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1.
Value Health ; 23(9): 1163-1170, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32940234

RESUMO

OBJECTIVES: The cardiovascular outcomes challenge examined the predictive accuracy of 10 diabetes models in estimating hard outcomes in 2 recent cardiovascular outcomes trials (CVOTs) and whether recalibration can be used to improve replication. METHODS: Participating groups were asked to reproduce the results of the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) and the Canagliflozin Cardiovascular Assessment Study (CANVAS) Program. Calibration was performed and additional analyses assessed model ability to replicate absolute event rates, hazard ratios (HRs), and the generalizability of calibration across CVOTs within a drug class. RESULTS: Ten groups submitted results. Models underestimated treatment effects (ie, HRs) using uncalibrated models for both trials. Calibration to the placebo arm of EMPA-REG OUTCOME greatly improved the prediction of event rates in the placebo, but less so in the active comparator arm. Calibrating to both arms of EMPA-REG OUTCOME individually enabled replication of the observed outcomes. Using EMPA-REG OUTCOME-calibrated models to predict CANVAS Program outcomes was an improvement over uncalibrated models but failed to capture treatment effects adequately. Applying canagliflozin HRs directly provided the best fit. CONCLUSIONS: The Ninth Mount Hood Diabetes Challenge demonstrated that commonly used risk equations were generally unable to capture recent CVOT treatment effects but that calibration of the risk equations can improve predictive accuracy. Although calibration serves as a practical approach to improve predictive accuracy for CVOT outcomes, it does not extrapolate generally to other settings, time horizons, and comparators. New methods and/or new risk equations for capturing these CV benefits are needed.


Assuntos
Modelos Econômicos , Avaliação de Resultados em Cuidados de Saúde/métodos , Compostos Benzidrílicos/uso terapêutico , Calibragem , Canagliflozina/uso terapêutico , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/uso terapêutico , Humanos , Medição de Risco , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
2.
Lancet ; 396(10254): 819-829, 2020 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-32877652

RESUMO

BACKGROUND: Both DAPA-HF (assessing dapagliflozin) and EMPEROR-Reduced (assessing empagliflozin) trials showed that sodium-glucose co-transporter-2 (SGLT2) inhibition reduced the combined risk of cardiovascular death or hospitalisation for heart failure in patients with heart failure with reduced ejection fraction (HFrEF) with or without diabetes. However, neither trial was powered to assess effects on cardiovascular death or all-cause death or to characterise effects in clinically important subgroups. Using study-level published data from DAPA-HF and patient-level data from EMPEROR-Reduced, we aimed to estimate the effect of SGLT2 inhibition on fatal and non-fatal heart failure events and renal outcomes in all randomly assigned patients with HFrEF and in relevant subgroups from DAPA-HF and EMPEROR-Reduced trials. METHODS: We did a prespecified meta-analysis of the two single large-scale trials assessing the effects of SGLT2 inhibitors on cardiovascular outcomes in patients with HFrEF with or without diabetes: DAPA-HF (assessing dapagliflozin) and EMPEROR-Reduced (assessing empagliflozin). The primary endpoint was time to all-cause death. Additionally, we assessed the effects of treatment in prespecified subgroups on the combined risk of cardiovascular death or hospitalisation for heart failure. These subgroups were based on type 2 diabetes status, age, sex, angiotensin receptor neprilysin inhibitor (ARNI) treatment, New York Heart Association (NYHA) functional class, race, history of hospitalisation for heart failure, estimated glomerular filtration rate (eGFR), body-mass index, and region (post-hoc). We used hazard ratios (HRs) derived from Cox proportional hazard models for time-to-first event endpoints and Cochran's Q test for treatment interactions; the analysis of recurrent events was based on rate ratios derived from the Lin-Wei-Yang-Ying model. FINDINGS: Among 8474 patients combined from both trials, the estimated treatment effect was a 13% reduction in all-cause death (pooled HR 0·87, 95% CI 0·77-0·98; p=0·018) and 14% reduction in cardiovascular death (0·86, 0·76-0·98; p=0·027). SGLT2 inhibition was accompanied by a 26% relative reduction in the combined risk of cardiovascular death or first hospitalisation for heart failure (0·74, 0·68-0·82; p<0·0001), and by a 25% decrease in the composite of recurrent hospitalisations for heart failure or cardiovascular death (0·75, 0·68-0·84; p<0·0001). The risk of the composite renal endpoint was also reduced (0·62, 0·43-0·90; p=0·013). All tests for heterogeneity of effect size between trials were not significant. The pooled treatment effects showed consistent benefits for subgroups based on age, sex, diabetes, treatment with an ARNI and baseline eGFR, but suggested treatment-by-subgroup interactions for subgroups based on NYHA functional class and race. INTERPRETATION: The effects of empagliflozin and dapagliflozin on hospitalisations for heart failure were consistent in the two independent trials and suggest that these agents also improve renal outcomes and reduce all-cause and cardiovascular death in patients with HFrEF. FUNDING: Boehringer Ingelheim.


