, treatment with TAF is not associated with significant renal proximal tubular accumulation of TFV. TAF is associated with a lower risk of acute kidney injury, chronic kidney disease, proteinuria and renal proximal tubular dysfunction than treatment with TDF. No cases of Fanconi syndrome have been reported in clinical trials of TAF. It is unknown whether treatment with TAF can lead to accumulation of TFV in proximal tubular cells and cause nephrotoxicity under certain clinical circumstances. CASE PRESENTATION: Here we report the case of a patient on stable TAF-based antiretroviral therapy with for HIV-1 infection who developed proximal tubulopathy when treated with gentamicin for febrile neutropenia in the context of relapsed Hodgkin lymphoma. Eighteen days after commencing chemotherapy for relapsed Hodgkin lymphoma the patient presented to hospital with fevers, hypotension and neutropenia. The patient was commenced on piperacillin, tazobactam and gentamicin. Within 24 h the patient developed marked hypokalaemia and hypophosphataemia requiring intravenous replacement therapy. There was proteinuria, glycosuria and evidence of marked urinary electrolyte wasting, consistent with acute proximal tubular dysfunction. Eleven days after the gentamicin was stopped the serum biochemistry normalised. The urinary electrolyte wasting and proteinuria had improved, and the glycosuria had resolved. CONCLUSION: This is the first case report to describe acute renal proximal tubulopathy in an HIV-infected patient treated with TAF and gentamicin. As the number of patients prescribed TAF outside the clinical trial setting increases, so too does the potential for previously unreported drug interactions and adverse events. Clinicians need to be aware of potential unreported adverse drug reactions as the use of TAF becomes increasingly common in clinical practice.
Assuntos
Alanina/efeitos adversos , Antibacterianos/efeitos adversos , Antivirais/efeitos adversos , Neutropenia Febril Induzida por Quimioterapia/tratamento farmacológico , Síndrome de Fanconi/induzido quimicamente , Gentamicinas/efeitos adversos , Infecções por HIV/tratamento farmacológico , Tenofovir/análogos & derivados , Doença Aguda , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neutropenia Febril Induzida por Quimioterapia/etiologia , Desprescrições , Interações Medicamentosas , Síndrome de Fanconi/metabolismo , Síndrome de Fanconi/terapia , Glicosúria/induzido quimicamente , Glicosúria/metabolismo , Glicosúria/terapia , Doença de Hodgkin/tratamento farmacológico , Humanos , Hipopotassemia/induzido quimicamente , Hipopotassemia/metabolismo , Hipopotassemia/terapia , Hipofosfatemia/induzido quimicamente , Hipofosfatemia/metabolismo , Hipofosfatemia/terapia , Masculino , Pessoa de Meia-Idade , Proteinúria/induzido quimicamente , Proteinúria/metabolismo , Proteinúria/terapia , Tenofovir/efeitos adversosAssuntos
Compostos Benzidrílicos/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Idoso , Compostos Benzidrílicos/efeitos adversos , Compostos Benzidrílicos/uso terapêutico , Diástole/efeitos dos fármacos , Diurese/efeitos dos fármacos , Feminino , Glucosídeos/efeitos adversos , Glucosídeos/uso terapêutico , Glicosúria/induzido quimicamente , Insuficiência Cardíaca/prevenção & controle , Insuficiência Cardíaca/psicologia , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , Hospitalização/estatística & dados numéricos , Humanos , Falência Renal Crônica/prevenção & controle , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Miocárdio/metabolismo , Natriurese/efeitos dos fármacos , Resistência Física/efeitos dos fármacos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Teste de Caminhada/métodosRESUMO
