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

Where Brain, Body and World Collide

The production cross section of electrons from semileptonic decays of beauty hadrons was measured at mid-rapidity (|y| < 0.8) in the transverse momentum range 1 < pt < 8 Gev/c with the ALICE experiment at the CERN LHC in pp collisions at a center of mass energy sqrt{s} = 7 TeV using an integrated luminosity of 2.2 nb^{-1}. Electrons from beauty hadron decays were selected based on the displacement of the decay vertex from the collision vertex. A perturbative QCD calculation agrees with the measurement within uncertainties. The data were extrapolated to the full phase space to determine the total cross section for the production of beauty quark-antiquark pairs

Effect of SGLT2 Inhibitors on Stroke and Atrial Fibrillation in Diabetic Kidney Disease: Results From the CREDENCE Trial and Meta-Analysis

BACKGROUND AND PURPOSE: Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus.METHODS: CREDENCE randomized 4401 participants with type 2 diabetes mellitus and chronic kidney disease to canagliflozin or placebo. Post hoc, we estimated effects on fatal or nonfatal stroke, stroke subtypes, and intermediate markers of stroke risk including AF/AFL. Stroke and AF/AFL data from 3 other completed large CVOTs and CREDENCE were pooled using random-effects meta-analysis.RESULTS: In CREDENCE, 142 participants experienced a stroke during follow-up (10.9/1000 patient-years with canagliflozin, 14.2/1000 patient-years with placebo; hazard ratio [HR], 0.77 [95% CI, 0.55-1.08]). Effects by stroke subtypes were: ischemic (HR, 0.88 [95% CI, 0.61-1.28]; n=111), hemorrhagic (HR, 0.50 [95% CI, 0.19-1.32]; n=18), and undetermined (HR, 0.54 [95% CI, 0.20-1.46]; n=17). There was no clear effect on AF/AFL (HR, 0.76 [95% CI, 0.53-1.10]; n=115). The overall effects in the 4 CVOTs combined were: total stroke (HRpooled, 0.96 [95% CI, 0.82-1.12]), ischemic stroke (HRpooled, 1.01 [95% CI, 0.89-1.14]), hemorrhagic stroke (HRpooled, 0.50 [95% CI, 0.30-0.83]), undetermined stroke (HRpooled, 0.86 [95% CI, 0.49-1.51]), and AF/AFL (HRpooled, 0.81 [95% CI, 0.71-0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate (P=0.01), with protection in the lowest estimated glomerular filtration rate (<45 mL/min/1.73 m2]) subgroup (HRpooled, 0.50 [95% CI, 0.31-0.79]).CONCLUSIONS: Although we found no clear effect of SGLT2i on total stroke in CREDENCE or across trials combined, there was some evidence of benefit in preventing hemorrhagic stroke and AF/AFL, as well as total stroke for those with lowest estimated glomerular filtration rate. Future research should focus on confirming these data and exploring potential mechanisms. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02065791

Kidney and Cardiovascular Effects of Canagliflozin According to Age and Sex: A Post Hoc Analysis of the CREDENCE Randomized Clinical Trial

