IMPORTANCE: Additional treatment options are needed for patients who do not achieve sufficient reduction in low-density lipoprotein cholesterol (LDL-C) level with available lipid-lowering therapies. ...OBJECTIVE: To assess the efficacy of bempedoic acid vs placebo in patients at high cardiovascular risk receiving maximally tolerated lipid-lowering therapy. DESIGN, SETTING, AND PARTICIPANTS: Phase 3, randomized, double-blind, placebo-controlled clinical trial conducted at 91 clinical sites in North America and Europe from November 2016 to September 2018, with a final date of follow-up of September 22, 2018. A total of 779 patients with atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both met randomization criteria, which included LDL-C level 70 mg/dL (1.8 mmol/L) or greater while receiving maximally tolerated lipid-lowering therapy. INTERVENTIONS: Patients were randomized 2:1 to treatment with bempedoic acid (180 mg) (n = 522) or placebo (n = 257) once daily for 52 weeks. MAIN OUTCOMES AND MEASURES: The primary end point was percent change from baseline in LDL-C level at week 12. Secondary measures included changes in levels of lipids, lipoproteins, and biomarkers. RESULTS: Among 779 randomized patients (mean age, 64.3 years; 283 women 36.3%), 740 (95.0%) completed the trial. At baseline, mean LDL-C level was 120.4 (SD, 37.9) mg/dL. Bempedoic acid lowered LDL-C levels significantly more than placebo at week 12 (–15.1% vs 2.4%, respectively; difference, –17.4% 95% CI, –21.0% to –13.9%; P < .001). Significant reductions with bempedoic acid vs placebo were observed at week 12 for non–high-density lipoprotein cholesterol (–10.8% vs 2.3%; difference, –13.0% 95% CI, –16.3% to –9.8%; P < .001), total cholesterol (–9.9% vs 1.3%; difference, –11.2% 95% CI, –13.6% to –8.8%; P < .001), apolipoprotein B (–9.3% vs 3.7%; difference, –13.0% 95% CI, –16.1% to –9.9%; P < .001), and high-sensitivity C-reactive protein (median, –18.7% vs –9.4%; difference, –8.7% asymptotic confidence limits, –17.2% to –0.4%; P = .04). Common adverse events included nasopharyngitis (5.2% vs 5.1% with bempedoic acid and placebo, respectively), urinary tract infection (5.0% vs 1.9%), and hyperuricemia (4.2% vs 1.9%). CONCLUSIONS AND RELEVANCE: Among patients at high risk for cardiovascular disease receiving maximally tolerated statins, the addition of bempedoic acid compared with placebo resulted in a significant lowering of LDL-C level over 12 weeks. Further research is needed to assess the durability and clinical effect as well as long-term safety. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02991118
Evinacumab in Patients with Refractory Hypercholesterolemia Rosenson, Robert S; Burgess, Lesley J; Ebenbichler, Christoph F ...
New England journal of medicine/The New England journal of medicine,
12/2020, Volume:
383, Issue:
24
Journal Article
Peer reviewed
Open access
Angiopoietin-like 3 is an inhibitor of lipoprotein lipase. Evinacumab is a monoclonal antibody that inhibits angiopoietin-like 3, activating lipoprotein lipase. In patients with hypercholesterolemia ...that is refractory to statin and PCSK9 inhibitor therapy, the use of evinacumab reduced plasma lipid levels by more than 50% at the maximum dose.
Abstract
This 2022 European Atherosclerosis Society lipoprotein(a) Lp(a) consensus statement updates evidence for the role of Lp(a) in atherosclerotic cardiovascular disease (ASCVD) and aortic valve ...stenosis, provides clinical guidance for testing and treating elevated Lp(a) levels, and considers its inclusion in global risk estimation. Epidemiologic and genetic studies involving hundreds of thousands of individuals strongly support a causal and continuous association between Lp(a) concentration and cardiovascular outcomes in different ethnicities; elevated Lp(a) is a risk factor even at very low levels of low-density lipoprotein cholesterol. High Lp(a) is associated with both microcalcification and macrocalcification of the aortic valve. Current findings do not support Lp(a) as a risk factor for venous thrombotic events and impaired fibrinolysis. Very low Lp(a) levels may associate with increased risk of diabetes mellitus meriting further study. Lp(a) has pro-inflammatory and pro-atherosclerotic properties, which may partly relate to the oxidized phospholipids carried by Lp(a). This panel recommends testing Lp(a) concentration at least once in adults; cascade testing has potential value in familial hypercholesterolaemia, or with family or personal history of (very) high Lp(a) or premature ASCVD. Without specific Lp(a)-lowering therapies, early intensive risk factor management is recommended, targeted according to global cardiovascular risk and Lp(a) level. Lipoprotein apheresis is an option for very high Lp(a) with progressive cardiovascular disease despite optimal management of risk factors. In conclusion, this statement reinforces evidence for Lp(a) as a causal risk factor for cardiovascular outcomes. Trials of specific Lp(a)-lowering treatments are critical to confirm clinical benefit for cardiovascular disease and aortic valve stenosis.
