Effects of canagliflozin on cardiovascular biomarkers in older adults with type 2 diabetes

Background: Sodium glucose co-transporter 2 (SGLT2) inhibitors may reduce cardiovascular and heart failure risk in patients with type 2 diabetes mellitus (T2DM). Objectives: To examine the effects of canagliflozin on cardiovascular biomarkers in older patients with T2DM. Methods: In 666 T2DM patients randomized to receive canagliflozin 100 or 300 mg or placebo, we assessed median percent change in serum N-terminal pro-B type natriuretic peptide (NT-proBNP), high-sensitivity troponin I (hsTnI) , soluble (s)ST2, and galectin-3 from baseline to 26, 52, and 104 weeks. Results: Both serum NT-proBNP and serum hsTnI levels increased in placebo recipients but remained largely unchanged in those randomized to canagliflozin. Hodges-Lehmann estimates of the difference in median percent change between pooled canagliflozin and placebo were –15.0%, –16.1%, and –26.8% for NT-proBNP, and –8.3%, –11.9%, and –10.0% for hsTnI at weeks 26, 52, and 104, respectively (all P <0.05). Serum sST2 was unchanged with canagliflozin and placebo over 104 weeks. Serum galectin-3 modestly increased from baseline with canagliflozin versus placebo, with significant differences observed at 26 and 52 weeks but not at 104 weeks. These results remained unchanged when only patients with complete samples were assessed. Conclusions: Compared to placebo, treatment with canagliflozin delayed rise in serum NT-proBNP and hsTnI over 2 years in older T2DM patients. These cardiac biomarker data provide support for beneficial cardiovascular effect of SGLT2 inhibitors in T2DM

Monitoring of biomarkers in heart failure.

The role of biomarkers is increasingly recognized in heart failure (HF) management, for diagnosis, prognostication, and screening of high-risk patients. Beyond natriuretic peptides and troponins, the utility of novel, emerging biomarkers is less established. This document reflects the key points of a Heart Failure Association of the European Society of Cardiology (ESC) consensus meeting on biomarker monitoring in HF

The Deuterium Abundance at z=0.701 towards QSO 1718+4807

We present constraints on the deuterium to hydrogen ratio (D/H) in the metal-poor gas cloud at redshift $z=0.701$ towards QSO 1718+4807. We use new Keck spectra in addition to Hubble Space Telescope (HST) and International Ultraviolet Explorer (IUE) spectra. We use an improved redshift and a lower \HI column density to model the absorption. The HST spectrum shows an asymmetric Lyman-$\alpha$ (\lya) feature which is produced by either \HI at a second velocity, or a high abundance of D. Three models with a single simple H+D component give $8 \times 10^{-5} < D/H < 57 \times 10^{-5}$ (95%), a much larger range than reported by Webb et al (1997a,b). A more sophisticated velocity distribution, or a second component is necessary for lower D/H. With two components, which could be a part of one absorbing structure, or separate clouds in a galaxy halo, we find $D/H < 50 \times 10^{-5}$. We do not know if this second component is present, but it is reasonable because 40 -- 100% of absorption systems with similar redshifts and \HI column densities have more than one component.Comment: 13 pages, 4 figures, to appear in the Astronomical Journal (Jan 1999

Effect of Natriuretic Peptide-Guided Therapy on Hospitalization or Cardiovascular Mortality in High-Risk Patients With Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial.

