Triglyceride Lowering with Pemafibrate to Reduce Cardiovascular Risk.

Background: High triglyceride levels are associated with increased cardiovascular risk, but whether reductions in these levels would lower the incidence of cardiovascular events is uncertain. Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, reduces triglyceride levels and improves other lipid levels.

Methods: In a multinational, double-blind, randomized, controlled trial, we assigned patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia (triglyceride level, 200 to 499 mg per deciliter), and high-density lipoprotein (HDL) cholesterol levels of 40 mg per deciliter or lower to receive pemafibrate (0.

Inflammation drives residual risk in chronic kidney disease: a CANTOS substudy.

Aims: Hyperlipidaemia and inflammation jointly contribute to atherosclerotic disease. Yet, after the initiation of statin therapy, the relative contributions of these processes may differ in patient groups, such as those with and without impaired kidney function.

Methods And Results: Among 9151 stable statin-treated post-myocardial infarction patients participating in the CANTOS trial, the contributions of residual cholesterol risk and residual inflammatory risk were evaluated as determinants of recurrent major adverse cardiovascular events (MACE) and total mortality, stratified by baseline estimated glomerular filtration rate (eGFR) above or below 60 mL/min/1.

Effects of Randomized Treatment With Icosapent Ethyl and a Mineral Oil Comparator on Interleukin-1β, Interleukin-6, C-Reactive Protein, Oxidized Low-Density Lipoprotein Cholesterol, Homocysteine, Lipoprotein(a), and Lipoprotein-Associated Phospholipase A2: A REDUCE-IT Biomarker Substudy.

Background: REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) reported a 25% relative risk reduction in major adverse cardiovascular events with use of icosapent ethyl compared with pharmaceutical grade mineral oil. The mechanisms underlying this benefit remain uncertain. We explored whether treatment allocation in REDUCE-IT might affect a series of biomarkers in pathways known to associate with atherosclerosis risk.

Canakinumab's Effect Against Subsequent Gout Flares and High-Sensitivity C-Reactive Protein Levels: A Causal Mediation Analysis.

Objective: The objective of this study was to quantify the value of early suppression of high-sensitivity C-reactive protein (hsCRP) levels as a biomarker of the protective role of canakinumab against future gout flares.

Methods: We conducted a post hoc causal mediation analysis of the Canakinumab Anti-Inflammatory Thrombosis Outcome Study for gout flares. The 3-month change in the log hsCRP level was the mediator of interest.

Adverse effects related to methotrexate polyglutamate levels: adjudicated results from the cardiovascular inflammation reduction trial.

Objectives: Methotrexate is widely used at low dosages (LD-MTX) for non-oncologic indications and is associated with a variety of adverse effects (AEs). We sought to determine whether concentrations of the active metabolite, MTX polyglutamates (MTX-PGs) 1-5, correlate with AEs.

Method: We examined data from the LD-MTX arm of the randomized double-blind Cardiovascular Inflammation Reduction Trial (CIRT).

Rosuvastatin for the prevention of venous thromboembolism: a pooled analysis of the HOPE-3 and JUPITER randomized controlled trials.

Aims: To examine the association between rosuvastatin and VTE risk, and whether effects vary in different subpopulations stratified by key demographic, cardiovascular disease (CVD) risk factors, and other risk factors associated with VTE.

Methods And Results: An individual participant data meta-analysis was conducted across two randomized controlled trials in 30 507 participants over a mean follow-up of 3.62 years, individuals had no prior history of vascular disease but were at intermediate CV risk.

The neutrophil-lymphocyte ratio and incident atherosclerotic events: analyses from five contemporary randomized trials.

Aims: The neutrophil-lymphocyte ratio (NLR) is a readily available inflammatory biomarker that may associate with atherosclerosis and predict cardiovascular (CV) events. The aims of this study are to determine whether the NLR predicts incident major adverse cardiovascular events (MACE) and is modified by anti-inflammatory therapy.

Methods And Results: Baseline and on-treatment NLRs were calculated from complete blood counts among 60 087 participants randomized in the CANTOS, JUPITER, SPIRE-1, SPIRE-2, and CIRT trials to receive placebo or canakinumab, rosuvastatin, bococizumab, or methotrexate, respectively, and followed up for MACE.

Adverse Effects of Low-Dose Methotrexate in a Randomized Double-Blind Placebo-Controlled Trial: Adjudicated Hematologic and Skin Cancer Outcomes in the Cardiovascular Inflammation Reduction Trial.

