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 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

Analysis of molecular mechanisms and anti-tumoural effects of zoledronic acid in breast cancer cells

Zoledronic acid (ZOL) is the most potent nitrogen-containing bisphosphonate (N-BPs) that strongly binds to bone mineral and acts as a powerful inhibitor of bone resorption, already clinically available for the treatment of patients with osteolytic metastases. Recent data also suggest that ZOL, used in breast cancer, may provide more than just supportive care modifying the course of the disease, though the possible molecular mechanism of action is still unclear.As breast cancer is one of the primary tumours with high propensity to metastasize to the bone, we investigated, for the first time, differential gene expression profile on Michigan Cancer Foundation-7 (MCF-7) breast cancer cells treated with low doses of ZOL (10 μM). Microarrays analysis was used to identify, describe and summarize evidence regarding the molecular basis of actions of ZOL and of their possible direct anti-tumour effects. We validated gene expression results of specific transcripts involved in major cellular process by Real Time and Western Blot analysis and we observed inhibition of proliferation and migration through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Matrigel assay. We then focused on changes in the cytoskeletal components as fibronectin 1 (FN1), actin, and anti angiogenic compounds as transforming growth factor-β1 (TGF-β1) and thrombospondin 1 (THBS1). The up-regulation of these products may have an important role in inhibiting proliferation, invasion and angiogenesis mediated by ZOL

The Atacama Cosmology Telescope: Detection of the pairwise kinematic Sunyaev-Zel’dovich effect with SDSS DR15 galaxies ()

We present a detection of the pairwise kinematic Sunyaev-Zeldovich (kSZ) effect using Atacama Cosmology Telescope (ACT) and Planck CMB observations in combination with Luminous Red Galaxy samples from the Sloan Digital Sky Survey (SDSS) DR15 catalog. Results are obtained using three ACT CMB maps: co-added 150 and 98&nbsp;GHz maps, combining observations from 2008-2018 (ACT DR5), which overlap with SDSS DR15 over 3,700&nbsp;sq.&nbsp;deg., and a component-separated map using night-time only observations from 2014-2015 (ACT DR4), overlapping with SDSS DR15 over 2,089&nbsp;sq.&nbsp;deg. Comparisons of the results from these three maps provide consistency checks in relation to potential frequency-dependent foreground contamination. A total of 343,647 galaxies are used as tracers to identify and locate galaxy groups and clusters from which the kSZ signal is extracted using aperture photometry. We consider the impact of various aperture photometry assumptions and covariance estimation methods on the signal extraction. Theoretical predictions of the pairwise velocities are used to obtain best-fit, mass-averaged, optical depth estimates for each of five luminosity-selected tracer samples. A comparison of the kSZ-derived optical depth measurements obtained here to those derived from the thermal SZ effect for the same sample is presented in a companion paper

The Atacama Cosmology Telescope: Probing the baryon content of SDSS DR15 galaxies with the thermal and kinematic Sunyaev-Zel’dovich effects

We present measurements of the average thermal Sunyaev Zel’dovich (tSZ) effect from optically selected galaxy groups and clusters at high signal-to-noise (up to 12σ) and estimate their baryon content within a 2.1′ radius aperture. Sources from the Sloan Digital Sky Survey (SDSS) Baryon Oscillation Spectroscopic Survey (BOSS) DR15 catalog overlap with 3,700 sq. deg. of sky observed by the Atacama Cosmology Telescope (ACT) from 2008 to 2018 at 150 and 98 GHz (ACT DR5), and 2,089 sq. deg. of internal linear combination component-separated maps combining ACT and Planck data (ACT DR4). The corresponding optical depths, ¯τ , which depend on the baryon content of the halos, are estimated using results from cosmological hydrodynamic simulations assuming an AGN feedback radiative cooling model. We estimate the mean mass of the halos in multiple luminosity bins, and compare the tSZ-based ¯τ estimates to theoretical predictions of the baryon content for a Navarro–Frenk–White profile. We do the same for ¯τ estimates extracted from fits to pairwise baryon momentum measurements of the kinematic Sunyaev-Zel’dovich effect (kSZ) for the same data set obtained in a companion paper. We find that the ¯τ estimates from the tSZ measurements in this work and the kSZ measurements in the companion paper agree within 1σ for two out of the three disjoint luminosity bins studied, while they differ by 2-3σ in the highest luminosity bin. The optical depth estimates account for one third to all of the theoretically predicted baryon content in the halos across luminosity bins. Potential systematic uncertainties are discussed. The tSZ and kSZ measurements provide a step towards empirical Compton-¯y-¯τ relationships to provide new tests of cluster formation and evolution models

