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

Small-scale moisture availability increase during the 8.2-ka climatic event inferred from biotic proxy records in the South Carpathians (SE Romania)

In this paper, we present high-resolution early Holocene pollen, plant macrofossil, charcoal, diatom, biogenic silica, and loss-on-ignition records from a mountain lake in the South Carpathians in order to reveal ecosystem response to the 8.2-ka climatic oscillation. We found significant changes both in terrestrial vegetation and lake diatom assemblages in the northern slope of the Retezat Mts between c. 8300 and 8000 cal. yr BP. Rapid changes in relative frequencies and pollen accumulation rates of the major deciduous pollen types associated with peaks in microcharcoal accumulation rates suggested that vegetation disturbance mainly took place in the mixed-deciduous forest zone, where woodland fires partially destroyed the populations of Fraxinus excelsior, Quercus, and Corylus avellana and facilitated the establishment of Carpinus betulus in the forest openings. The diatom record furthermore showed the spread of a planktonic diatom species, Aulacoseira valida, at 8150 cal. yr BP, coincidently with a short-lived expansion of C. betulus. Since diatom blooms mainly occur in spring in the Retezat Mts, increased spring water depth and increased water turbulence were inferred from these data. The expansion of C. betulus against F. excelsior and C. avellana at the same time suggested a modest increase in available moisture during the growing season. Taken together, these data imply that during the 8.2-ka event, winter and spring season available moisture increased, while summers were characterized by alternating moist/cool and dry/warm conditions

Temporal changes in tritium and radiocarbon concentrations in the western North Pacific Ocean (1993-2012)

http://www.godac.jamstec.go.jp/darwin/cruise/mirai/mr05-02/

Gas Ion Source Performance of the EnvironMICADAS at HEKAL Laboratory, Debrecen, Hungary

A coupled accelerator mass spectrometer–gas interface system has been successfully operating at the Hertelendi Laboratory of Environmental Studies, Debrecen, Hungary, since 2013. Over the last 6 years more than 500 gas targets were measured below 100 µg carbon content for carbon isotopic composition. The system was tested with blanks, OxII, IAEA-C1, IAEA-C2, and IAEA-C7 standards. The performance of our instrumentation shows good agreement with other published gas-interface system data and also shows a quite good agreement with the nominal value of international standard samples. There is a measurable but quite small memory effect after modern samples, but this does not significantly affect the final results. Typical ion currents at the low energy side were between 10–15 µA with a 5% CO2 in He mixing ratio. The relative errors average ±6% for samples greater than or equal to 10 µgC sample with mean count rates of 300 counts per microgram C for OxII. The blank is comparable with other systems, which is 0.0050 ± 0.0018 F14C or 34,000–47,000 yr BP, which allows for the routine measurement of both of small environmental and archeological samples