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1.
BMJ ; 369: m1186, 2020 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-32349963

RESUMO

OBJECTIVE: To assess the association between use of sodium-glucose co-transporter 2 (SGLT2) inhibitors and risk of serious renal events in data from routine clinical practice. DESIGN: Cohort study using an active comparator, new user design and nationwide register data. SETTING: Sweden, Denmark, and Norway, 2013-18. PARTICIPANTS: Cohort of 29 887 new users of SGLT2 inhibitors (follow-up time: dapagliflozin 66.1%; empagliflozin 32.6%; canagliflozin 1.3%) and 29 887 new users of an active comparator, dipeptidyl peptidase-4 inhibitors, matched 1:1 on the basis of a propensity score with 57 variables. Mean follow-up time was 1.7 (SD 1.0) years. EXPOSURES: SGLT2 inhibitors versus dipeptidyl peptidase-4 inhibitors, defined by filled prescriptions and analysed according to intention to treat. MAIN OUTCOME MEASURES: The main outcome was serious renal events, a composite including renal replacement therapy, death from renal causes, and hospital admission for renal events. Secondary outcomes were the individual components of the main outcome. RESULTS: The mean age of the study population was 61.3 (SD 10.5) years; 11 108 (19%) had cardiovascular disease, and 1974 (3%) had chronic kidney disease. Use of SGLT2 inhibitors, compared with dipeptidyl peptidase-4 inhibitors, was associated with a reduced risk of serious renal events (2.6 events per 1000 person years versus 6.2 events per 1000 person years; hazard ratio 0.42 (95% confidence interval 0.34 to 0.53); absolute difference -3.6 (-4.4 to -2.8) events per 1000 person years). In secondary outcome analyses, the hazard ratio for use of SGLT2 inhibitors versus dipeptidyl peptidase-4 inhibitors was 0.32 (0.22 to 0.47) for renal replacement therapy, 0.41 (0.32 to 0.52) for hospital admission for renal events, and 0.77 (0.26 to 2.23) for death from renal causes. In sensitivity analyses in each of the Swedish and Danish parts of the cohort, the model was further adjusted for glycated haemoglobin and estimated glomerular filtration rate (Sweden and Denmark) and for blood pressure, body mass index, and smoking (Sweden only); in these analyses, the hazard ratio moved from 0.41 (0.26 to 0.66) to 0.50 (0.31 to 0.81) in Sweden and from 0.42 (0.32 to 0.56) to 0.55 (0.41 to 0.74) in Denmark. CONCLUSIONS: In this analysis using nationwide data from three countries, use of SGLT2 inhibitors, compared with dipeptidyl peptidase-4 inhibitors, was associated with a significantly reduced risk of serious renal events.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Nefropatias/epidemiologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Lesão Renal Aguda/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Compostos Benzidrílicos/uso terapêutico , Canagliflozina/uso terapêutico , Doenças Cardiovasculares/epidemiologia , Estudos de Casos e Controles , Estudos de Coortes , Comorbidade , Dinamarca/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Glucosídeos/uso terapêutico , Hospitalização/estatística & dados numéricos , Humanos , Nefropatias/mortalidade , Nefropatias/terapia , Masculino , Pessoa de Meia-Idade , Noruega/epidemiologia , Modelos de Riscos Proporcionais , Insuficiência Renal Crônica/epidemiologia , Terapia de Substituição Renal/estatística & dados numéricos , Suécia/epidemiologia
3.
Life Sci ; 247: 117414, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32035928