Assuntos
Compostos Benzidrílicos/efeitos adversos , Glucosídeos/efeitos adversos , Insuficiência Cardíaca/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Volume Sistólico/efeitos dos fármacos , Idoso , Antagonistas de Receptores de Angiotensina/uso terapêutico , Compostos Benzidrílicos/uso terapêutico , Índice de Massa Corporal , Estudos de Casos e Controles , Causas de Morte/tendências , Ensaios Clínicos como Assunto , Morte , Diabetes Mellitus Tipo 2/complicações , Quimioterapia Combinada , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Taxa de Filtração Glomerular/fisiologia , Glucosídeos/uso terapêutico , Insuficiência Cardíaca/classificação , Insuficiência Cardíaca/fisiopatologia , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Neprilisina/antagonistas & inibidores , Avaliação de Resultados da Assistência ao Paciente , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
3.
Lancet Diabetes Endocrinol ; 8(10): 845-854, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32946821

RESUMO

BACKGROUND: The DEPICT-1 and DEPICT-2 studies showed that dapagliflozin as an adjunct to insulin in individuals with inadequately controlled type 1 diabetes improved glycaemic control and bodyweight, without increase in risk of hypoglycaemia. We aimed to determine the effect of dapagliflozin on urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) using pooled data from the DEPICT studies. METHODS: In this post-hoc analysis, we used data pooled from both DEPICT studies (DEPICT-1 ran from Nov 11, 2014, to Aug 25, 2017; DEPICT-2 ran from July 8, 2015, to April 18, 2018), in which participants were aged 18-75 years, with inadequately controlled type 1 diabetes and with a baseline UACR of at least 30 mg/g. In the DEPICT studies, participants were randomly assigned (1:1:1) to receive dapagliflozin (5 mg or 10 mg) or placebo all plus insulin, for 24 weeks, with a 28-week long-term extension (ie, 52 weeks in total). In this post-hoc analysis, we assessed the percentage change from baseline in UACR and in eGFR, up to 52 weeks. UACR, eGFR, and safety were assessed in all eligible participants who had received at least one dose of study drug. HbA1c, bodyweight, and systolic blood pressure were assessed in all participants who received at least one dose of study drug during the first 24-week period, and who had a baseline and any post-baseline assessment for that parameter. The DEPICT trials were registered with ClinicalTrials.gov, NCT02268214 (DEPICT-1), NCT02460978 (DEPICT-2), and are now complete. RESULTS: 251 participants with albuminuria at baseline were included in this post-hoc analysis; of whom 80 (32%) had been randomly assigned to dapagliflozin 5 mg, 84 (33%) to dapagliflozin 10 mg, and 87 (35%) to placebo. Compared with placebo, treatment with both dapagliflozin doses improved UACR over 52 weeks. At week 52, mean difference in change from baseline versus placebo in UACR was -13·3% (95% CI -37·2 to 19·8) for dapagliflozin 5 mg and -31·1% (-49·9 to -5·2) for dapagliflozin 10 mg. No notable change from baseline was seen in eGFR, with a mean difference in change from baseline versus placebo of 3·27 mL/min per 1·73 m2 (95% CI -0·92 to 7·45) for dapagliflozin 5 mg and 2·12 mL/min per 1·73 m2 (-2·03 to 6·27) for dapagliflozin 10 mg. Similar proportions of participants in each treatment group had adverse events and serious adverse events, including hypoglycaemia and diabetic ketoacidosis; no new safety signals were identified in this population. INTERPRETATION: Treatment with dapagliflozin resulted in UACR reduction, which might provide renoprotective benefits in individuals with type 1 diabetes and albuminuria. Dedicated prospective studies are needed to confirm these findings as prespecified endpoints. FUNDING: AstraZeneca.