Importance: The natriuretic peptides are biochemical markers of heart failure (HF) severity and predictors of adverse outcomes. Smaller studies have evaluated adjusting HF therapy based on natriuretic peptide levels ( guided therapy ) with inconsistent results. Objective: To determine whether an amino-terminal pro-B-type natriuretic peptide (NT-proBNP)-guided treatment strategy improves clinical outcomes vs usual care in high-risk patients with HF and reduced ejection fraction (HFrEF). Design, Settings, and Participants: The Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure (GUIDE-IT) study was a randomized multicenter clinical trial conducted between January 16, 2013, and September 20, 2016, at 45 clinical sites in the United States and Canada. This study planned to randomize 1100 patients with HFrEF (ejection fraction ≤40%), elevated natriuretic peptide levels within the prior 30 days, and a history of a prior HF event (HF hospitalization or equivalent) to either an NT-proBNP-guided strategy or usual care. Interventions: Patients were randomized to either an NT-proBNP-guided strategy or usual care. Patients randomized to the guided strategy (n = 446) had HF therapy titrated with the goal of achieving a target NT-proBNP of less than 1000 pg/mL. Patients randomized to usual care (n = 448) had HF care in accordance with published guidelines, with emphasis on titration of proven neurohormonal therapies for HF. Serial measurement of NT-proBNP testing was discouraged in the usual care group. Main Outcomes and Measures: The primary end point was the composite of time-to-first HF hospitalization or cardiovascular mortality. Prespecified secondary end points included all-cause mortality, total hospitalizations for HF, days alive and not hospitalized for cardiovascular reasons, the individual components on the primary end point, and adverse events. Results: The data and safety monitoring board recommended stopping the study for futility when 894 (median age, 63 years; 286 [32%] women) of the planned 1100 patients had been enrolled with follow-up for a median of 15 months. The primary end point occurred in 164 patients (37%) in the biomarker-guided group and 164 patients (37%) in the usual care group (adjusted hazard ratio [HR], 0.98; 95% CI, 0.79-1.22; P = .88). Cardiovascular mortality was 12% (n = 53) in the biomarker-guided group and 13% (n = 57) in the usual care group (HR, 0.94; 95% CI; 0.65-1.37; P = .75). None of the secondary end points nor the decreases in the NT-proBNP levels achieved differed significantly between groups. Conclusions and Relevance: In high-risk patients with HFrEF, a strategy of NT-proBNP-guided therapy was not more effective than a usual care strategy in improving outcomes. Trial Registration: clinicaltrials.gov Identifier: NCT01685840

Rationale and design of the GUIDE-IT study: Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure.

OBJECTIVES: The GUIDE-IT (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure) study is designed to determine the safety, efficacy, and cost-effectiveness of a strategy of adjusting therapy with the goal of achieving and maintaining a target N-terminal pro-B-type natriuretic peptide (NT-proBNP) level of BACKGROUND: Elevations in natriuretic peptide (NP) levels provide key prognostic information in patients with HF. Therapies proven to improve outcomes in patients with HF are generally associated with decreasing levels of NPs, and observational data show that decreases in NP levels over time are associated with favorable outcomes. Results from smaller prospective, randomized studies of this strategy thus far have been mixed, and current guidelines do not recommend serial measurement of NP levels to guide therapy in patients with HF. METHODS: GUIDE-IT is a prospective, randomized, controlled, unblinded, multicenter clinical trial designed to randomize approximately 1,100 high-risk subjects with systolic HF (left ventricular ejection fraction ≤40%) to either usual care (optimized guideline-recommended therapy) or a strategy of adjusting therapy with the goal of achieving and maintaining a target NT-proBNP level of CONCLUSIONS: The GUIDE-IT study is designed to definitively assess the effects of an NP-guided strategy in high-risk patients with systolic HF on clinically relevant endpoints of mortality, hospitalization, quality of life, and medical resource use. (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure [GUIDE-IT]; NCT01685840)

Elevated plasma galectin-3 is associated with near-term rehospitalization in heart failure:A pooled analysis of 3 clinical trials