Objective: Low-dose methotrexate (LD-MTX), a cornerstone in the treatment of rheumatoid arthritis, is associated with a moderately increased risk of anemia, leukopenia, and skin cancers, but the risks of myelosuppression and malignancy during LD-MTX use remain incompletely described. We examined the risks of cytopenias and skin cancers among patients taking LD-MTX versus placebo in a large randomized controlled trial (RCT).

Methods: We prespecified secondary analyses of a double-blind, placebo-controlled RCT that included adults with known cardiovascular disease and diabetes or metabolic syndrome in the United States and Canada.

Inhibition of Interleukin-1β and Reduction in Atherothrombotic Cardiovascular Events in the CANTOS Trial.

Background: Inflammation reduction with the interleukin (IL)-1β inhibitor canakinumab significantly reduces the first major adverse cardiovascular event in patients with prior myocardial infarction (MI) and residual inflammatory risk (high-sensitivity C-reactive protein ≥ 2 mg/l). However, the effect of canakinumab on the total number of cardiovascular events, including recurrent events collected after a first event, is unknown.

Objectives: This study sought to determine whether randomly allocated canakinumab would reduce the total burden of serious cardiovascular events.

Comparison of interleukin-6, C-reactive protein, and low-density lipoprotein cholesterol as biomarkers of residual risk in contemporary practice: secondary analyses from the Cardiovascular Inflammation Reduction Trial.

Aims: In epidemiologic cohorts initiated >30 years ago, inflammatory biomarkers, such as interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hsCRP) were shown to independently predict future cardiovascular events with a magnitude of effect comparable to that of low-density lipoprotein cholesterol (LDLC). Whether aggressive contemporary therapy for atherosclerosis has altered these relationships is unknown yet has major implications for future drug development.

Methods And Results: Interleukin-6, hsCRP, and LDLC were measured at baseline in up to 4168 North American patients enrolled in the contemporary Cardiovascular Inflammation Reduction Trial with prior myocardial infarction or multivessel coronary disease who additionally had diabetes or metabolic syndrome and were followed for a period of up to 5 years for incident major recurrent cardiovascular events and all-cause mortality.

Effects of Interleukin-1β Inhibition on Incident Anemia: Exploratory Analyses From a Randomized Trial.

Background: Inflammatory cytokines, such as interleukin (IL)-1β, alter iron homeostasis and erythropoiesis, resulting in anemia, but whether inhibition of IL-1β can reverse these effects is unclear.

Objective: To determine whether IL-1β inhibition with canakinumab reduces incident anemia and improves hemoglobin levels among those with prevalent anemia.

Design: Exploratory analysis of a randomized controlled trial.

Adverse Effects of Low-Dose Methotrexate: A Randomized Trial.

Background: Low-dose methotrexate (LD-MTX) is the most commonly used drug for systemic rheumatic diseases worldwide and is the recommended first-line agent for rheumatoid arthritis. Despite extensive clinical use for more than 30 years, few data on adverse event (AE) rates derive from randomized, placebo-controlled trials, where both causality and magnitude of risk can be inferred.

Objective: To investigate AE rates, risk, and risk differences comparing LD-MTX versus placebo.

Effects of Interleukin-1β Inhibition on Blood Pressure, Incident Hypertension, and Residual Inflammatory Risk: A Secondary Analysis of CANTOS.

While hypertension and inflammation are physiologically inter-related, the effect of therapies that specifically target inflammation on blood pressure is uncertain. The recent CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) afforded the opportunity to test whether IL (interleukin)-1β inhibition would reduce blood pressure, prevent incident hypertension, and modify relationships between hypertension and cardiovascular events. CANTOS randomized 10 061 patients with prior myocardial infarction and hsCRP (high sensitivity C-reactive protein) ≥2 mg/L to canakinumab 50 mg, 150 mg, 300 mg, or placebo.

Exercise reduces inflammatory cell production and cardiovascular inflammation via instruction of hematopoietic progenitor cells.

A sedentary lifestyle, chronic inflammation and leukocytosis increase atherosclerosis; however, it remains unclear whether regular physical activity influences leukocyte production. Here we show that voluntary running decreases hematopoietic activity in mice. Exercise protects mice and humans with atherosclerosis from chronic leukocytosis but does not compromise emergency hematopoiesis in mice.