Assuntos
Albuminúria/prevenção & controle , Compostos Benzidrílicos/uso terapêutico , Biomarcadores/análise , Diabetes Mellitus Tipo 1/tratamento farmacológico , Cetoacidose Diabética/prevenção & controle , Glucosídeos/uso terapêutico , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Adolescente , Adulto , Idoso , Glicemia/análise , Creatinina/sangue , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Seguimentos , Taxa de Filtração Glomerular , Hemoglobina A Glicada/análise , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Adulto Jovem
4.
Medicine (Baltimore) ; 99(39): e22224, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32991416

RESUMO

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by erosion of joints and surrounding tissues. RA not only causes the decline of patients' physical function and quality of life, but also brings huge economic burden to patients' families and society. Total glucosides of paeony (TGP) is commonly used in treating RA in China. At present, there are many clinical reports about this medicine, but these reports have their own flaws. Therefore, there is an urgent need for systematic review and meta-analysis of the existing clinical evidence. METHODS AND ANALYSIS: Literature search will be carried out in 6 databases, and the literatures will be screened according to the inclusion and exclusion criteria. The clinical effective rate will be taken as primary outcome. Serum rheumatoid factor, C-reactive protein, erythrocyte sedimentation rate, Western Ontario and McMaster before and after treatment and adverse effects will be secondary outcomes. The heterogeneity of the study will be examined by χ and I test. To identify the source of heterogeneity, subgroup analysis will be carried out. The sensitivity test will be conducted investigate the stability of results. Funnel plot and Egger test will be used to evaluate publication bias. Finally, the quality of evidence will be summarized. RESULTS: The results will be published in peer-reviewed journals. CONCLUSIONS: This study will systematically evaluate the efficacy of TGP in the treatment of RA. The results of this study can better guide clinical practice. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/85QVF.


Assuntos
Artrite Reumatoide/terapia , Medicamentos de Ervas Chinesas/uso terapêutico , Glucosídeos/uso terapêutico , Paeonia , Humanos , Metanálise como Assunto , Revisões Sistemáticas como Assunto
5.
Medicine (Baltimore) ; 99(30): e21409, 2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32791755

RESUMO

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.


Assuntos
Adamantano/análogos & derivados , Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptídeos/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Glucosídeos/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Adamantano/farmacologia , Adamantano/uso terapêutico , Glicemia/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Dipeptídeos/farmacologia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Quimioterapia Combinada , Humanos , Hipoglicemiantes/uso terapêutico , Metformina/farmacologia , Metformina/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
6.
PLoS Comput Biol ; 16(8): e1008074, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32804929

RESUMO

Congestive heart failure is characterized by suppressed cardiac output and arterial filling pressure, leading to renal retention of salt and water, contributing to further volume overload. Mathematical modeling provides a means to investigate the integrated function and dysfunction of heart and kidney in heart failure. This study updates our previously reported integrated model of cardiac and renal functions to account for the fluid exchange between the blood and interstitium across the capillary membrane, allowing the simulation of edema. A state of heart failure with reduced ejection fraction (HF-rEF) was then produced by altering cardiac parameters reflecting cardiac injury and cardiovascular disease, including heart contractility, myocyte hypertrophy, arterial stiffness, and systemic resistance. After matching baseline characteristics of the SOLVD clinical study, parameters governing rates of cardiac remodeling were calibrated to describe the progression of cardiac hemodynamic variables observed over one year in the placebo arm of the SOLVD clinical study. The model was then validated by reproducing improvements in cardiac function in the enalapril arm of SOLVD. The model was then applied to prospectively predict the response to the sodium-glucose co-transporter 2 (SGLT2) inhibitor dapagliflozin, which has been shown to reduce heart failure events in HF-rEF patients in the recent DAPAHF clinical trial by incompletely understood mechanisms. The simulations predict that dapagliflozin slows cardiac remodeling by reducing preload on the heart, and relieves congestion by clearing interstitial fluid without excessively reducing blood volume. This provides a quantitative mechanistic explanation for the observed benefits of SGLT2i in HF-rEF. The model also provides a tool for further investigation of heart failure drug therapies.


