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

Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes.

Abstract BACKGROUND: The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown. METHODS: We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy. RESULTS: In all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and in 905 of 7396 patients (12.2%; 4.0 events per 100 person-years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intention-to-treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P<0.001 for noninferiority) but was not superior to placebo with respect to efficacy (P=0.06 for superiority). The rates of death from cardiovascular causes, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for acute coronary syndrome, and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events did not differ significantly between the two groups. CONCLUSIONS: Among patients with type 2 diabetes with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo. (Funded by Amylin Pharmaceuticals; EXSCEL ClinicalTrials.gov number, NCT01144338 .)

Long-term treatment of cancer-associated thrombosis: the choice of the optimal anticoagulant

Patients with cancer-associated thrombosis (CAT) carry a higher risk of recurrence, bleeding and mortality as compared with non-cancer patients. The specific profiles of cancer patients, combining frequent co-morbidities, the use of anti-tumoral therapies and the cancer progression itself, represent a major therapeutic challenge for choosing a long-term anticoagulant treatment. This review discusses the practical basis of making a choice between the available drugs for a long-term antithrombotic strategy, linked to their pharmacology, mechanism of action, evidence of clinical benefits, and advantages and limitations in such a complex clinical context. In patients with cancer, low-molecular-weight heparins (LMWHs) are the preferred option for the secondary prevention of venous thromboembolism according to current guidelines, because their efficacy is significantly superior to vitamin K antagonists (VKAs). Even though LMWHs are effective and safe in cancer patients, they require daily subcutaneous injections, which may be problematic for a long-term therapy that may exceed 6 months' duration. Compared with VKAs, non-vitamin-K antagonist oral anticoagulants or direct oral anticoagulants (DOACs) are more target specific and do not require laboratory monitoring, whereas the oral route of administration makes them potentially attractive alternatives to LMWH. In randomized controlled trials in the general population DOACs have been shown to be non-inferior to VKAs in terms of efficacy with a lower rate of clinically relevant or major bleeding. However, given the limited number of cancer patients enrolled in these studies (with poorly defined active cancer), available trials are inconclusive regarding the usefulness of DOACs in the cancer setting. Ongoing head-to-head comparisons vs. LMWH in patients with CAT may allow an informed choice to be made regarding the DOAC option

Permanent Genetic Resources added to Molecular Ecology Resources Database 1 April 2013-31 May 2013

This article documents the addition of 234 microsatellite marker loci to the Molecular Ecology Resources Database. Loci were developed for the following species: Acipenser sinensis, Aleochara bilineata, Aleochara bipustulata, Barbus meridionalis, Colossoma macropomum, Delia radicum, Drosophila nigrosparsa, Fontainea picrosperma, Helianthemum cinereum, Liomys pictus, Megabalanus azoricus, Pelteobagrus vachelli, Pleuragramma antarcticum, Podarcis hispanica type 1A, Sardinella brasiliensis and Sclerotinia homoeocarpa. These loci were cross-tested on the following species: Acipenser dabryanus, Barbus balcanicus, Barbus barbus, Barbus cyclolepis, Drosophila hydei, Drosophila melanogaster, Drosophila obscura, Drosophila subobscura, Fontainea australis, Fontainea fugax, Fontainea oraria, Fontainea rostrata, Fontainea venosa, Podarcis bocagei, Podarcis carbonelli, Podarcis liolepis, Podarcis muralis and Podarcis vaucheri

Permanent Genetic Resources added to Molecular Ecology Resources Database 1 April 2013-31 May 2013

This article documents the addition of 234 microsatellite marker loci to the Molecular Ecology Resources Database. Loci were developed for the following species: Acipenser sinensis, Aleochara bilineata, Aleochara bipustulata, Barbus meridionalis, Colossoma macropomum, Delia radicum, Drosophila nigrosparsa, Fontainea picrosperma, Helianthemum cinereum, Liomys pictus, Megabalanus azoricus, Pelteobagrus vachelli, Pleuragramma antarcticum, Podarcis hispanica type 1A, Sardinella brasiliensis and Sclerotinia homoeocarpa. These loci were cross-tested on the following species: Acipenser dabryanus, Barbus balcanicus, Barbus barbus, Barbus cyclolepis, Drosophila hydei, Drosophila melanogaster, Drosophila obscura, Drosophila subobscura, Fontainea australis, Fontainea fugax, Fontainea oraria, Fontainea rostrata, Fontainea venosa, Podarcis bocagei, Podarcis carbonelli, Podarcis liolepis, Podarcis muralis and Podarcis vaucheri

Outcomes during anticoagulation in patients with symptomatic vs. incidental splanchnic vein thrombosis

Introduction: Current guidelines recommend the use of anticoagulant therapy in patients with symptomatic splanchnic vein thrombosis (SVT) and suggest no routine anticoagulation in those with incidental SVT. Methods: We used the RIETE (Registro Informatizado Enfermedad Trombo Emb\uf3lica) registry to assess the rate and severity of symptomatic venous thromboembolism (VTE) recurrences and major bleeding events appearing during the course of anticoagulation in patients with symptomatic or incidental SVT. Results: In March 2017, 521 patients with SVT were recruited. Of them, 212 (41%) presented with symptomatic SVT and 309 had incidental SVT. Most (93%) patients received anticoagulant therapy (median, 147 days). During the course of anticoagulation, 20 patients developed symptomatic VTE recurrences (none died) and 26 had major bleeding (fatal bleeding, 5). On multivariable analysis, patients with incidental SVT had a non-significantly higher risk for symptomatic VTE recurrences (adjusted hazard ratio [HR]: 2.04; 95%CI: 0.71\u20135.88) and a similar risk for major bleeding (HR: 1.12; 95%CI: 0.47\u20132.63) than those with symptomatic SVT. Active cancer was associated with at increased risk for VTE recurrences (HR: 3.06; 95%CI: 1.14\u20138.17) and anaemia (HR: 4.11; 95%CI: 1.45\u201311.6) or abnormal prothrombin time (HR: 4.10; 95%CI: 1.68\u201310.1) were associated with at increased risk for major bleeding. Conclusions: The rates of recurrent SVT and major bleeding were similar between patients with incidental or symptomatic SVT. Because the severity of bleeding complications during anticoagulation may outweigh the severity of VTE recurrences in both groups, further studies should identify those SVT patients who benefit from anticoagulant therapy