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

Improved Constraints on Models of Glacial Isostatic Adjustment: A Review of the Contribution of Ground-based Geodetic Observations

The provision of accurate models of Glacial Isostatic Adjustment (GIA) is presently a priority need in climate studies, largely due to the potential of the Gravity Recovery and Climate Experiment (GRACE) data to be used to determine accurate and continent-wide assessments of ice mass change and hydrology. However, modelled GIA isuncertain due to insufficient constraints on our knowledge of past glacial changes and to large simplifications in the underlying Earth models. Consequently, we show differences between models that exceed several mm/year in terms of surface displacement for the two major ice sheets: Greenland and Antarctica. Geodetic measurements of surface displacement offer the potential for new constraints to be made on GIA models, especially when they are used to improve structural features of the Earth’s interior as to allow for a more realistic reconstruction of the glaciation history. We present the distribution of presently available campaign and continuous geodetic measurements in Greenland and Antarctica and summarise surface velocities published to date, showing substantial disagreement between techniques and GIA models alike. We review the current state-of-the-art in ground-based geodesy (GPS, VLBI, DORIS, SLR) in determining accurate and precise surface velocities. In particular, we focus on known areas of need in GPS observation level models and the terrestrial reference frame in order to advance geodetic observation precision/ accuracy toward 0.1 mm/year and therefore further constrain models of GIA and subsequent present-day ice mass change estimates