Rationale & Objective: It is unclear whether the effect of canagliflozin on adverse kidney and cardiovascular events in those with diabetic kid-ney disease varies by age and sex. We assessed the effects of canagliflozin among age group categories and between sexes in the Canagli-flozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study.Study Design: Secondary analysis of a random-ized controlled trial. Setting & Participants: Participants in the CREDENCE trial. Intervention: Participants were randomly assigned to receive canagliflozin 100 mg/d or placebo.Outcomes: Primary composite outcome of kid-ney failure, doubling of serum creatinine con-centration, or death due to kidney or cardiovascular disease. Prespecified secondary and safety outcomes were also analyzed. Out-comes were evaluated by age at baseline (<60, 60-69, and >_70 years) and sex in the intention-to-treat population using Cox regression models.Results: The mean age of the cohort was 63.0 & PLUSMN; 9.2 years, and 34% were female. Older age and female sex were independently associ-ated with a lower risk of the composite of adverse kidney outcomes. There was no evidence that the effect of canagliflozin on the primary outcome (acomposite of kidney failure, a doubling of serum creatinine concentration, or death from kidney or cardiovascular causes) differed between age groups (HRs, 0.67 [95% CI, 0.52-0.87], 0.63 [0.4 8-0.82], and 0.89 [0.61-1.29] for ages <60, 60-69, and >_70 years, respectively; P = 0.3 for interaction) or sexes (HRs, 0.71 [95% CI, 0.5 4-0.95] and 0.69 [0.56-0.8 4] in women and men, respectively; P = 0.8 for interaction). No differences in safety outcomes by age group or sex were observed.Limitations: This was a post hoc analysis with multiple comparisons.Conclusions: Canagliflozin consistently reduced the relative risk of kidney events in people with diabetic kidney disease in both sexes and across age subgroups. As a result of greater background risk, the absolute reduction in adverse kidney outcomes was greater in younger participants.Funding: This post hoc analysis of the CREDENCE trial was not funded. The CREDENCE study was sponsored by Janssen Research and Development and was conducted collaboratively by the sponsor, an academic-led steering committee, and an academic research organization, George Clinical.Trial Registration: The original CREDENCE trial was registered at ClinicalTrials.gov with study number NCT02065791

Inclusive quarkonium production in pp collisions at s=5.02\sqrt{s} = 5.02 TeV

This article reports on the inclusive production cross section of several quarkonium states, $\mathrm{J}/\psi$, $\psi {\rm (2S)}$, $\Upsilon\rm(1S)$, $\Upsilon\rm(2S)$, and $\Upsilon\rm(3S)$, measured with the ALICE detector at the LHC, in \pp collisions at $\sqrt{s} = 5.02$ TeV. The analysis is performed in the dimuon decay channel at forward rapidity ($2.5 < y < 4$). The measured cross sections, assuming unpolarized quarkonia, are: $\sigma_{\mathrm{J}/\psi} = 5.88 \pm 0.03 \pm 0.34\ \mu$b, $\sigma_{\psi {\rm (2S)}} = 0.87 \pm 0.06 \pm 0.10\ \mu$b, $\sigma_{\Upsilon\rm(1S)} = 45.5 \pm 3.9 \pm 3.5$ nb, $\sigma_{\Upsilon\rm(2S)} = 22.4 \pm 3.2 \pm 2.7$ nb, and $\sigma_{\Upsilon\rm(3S)} = 4.9 \pm 2.2 \pm 1.0$ nb, where the first (second) uncertainty is the statistical (systematic) one. The transverse-momentum ($p_{\rm T}$) and rapidity ($y$) differential cross sections for $\mathrm{J}/\psi$, $\psi {\rm (2S)}$, $\Upsilon\rm(1S)$, and the $\psi {\rm (2S)}$-to-$\mathrm{J}/\psi$ cross section ratios are presented. For the first time, the cross sections of the three $\Upsilon$ states, as well as the $\psi {\rm (2S)}$ one as a function of $p_{\rm T}$ and $y$, are measured at $\sqrt{s} = 5.02$ TeV at forward rapidity. These measurements also significantly extend the $\mathrm{J}/\psi$$p_{\rm T}$ reach with respect to previously published results. A comparison with ALICE measurements in pp collisions at $\sqrt{s} = 2.76$, 7, 8, and 13 TeV is presented and the energy dependence of quarkonium production cross sections is discussed. Finally, the results are compared with the predictions from several production models