RESUMO

AIMS: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been reported to significantly reduce body weight. This study investigated whether SGLT2 inhibitors directly affect adipose tissues and the underlying mechanisms in vivo and in vitro. MAIN METHODS: Male C57BL/6 mice were fed a normal diet, high-fat diet (HFD), or HFD with canagliflozin for 14 weeks. 3T3-L1 adipocytes were treated with canagliflozin. Metabolic parameters were measured. KEY FINDINGS: Canagliflozin reduced body weight, fat mass, and white adipose tissue (WAT) weight and inhibited adipocyte hypertrophy. Canagliflozin improved glucose and lipid metabolic disorders induced by HFD. Furthermore, canagliflozin treatment reversed the suppressed mRNA and protein expression of PGC-1α, NRF1, tfam and CPT1b, which are markers of mitochondrial biogenesis, function and fatty acid oxidation in mice with obesity. In vitro, canagliflozin increased mitochondrial DNA to nuclear DNA and upregulated the expression of PGC-1α, NRF1, tfam, COX5b, COX8b, Atp5o, and CPT1b mRNA and PGC-1α, NRF1, tfam, COX5b, CPT1b protein in 3T3-L1 adipocytes in a dose-dependent manner, while these increases were inhibited by GW6471, a PPARα antagonist. SIGNIFICANCE: Our study showed that canagliflozin protected against HFD-induced obesity and obesity-related metabolic disorders by improving mitochondrial function and fatty acid oxidation in adipose tissue and adipocytes. Such energy-dissipating effects of canagliflozin may be mediated by PPARα.


Assuntos
Canagliflozina/uso terapêutico , Ácidos Graxos/metabolismo , Mitocôndrias/metabolismo , Obesidade/tratamento farmacológico , PPAR alfa/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Células 3T3-L1 , Adipócitos/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Canagliflozina/farmacologia , Dieta Hiperlipídica , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , PPAR alfa/genética , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
4.
Rev Assoc Med Bras (1992) ; 66Suppl 1(Suppl 1): s17-s24, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31939531

RESUMO

Type 2 diabetes mellitus is an important public health problem, with a significant impact on cardiovascular morbidity and mortality and an important risk factor for chronic kidney disease. Various hypoglycemic therapies have proved to be beneficial to clinical outcomes, while others have failed to provide an improvement in cardiovascular and renal failure, only reducing blood glucose levels. Recently, sodium-glucose cotransporter-2 (SGLT2) inhibitors, represented by the empagliflozin, dapagliflozin, and canagliflozin, have been showing satisfactory and strong results in several clinical trials, especially regarding the reduction of cardiovascular mortality, reduction of hospitalization due to heart failure, reduction of albuminuria, and long-term maintenance of the glomerular filtration rate. The benefit from SGLT2 inhibitors stems from its main mechanism of action, which occurs in the proximal tubule of the nephron, causing glycosuria, and a consequent increase in natriuresis. This leads to increased sodium intake by the juxtaglomerular apparatus, activating the tubule glomerular-feedback and, finally, reducing intraglomerular hypertension, a frequent physiopathological condition in kidney disease caused by diabetes. In addition, this class of medication presents an appropriate safety profile, and its most frequently reported complication is an increase in the incidence of genital infections. Thus, these hypoglycemic agents gained space in practical recommendations for the management of type 2 diabetes mellitus and should be part of the initial therapeutic approach to provide, in addition to glycemic control, cardiovascular outcomes, and the renoprotection in the long term.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Nefropatias/prevenção & controle , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Transportador 2 de Glucose-Sódio/farmacologia , Compostos Benzidrílicos/uso terapêutico , Canagliflozina/uso terapêutico , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/mortalidade , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/prevenção & controle , Taxa de Filtração Glomerular , Glucose/metabolismo , Glucosídeos/uso terapêutico , Humanos , Hipoglicemiantes/uso terapêutico , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/fisiopatologia , Nefropatias/etiologia , Nefropatias/metabolismo , Transportador 2 de Glucose-Sódio/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
5.
Int J Clin Pharmacol Ther ; 58(1): 57-65, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31347489