Assuntos
Insuficiência Cardíaca/fisiopatologia , Rim/fisiopatologia , Modelos Cardiovasculares , Volume Sistólico/fisiologia , Compostos Benzidrílicos/uso terapêutico , Cardiomegalia/fisiopatologia , Líquido Extracelular/fisiologia , Glucosídeos/uso terapêutico , Coração/fisiopatologia , Insuficiência Cardíaca/tratamento farmacológico , Hemodinâmica/fisiologia , Humanos , Miócitos Cardíacos/fisiologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
7.
Life Sci ; 259: 118356, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32861798

RESUMO

Curculigoside (CUR) is natural ingredient from Curculigo orchioides Gaertn with multiple biological activities. However, whether CUR protects from ulcerative colitis (UC) and underlying mechanisms are unclear. Herein, mice challenged with dextran sulfate sodium (DSS) were established and administrated with CUR for 7 days. Then histological pathologies and ferroptosis regulators were determined in vivo. The ferroptotic IEC-6 cells were prepared to investigate the underlying mechanism of CUR. Results showed that CUR inhibited the disease activity index, histological damage and cell death in mice with colitis. We also found that ferroptosis was induced in mice with colitis, as evidenced by iron overload, GSH depletion, ROS and MDA production, accompanied by decreased expression of SOD and GPX4. CUR treatment significantly reversed these alterations of ferroptotic features in DSS-induced mice. Furthermore, similar effects of CUR on ferroptosis were observed in IEC-6 cells under the combined treatment of H2O2 and iron chloride hexahydrate. Interestingly, we found that CUR could increase the selenium sensitivity and promote GPX4 transcription level in IEC-6 cells. Knockdown of GPX4 significantly blocked the protective effects of CUR on cell death, GSH and MDA contents as well as LDH activity in ferroptotic IEC-6 cells. Taken together, these findings suggest that CUR protects against ferroptosis in UC by the induction of GPX4, which presents a potential agent for UC treatment.


Assuntos
Benzoatos/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Ferroptose/efeitos dos fármacos , Glucosídeos/uso terapêutico , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Animais , Western Blotting , Linhagem Celular , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Colo/química , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Ferro/análise , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Reação em Cadeia da Polimerase em Tempo Real
10.
Life Sci ; 258: 118158, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32750435

RESUMO

AIMS: Glioblastoma multiforme (GBM) is characterized by aggressive infiltration and terrible lethality. The overwhelming majority of chemotherapeutic drugs fail to exhibit the desired treatment effects. Polydatin (PD), which was initially extracted from Polygonum cuspidatum, is distinguished for its outstanding cardioprotective, hepatoprotective, and renal protective effects, as well as significant anticancer activities. However, the anti-GBM effect of PD is unclear. MATERIALS AND METHODS: Cell proliferation and apoptosis after PD intervention were estimated using MTT, colony formation and flow cytometry assays in vitro, while wound-healing and Transwell assays were applied to assess cell migration and invasion. In addition, the anti-GBM effects of PD in vivo were detected in the subcutaneous tumor model of nude mice. Moreover, Western blot, immunofluorescence and immunohistochemical staining assays were employed to elaborate the relevant molecular mechanisms. KEY FINDINGS: The present study demonstrated that PD repressed cell proliferation, migration, invasion and stemness and promoted apoptosis in GBM cells. Moreover, by correlating the molecular characteristics of cancer cells with different sensitivities to PD and employing diverse analytical methods, we ultimately verified that the cytotoxicity of PD was related to EGFR-AKT/ERK1/2/STAT3-SOX2/Snail signaling pathway inhibition, in which multiple components were vital therapeutic targets of GBM. SIGNIFICANCE: This work demonstrated that PD could inhibit proliferation, migration, invasion and stemness and induce apoptosis by restraining multiple components of the EGFR-AKT/ERK1/2/STAT3-SOX2/Snail signaling pathway in GBM cells.


Assuntos
Antineoplásicos/uso terapêutico , Glioblastoma/tratamento farmacológico , Glucosídeos/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Estilbenos/uso terapêutico , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Receptores ErbB/metabolismo , Glioblastoma/metabolismo , Glucosídeos/farmacologia , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fatores de Transcrição SOXB1/metabolismo , Fator de Transcrição STAT3/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Estilbenos/farmacologia
11.
Medicine (Baltimore) ; 99(27): e20936, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32629695

