Canagliflozin reduces cardiovascular events including hospitalization for heart failure (HHF) in patients with type 2 diabetes and cardiovascular risk. Elevated amino-terminal pro-B-type natriuretic ...peptide (NT-proBNP) concentrations are associated with HF diagnosis and predict cardiovascular risk.
The purpose of this study was to measure NT-proBNP in CANVAS (Canagliflozin Cardiovascular Assessment Study) participants.
Associations between baseline NT-proBNP and cardiovascular, renal, and mortality outcomes and intervention-associated changes were determined.
Of the 4,330 participants in the CANVAS trial, NT-proBNP was measured in 3,587, 2,918, and 995 participants at baseline, 1 year, and 6 years, respectively. The median baseline NT-proBNP concentration was 91 pg/ml, and 39.3% had NT-proBNP ≥125 pg/ml. NT-proBNP was higher in those with investigator-reported HF (13% of participants at baseline) versus those without (187 pg/ml vs. 81 pg/ml), with substantial overlap between groups. By 1 year, NT-proBNP increased with placebo, whereas canagliflozin reduced NT-proBNP by 11% (geometric mean ratio for canagliflozin vs. placebo = 0.89 95% confidence interval (CI): 0.84 to 0.94; p < 0.001). Lower NT-proBNP with canagliflozin was also observed at 6 years (p = 0.004). In adjusted models, baseline NT-proBNP ≥125 pg/ml was prognostic for incident HHF (hazard ratio HR: 5.40; 95% CI: 2.67 to 10.9), HHF/cardiovascular death (HR: 3.52; 95% CI: 2.38 to 5.20), and all-cause death (HR: 2.53; 95% CI: 1.78 to 3.61). Mediation analyses suggested that 10.4% of the effects of canagliflozin on HHF were reflected in NT-proBNP lowering.
A substantial percentage of patients in the CANVAS trial had elevated NT-proBNP values. Canagliflozin reduced NT-proBNP concentrations versus placebo; however, reduction in NT-proBNP explained only a small proportion of the benefit of canagliflozin on HF events. (CANVAS CANagliflozin cardioVascular Assessment Study; NCT01032629).
Acute Heart Failure (AHF) is a " multi-event disease" and hospitalisation is a critical event in the clinical course of HF. Despite relatively rapid relief of symptoms, hospitalisation for AHF is ...followed by an increased risk of death and re-hospitalisation. In AHF, risk stratification from clinically available data is increasingly important in evaluating long-term prognosis. From the perspective of patients, information on the risk of mortality and re-hospitalisation would be helpful in providing patients with insight into their disease. From the perspective of care providers, it may facilitate management decisions, such as who needs to be admitted and to what level of care (i.e. floor, step-down, ICU). Furthermore, risk-stratification may help identify patients who need to be evaluated for advanced HF therapies (i.e. left-ventricle assistance device or transplant or palliative care), and patients who need early a post-discharge follow-up plan. Finally, risk stratification will allow for more robust efforts to identify among risk markers the true targets for therapies that may direct treatment strategies to selected high-risk patients. Further clinical research will be needed to evaluate if appropriate risk stratification of patients could improve clinical outcome and resources allocation.
Oral sodium zirconium cyclosilicate (formerly ZS-9) binds and removes potassium
the gastrointestinal tract. Sodium zirconium cyclosilicate-associated restoration and maintenance of normokalemia and ...adverse events were evaluated in a two-part, open label, phase 3 trial.
In the correction phase, adult outpatients with plasma potassium ≥5.1 mmol/L (i-STAT Point-of-Care) received sodium zirconium cyclosilicate 10 g three times daily for 24-72 hours until normokalemic (potassium =3.5-5.0 mmol/L). Qualifying participants entered the ≤12-month maintenance phase and received sodium zirconium cyclosilicate 5 g once daily titrated to maintain normokalemia without dietary or medication restrictions. Prespecified primary end points were restoration of normal serum potassium values (3.5-5.0 mmol/L) during the correction phase and maintenance of serum potassium ≤5.1 mmol/L during the maintenance phase. Adverse events were assessed throughout.
Of 751 participants, 746 (99%) achieved normokalemia during the correction phase (mean serum potassium =4.8 mmol/L; 95% confidence interval, 4.7 to 4.8) and entered the maintenance phase; 466 (63%) participants completed the 12-month trial. Participants were predominantly white, men, and age ≥65 years old; 74% had an eGFR<60 ml/min per 1.73 m
, and 65% used renin-angiotensin-aldosterone system inhibitors. Mean time on sodium zirconium cyclosilicate was 286 days. Mean daily sodium zirconium cyclosilicate dose was 7.2 g (SD=2.6). Over months 3-12, mean serum potassium was 4.7 mmol/L (95% confidence interval, 4.6 to 4.7); mean serum potassium values ≤5.1 and ≤5.5 mmol/L were achieved by 88% and 99% of participants, respectively. Of 483 renin-angiotensin-aldosterone system inhibitor users at baseline, 87% continued or had their dose increased; 11% discontinued. Among 263 renin-angiotensin-aldosterone system inhibitor-naïve participants, 14% initiated renin-angiotensin-aldosterone system inhibitor therapy. Overall, 489 (66%) participants experienced adverse events during the maintenance phase, and 22% experienced a serious adverse event. Of eight (1%) deaths, none were considered related to sodium zirconium cyclosilicate. Nine (1%) and 34 (5%) participants experienced serum potassium <3.0 and 3.0-3.4 mmol/L, respectively.
After achieving normokalemia, individualized once daily sodium zirconium cyclosilicate was associated with maintenance of normokalemia without substantial renin-angiotensin-aldosterone system inhibitor changes for ≤12 months.