RESUMO

OBJECTIVE: This study was conducted to evaluate the pharmacokinetic properties and bioequivalence of two oral formulations of canagliflozin: a newly developed generic formulation (test) and a branded formulation (reference). MATERIALS AND METHODS: A randomized, open-label, two-way crossover study was conducted in 55 healthy Chinese subjects. They were randomized to receive a single oral dose of 100 mg of test or reference canagliflozin tablets according to an open crossover design under fasting and fed states. Plasma canagliflozin concentrations were determined by liquid chromatography-tandem mass spectrometry, and the pharmacokinetic parameters maximum concentration (Cmax) and area under the concentration-time curve (AUC0-t and AUC0-∞) were used to evaluate bioequivalence. RESULTS: The geometric mean ratio 90% confidence intervals for fasting Cmax, AUC0-t, and AUC0-∞ were 85.14 - 114.40%, 102.14 - 106.51%, and 102.21 - 106.85%, respectively, and fed Cmax, AUC0-t, and AUC0-∞ were 90.15 - 107.17%, 97.38 - 102.19%, and 96.78 - 101.92%, respectively. The mean values of tmax were prolonged in the test compared with the reference formulations. In addition, the mean values of tmax and Cmax for both formulations were significantly different under fed compared with fasting conditions, while there was no significant difference in AUC0-t or AUC0-∞. CONCLUSION: The two types of canagliflozin tablets were bioequivalent under both fasting and fed states, and both were generally well tolerated.


Assuntos
Canagliflozina/administração & dosagem , Canagliflozina/farmacocinética , Administração Oral , Área Sob a Curva , Cromatografia Líquida , Estudos Cross-Over , Humanos , Comprimidos , Equivalência Terapêutica
6.
PLoS Med ; 16(12): e1002983, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31815931

RESUMO

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2is) represent a new class of oral hypoglycemic agents used in the treatment of type 2 diabetes mellitus. They have a positive effect on the progression of chronic kidney disease, but there is a concern that they might cause acute kidney injury (AKI). METHODS AND FINDINGS: We conducted a systematic review and meta-analysis of the effect of SGLT2is on renal adverse events (AEs) in randomized controlled trials and controlled observational studies. PubMed, EMBASE, Cochrane library, and ClinicalTrials.gov were searched without date restriction until 27 September 2019. Data extraction was performed using a standardized data form, and any discrepancies were resolved by consensus. One hundred and twelve randomized trials (n = 96,722) and 4 observational studies with 5 cohorts (n = 83,934) with a minimum follow-up of 12 weeks that provided information on at least 1 adverse renal outcome (AKI, combined renal AE, or hypovolemia-related events) were included. In 30 trials, 410 serious AEs due to AKI were reported. SGLT2is reduced the odds of suffering AKI by 36% (odds ratio [OR] 0.64 [95% confidence interval (CI) 0.53-0.78], p < 0.001). A total of 1,089 AKI events of any severity (AEs and serious AEs [SAEs]) were published in 41 trials (OR 0.75 [95% CI 0.66-0.84], p < 0.001). Empagliflozin, dapagliflozin, and canagliflozin had a comparable benefit on the SAE and AE rate. AEs related to hypovolemia were more commonly reported in SGLT2i-treated patients (OR 1.20 [95% CI 1.10-1.31], p < 0.001). In the observational studies, 777 AKI events were reported. The odds of suffering AKI were reduced in patients receiving SGLT2is (OR 0.40 [95% CI 0.33-0.48], p < 0.001). Limitations of this study are the reliance on nonadjudicated safety endpoints, discrepant inclusion criteria and baseline hypoglycemic therapy between studies, inconsistent definitions of renal AEs and hypovolemia, varying follow-up times in different studies, and a lack of information on the severity of AKI (stages I-III). CONCLUSIONS: SGLT2is reduced the odds of suffering AKI with and without hospitalization in randomized trials and the real-world setting, despite the fact that more AEs related to hypovolemia are reported.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Compostos Benzidrílicos/uso terapêutico , Canagliflozina/uso terapêutico , Diabetes Mellitus Tipo 2/induzido quimicamente , Glucosídeos/uso terapêutico , Humanos , Hipoglicemiantes/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
9.
Rev Med Liege ; 74(10): 508-513, 2019 Oct.
Artigo em Francês | MEDLINE | ID: mdl-31609553

RESUMO

Canagliflozin, a sodium-glucose cotransporter type 2 inhibitor, has been evaluated in two large clinical trials, CANVAS that focused on cardiovascular (CV) risk and CREDENCE that focused on renal risk. CANVAS recruited type 2 diabetic patients (T2D) at high CV risk (65 % in secondary prevention) and demonstrated that canagliflozin significantly reduces major CV events, hospitalisations for heart failure and renal outcomes when compared to placebo. CREDENCE specifically enrolled T2D patients with albuminuric renal disease (50 % in secondary CV prevention). This trial confirmed the cardiovascular protection reported in CANVAS with canagliflozin and more specifically demonstrated a renal protection, including a reduced progression towards end-stage renal disease, in this particular population. Finally, CREDENCE did not observe the increased risk for bone fractures and lower-limb amputations previously reported in CANVAS. Globally, these two studies emphasize a favourable benefit/risk balance of canagliflozin in a T2D population at CV or renal risk, including in patients with a glomerular filtration rate comprised between 30 et 60 ml/min/1.73 m².