Inclusive quarkonium production in pp collisions at s=5.02\sqrt{s} = 5.02 TeV

This article reports on the inclusive production cross section of several quarkonium states, $\mathrm{J}/\psi$, $\psi {\rm (2S)}$, $\Upsilon\rm(1S)$, $\Upsilon\rm(2S)$, and $\Upsilon\rm(3S)$, measured with the ALICE detector at the LHC, in \pp collisions at $\sqrt{s} = 5.02$ TeV. The analysis is performed in the dimuon decay channel at forward rapidity ($2.5 < y < 4$). The measured cross sections, assuming unpolarized quarkonia, are: $\sigma_{\mathrm{J}/\psi} = 5.88 \pm 0.03 \pm 0.34\ \mu$b, $\sigma_{\psi {\rm (2S)}} = 0.87 \pm 0.06 \pm 0.10\ \mu$b, $\sigma_{\Upsilon\rm(1S)} = 45.5 \pm 3.9 \pm 3.5$ nb, $\sigma_{\Upsilon\rm(2S)} = 22.4 \pm 3.2 \pm 2.7$ nb, and $\sigma_{\Upsilon\rm(3S)} = 4.9 \pm 2.2 \pm 1.0$ nb, where the first (second) uncertainty is the statistical (systematic) one. The transverse-momentum ($p_{\rm T}$) and rapidity ($y$) differential cross sections for $\mathrm{J}/\psi$, $\psi {\rm (2S)}$, $\Upsilon\rm(1S)$, and the $\psi {\rm (2S)}$-to-$\mathrm{J}/\psi$ cross section ratios are presented. For the first time, the cross sections of the three $\Upsilon$ states, as well as the $\psi {\rm (2S)}$ one as a function of $p_{\rm T}$ and $y$, are measured at $\sqrt{s} = 5.02$ TeV at forward rapidity. These measurements also significantly extend the $\mathrm{J}/\psi$$p_{\rm T}$ reach with respect to previously published results. A comparison with ALICE measurements in pp collisions at $\sqrt{s} = 2.76$, 7, 8, and 13 TeV is presented and the energy dependence of quarkonium production cross sections is discussed. Finally, the results are compared with the predictions from several production models

K*(892)0 and ϕ(1020) production in p-Pb collisions at sNN\sqrt{s_{NN}} = 8.16 TeV

The production of K∗(892)0 and ϕ(1020) resonances has been measured in p-Pb collisions at sNN−−−√ = 8.16 TeV using the ALICE detector. Resonances are reconstructed via their hadronic decay channels in the rapidity interval −0.5 8 GeV/c), the RpPb values of all hadrons are consistent with unity within uncertainties. The RpPb of K∗(892)0 and ϕ(1020) at sNN−−−√ = 8.16 and 5.02 TeV show no significant energy dependence

Constraining hadronization mechanisms with Λc+\rm \Lambda_{\rm c}^{+}/D0^0 production ratios in Pb-Pb collisions at sNN=5.02\sqrt{s_{\rm NN}} = 5.02 TeV

The production of prompt $\rm \Lambda_{\rm c}^{+}$ baryons at midrapidity ($|y|<0.5$) was measured in central (0-10%) and mid-central (30-50%) Pb-Pb collisions at the center-of-mass energy per nucleon-nucleon pair $\sqrt{s_{\rm NN}} = 5.02$ TeV with the ALICE detector. The $\rm \Lambda_{\rm c}^{+}$ production yield, the $\rm \Lambda_{\rm c}^{+}$/D$^0$ production ratio, and the $\rm \Lambda_{\rm c}^{+}$ nuclear modification factor $R_{\rm AA}$ are reported. The results are more precise and more differential in transverse momentum ($p_{\rm T}$) and centrality with respect to previous measurements. The $\rm \Lambda_{\rm c}^{+}$/D$^0$ ratio, which is enhanced with respect to the pp measurement for $4< p_{\rm T} < 8$ GeV/$c$, is described by theoretical calculations that model the charm-quark transport in the quark-gluon plasma and include hadronization via both coalescence and fragmentation mechanisms