OBJECTIVE: Sodium-glucose cotransporter 2 (SGLT2) inhibition causes an increase in endogenous glucose production (EGP). However, the mechanisms are unclear. We studied the effect of SGLT2 inhibitors on EGP in subjects with type 2 diabetes (T2D) and without diabetes (non-DM) in kidney transplant recipients with renal denervation. RESEARCH DESIGN AND METHODS: Fourteen subjects who received a renal transplant (six with T2D [A1C 7.2 ± 0.1%] and eight non-DM [A1C 5.6 ± 0.1%) underwent measurement of EGP with [3-3H]glucose infusion following dapagliflozin (DAPA) 10 mg or placebo. Plasma glucose, insulin, C-peptide, glucagon, and titrated glucose-specific activity were measured. RESULTS: Following placebo in T2D, fasting plasma glucose (FPG) (143 ± 14 to 124 ± 10 mg/dL; P = 0.02) and fasting plasma insulin (12 ± 2 to 10 ± 1.1 µU/mL; P < 0.05) decreased; plasma glucagon was unchanged, and EGP declined. After DAPA in T2D, FPG (143 ± 15 to 112 ± 9 mg/dL; P = 0.01) and fasting plasma insulin (14 ± 3 to 11 ± 2 µU/mL; P = 0.02) decreased, and plasma glucagon increased (all P < 0.05 vs. placebo). EGP was unchanged from baseline (2.21 ± 0.19 vs. 1.96 ± 0.14 mg/kg/min) in T2D (P < 0.001 vs. placebo). In non-DM following DAPA, FPG and fasting plasma insulin decreased, and plasma glucagon was unchanged. EGP was unchanged from baseline (1.85 ± 0.10 to 1.78 ± 0.10 mg/kg/min) after DAPA, whereas EGP declined significantly with placebo. When the increase in EGP production following DAPA versus placebo was plotted against the difference in urinary glucose excretion (UGE) for all patients, a strong correlation (r = 0.824; P < 0.001) was observed. CONCLUSIONS: Renal denervation in patients who received a kidney transplant failed to block the DAPA-mediated stimulation of EGP in both individuals with T2D and non-DM subjects. The DAPA-stimulated rise in EGP is strongly related to the increase in UGE, blunting the decline in FPG.
Assuntos
Denervação , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucose/metabolismo , Glicosúria/urina , Rim/inervação , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Compostos Benzidrílicos/farmacologia , Compostos Benzidrílicos/uso terapêutico , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/cirurgia , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/cirurgia , Jejum/sangue , Feminino , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Glicosúria/induzido quimicamente , Glicosúria/metabolismo , Humanos , Rim/cirurgia , Transplante de Rim , Masculino , Pessoa de Meia-Idade , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , TransplantadosRESUMO
OBJECTIVE: To examine the effect of combination therapy with canagliflozin plus liraglutide on HbA1c, endogenous glucose production (EGP), and body weight versus each therapy alone. RESEARCH DESIGN AND METHODS: Forty-five patients with poorly controlled (HbA1c 7-11%) type 2 diabetes mellitus (T2DM) on metformin with or without sulfonylurea received a 9-h measurement of EGP with [3-3H]glucose infusion, after which they were randomized to receive 1) liraglutide 1.2 mg/day (LIRA), 2) canagliflozin 100 mg/day (CANA), or 3) liraglutide 1.2 mg plus canagliflozin 100 mg (CANA/LIRA) for 16 weeks. At 16 weeks, the EGP measurement was repeated. RESULTS: The mean decrease from baseline to 16 weeks in HbA1c was -1.67 ± 0.29% (P = 0.0001), -0.89 ± 0.24% (P = 0.002), and -1.44 ± 0.39% (P = 0.004) in patients receiving CANA/LIRA, CANA, and LIRA, respectively. The decrease in body weight was -6.0 ± 0.8 kg (P < 0.0001), -3.5 ± 0.5 kg (P < 0.0001), and -1.9 ± 0.8 kg (P = 0.03), respectively. CANA monotherapy caused a 9% increase in basal rate of EGP (P < 0.05), which was accompanied by a 50% increase (P < 0.05) in plasma glucagon-to-insulin ratio. LIRA monotherapy reduced plasma glucagon concentration and inhibited EGP. In CANA/LIRA-treated patients, EGP increased by 15% (P < 0.05), even though the plasma insulin response was maintained at baseline and the CANA-induced rise in plasma glucagon concentration was blocked. CONCLUSIONS: These results demonstrate that liraglutide failed to block the increase in EGP caused by canagliflozin despite blocking the rise in plasma glucagon and preventing the decrease in plasma insulin concentration caused by canagliflozin. The failure of liraglutide to prevent the increase in EGP caused by canagliflozin explains the lack of additive effect of these two agents on HbA1c.
