Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to 300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m 2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Effects of composition and heat treatment on the mechanical behavior of Ti-Cu alloys

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Ti alloys are applied extensively in several fields, particularly in the aerospace, chemical, dental and medical industries, due to their outstanding properties. The mechanical behavior of Ti alloys depends on microstructural characteristics that are dictated by the amount and type of alloying elements and the processing routes employed. The aim of this work is to evaluate the effect of the cooling rate, composition and heat treatment on the microstructure and mechanical behavior of Ti-Cu hypo-, hyper- and eutectoid alloys. To this end, samples of different compositions were prepared in an arc furnace with non-consumable tungsten electrode and a water-cooled copper crucible in a high purity argon atmosphere. The samples were then cast in an arc-melting centrifugal casting machine in an argon atmosphere and copper molds. To obtain a room-temperature microstructure with stable phases, some of the cast samples were then beta solution-treated at 900 degrees C for 2 h and furnace cooled. Microstructural and mechanical characterizations were performed by X-ray diffraction, Vickers hardness measurements, scanning electron microscopy, transmission electron microscopy, tensile test, differential scanning calorimetry and ultrasonic methods for the determination of Young's modulus. The microstructure of cast samples displays a martensitic structure and heat-treated samples a microstructure composed of alpha/alpha ' and Ti2Cu intermetallic phases formed during eutectoid transformation. The mechanical characterization of the cast samples show low ductility and high mechanical strength while the heat-treated samples display slightly higher ductility and low mechanical strength. (C) 2013 Elsevier Ltd. All rights reserved.5510061013Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES

Correlations between aging heat treatment, omega phase precipitation and mechanical properties of a cast Ti-Nb alloy

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Ti-Nb alloys were arc melted in a water-cooled copper hearth in an inert atmosphere. After preparation, the samples were centrifugally cast in copper molds, and rapidly cooled, resulting in a martensitic microstructure. They were then aged at different temperatures. The microstructural characterization of this material suggested that martensite decomposition occurred, leading to precipitation of alpha, beta and omega phases. Aging at higher temperatures led to to phase decay. Mechanical characterization indicated that the heat treatment enhanced the strength and ductility of the alloys. Correlations between heat treatment, omega precipitation and mechanical behavior are discussed. (C) 2010 Elsevier Ltd. All rights reserved.32423872390Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Fracture toughness of a directionally solidified Al-Nb-Ni ternary eutectic

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fracture toughness (K(IC)), an important property of brittle materials, can be determined by indentation cracking tests. This paper reports on an investigation of the fracture toughness of a directionally solidified Al(3)Nb-Nb(2)Al-AlNbNi ternary eutectic, based on the Vickers indentation test applied to longitudinal and transverse sections of its microstructure. The measurements were taken using indentation loads varying from 2.45 to 24.5 N. Correlations between the resulting crack parameters and indentation load were evaluated using Palmqvist and half-penny cracks models. In the range of indentation loads studied, the results suggested that the Palmqvist model provided a better fit to the experimental data. Fracture toughness was calculated using equations developed for Palmqvist crack mode. The indentation fracture toughness values for longitudinal and transverse sections are in the range of 2.82-3.05 MPa m(1/2) and 2.98-3.59 MPa m(1/2), respectively. It was found that the addition of Ni and incorporation of a third phase to the Al(3)Nb-Nb(2)Al eutectic improved fracture toughness of this in situ composite material. (C) 2011 Elsevier Ltd. All rights reserved.33563568Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Effects of the microstructural characteristics of a metastable beta Ti alloy on its corrosion fatigue properties

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)In the field of biomedicine, preventing the corrosion fatigue of metallic biomaterials for use in hard tissue replacement implants is of paramount importance. Corrosion fatigue of implants is caused by their contact with body fluids, as well as cyclic stresses resulting from body movements. The metallic biomaterials most widely used today are titanium alloys. It is a well known fact that the mechanical behavior of titanium alloys is determined by their chemical composition and thermomechanical processing. This study involved an evaluation of the influence of the microstructure on the corrosion fatigue of Ti-35Nb (wt.%) alloy samples in NaCl 0.9% solution. The samples were subjected to two different cooling rates from beta phase field temperatures. The distinct cooling rates resulted in microstructures composed of beta and alpha' phases (160 degrees C/s) and alpha, beta and omega phases (0.04 degrees C/s). The samples were characterized microstructurally by optical, scanning electron and transmission electron microscopy and X-ray diffraction. Their high-cycle corrosion fatigue properties were evaluated based on fatigue tests in NaCl 0.9% solution, under stresses ranging from 150 to 450 MPa. The results suggest that the furnace cooled sample showed lower corrosion fatigue. (C) 2013 Elsevier Ltd. All rights reserved.543237Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Hexagonal martensite decomposition and phase precipitation in Ti-Cu alloys

