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

Postpartum psychosis in bipolar disorder: no evidence of association with personality traits, cognitive style or affective temperaments

Background: Bipolar disorder has been associated with several personality traits, cognitive styles and affective temperaments. Women who have bipolar disorder are at increased risk of experiencing postpartum psychosis, however little research has investigated these traits and temperaments in relation to postpartum psychosis. The aim of this study is to establish whether aspects of personality, cognitive style and affective temperament that have been associated with bipolar disorder also confer vulnerability to postpartum psychosis over and above their known association with bipolar disorder. Methods: Personality traits (neuroticism, extraversion, schizotypy and impulsivity), cognitive styles (low self-esteem and dysfunctional attitudes) and affective temperaments (including cyclothymic and depressive temperaments) were compared between two groups of parous women with DSM-IV bipolar I disorder: i) 284 with a lifetime history of postpartum psychosis within 6 weeks of delivery (PP group), ii) 268 without any history of mood episodes with onset during pregnancy or within 6 months of delivery (no perinatal mood episode, No PME group). Results: After controlling for current mood state, and key demographic, clinical and pregnancy-related variables, there were no statistically significant differences between the PP and No PME groups on any of the personality, cognitive style or affective temperament measures. Conclusions: Personality traits, cognitive styles and affective temperaments previously shown to be associated with bipolar disorder in general were not specifically associated with the occurrence of postpartum psychosis. These factors may not be relevant for predicting risk of postpartum psychosis in women with bipolar disorder

Protective effect of gamma-tocopherol-enriched diet on N-methyl-N-nitrosourea-induced epithelial dysplasia in rat ventral prostate

Despite recent advances in understanding the biological basis ofprostate cancer (PCa), the management of this disease remains a challenge. Chemoprotective agents have been usedto protect against or eradicateprostatemalignancies. Here, we investigated the protective effect of -tocopherol on N-methyl-N-nitrosourea (MNU)-induced epithelial dysplasia in the rat ventral prostate (VP). Thirty-two male Wistar rats were divided into four groups (n=8): control (CT): healthy control animals fed a standard diet; control+-tocopherol (CT+T): healthy control animals without intervention fed a -tocopherol-enriched diet (20mg/kg); N-methyl-N-nitrosourea (MNU): rats that received a single dose of MNU (30mg/kg) plus testosterone propionate (100mg/kg) and were fed a standard diet; and MNU+-tocopherol (MNU+T): rats that received the same treatment of MNU plus testosterone and were fed with a -tocopherol-enriched diet (20mg/kg). After 4months, the VPs were excised to evaluate morphology, cell proliferation and apoptosis, as well as cyclooxygenase-2 (Cox-2), glutathione-S-transferase-pi (GST-pi) and androgen receptor (AR) protein expression, and matrix metalloproteinase-9 (MMP-9) activity. An increase in the incidence of epithelial dysplasias, such as stratified epithelial hyperplasia and squamous metaplasia, in the MNU group was accompanied by augmented cell proliferation, GST-pi and Cox-2 immunoexpression and pro-MMP-9 activity. Stromal thickening and inflammatory foci were also observed. The administration of a -tocopherol-enriched diet significantly attenuated the adverse effects of MNU in the VP. The incidence of epithelial dysplasia decreased, along with the cell proliferation index, GST-pi and Cox-2 immunoexpression. The gelatinolytic activity of pro-MMP-9 returned to the levels observed for the CT group. These results suggest that -tocopherol acts as a protective agent against MNU-induced prostatic disorders in the rat ventral prostate.946362372Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG)Minas Gerais State Research Foundation (FAPEMIG) [APQ-01275-10