Sodium–glucose co‐transporter 2 (SGLT2) inhibitors have recently been recommended as a foundational therapy for patients with heart failure (HF) and reduced ejection fraction (HFrEF) because of their ...favourable effects on mortality, clinical events and quality of life. While clinical practice guidelines have recommended dapagliflozin or empagliflozin in all patients with HFrEF, or sotagliflozin in those with HFrEF and concomitant diabetes, the timing and practical integration of these drugs in clinical practice is less well defined. We propose that these drugs are candidates for early, upfront administration to patients with newly diagnosed HFrEF and for patients hospitalized with HF. Growing evidence has established early benefits, with clinically meaningful reductions in clinical events that reach statistical significance within days to weeks, following dapagliflozin, empagliflozin or, in diabetic patients, sotagliflozin initiation. Secondly, although major clinical trials have tested these drugs in patients already receiving background HF therapy, secondary analyses showed that their efficacy is independent of that. Third, SGLT2 inhibitors are generally safe and well tolerated, with clinical trial data reporting minimal effects on blood pressure, glycaemia‐related adverse events, and no excess in acute kidney injury. Rather, they exert renal protective effects and reduce risk of hyperkalaemia, properties that favour initiation, tolerance and persistence of renin–angiotensin system inhibitors and mineralocorticoid receptor antagonists. This review supports the early initiation of dapagliflozin and empagliflozin (or sotagliflozin limited to patients with diabetes) to rapidly improve clinical outcome and quality of life of HFrEF patients.
When and how to initiate sodium–glucose co‐transporter 2 (SGLT2) inhibitors. Data based on enrolment criteria of the DAPA‐HF, EMPEROR‐Reduced and EMPULSE trials. eGFR, estimated glomerular filtration rate; HFrEF, heart failure with reduced ejection fraction.
INTRODUCTION/PURPOSEInflammation contributes to heart failure (HF) progression and the interleukin (IL)-1 cytokine IL-1β is implicated in this process. The adaptor protein apoptosis-associated ...speck-like protein containing a caspase recruitment domain (ASC) is necessary for inflammasome activation of IL-1β. Lower ASC methylation is associated with worse outcomes in HF. The purpose of this study was to examine the effects of exercise on changes in ASC methylation and activation of the IL-1 family cytokine IL-1β in persons with HF.
METHODSParticipants (N = 54) were randomized to receive exercise intervention (n = 38) or attention control (n = 16) for 3 months. Percent methylation of the ASC gene, plasma IL-1β, and ASC mRNA and were obtained at baseline, 3 months, and 6 months.
RESULTSASC methylation was higher in the exercise group as compared to control at 3 months (6.10% ± 0.5% vs 5.80% ± 0.4%; P = 0.04) and 6 months (6.07 ± 0.4 vs 5.82 ± 0.4; P = 0.04). Plasma IL-1β was lower in the exercise group at 3 months (1.43 ± 0.5 pg·mL vs 2.09 ± 1.3 pg·mL; P = 0.02) and 6 months (1.49 ± 0.5 pg·mL vs 2.13 ± 1.4 pg·mL; P = 0.004). ASC mRNA expression was negatively associated with ASC methylation at baseline (r = −0.97, P = 0.001), 3 months (r = −0.90, P = 0.001), and 6 months (r = −0.81, P = 0.001). ASC mRNA was lower than baseline at 3 months (P = 0.004) and 6 months (P = 0.002) among those in the exercise group. ASC methylation was positively associated with 6-min walk test at baseline (r = 0.517, P < 0.001), 3 months (r = 0.464, P = 0.004), and 6 months (r = 497, P = 0.05).
CONCLUSIONSExercise was related to increased mean percent ASC methylation and decreased IL-1β and ASC mRNA gene expression in HF. Epigenetic regulation of ASC can be a biological mechanism by which exercise can promote better outcomes in HF.
Patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) are at risk of atrial fibrillation or flutter (AFF) due to cardiac remodeling and kidney complications. Finerenone, a novel, ...selective, nonsteroidal mineralocorticoid receptor antagonist, inhibited cardiac remodeling in preclinical models.
This work aims to examine the effect of finerenone on new-onset AFF and cardiorenal effects by history of AFF in the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) study.
Patients with CKD and T2D were randomized (1:1) to finerenone or placebo. Eligible patients had a urine albumin-to-creatinine ratio ≥30 to ≤5,000 mg/g, an estimated glomerular filtration rate (eGFR) ≥25 to <75 ml/min/1.73 m2 and received optimized doses of renin–angiotensin system blockade. Effect on new-onset AFF was evaluated as a pre-specified outcome adjudicated by an independent cardiologist committee. The primary composite outcome (time to first onset of kidney failure, a sustained decrease of ≥40% in eGFR from baseline, or death from renal causes) and key secondary outcome (time to first onset of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) were analyzed by history of AFF.
Of 5,674 patients, 461 (8.1%) had a history of AFF. New-onset AFF occurred in 82 (3.2%) patients on finerenone and 117 (4.5%) patients on placebo (hazard ratio: 0.71; 95% confidence interval: 0.53–0.94; p = 0.016). The effect of finerenone on primary and key secondary kidney and cardiovascular outcomes was not significantly impacted by baseline AFF (interaction p value: 0.16 and 0.85, respectively).
In patients with CKD and T2D, finerenone reduced the risk of new-onset AFF. The risk of kidney or cardiovascular events was reduced irrespective of history of AFF at baseline. (EudraCT 2015-000990-11 A randomized, double-blind, placebo-controlled, parallel-group, multicenter, event-driven Phase III study to investigate the efficacy and safety of finerenone, in addition to standard of care, on the progression of kidney disease in subjects with type 2 diabetes mellitus and the clinical diagnosis of diabetic kidney disease; Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease FIDELIO-DKD; NCT02540993)
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