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

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

Measuring Omega/b with weak lensing

A correlation between the surface density of foreground galaxies tracing the Large Scale Structure and the position of distant galaxies and quasars is expected from the magnification bias effect (Canizares 1981). We show that this foreground--background correlation function w_{fb} can be used as a straightforward and almost model-free method to measure the cosmological ratio Omega/b. For samples with appropriate redshift distributions, w_{fb} is proportional to Omega, where delta and g are respectively the foreground dark matter and galaxy surface density fluctuations. Therefore, Omega/b is proportional to the ratio w_{fb}/w, where w is equivalent to , the foreground galaxy angular two-point correlation function, b is the biasing factor, and the proportionality factor is independent of the dark matter power spectrum. Simple estimations show that the application of this method to the galaxy and quasar samples generated by the upcoming Sloan Sky Digital Survey will achieve a highly accurate and well resolved measurement of the ratio Omega/b.Comment: 6 pages, 2 figures, uses macro emulateapj.sty. To appear in ApJLetter

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

Radio Galaxies at z = 1.1 to 3.8: Adaptive-Optics Imaging and Archival Hubble Space Telescope Data

We have undertaken a program of high-resolution imaging of high-redshift radio galaxies (HzRGs) using adaptive optics on the Canada-France-Hawaii Telescope. We report on deep imaging in J, H,and K bands of 6 HzRGs in the redshift range 1.1 to 3.8. At these redshifts, near-infrared bandpasses sample the rest-frame visible galaxian light. The radio galaxy is resolved in all the fields and is generally elongated along the axis of the radio lobes. These images are compared to archival Hubble Space Telescope Wide-Field Planetary Camera 2 optical observations of the same fields and show the HzRG morphology in rest-frame ultraviolet and visible light is generally very similar: a string of bright compact knots. Furthermore, this sample - although very small - suggests the colors of the knots are consistent with light from young stellar populations. If true, a plausible explanation is that these objects are being assembled by mergers at high redshift.Comment: 32 pages, 8 figures, accepted for publication in the Astrophysical Journa

Association of Novel Biomarkers of Cardiovascular Stress With Left Ventricular Hypertrophy and Dysfunction: Implications for Screening

Background: Currently available screening tools for left ventricular (LV) hypertrophy (LVH) and systolic dysfunction (LVSD) are either expensive (echocardiography) or perform suboptimally (B‐type natriuretic peptide [BNP]). It is unknown whether newer biomarkers are associated with LVH and LVSD and can serve as screening tools. Methods and Results: We studied 2460 Framingham Study participants (mean age 58 years, 57% women) with measurements of biomarkers mirroring cardiac biomechanical stress (soluble ST‐2 [ST2], growth differentiation factor‐15 [GDF‐15] and high‐sensitivity troponin I [hsTnI]) and BNP. We defined LVH as LV mass/height2 ≥the sex‐specific 80th percentile and LVSD as mild/greater impairment of LV ejection fraction (LVEF) or a fractional shortening <0.29. Adjusting for standard risk factors in logistic models, BNP, GDF‐15, and hsTnI were associated with the composite echocardiographic outcome (LVH or LVSD), odds ratios (OR) per SD increment in log‐biomarker 1.29, 1.14, and 1.18 (95% CI: 1.15 to 1.44, 1.004 to 1.28, and 1.06 to 1.31), respectively. The C‐statistic for the composite outcome increased from 0.765 with risk factors to 0.770 adding BNP, to 0.774 adding novel biomarkers. The continuous Net Reclassification Improvement was 0.212 (95% CI: 0.119 to 0.305, P<0.0001) after adding the novel biomarkers to risk factors plus BNP. BNP was associated with LVH and LVSD in multivariable models, whereas GDF‐15 was associated with LVSD (OR 1.41, 95% CI: 1.16 to 1.70), and hsTnI with LVH (OR 1.22, 95% CI: 1.09 to 1.36). ST2 was not significantly associated with any outcome. Conclusions: Our community‐based investigation suggests that cardiac stress biomarkers are associated with LVH and LVSD but may have limited clinical utility as screening tools