Assuntos
Canagliflozina , Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Inibidores do Transportador 2 de Sódio-Glicose , Canagliflozina/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Taxa de Filtração Glomerular , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
10.
Int J Clin Pharmacol Ther ; 57(12): 590-595, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31587751

RESUMO

OBJECTIVES: This aim of this study is to investigate the regulation of serum uric acid (SUA) levels with canagliflozin in relation to diabetic parameters. MATERIALS AND METHODS: Drug-naïve subjects with type 2 diabetes (T2DM) received 50 - 100 mg/day canagliflozin monotherapy (n = 40) for 3 months. Levels of SUA and some diabetic parameters were monitored. RESULTS: In the overall subjects, significant negative correlations were observed between the changes (Δ) of SUA and the baseline SUA levels (R = -0.392, p < 0.02). The subjects were divided into two subgroups (n = 20 each) according to the changes of SUA levels (above the median (group A): from 4.79 ± 1.22 to 5.34 ± 1.39 mg/dL; and below the median (group B): from 5.80 ± 1.08 to 4.98 ± 0.97 mg/dL). Significant increases of SUA levels were observed in group A (11.4%, p < 0.0002), while significant decreases of SUA levels were seen in group B (-14.1%, p < 0.00001). Significant correlations were seen between the baseline levels of SUA and those of homeostasis model assessment (HOMA)-B (R = 0.463, p < 0.04) and between the changes of SUA and those of HOMA-B (R = 0.420, p < 0.05) only in group A. Higher degrees of elevations of HOMA-B and decreases of HbA1c/fasting blood glucose (FBG) were seen in group A versus group B. CONCLUSION: These results suggest that 1) high SUA levels decreased while low SUA levels increased with canagliflozin; 2) better glycemic efficacies and higher degrees of enhancement of ß-cell function were observed in those with elevated SUA levels with canagliflozin; 3) SUA might be linked to modulation of ß-cell function.


Assuntos
Canagliflozina/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Células Secretoras de Insulina/fisiologia , Ácido Úrico/sangue , Glicemia , Humanos
11.
J Assoc Physicians India ; 67(10): 36-38, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31571450

RESUMO

Objective: Canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, has been associated with HbA1c reduction and weight loss in a broad range of patients with type 2 diabetes mellitus (T2DM). This analysis evaluated changes in HbA1c and body weight in patients who were inadequately responding to maximum dose of three oral hypoglycemic agents and reluctant to take insulin therapy. Methods: In this open label interventional single arm study, patients aged 18 to 65 years (N=118) received Canagliflozin 100 mg for in addition to an ongoing triple drug oral hypoglycemic agents (OHA) regimen for a period of 12 weeks. The said population was inadequately responding to maximum dose of three oral hypoglycemic agents and was reluctant to take insulin therapy. Percent change from baseline in HbA1c and body weight was evaluated in the study. Results: Canagliflozin 100 mg additional dose above a triple OHA provided significant HbA1c reduction by 1.9% and weight reduction by 3.01kg over 12 weeks from baseline. Canagliflozin was generally well tolerated, with 2.54% of the patient population reporting Urinary tract infection (UTI) who were withdrawn from study and given appropriate treatment. Conclusion: Canagliflozin 100 mg (One tablet) administered to patients in addition to the inadequately controlled triple drug OHAs who were reluctant for an insulin therapy provided a significant reduction in HbA1c and body weight over 12 weeks. Canagliflozin a SGLT 2 inhibitor is a promising new drug in patients with T2DM in patients who are inadequately controlled on triple therapy and are reluctant to insulin therapy.