The Atacama Cosmology Telescope: Detection of the pairwise kinematic Sunyaev-Zel’dovich effect with SDSS DR15 galaxies

We present a 5.4σ detection of the pairwise kinematic Sunyaev-Zel’dovich (kSZ) effect using At- acama Cosmology Telescope (ACT) and Planck CMB observations in combination with Luminous Red Galaxy samples from the Sloan Digital Sky Survey (SDSS) DR15 catalog. Results are obtained using three ACT CMB maps: co-added 150 GHz and 98 GHz maps, combining observations from 2008-2018 (ACT DR5), which overlap with SDSS DR15 over 3,700 sq. deg., and a component- separated map using night-time only observations from 2014-2015 (ACT DR4), overlapping with SDSS DR15 over 2,089 sq. deg. Comparisons of the results from these three maps provide con- sistency checks in relation to potential frequency-dependent foreground contamination. A total of 343,647 galaxies are used as tracers to identify and locate galaxy groups and clusters from which the kSZ signal is extracted using aperture photometry. We consider the impact of various aperture photometry assumptions and covariance estimation methods on the signal extraction. Theoretical predictions of the pairwise velocities are used to obtain best-fit, mass-averaged, optical depth esti- mates for each of five luminosity-selected tracer samples. A comparison of the kSZ-derived optical depth measurements obtained here to those derived from the thermal SZ effect for the same sample is presented in a companion paper

The Atacama Cosmology Telescope: Probing the baryon content of SDSS DR15 galaxies with the thermal and kinematic Sunyaev-Zel’dovich effects

We present measurements of the average thermal Sunyaev Zel’dovich (tSZ) effect from optically selected galaxy groups and clusters at high signal-to-noise (up to ) and estimate their baryon content within a radius aperture. Sources from the Sloan Digital Sky Survey Baryon Oscillation Spectroscopic Survey DR15 catalog overlap with 3,700 sq deg of sky observed by the Atacama Cosmology Telescope (ACT) from 2008 to 2018 at 150 and 98&nbsp;GHz (ACT DR5), and 2,089 sq deg of internal linear combination component-separated maps combining ACT and Planck data (ACT DR4). The corresponding optical depths , which depend on the baryon content of the halos, are estimated using results from cosmological hydrodynamic simulations assuming an active galactic nuclei feedback radiative cooling model. We estimate the mean mass of the halos in multiple luminosity bins, and compare the tSZ-based estimates to theoretical predictions of the baryon content for a Navarro-Frenk-White profile. We do the same for estimates extracted from fits to pairwise baryon momentum measurements of the kinematic Sunyaev-Zel’dovich effect (kSZ) for the same dataset obtained in a companion paper. We find that the estimates from the tSZ measurements in this work and the kSZ measurements in the companion paper agree within for two out of the three disjoint luminosity bins studied, while they differ by in the highest luminosity bin. The optical depth estimates account for one-third to all of the theoretically predicted baryon content in the halos across luminosity bins. Potential systematic uncertainties are discussed. The tSZ and kSZ measurements provide a step toward empirical Compton- relationships to provide new tests of cluster formation and evolution models