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

The Ediacaran Rio Doce magmatic arc revisited, Ara?ua?-Ribeira orogenic system, SE Brazil.

Described half a century ago, the Galil eia tonalite represents a milestone in the discovery of plate margin magmatic arcs in the Ara?ua?-Ribeira orogenic system (southeastern Brazil). In the 1990's, analytical studies on the Galil eia tonalite finally revealed the existence of a Late Neoproterozoic calc-alkaline magmatic arc in the Ara?ua? orogen. Meanwhile, the name Rio Doce magmatic arc was applied to calc-alkaline plutons found in the Ara?ua?-Ribeira boundary. After those pioneer studies, the calc-alkaline plutons showing a pre-collisional volcanic arc signature and age between 630 Ma and 585 Ma have been grouped in the G1 supersuite, corresponding to the Rio Doce arc infrastructure. Here, we revisit the Rio Doce arc with our solid field knowledge of the region and a robust analytical database (277 lithochemical analyses, and 47 UePb, 53 SmeNd, 25 87Sr/86Sr and 7 LueHf datasets). The G1 supersuite consists of regionally deformed, tonalitic to granodioritic batholiths and stocks, generally rich in melanocratic to mesocratic enclaves and minor gabbroic to dioritic plutons. Gabbroic to dioritic enclaves show evidence of magma mixing processes. The lithochemical and isotopic signatures clearly reveal a volcanic arc formed on a continental margin setting. Melts from a Rhyacian basement form the bulk of the magma produced, whilst gabbroic plutons and enclaves record involvement of mantle magmas in the arc development. Tonalitic stocks (UePb age: 618e575 Ma, ?Nd(t): 5.7 to 7.8, Nd TDM ages: 1.28e1.68 Ga, 87Sr/86Sr(t): 0.7059e0.7118, and ?Hf(t): 5.2 to 11.7) form the northernmost segment of the Rio Doce arc, which dies out in the ensialic sector of the Ara?ua? orogen. At arc eastern and central zones, several batholiths (e.g., Alto Capim, Baixo Guandu, Galil eia, Muniz Freire, S~ao V?tor) record a long-lasting magmatic history (632e580 Ma; ?Nd(t): 5.6 to 13.3; Nd TDM age: 1.35e1.80 Ga; 87Sr/86Sr(t): 0.7091 e0.7123). At arc western border, the magmatic evolution started with gabbro-dioritic and tonalitic plutons (e.g., Chaves pluton, UePb age: 599 ? 15 Ma, ?Nd(t): 4.8 to 6.8, Nd TDM ages: 1.48e1.68 Ga, 87Sr/86Sr(t): 0.7062e0.7068, and ?Hf(t): 4.3 to 9.7; and Brasil^andia pluton, UePb age: 581 ? 11 Ma, ?Nd(t): 8.2 to 10.2, Nd TDM ages: 1.63e1.68 Ga, 87Sr/86Sr(t): 0.7088e0.7112, ?Hf(t): 12.3 to 14.9),followed by late granodioritic intrusions (e.g., Guarataia pluton, UePb age: 576 ? 9 Ma, ?Nd(t): 12.52 to 13.11, Nd TDM age: 1.74e2.06 Ga, 87Sr/86Sr(t): 0.7104e0.7110, ?Hf(t): 12.9 to 21.6). The Muria e batholith (UePb age: 620e592 Ma, ?Nd(t): 8.2 to 13.6, Nd TDM age: 1.41e1.88 Ga) and the Concei?~ao da Boa Vista (586 ? 7 Ma) and Serra do Valentim (605 ? 8 Ma) stocks represent a segment of the Rio Doce arc correlated to the Serra da Bol?via and Marceleza complexes, making the link between the Ara?ua? and Ribeira orogenic domains. We suggest three phases of arc development: i) eastward migration of arc front (632e605 Ma), ii) widespread magma production in the whole arc (605e585 Ma), and iii) late plutonism in the western arc region (585e575 Ma). Usual processes of volcanic arc development, like subduction of oceanic lithosphere under a continental margin, followed by asthenosphere ascent related to slab retreating and break-off may explain the Rio Doce arc evolution