Assuntos
Canagliflozina/administração & dosagem , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hemoglobinas Glicadas/efeitos dos fármacos , Liraglutida/administração & dosagem , Redução de Peso/efeitos dos fármacos , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Canagliflozina/efeitos adversos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/urina , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Hemoglobinas Glicadas/metabolismo , Controle Glicêmico , Glicosúria/induzido quimicamente , Glicosúria/urina , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Liraglutida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Selective inhibitors of sodium-glucose cotransporter belong to a new class of drugs for the treatment of type 2 diabetes mellitus. The mechanism of their action is based on insulin-independent reduction of glucose reabsorption in the proximal renal tubules, which leads to stimulation of its excretion in the urine and, accordingly, to a decrease in the concentration of glucose in the blood plasma. Drugs of this group demonstrate effectiveness in the treatment of type 2 diabetes, but their use may be associated with an increased frequency of urinary tract infections. Pharmacological glucosuria, which leads to a decrease in the concentration of glucose in the blood, creates the preconditions for the occurrence of urinary tract infections. Urinary tract and genital infections are the most common adverse events associated with the use of sodium-glucose cotransporter inhibitors. In the presented literature review for 20162019, the relationship between urinary tract infections in patients with type 2 diabetes mellitus and therapy with sodium-glucose cotransporter inhibitors was analyzed.
Assuntos
Diabetes Mellitus Tipo 2 , Glicosúria , Inibidores do Transportador 2 de Sódio-Glicose , Infecções Urinárias , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glicosúria/induzido quimicamente , Humanos , Hipoglicemiantes/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Infecções Urinárias/tratamento farmacológicoAssuntos
Acidose , Canagliflozina , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cetoacidose Diabética , Hidratação/métodos , Glucose , Glicosúria , Equilíbrio Ácido-Base , Acidose/sangue , Acidose/diagnóstico , Acidose/etiologia , Acidose/terapia , Bicarbonatos/sangue , Canagliflozina/administração & dosagem , Canagliflozina/efeitos adversos , Cetoacidose Diabética/induzido quimicamente , Cetoacidose Diabética/diagnóstico , Cetoacidose Diabética/fisiopatologia , Diagnóstico Diferencial , Feminino , Glucose/análise , Glucose/metabolismo , Glucose/uso terapêutico , Glicosúria/induzido quimicamente , Glicosúria/diagnóstico , Humanos , Pessoa de Meia-Idade , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Resultado do TratamentoRESUMO
Hexachlorobutadien is nephrotoxic agent in rodents. The mechanism of toxicity includes generation of free radicals, depletion of thiol groups and production of toxic metabolites. Antioxidant compounds may reduce HCBD-nephrotoxicity. In this research we investigated the effect of Rheum turkeatanicum extract against HCBD-toxicity. The animals were divided to 4 groups which were including control (saline, 1 mL/kg), HCBD (100 mg/kg) and treatment groups which received extract at doses 100 and 200 mg/kg. The extract were administered as intraperitoneally (i.p.) 1 h before HCBD injection (i.p.). The animals were anesthetized by ether, 24 h after HCBD administration. The results showed elevation of serum creatinine, serum urea, urinary protein, urinary glucose, malondialdehyde levels in kidney and reduction of thiol in kidney by HCBD. The histopathological studies showed that there was apoptosis and necrosis in HCBD treated groups. Administration of R.turkestanicum reduced HCBD toxicity. The extract reduced hitopathological changes in kidney. It may be concluded that the nephroprotective effect of extract may be due to different mechanisms such as antioxidant activity or by decreasing the toxic metabolites of HCBD or inhibition of enzymes which are involved in the bioactivation of HCBD such as glutathione-S-transferase (GST) or cysteine-S-conjugate ß-lyase.