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

Rates of rockwall slope erosion in the upper Bhagirathi catchment, Garhwal Himalaya

Rockwall slope erosion is defined for the upper Bhagirathi catchment using cosmogenic Beryllium-10 (10Be) concentrations in sediment from medial moraines on Gangotri glacier. Beryllium-10 concentrations range from 1.1 ± 0.2 to 2.7 ± 0.3 × 104 at/g SiO2, yielding rockwall slope erosion rates from 2.4 ± 0.4 to 6.9 ± 1.9 mm/a. Slope erosion rates are likely to have varied over space and time and responded to shifts in climate, geomorphic and/or tectonic regime throughout the late Quaternary. Geomorphic and sedimentological analyses confirm that the moraines are predominately composed of rockfall and avalanche debris mobilized from steep relief rockwall slopes via periglacial weathering processes. The glacial rockwall slope erosion affects sediment flux and storage of snow and ice at the catchment head on diurnal to millennial timescales, and more broadly influences catchment configuration and relief, glacier dynamics and microclimates. The slope erosion rates exceed the averaged catchment-wide and exhumation rates of Bhagirathi and the Garhwal region on geomorphic timescales (103−105 years), supporting the view that erosion at the headwaters can outpace the wider catchment. The 10Be concentrations of medial moraine sediment for the upper Bhagirathi catchment and the catchments of Chhota Shigri in Lahul, northern India and Baltoro glacier in Central Karakoram, Pakistan show a tentative relationship between 10Be concentration and precipitation. As such there is more rapid glacial rockwall slope erosion in the monsoon-influenced Lesser and Greater Himalaya compared to the semi-arid interior of the orogen. Rockwall slope erosion in the three study areas, and more broadly across the northwest Himalaya is likely governed by individual catchment dynamics that vary across space and time. © 2019 The Authors. Earth Surface Processes and Landforms Published by John Wiley & Sons, Ltd