RESUMO

BACKGROUND: Hypertension is a common chronic disease and poses a huge burden to health care systems. Recent studies have shown that gastrodin injection (GI) has a potential supplementary therapeutic effect on hypertension. OBJECTIVES: To systematically assess the efficacy and safety of GI in treatment of hypertension. METHODS: Systematic search was conducted on 7 databases (PubMed, Cochrane Library, Embase, Wanfang database, China biomedical literature service system, VIP Chinese Sci-tech journal database and China national knowledge internet). The retrieval time was from the establishment of database to February 15, 2020. Two researchers independently selected literature, extracted data and evaluated the risk of bias in the study. The methodological quality was evaluated with Cochrane handbook. The meta-analysis was performed with Stata 14.0 software. RESULTS: Thirteen studies were included in this study involving 1525 patients. Compared with using conventional therapy alone, GI combined with conventional therapy can decrease systolic blood pressure (weighted mean difference [WMD] -6.67, 95% confidence interval [CI]: -10.30, -3.04. number of estimates [k] = 9, I = 89.3%), diastolic blood pressure (WMD -4.52, 95% CI: -7.79, -1.26. k = 9, I = 92.3%), and improve the clinical efficacy (relative risk [RR] 1.18, 95% CI: 1.10, 1.26. k = 6, I = 12.6%). CONCLUSIONS: The current evidence showed that GI combined with conventional therapy can improve systolic blood pressure, diastolic blood pressure and clinical efficacy. GI can become a supplementary treatment for hypertension.


Assuntos
Álcoois Benzílicos/uso terapêutico , Glucosídeos/uso terapêutico , Hipertensão/tratamento farmacológico , Álcoois Benzílicos/administração & dosagem , Pressão Sanguínea , Glucosídeos/administração & dosagem , Humanos , Injeções
13.
Diab Vasc Dis Res ; 17(4): 1479164120945674, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32722930

RESUMO

AIM: We examined eligibility and preventable cardiovascular disease events in US adults with diabetes mellitus from the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME). METHODS: We identified adults with diabetes mellitus eligible for EMPA-REG OUTCOME based on trial eligibility criteria available from the National Health and Nutrition Examination Surveys, 2007-2016. We estimated composite cardiovascular disease endpoints, as well as all-cause deaths, death from cardiovascular disease and hospitalizations for heart failure from trial treatment and placebo event rates, the difference indicating the preventable events. RESULTS: Among 29,629 US adults aged ⩾18 years (representing 231.9 million), 4672 (27.3 million) had diabetes mellitus, with 342 (1.86 million) meeting eligibility criteria of EMPA-REG OUTCOME. We estimated from trial primary endpoint event rates of 10.5% and 12.1% in the empagliflozin and placebo groups, respectively, that based on the 'treatment' of our 1.86 million estimated EMPA-REG OUTCOME eligible subjects, 12,066 (95% confidence interval: 10,352-13,780) cardiovascular disease events could be prevented annually. Estimated annual preventable deaths from any cause, cardiovascular causes and hospitalizations from heart failure were 17,078 (95% confidence interval: 14,652-19,504), 14,479 (95% confidence interval: 12,422-16,536) and 9467 (95% confidence interval: 8122-10,812), respectively. CONCLUSION: Empagliflozin, if provided to EMPA-REG OUTCOME eligible US adults, may prevent many cardiovascular disease events, cardiovascular and total deaths, as well as heart failure hospitalizations.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Tomada de Decisão Clínica , Diabetes Mellitus Tipo 2/tratamento farmacológico , Definição da Elegibilidade , Glucosídeos/uso terapêutico , Seleção de Pacientes , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Idoso , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/mortalidade , Ensaios Clínicos como Assunto , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/mortalidade , Progressão da Doença , Feminino , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/prevenção & controle , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos Nutricionais , Fatores de Proteção , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Estados Unidos/epidemiologia
14.
PLoS One ; 15(6): e0234065, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32502190

