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

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 <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >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 m2), 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

A Multi-Core Ready Discrete Element Method With Triangles Using Dynamically Adaptive Multiscale Grids

The simulation of vast numbers of rigid bodies of non‐analytical shapes and of tremendously different sizes that collide with each other is computationally challenging. A bottleneck is the identification of all particle contact points per time step. We propose a tree‐based multilevel meta data structure to administer the particles. The data structure plus a purpose‐made tree traversal identifying the contact points introduce concurrency to the particle comparisons, whilst they keep the absolute number of particle‐to‐particle comparisons low. Furthermore, a novel adaptivity criterion allows explicit time stepping to work with comparably large time steps. It optimises both toward low algorithmic complexity per time step and low numbers of time steps. We study three different parallelisation strategies exploiting our traversal's concurrency. The fusion of two of them yields promising speedups once we rely on maximally asynchronous task‐based realisations. Our work shows that new computer architecture can push the boundary of rigid particle computability, yet if and only if the right data structures and data processing schemes are chosen

Rapid Screening of Antioxidant Anthocyanins in Autochthonous Nero d’Avola Grape Clones by Pre-column DPPH Reaction Coupled to UHPLC-UV/Vis-IT-TOF: a Strategy to Combine Chemical data and Genetic Diversity

Grape is a rich source of bioactive compounds; among them anthocyanins are associated to many healthy properties, possessing a good antioxidant activity. In this work, we developed a fast and simple screening of antioxidant anthocyanins in six Sicilian Nero d’Avola autochthonous grape clones. The method was based on the pre-column reaction with 2,2′-diphenyl-1-picrylhydrazyl radical followed by the rapid separation by ultra high-pressure liquid chromatography coupled with ultraviolet and tandem mass spectrometry detection. Peak areas of antioxidant anthocyanins significantly reduced or even disappeared. The entire method took only 45 min per sample, showing good retention time and peak area repeatability with maximum CV% values ≤0.86 and 6.84, respectively. Samples rich in delphinidin derivatives showed lowest IC50 values, since those compounds possess the highest scavenging ability. The developed setup was less complex than online approaches and faster with respect to conventional high-performance liquid chromatography methods, taking advantage of ultra high-performance conditions, coupled for the first time with pre-column 2,2′-diphenyl-1-picrylhydrazyl assay. The proposed strategy is a valid tool for a rapid screening of antioxidant anthocyanins in grape samples, useful to correlate the genetic diversity with the production of secondary metabolites as well to assess their activity in nutraceutical products rich in anthocyanins