Assuntos
Canagliflozina/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Adolescente , Adulto , Idoso , Humanos , Hipoglicemiantes , Pessoa de Meia-Idade , Adulto Jovem
17.
Internist (Berl) ; 60(9): 903-911, 2019 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-31375850

RESUMO

BACKGROUND: Inhibitors of sodium-glucose cotransporters type 2 (SGLT-2) are a class of oral antidiabetic drugs with a novel specific mode of action in the kidneys. OBJECTIVE: The effects of SGLT-2 inhibitors on cardiovascular (CV) and renal endpoints in outcome trials with type 2 diabetes patients. MATERIAL AND METHODS: Differential analysis and interpretation of the results of outcome trials with the SGLT-2 inhibitors empagliflozin, canagliflozin and dapagliflozin in type 2 diabetes mellitus. RESULTS: In the EMPA-REG OUTCOME trial, empagliflozin demonstrated a significant reduction in major cardiac adverse events (MACE), hospitalization for heart failure (HHI), renal endpoints, CV and total mortality vs. placebo in >7000 patients with type 2 diabetes and established CV disease over 3.1 years. In the CANVAS program, canagliflozin demonstrated a significant reduction of MACE, HHI and renal endpoints vs. placebo in >10,000 patients with type 2 diabetes and high CV risk over 2.4 years. In the CREDENCE trial, canagliflozin demonstrated a significant reduction of a combined renal endpoint and CV endpoints vs. placebo in >4000 patients with type 2 diabetes and established kidney disease with albuminuria over 2.6 years. In the DECLARE-TIMI 58 trial, dapagliflozin demonstrated a significant reduction in a combined endpoint of CV death and HHI vs. placebo in >17,000 patients with type 2 diabetes and established CV disease or with multiple CV risk factors over 3.1 years. CONCLUSION: Outcome trials with SGLT-2 inhibitors have collectively demonstrated cardioprotective and nephroprotective effects in patients with type 2 diabetes and high CV risk. The use of SGLT-2 inhibitors is recommended in current guidelines and consensus statements as primary combination partners for metformin in patients with type 2 diabetes and established CV disease, high CV risk, heart failure or kidney disease.


Assuntos
Canagliflozina/uso terapêutico , Doenças Cardiovasculares/fisiopatologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/terapia , Nefropatias/fisiopatologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Canagliflozina/efeitos adversos , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Hipoglicemiantes/uso terapêutico , Guias de Prática Clínica como Assunto , Transportador 2 de Glucose-Sódio/efeitos dos fármacos , Transportador 2 de Glucose-Sódio/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Resultado do Tratamento
20.
Phytother Res ; 33(10): 2518-2530, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31359514

RESUMO

Diabetes mellitus currently affects as many as 400 million people worldwide, creating a heavy economic burden and stretching health care resources. A dysfunction of glucose homeostasis underlies the disease. Despite advances in the treatment of diabetes, many patients still suffer from complications and side effects; hence, development of more effective treatments for diabetes is still desirable. SGLT2 is the principle cotransporter involved in glucose reabsorption in the kidney. SGLT2 inhibition reduces glucose reabsorption by the kidney and ameliorates plasma glucose concentration. The interest in natural products that can be used for the inhibition of SGLT2 is growing. The flavonoid phlorizin, which can be isolated from the bark of apple trees, has been used as lead structure due to its inhibitory activity of SGLT1 and SGLT2. Some phlorizin-derived synthetic compounds, including canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, and ertugliflozin, are approved by the food and drug administration to treat type 2 diabetes mellitus (T2DM), whereas others are under clinical trials investigation. In addition, other natural product-derived compounds have been investigated for their ability to improve blood glucose control. The present review summarizes the natural products with SGLT2 inhibitory activity, and the synthetic compounds obtained from them, and discusses their application for the treatment of diabetes.


Assuntos
Produtos Biológicos/uso terapêutico , Diabetes Mellitus/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Compostos Benzidrílicos/uso terapêutico , Canagliflozina/uso terapêutico , Glucosídeos/uso terapêutico , Humanos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Tiofenos/uso terapêutico
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