Residual inflammatory risk associated with interleukin-18 and interleukin-6 after successful interleukin-1β inhibition with canakinumab: further rationale for the development of targeted anti-cytokine therapies for the treatment of atherothrombosis.

Aims: The Canakinumab Antiinflammatory Thrombosis Outcomes Study (CANTOS) established that targeting inflammation with interleukin-1β (IL-1β) inhibition can significantly reduce cardiovascular (CV) event rates in the absence of any beneficial effects on cholesterol. Yet, CANTOS participants treated with both high-intensity statins and canakinumab remain at considerable risk for recurrent CV events. Both interleukin-18 (IL-18, which like IL-1β requires the NLRP3 inflammasome for activation) and interleukin-6 (IL-6, a pro-inflammatory cytokine downstream of IL-1) may contribute to the recurrent events that occur even on canakinumab therapy, and thus represent novel targets for treating atherothrombosis.

Low-Dose Methotrexate for the Prevention of Atherosclerotic Events.

Background: Inflammation is causally related to atherothrombosis. Treatment with canakinumab, a monoclonal antibody that inhibits inflammation by neutralizing interleukin-1β, resulted in a lower rate of cardiovascular events than placebo in a previous randomized trial. We sought to determine whether an alternative approach to inflammation inhibition with low-dose methotrexate might provide similar benefit.

Relationship of Interleukin-1β Blockade With Incident Gout and Serum Uric Acid Levels: Exploratory Analysis of a Randomized Controlled Trial.

Background: Although studies have shown that interleukin-1β (IL-1β) inhibitors can shorten gout attacks, whether they can prevent gout attacks is unclear.

Objective: To examine the relationship among canakinumab, a monoclonal antibody targeting IL-1β; serum uric acid levels; and the incidence of gout attacks.

Design: Secondary exploratory analysis of a randomized controlled trial.

Modulation of the interleukin-6 signalling pathway and incidence rates of atherosclerotic events and all-cause mortality: analyses from the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS).

Aims: Canakinumab, a monoclonal antibody targeting interleukin (IL)-1β, reduces rates of recurrent cardiovascular events without lowering lipids. It is uncertain, however, to what extent these beneficial cardiovascular outcomes are mediated through interleukin-6 (IL-6) signalling, an issue with substantial pathophysiologic consequences and therapeutic implications.

Methods And Results: A total of 4833 stable atherosclerosis patients in the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) had IL-6 levels measured before randomization and after treatment with placebo or one of three doses of canakinumab (50 mg, 150 mg, or 300 mg) given subcutaneously once every 3 months.

Inhibition of Interleukin-1β by Canakinumab and Cardiovascular Outcomes in Patients With Chronic Kidney Disease.

Background: Inflammation contributes to chronic kidney disease (CKD), in part mediated through activation of interleukin (IL)-1β by the NLRP3 inflammasome within the kidney. This process also likely contributes to the accelerated atherosclerosis associated with nephropathy.

Objectives: The authors hypothesized that canakinumab, a human monoclonal antibody targeting IL-1β, might reduce cardiovascular event rates and improve renal function among post-myocardial infarction patients with CKD.

Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial.

Background: Canakinumab, a monoclonal antibody targeting interleukin-1β, reduces inflammation and cardiovascular event rates with no effect on lipid concentrations. However, it is uncertain which patient groups benefit the most from treatment and whether reductions in the inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) correlate with clinical benefits for individual patients.

Methods: The Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) used computer-generated codes to randomly allocate 10 061 men and women with a history of myocardial infarction to placebo or one of three doses of canakinumab (50 mg, 150 mg, or 300 mg) given subcutaneously once every 3 months.

Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial.

Background: Inflammation in the tumour microenvironment mediated by interleukin 1β is hypothesised to have a major role in cancer invasiveness, progression, and metastases. We did an additional analysis in the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), a randomised trial of the role of interleukin-1β inhibition in atherosclerosis, with the aim of establishing whether inhibition of a major product of the Nod-like receptor protein 3 (NLRP3) inflammasome with canakinumab might alter cancer incidence.

Methods: We did a randomised, double-blind, placebo-controlled trial of canakinumab in 10 061 patients with atherosclerosis who had had a myocardial infarction, were free of previously diagnosed cancer, and had concentrations of high-sensitivity C-reactive protein (hsCRP) of 2 mg/L or greater.

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease.

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved.

Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter.