Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups

Background: Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without previous cardiovascular disease (primary prevention). Methods: In CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), 4401 participants with type 2 diabetes mellitus and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care. Results: Primary prevention participants (n=2181, 49.6%) were younger (61 versus 65 years), were more often female (37% versus 31%), and had shorter duration of diabetes mellitus (15 years versus 16 years) compared with secondary prevention participants (n=2220, 50.4%). Canagliflozin reduced the risk of major cardiovascular events overall (hazard ratio [HR], 0.80 [95% CI, 0.67-0.95]; P=0.01), with consistent reductions in both the primary (HR, 0.68 [95% CI, 0.49-0.94]) and secondary (HR, 0.85 [95% CI, 0.69-1.06]) prevention groups (P for interaction=0.25). Effects were also similar for the components of the composite including cardiovascular death (HR, 0.78 [95% CI, 0.61-1.00]), nonfatal myocardial infarction (HR, 0.81 [95% CI, 0.59-1.10]), and nonfatal stroke (HR, 0.80 [95% CI, 0.56-1.15]). The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalization for heart failure were also consistently reduced in both the primary and secondary prevention groups (P for interaction >0.5 for each outcome). Conclusions: Canagliflozin significantly reduced major cardiovascular events and kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, including in participants who did not have previous cardiovascular disease

Biotransformation of the Diterpene Ent

The diterpene ent-18,19-dihydroxytrachylobane was biotransformed for the first time by Rhizopus stolonifer, and yielded the new ent-11β,18,19-trihydroxytrachylobane derivative besides the new ent-kaur-11-ene diterpenes ent-16α,18,19-trihydroxykaur-11-ene and ent-18,19-dihydroxy-16α-methoxykaur-11-ene. Their structures were determined by spectrometric methods

Baseline characteristics of patients with HF with mildly reduced and preserved ejection fraction: DELIVER trial

Objectives: This report describes the baseline clinical profiles and management of DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trial participants and how these compare with those in other contemporary heart failure with preserved ejection fraction trials. Background: The DELIVER trial was designed to evaluate the effects of the sodium-glucose cotransporter–2 inhibitor dapagliflozin on cardiovascular death, heart failure (HF) hospitalization, or urgent HF visits in patients with HF with mildly reduced and preserved left ventricular ejection fraction (LVEF). Methods: Adults with symptomatic HF and LVEF >40%, with or without type 2 diabetes mellitus, elevated N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels, and evidence of structural heart disease were randomized to dapagliflozin 10 mg once daily or matching placebo. Results: A total of 6,263 patients were randomized (mean age: 72 ± 10 years; 44% women; 45% type 2 diabetes mellitus; 45% with body mass index ≥30 kg/m2; and 57% with history of atrial fibrillation or flutter). Most participants had New York Heart Association functional class II symptoms (75%). Baseline mean LVEF was 54.2 ± 8.8% and median NT-proBNP of 1,399 pg/mL (IQR: 962 to 2,210 pg/mL) for patients in atrial fibrillation/flutter compared with 716 pg/mL (IQR: 469 to 1,281 pg/mL) in those who were not. Patients in both hospitalized and ambulatory settings were enrolled, including 10% enrolled in-hospital or within 30 days of a hospitalization for HF. Eighteen percent of participants had HF with improved LVEF. Conclusions: DELIVER is the largest and broadest clinical trial of this population to date and enrolled high-risk, well-treated patients with HF with mildly reduced and preserved LVEF. (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [NCT03619213])

Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction

Background: Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death among patients with chronic heart failure and a left ventricular ejection fraction of 40% or less. Whether SGLT2 inhibitors are effective in patients with a higher left ventricular ejection fraction remains less certain. Methods: We randomly assigned 6263 patients with heart failure and a left ventricular ejection fraction of more than 40% to receive dapagliflozin (at a dose of 10 mg once daily) or matching placebo, in addition to usual therapy. The primary outcome was a composite of worsening heart failure (which was defined as either an unplanned hospitalization for heart failure or an urgent visit for heart failure) or cardiovascular death, as assessed in a time-to-event analysis. Results: Over a median of 2.3 years, the primary outcome occurred in 512 of 3131 patients (16.4%) in the dapagliflozin group and in 610 of 3132 patients (19.5%) in the placebo group (hazard ratio, 0.82; 95% confidence interval [CI], 0.73 to 0.92; P<0.001). Worsening heart failure occurred in 368 patients (11.8%) in the dapagliflozin group and in 455 patients (14.5%) in the placebo group (hazard ratio, 0.79; 95% CI, 0.69 to 0.91); cardiovascular death occurred in 231 patients (7.4%) and 261 patients (8.3%), respectively (hazard ratio, 0.88; 95% CI, 0.74 to 1.05). Total events and symptom burden were lower in the dapagliflozin group than in the placebo group. Results were similar among patients with a left ventricular ejection fraction of 60% or more and those with a left ventricular ejection fraction of less than 60%, and results were similar in prespecified subgroups, including patients with or without diabetes. The incidence of adverse events was similar in the two groups. Conclusions: Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure and a mildly reduced or preserved ejection fraction. (Funded by AstraZeneca; DELIVER ClinicalTrials.gov number, NCT03619213.)

Dissolved organic nutrients (C, N, P) in seawater on the continental shelf in the Southwestern South Atlantic with emphasis State Marine Park of Laje de Santos (SMPLS) - São Paulo - Brazil

O principal objetivo deste trabalho é avaliar distribuição sazonal e espacial do carbono orgânico dissolvido (COD), nitrogênio orgânico (NOD), fósforo orgânico dissolvido (POD) e ureia em 10 estações do Parque Estadual Marinho da Laje de Santos (PEMLS). As estações 1 a 4 (mais próximas do continente) e as estações de 5 a 10 (mais próximas do parque marinho), todas na plataforma continental. Os resultados mostram que não foram observadas variações sazonais estatisticamente significativas para o COD e POD, todavia, o COD e o NOD, no período de verão apresentaram um pequeno aumento mostrando o aumento da atividade biológica e a influencia continental. Por outro lado, o NOD apresentou valores elevados em junho (2014 - inverno) e janeiro de 2015, variando de 12.51 a 32.76 µmol L-1, segundo o método de análise ANOVA (p< 0,01). Foram observados baixos valores de NOD em janeiro de 2014 (0,32-8,98 µmol L-1), em um verão anormalmente seco, enquanto que os valores mais elevados foram observados em julho de 2014 (27.50 µmol L-1). Ureia apresentou valores baixos na região do PEMLS e zonas costeiras atingindo 4,00 µmol L-1. Muitas vezes, a concentração de ureia pode estar associada com atividade de mergulho no parque. COD, NOD e ureia apresentaram valores ou diferenças entre as estações no PEMLS (5-10) e aquelas mais costeiras (1-4). O COD nas estações costeiras atingiu 267 µmol L-1, enquanto que no PEMLS, o valor máximo foi de 100 µmol L-1. Nenhuma variação significativa foi observada quanto à distribuição espacial entre as estações costeiras e as do parque para o POD (ANOVA pThe main objective of this work is evaluate seasonal and spatial distribution of dissolved organic carbon (DOC), dissolved organic nitrogen (DON), dissolved organic phosphorus (DOP) and urea in 10 stations of the State Marine Park of Laje de Santos (SMPLS). Stations 1 to 4 (nearest the continent) and the stations 5 to 10 (nearest the marine park) all of them were on the continental shelf. The results show that no statistic significant seasonal variations were found for the DOC and DOP nevertheless DOC and DON in summer period were lightly above the winter period showing the increase in biological activities and continental influence. On the other hand, DON showed high values in June (2014 - winter) to January 2015, ranging from 12.51 to 32.76 µmol L-1 according to the ANOVA method (

European contribution to the study of ROS:a summary of the findings and prospects for the future from the COST action BM1203 (EU-ROS)

Abstract The European Cooperation in Science and Technology (COST) provides an ideal framework to establish multi-disciplinary research networks. COST Action BM1203 (EU-ROS) represents a consortium of researchers from different disciplines who are dedicated to providing new insights and tools for better understanding redox biology and medicine and, in the long run, to finding new therapeutic strategies to target dysregulated redox processes in various diseases. This report highlights the major achievements of EU-ROS as well as research updates and new perspectives arising from its members. The EU-ROS consortium comprised more than 140 active members who worked together for four years on the topics briefly described below. The formation of reactive oxygen and nitrogen species (RONS) is an established hallmark of our aerobic environment and metabolism but RONS also act as messengers via redox regulation of essential cellular processes. The fact that many diseases have been found to be associated with oxidative stress established the theory of oxidative stress as a trigger of diseases that can be corrected by antioxidant therapy. However, while experimental studies support this thesis, clinical studies still generate controversial results, due to complex pathophysiology of oxidative stress in humans. For future improvement of antioxidant therapy and better understanding of redox-associated disease progression detailed knowledge on the sources and targets of RONS formation and discrimination of their detrimental or beneficial roles is required. In order to advance this important area of biology and medicine, highly synergistic approaches combining a variety of diverse and contrasting disciplines are needed