RESUMO

BACKGROUND: The association between sodium-glucose cotransporter 2 inhibitors (SGLT2i's) and lower extremity amputation is unclear. PURPOSE: To systematically review randomized control trials (RCTs) and observational studies quantifying risk of lower extremity amputations associated with SGLT2i use. DATA SOURCES AND STUDY SELECTION: We searched PubMed, EMBASE, Scopus, and the Cochrane Central Register of Controlled Trials from January 2011 to February 2020 for RCTs and observational studies including lower extremity amputation outcomes for individuals with type 2 diabetes mellitus treated with SGLT2i's vs. alternative treatments or placebo. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted data. MAIN OUTCOMES AND MEASURES: Our primary outcome was risk of lower limb amputation. Secondary outcomes included peripheral arterial disease, peripheral vascular disease, venous ulcerations, and diabetic foot infections. We also evaluated the risk of bias. We conducted random and fixed effects relative risk meta-analysis of RCTs. RESULTS: After screening 2,006 studies, 12 RCTs and 18 observational studies were included, of which 7 RCTs and 18 observational studies had at least one event. The random effects meta-analysis of 7 RCTs suggested the absence of a statistically significant association between SGLT2i exposure with evidence of substantial statistical heterogeneity (n = 424/23,716 vs n = 267/18,737 in controls; RR 1.28, CI's 0.93-1.76; I2 = 62.0%; p = 0.12) whereas fixed effects analysis showed an increased risk with statistical heterogeneity (RR 1.27, 1.09-1.48; I2 = 62%; p = 0.003). Subgroup analysis of canagliflozin vs placebo showed a statistically significantly increased risk in a fixed effects meta-analysis (n = 2 RCTs, RR 1.59, 1.26-2.01; I2 = 88%; p = 0.0001) whereas the meta-analysis of dapagliflozin or empagliflozin (n = 2 RCTs each) and a single RCT for ertugliflozin did not show a significantly increased risk. The findings from observational studies were too heterogeneous to be pooled in a meta-analysis and draw meaningful conclusions. Both randomized and observational studies were of generally good methodological quality. CONCLUSIONS: Overall, there was no consistent evidence of SGLT2i exposure and increased risk of amputation. The increased risk of amputation seen in the large, long-term Canagliflozin Cardiovascular Assessment Study (CANVAS) trial for canagliflozin, and select observational studies, merits continued exploration.


Assuntos
Amputação , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Compostos Benzidrílicos/efeitos adversos , Compostos Benzidrílicos/uso terapêutico , Glucosídeos/efeitos adversos , Glucosídeos/uso terapêutico , Humanos , Extremidade Inferior , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/etiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Risco , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Compostos de Sulfonilureia/efeitos adversos , Compostos de Sulfonilureia/uso terapêutico
15.
Medicine (Baltimore) ; 99(21): e20228, 2020 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-32481295

RESUMO

RATIONALE: Rare cases of euglycemic diabetic ketoacidosis (eu-DKA) have been reported after the administration of sodium-glucose cotransporter-2 (SGLT-2) inhibitors. No reports have described eu-DKA complicated by hypernatremia due to SGLT-2 inhibitors. PATIENT CONCERNS: A 76-year-old woman with a 40-year history of type 2 diabetes mellitus (DM), for which metformin (1000 mg/day) and dapagliflozin (10 mg/day) were prescribed, presented with malaise, fever, and oliguria. On presentation, her white blood cell count (11,800/µL), serum creatinine (3.2 mg/dL), and C-reactive protein (54 mg/L) were abnormal. Bilateral pyeloureteritis and diffuse paralytic ileus were present. She received intravenous antibiotics and total parenteral nutrition, and was asked to fast. Her renal function and ileus briefly improved. Oral hypoglycemic agents, metformin and dapagliflozin, along with enteral feeding were reinstituted on day 3 of hospitalization. However, on day 6 of hospitalization, the patient developed an altered state of consciousness including confusion, lethargy, and stupor. Several laboratory abnormalities suggestive of ketoacidosis with euglycemia were noted. DIAGNOSES: The patient was diagnosed with eu-DKA accompanied by severe hypernatremia (corrected serum Na concentration, 163 mEq/L) and hypokalemia following dapagliflozin re-administration. INTERVENTIONS: The patient was treated with indicated intravenous fluid therapy. Dapagliflozin use was discontinued. OUTCOMES: The patient's mental status and laboratory findings improved gradually, and she was discharged on maintenance doses of insulin and metformin on day 14 of hospitalization. LESSONS: Acute illnesses such as diffuse paralytic ileus and urinary tract infection, and dietary restrictions or fasting in patients with DM can be considered potential predisposing factors for SGLT-2 inhibitor-associated eu-DKA. For patients with diabetes in the setting of acute morbidity, timely resumption of the SGLT-2 inhibitor therapy should be carefully determined. In addition, eu-DKA due to SGLT-2 inhibitor use may be accompanied by electrolyte disturbances such as hypernatremia and hypokalemia.