BackgroundRehospitalization is a major cause for heart failure (HF)–related morbidity and is associated with considerable loss of quality of life and costs. The rate of unplanned rehospitalization in patients with HF is unacceptably high; current risk stratification to identify patients at risk for rehospitalization is inadequate. We evaluated whether measurement of galectin-3 would be helpful in identifying patients at such risk.MethodsWe analyzed pooled data from patients (n = 902) enrolled in 3 cohorts (COACH, n = 592; PRIDE, n = 181; and UMD H-23258, n = 129) originally admitted because of HF. Mean patient age was between 61.6 and 72.9 years across the cohorts, with a wide range of left ventricular ejection fraction. Galectin-3 levels were measured during index admission. We used fixed and random-effects models, as well as continuous and categorical reclassification statistics to assess the association of baseline galectin-3 levels with risk of postdischarge rehospitalization at different time points and the composite end point all-cause mortality and rehospitalization.ResultsCompared with patients with galectin-3 concentrations less than 17.8 ng/mL, those with results exceeding this value were significantly more likely to be rehospitalized for HF at 30, 60, 90, and 120 days after discharge, with odds ratios (ORs) of 2.80 (95% CI 1.41-5.57), 2.61 (95% CI 1.46-4.65), 3.01 (95% CI 1.79-5.05), and 2.79 (95% CI 1.75-4.45), respectively. After adjustment for age, gender, New York Heart Association class, renal function (estimated glomerular filtration rate), left ventricular ejection fraction, and B-type natriuretic peptide, galectin-3 remained an independent predictor of HF rehospitalization. The addition of galectin-3 to risk models significantly reclassified patient risk of postdischarge rehospitalization and fatal event at each time point (continuous net reclassification improvement at 30 days of +42.6% [95% CI +19.9%-65.4%], P < .001).ConclusionsAmong patients hospitalized for HF, plasma galectin-3 concentration is useful for the prediction of near-term rehospitalization

Cardiorenal Biomarkers, Canagliflozin, and Outcomes in Diabetic Kidney Disease: The CREDENCE Trial

BACKGROUND: People with type 2 diabetes and albuminuria are at an elevated risk for cardiac and renal events. The optimal biomarkers to aid disease prediction and to understand the benefits of sodium-glucose cotransporter-2 inhibition remain unclear. METHODS: Among 2627 study participants in the CREDENCE trial (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), concentrations of NT-proBNP (N-terminal pro-B-type natriuretic peptide), high-sensitivity cardiac troponin T, growth differentiation factor-15, and IGFBP7 (insulin-like growth factor binding protein 7) were measured. The effect of canagliflozin on biomarker concentrations was evaluated. The prognostic potential of each biomarker on the primary outcome (a composite of end-stage kidney disease [dialysis, transplantation, or a sustained estimated glomerular filtration rate of <15 mL·min-1·1.73 m-2], doubling of the serum creatinine level, or renal death or cardiovascular death) was assessed. RESULTS: The median (quartiles 1 and 3) concentration of each biomarker was generally elevated: NT-proBNP, 180 ng/L (82, 442 ng/L); high-sensitivity cardiac troponin T, 19 ng/L (12, 29 ng/L); growth differentiation factor-15, 2595 ng/L (1852, 3775 ng/L); and IGFBP7, 121.8 ng/mL (105.4, 141.5 ng/mL). At 1 year, the biomarkers all rose by 6% to 29% in the placebo arm but only by 3% to 10% in the canagliflozin arm (all P<0.01 in multivariable linear mixed-effect models). Baseline concentrations of each biomarker were strongly predictive of cardiac and renal outcomes. When the biomarkers were analyzed together in a multimarker panel, individuals with high risk scores (hazard ratio [HR], 4.01 [95% CI, 2.52-6.35]) and moderate risk scores (HR, 2.39 [95% CI, 1.48-3.87]) showed a higher risk for the primary outcome compared with those with low risk scores. By 1 year, a 50% increase in NT-proBNP (HR, 1.11 [95% CI, 1.08-1.15]), high-sensitivity cardiac troponin T (HR, 1.86 [95% CI, 1.64-2.10]), growth differentiation factor-15 (HR, 1.45 [95% CI, 1.24-1.70]), and IGFBP7 (HR, 3.76 [95% CI, 2.54-5.56]) was associated with risk of the primary outcome. CONCLUSIONS: Multiple cardiorenal stress biomarkers are strongly prognostic in people with type 2 diabetes and albuminuria. Canagliflozin modestly reduced the longitudinal trajectory of rise in each biomarker. Change in the biomarker level in addition to the baseline level augments the primary outcome prediction. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02065791