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)The mechanical behavior of Ti-Cu alloys can be improved by controlling Ti(2)Cu precipitation. In eutectoid alloys, such precipitation can be achieved by the decomposition of martensite in response to aging heat treatment. The purpose of this work is to discuss the evolution of precipitates during the decomposition of hexagonal martensite in Ti-Cu alloys. First, samples with near-eutectoid compositions were prepared in an arc furnace equipped with a non-consumable tungsten electrode and water-cooled copper hearth under a high purity argon atmosphere. After chemical homogenization at a temperature in the beta field, the samples were water-quenched and examined by differential scanning calorimetry and high-temperature X-ray diffraction. The results indicate that rapidly quenched near-eutectoid Ti-Cu alloys present Ti(2)Cu precipitates. Regardless of the cooling rate applied, such precipitation is unavoidable. No evidence of beta phase stabilization was found in the rapidly quenched samples. Precipitation temperatures of coherent and incoherent phases of 415 degrees C and 550 degrees C, respectively, were determined from the differential scanning calorimetry measurements. Ti(2)Cu precipitation was examined in situ by high temperature X-ray diffraction experiments. The total decay of martensite was found to occur above 575 degrees C. Vickers hardness testing of aged samples revealed a correlation between phase precipitation and hardening. (C) 2011 Elsevier Ltd. All rights reserved.324189046084613Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Microstructure of directionally solidified Ti-Fe eutectic alloy with low interstitial and high mechanical strength

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)The performance of Ti alloys can be considerably enhanced by combining Ti and other elements, causing an eutectic transformation and thereby producing composites in situ from the liquid phase. This paper reports on the processing and characterization of a directionally solidified Ti-Fe eutectic alloy. Directional solidification at different growth rates was carried out in a setup that employs a watercooled copper crucible combined with a voltaic electric arc moving through the sample. The results obtained show that a regular fiber-like eutectic structure was produced and the interphase spacing was found to be a function of the growth rate. Mechanical properties were measured using compression, microindentation and nanoindentation tests to determine the Vickers hardness, compressive strength and elastic modulus. Directionally solidified eutectic samples presented high values of compressive strength in the range of 1844-3000 MPa and ductility between 21.6 and 25.2%. (C) 2011 Elsevier B.V. All rights reserved.33314047Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) Study Rationale, Design, and Baseline Characteristics

Background: People with diabetes and kidney disease have a high risk of cardiovascular events and progression of kidney disease. Sodium glucose co-transporter 2 inhibitors lower plasma glucose by reducing the uptake of filtered glucose in the kidney tubule, leading to increased urinary glucose excretion. They have been repeatedly shown to induce modest natriuresis and reduce HbA1c, blood pressure, weight, and albuminuria in patients with type 2 diabetes. However, the effects of these agents on kidney and cardiovascular events have not been extensively studied in patients with type 2 diabetes and established kidney disease. Methods: The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial aims to compare the efficacy and safety of canagliflozin ­versus placebo at preventing clinically important kidney and cardiovascular outcomes in patients with diabetes and established kidney disease. CREDENCE is a randomized, double-blind, event-driven, placebo-controlled trial set in in 34 countries with a projected duration of â\u88¼5.5 years and enrolling 4,401 adults with type 2 diabetes, estimated glomerular filtration rate â\u89¥30 to 300 to â\u89¤5,000 mg/g). The study has 90% power to detect a 20% reduction in the risk of the primary outcome (α = 0.05), the composite of end-stage kidney disease, doubling of serum creatinine, and renal or cardiovascular death. Conclusion: CREDENCE will provide definitive evidence about the effects of canagliflozin on renal (and cardiovascular) outcomes in patients with type 2 diabetes and established kidney disease. Trial Registration: EudraCT number: 2013-004494-28; ClinicalTrials.gov identifier: NCT02065791