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

Branched-linear polyion complexes at variable charge densities

Structural behavior of complexes formed by a charged and branched copolymer and an oppositely charged and linear polyion was examined by Monte Carlo simulations employing a coarse-grained bead-spring model. The fractional bead charge and the branching density were systematically varied; the former between 0e and 1e and the latter such that both the comb-polymer and the bottle-brush limits were included. The number of beads of the main chain of the branched copolymer and of the linear polyion was always kept constant and equal, and a single side-chain length was used. Our analysis involved characterization of the complex as well as investigation of size, shape, and flexibility of the charged moieties. An interplay between Coulomb interaction and side-chain repulsion governed the structure of the polyion complex. At strong Coulomb interaction, the complexes underwent a gradual transition from a globular structure at low branching density to an extended one at high branching density. As the electrostatic coupling was decreased, the transition was smoothened and shifted to lower branching density, and, eventually, a behavior similar to that found for neutral branched polymer was observed. Structural analogies and dissimilarities with uncharged branched polymers in poor solutions are discussed

Monte Carlo Simulations of Multigraft Homopolymers in Good Solvent

Multigraft polymers comprise a subclass of branched polymers where more than one side chain is attached to each node (branching point) of the main chain. We have investigated structural properties of single multigraft polymers under good solvent conditions by Monte Carlo simulations, employing a flexible bead-spring model. Beside the grafting density, denoting the linear density of grafted side chains, we have introduced the concept of branching density, denoting the linear density of nodes. At high branching density, both the branching density and the branching multiplicity controlled the structure of the side chains, whereas at lower branching density only the branching multiplicity influenced the side-chain structure. The spatial extension of the main chain and side chains as a function of side-chain length and grafting density was analyzed using scaling formalism. The dependence of the main-chain extension on side-chain length, branching density, and branching multiplicity could be collapsed on a universal curve upon relevant rescaling. Multigraft polymers with equal number of side-chain beads but unequal numbers and lengths of side chains displayed unconventional bending properties. Few and long side chains gave rise to a still relative low locally stiffness but considerable long-range rigidity, whereas more numerous and shorter side chains lead to a higher local stiffness but to a smaller long-range rigidity

Branched-linear polyion complexes investigated by Monte Carlo simulations

Complexes formed by one charged and branched copolymer with an oppositely charged and linear polyion have been investigated by Monte Carlo simulations. A coarse-grained description has been used, in which the main chain of the branched polyion and the linear polyion possess the same absolute charge and charge density. The spatial extension and other structural properties, such as bond-angle orientational correlation function, asphericity, and scaling analysis of formed complexes, at varying branching density and side-chain length of the branched polyion, have been explored. In particular, the balance between cohesive Coulomb attraction and side-chain repulsions resulted in two main structures of a polyion complex. These structures are (i) a globular polyion core surrounded by side chains appearing at low branching density and (ii) an extended polyion core with side chains still being expelled at high branching density. The globule-to-extended transition occurred at a crossover branching density being practically independent of the side chain length

Phase diagrams of non-ionic microemulsions containing reducing agents and metal salts as bases for the synthesis of bimetallic nanoparticles

Phase diagrams of microemulsions containing metal salt(s) and reducing agent, respectively, were studied in detail. The microemulsions were based on non-ionic surfactants, namely pure tetraethyleneglycol monododecylether, C12E4, and technical grade Brij30. We studied the influence of the metal salts H2PtCl6, Pb(NO3)2, Bi(NO3)3, H2PtCl6 + Pb(NO3)2 (1:1 mixture), and H2PtCl6 + Bi(NO3)3 (1:1 mixture) as well as of the reducing agent NaBH4 on the location of the phase boundaries. The focus was on the water emulsification failure boundary (wefb) where the aqueous phase forms spherical droplets. The temperature shifts of the wefb, which were caused by the presence of the salt(s), are directly related with the shift of the clouding points of the corresponding oil-free systems. The location of the wefb is affected in a complex manner by the pH (the lower the pH the higher the temperature at which the wefb occurred), the ionic strength and by specific salting-in or salting-out effects of the electrolyte ions. The desired overlap of the wefb of the microemulsions containing the metal salt(s) and the reducing agent, respectively, could be achieved by adding NaOH to the C12E4-based microemulsions and by titrating 1-octanol to the Brij30-based microemulsions, respectively.Science Foundation IrelandOther funderUniversity College Dublin. Center for Synthesis and Chemical Biology (CSCB

Phase diagrams of non-ionic microemulsions containing reducing agents and metal salts as bases for the synthesis of bimetallic nanoparticles

Phase diagrams of microemulsions containing metal salt(s) and reducing agent, respectively, were studied in detail. The microemulsions were based on non-ionic surfactants, namely pure tetraethyleneglycol monododecylether, C12E4, and technical grade Brij30. We studied the influence of the metal salts H2PtCl6, Pb(NO3)2, Bi(NO3)3, H2PtCl6 + Pb(NO3)2 (1:1 mixture), and H2PtCl6 + Bi(NO3)3 (1:1 mixture) as well as of the reducing agent NaBH4 on the location of the phase boundaries. The focus was on the water emulsification failure boundary (wefb) where the aqueous phase forms spherical droplets. The temperature shifts of the wefb, which were caused by the presence of the salt(s), are directly related with the shift of the clouding points of the corresponding oil-free systems. The location of the wefb is affected in a complex manner by the pH (the lower the pH the higher the temperature at which the wefb occurred), the ionic strength and by specific salting-in or salting-out effects of the electrolyte ions. The desired overlap of the wefb of the microemulsions containing the metal salt(s) and the reducing agent, respectively, could be achieved by adding NaOH to the C12E4-based microemulsions and by titrating 1-octanol to the Brij30-based microemulsions, respectively.Science Foundation IrelandOther funderUniversity College Dublin. Center for Synthesis and Chemical Biology (CSCB