Constraining the black hole mass and accretion rate in the narrow-line Seyfert 1 RE J1034+396

We present a comprehensive study of the spectrum of the narrow-line Seyfert 1 galaxy RE J1034+396, summarizing the information obtained from the optical to X-rays with observations from the William Herschel 4.2m Telescope (WHT), the Hubble Space Telescope, the Extreme UltraViolet Explorer, ROSAT, ASCA and BeppoSAX. The BeppoSAX spectra reveal a soft component which is well-represented by two blackbodies with kT of about 60 eV and 160 eV, mimicking that expected from a hot, optically-thick accretion disc around a low-mass black hole. This is borne out by our modeling of the optical to X-ray nuclear continuum, which constrains the physical parameters of a NLS1 for the first time. The models demonstrate that RE J1034+396 is likely to be a system with a nearly edge-on accretion disk (60 to 75 degrees from the disk axis), accreting at nearly Eddington rates (0.3 to 0.7 L_edd) onto a low mass (about 2 million solar masses) black hole (abridged).Comment: ApJ accepte

Neprilysin inhibition, endorphin dynamics, and early symptomatic improvement in heart failure : a pilot study

Altres ajuts: This work was supported in part by Fundació La Marató de TV3 (201516-10, 201502-30), Societat Catalana de Cardiologia, "la Caixa" Banking Foundation.Sacubitril/valsartan is a first-in-class angiotensin receptor-neprilysin inhibitor developed for the treatment of heart failure with reduced ejection fraction. Its benefits are achieved through the inhibition of neprilysin (NEP) and the specific blockade of the angiotensin receptor AT1. The many peptides metabolized by NEP suggest multifaceted potential consequences of its inhibition. We sought to evaluate the short-term changes in serum endorphin (EP) values and their relation with patients' physical functioning after initiation of sacubitril/valsartan treatment. A total of 105 patients with heart failure with reduced ejection fraction, who were candidates for sacubitril/valsartan treatment, were included in this prospective, observational, multicentre, and international study. In a first visit, and in agreement with current guidelines, treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blocker was replaced by sacubitril/valsartan because of clinical indication by the responsible physician. By protocol, patients were reevaluated at 30 days after the start of sacubitril/valsartan. Serum levels of α- (α-EP), γ-Endorphin (γ-EP), and soluble NEP (sNEP) were measured using enzyme-linked immunoassays. New York Heart Association (NYHA) functional class was used as an indicator of patient's functional status. Baseline median levels of circulating α-EP, γ-EP, and sNEP were 582 (160-772), 101 (37-287), and 222 pg/mL (124-820), respectively. There was not a significant increase in α-EP nor γ-EP serum values after sacubitril/valsartan treatment (P value = 0.194 and 0.102, respectively). There were no significant differences in sNEP values between 30 days and baseline (P value = 0.103). Medians (IQR) of Δα-EP, Δγ-EP, and ΔsNEP between 30 days and baseline were 9.3 (−34 − 44), −3.0 (−46.0 − 18.9), and 0 units (−16.4 − 157.0), respectively. In a pre-post sacubitril/valsartan treatment comparison, there was a significant improvement in NYHA class, with 36 (34.3%) patients experiencing improvement by at least one NYHA class category. Δα-EP and ΔsNEP showed to be significantly associated with NYHA class after 30 days of treatment (P = 0.014 and P < 0.001, respectively). Δα-EP was linear and significantly associated with NYHA class improvement after 30 days of sacubitril/valsartan treatment. These preliminary data suggest that beyond the haemodynamic benefits achieved with sacubitril/valsartan, the altered cleavage of endorphin peptides by NEP inhibition may participate in patients' symptoms improvement