Assuntos
Compostos Benzidrílicos/efeitos adversos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cetoacidose Diabética/induzido quimicamente , Glucosídeos/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Administração Intravenosa , Idoso , Antibacterianos/uso terapêutico , Compostos Benzidrílicos/administração & dosagem , Compostos Benzidrílicos/uso terapêutico , Glicemia/análise , Diabetes Mellitus Tipo 2/complicações , Cetoacidose Diabética/complicações , Cetoacidose Diabética/terapia , Feminino , Hidratação/métodos , Glucosídeos/administração & dosagem , Glucosídeos/uso terapêutico , Humanos , Hipernatremia/induzido quimicamente , Hipoglicemiantes/uso terapêutico , Hipopotassemia/induzido quimicamente , Insulina/uso terapêutico , Pseudo-Obstrução Intestinal/etiologia , Pelve Renal/microbiologia , Pelve Renal/patologia , Metformina/uso terapêutico , Alta do Paciente , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Ureter/microbiologia , Ureter/patologia , Suspensão de Tratamento
16.
Obesity (Silver Spring) ; 28(7): 1254-1262, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32568464

RESUMO

OBJECTIVE: The aim of this study was to determine the effects of empagliflozin on glycerol-derived hepatic gluconeogenesis in adults with obesity without type 2 diabetes mellitus (T2DM) using oral carbon 13 (13 C)-labeled glycerol. METHODS: A randomized, double-blind, placebo-controlled trial was performed in participants with magnetic resonance imaging assessment of body fat and measurement of glycerol-derived 13 C enrichment in plasma glucose by nuclear magnetic resonance spectroscopy following ingestion of [U-13 C3 ]glycerol. Participants were randomized to oral empagliflozin 10 mg once daily or placebo for 3 months. Glycerol-derived 13 C enrichment studies were repeated, and treatment differences in the mean percentage of 13 C glycerol enrichment in glucose were compared using mixed linear models. RESULTS: Thirty-five participants completed the study. Empagliflozin increased glycerol-derived 13 C enrichment between baseline and follow-up by 6.5% (P = 0.005), consistent with less glycerol from visceral adipose tissue (VAT). No difference was found with placebo. Glycerol-derived 13 C enrichment was lower in participants with high VAT compared with low VAT by 12.6% (P = 0.04), but there was no heterogeneity of the treatment effect by baseline VAT. Glycerol-derived 13 C enrichment was inversely correlated with VAT but was not correlated with weight loss. CONCLUSIONS: VAT is associated with endogenous glycerol-derived hepatic gluconeogenesis, and empagliflozin reduces endogenous glycerol gluconeogenesis in adults with obesity without T2DM. These findings suggest a mechanism by which sodium-glucose cotransporter 2 inhibitors may prevent T2DM in obesity.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Gluconeogênese/efeitos dos fármacos , Glucosídeos/uso terapêutico , Glicerol/metabolismo , Fígado/efeitos dos fármacos , Obesidade/tratamento farmacológico , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Adulto , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Método Duplo-Cego , Feminino , Humanos , Gordura Intra-Abdominal , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/metabolismo , Placebos , Perda de Peso/efeitos dos fármacos
17.
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
18.
Postgrad Med ; 132(4): 337-345, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366156

RESUMO

OBJECTIVES: Fixed-dose combination (FDC) therapy can improve outcomes in type 2 diabetes (T2D). We evaluated the bioequivalence of 2 doses of an FDC of extended-release metformin (metformin XR), empagliflozin, a sodium-glucose co-transporter 2 inhibitor, and linagliptin, a dipeptidyl peptidase-4 inhibitor, versus corresponding free tablet combinations. METHODS: Two randomized, open-label, two-way crossover studies in healthy adults compared: 2 FDC tablets of empagliflozin 5 mg/linagliptin 2.5 mg/metformin XR 1000 mg (Study 1; N = 30), 1 FDC tablet of empagliflozin 25 mg/linagliptin 5 mg/metformin XR 1000 mg (Study 2; N = 30) versus corresponding dose of free combinations. Subjects received study medication under fed conditions; washout was ≥35 days between treatments. Primary endpoints: area under the plasma concentration-time curve (AUC) from time 0 to last quantifiable data point for empagliflozin and metformin; AUC from time 0 to 72 hours for linagliptin, and peak plasma concentration (Cmax) for empagliflozin, linagliptin, and metformin. Bioequivalence was defined as adjusted geometric mean ratios (FDC: free combination) and two-sided 90% confidence intervals (CIs) of AUC and Cmax for each component within 80.00-125.00%. RESULTS: Study 1: 27/29 and 28/30 treated participants were included in the pharmacokinetic analysis for the FDC and free combination periods, respectively. Study 2: 29/29 treated participants were included in the pharmacokinetic analysis for both periods. The adjusted geometric mean ratios of FDCs to their respective free tablet combinations and two-sided 90% CIs were all within the predefined range. The shapes of the mean plasma concentration-time profile of empagliflozin, linagliptin, and metformin XR were similar for subjects in the FDC and free combination groups in both studies. No serious adverse events were reported. CONCLUSION: The evaluated doses of empagliflozin/linagliptin/metformin XR FDC tablets were bioequivalent to the corresponding free combinations. Based on these two bioequivalence studies and existing phase 3 data, the FDA has recently approved this triple FDC to improve glycemic control in adults with T2D.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Tipo 2/terapia , Glucosídeos/uso terapêutico , Hipoglicemiantes/uso terapêutico , Linagliptina/uso terapêutico , Metformina/uso terapêutico , Adolescente , Adulto , Área Sob a Curva , Compostos Benzidrílicos/administração & dosagem , Compostos Benzidrílicos/efeitos adversos , Estudos Cross-Over , Preparações de Ação Retardada , Combinação de Medicamentos , Feminino , Glucosídeos/administração & dosagem , Glucosídeos/efeitos adversos , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Linagliptina/administração & dosagem , Linagliptina/efeitos adversos , Masculino , Adesão à Medicação , Metformina/administração & dosagem , Metformina/efeitos adversos , Pessoa de Meia-Idade , Equivalência Terapêutica , Adulto Jovem
19.
Life Sci ; 254: 117756, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32389832

RESUMO

Polydatin (PD) is a monocrystalline metabolite from the underground parts of Polygonum cuspidatum Sieb. et Zucc., a member of the Polygonaceae family, which has been traditionally used in Asian countries as both foodstuffs and medicine. PD, also reckoned as pieceid, 3,4',5-trihydroxystilbene-3-ß-D-glucoside, (E)-piceid, (E)-polydatin, and trans-polydatin. It possesses potent biological activities i.e. analgesic, anti-inflammatory, antidiabetic, anticancer, and anti-atherosclerotic properties. The initial part of this report specifically explains distinct sequential mechanisms underlying the initiation and development of atherosclerotic plaques and later part deals with the pharmacological efficacy of PD in the management of major cardiac event i.e. atherosclerotic cardiovascular diseases (ASCVD) via modulation of a set of molecular mechanisms i.e. antioxidant potential, lipid and lipoprotein metabolism including total cholesterol (TC) and low density lipoprotein (LDL) levels, ß-hydroxy-ß-methyl-glutaryl-CoA reductase (HMG-R) expression and functionality, SIRT signalling, LDL-receptor (LDL-R), LDL oxidation status (Ox-LDL), effects on endothelial cells (ECs), smooth muscle cells (SMCs), macrophage, foam cell formation and plaque stabilization, inflammatory signalling pathways and hypertension. In contrast, one of the major insight into the potential cardioprotective molecular mechanism is the PD-mediated targeting of proprotein convertase subtilisin/kexin type-9 (PCSK-9) and LDL-R pathway, both at transcriptional and protein functional level, which makes it a better alternative therapeutic medicinal candidate to treat hypercholesterolemia, especially for the patients facing inadequate lipid lowering with classical HMG-R inhibitors (statins) and statin intolerance. Finally, to sum up the whole, we concluded that PD may be promoted from alternative to mainstream medicine in targeting risk factors mediated ASCVD.


Assuntos
Aterosclerose/tratamento farmacológico , Glucosídeos/farmacologia , Estilbenos/farmacologia , Anticolesterolemiantes/uso terapêutico , LDL-Colesterol/metabolismo , Células Endoteliais/metabolismo , Fallopia japonica/metabolismo , Glucosídeos/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Hiperlipidemias/tratamento farmacológico , Lipoproteínas LDL , Placa Aterosclerótica/tratamento farmacológico , Receptores de LDL/metabolismo , Fatores de Risco , Estilbenos/uso terapêutico
20.
Obesity (Silver Spring) ; 28(6): 1068-1074, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32352644

RESUMO

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.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/uso terapêutico , Hipoglicemiantes/uso terapêutico , Obesidade/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Compostos Benzidrílicos/farmacologia , Método Duplo-Cego , Feminino , Glucosídeos/farmacologia , Humanos , Hipoglicemiantes/farmacologia , Masculino , Pessoa de Meia-Idade , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
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