There is a growing body of research on the neural control of immunity and inflammation. However, it is not known whether the nervous system can regulate the production of inflammatory myeloid cells ...from hematopoietic progenitor cells in disease conditions. Myeloid cell numbers in diabetic patients were strongly correlated with plasma concentrations of norepinephrine, suggesting the role of sympathetic neuronal activation in myeloid cell production. The spleens of diabetic patients and mice contained higher numbers of tyrosine hydroxylase (TH)-expressing leukocytes that produced catecholamines. Granulocyte macrophage progenitors (GMPs) expressed the β2 adrenergic receptor, a target of catecholamines. Ablation of splenic sympathetic neuronal signaling using surgical, chemical, and genetic approaches diminished GMP proliferation and myeloid cell development. Finally, mice lacking TH-producing leukocytes had reduced GMP proliferation, resulting in diminished myelopoiesis. Taken together, our study demonstrates that catecholamines produced by leukocytes and sympathetic nerve termini promote GMP proliferation and myeloid cell development.
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•Sympathetic nervous system (SNS) mediates differentiation of myeloid progenitors•TH+ leukocytes express high amounts of neuropeptide Y receptors (NPYRs)•TH+ cells are required for myeloid cell generation during “emergency” hematopoiesis•Regulation of myelopoiesis by the β2 adrenergic receptor expressed by GMPs
Neural control of immunity and inflammation has been reported. Vasamsetti and colleagues demonstrate that the sympathetic nervous system controls the development of inflammatory myeloid cells from their progenitors in inflammatory conditions.
Bhatt et al. report in the
Journal
the results of the Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT), in which 8179 high-risk patients who had elevated ...triglyceride levels and had been receiving statin therapy were randomly assigned to receive 2 g of icosapent ethyl twice daily or placebo containing mineral oil.
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The patients were enrolled mostly on the basis of secondary prevention (71%), and almost 60% had diabetes. At baseline, low-density lipoprotein (LDL) cholesterol levels were well controlled among the patients (median value, 75.0 mg per deciliter 1.94 mmol per liter), and triglyceride levels were slightly elevated (median . . .
Background Inability to tolerate statins because of muscle symptoms contributes to uncontrolled cholesterol levels and insufficient cardiovascular risk reduction. Bempedoic acid, a prodrug that is ...activated by a hepatic enzyme not present in skeletal muscle, inhibits ATP -citrate lyase, an enzyme upstream of β-hydroxy β-methylglutaryl-coenzyme A reductase in the cholesterol biosynthesis pathway. Methods and Results The phase 3, double-blind, placebo-controlled CLEAR (Cholesterol Lowering via Bempedoic acid, an ACL-Inhibiting Regimen) Serenity study randomized 345 patients with hypercholesterolemia and a history of intolerance to at least 2 statins (1 at the lowest available dose) 2:1 to bempedoic acid 180 mg or placebo once daily for 24 weeks. The primary end point was mean percent change from baseline to week 12 in low-density lipoprotein cholesterol. The mean age was 65.2 years, mean baseline low-density lipoprotein cholesterol was 157.6 mg/dL, and 93% of patients reported a history of statin-associated muscle symptoms. Bempedoic acid treatment significantly reduced low-density lipoprotein cholesterol from baseline to week 12 (placebo-corrected difference, -21.4% 95% CI, -25.1% to -17.7%; P<0.001). Significant reductions with bempedoic acid versus placebo were also observed in non-high-density lipoprotein cholesterol (-17.9%), total cholesterol (-14.8%), apolipoprotein B (-15.0%), and high-sensitivity C-reactive protein (-24.3%; P<0.001 for all comparisons). Bempedoic acid was safe and well tolerated. The most common muscle-related adverse event, myalgia, occurred in 4.7% and 7.2% of patients who received bempedoic acid or placebo, respectively. Conclusions Bempedoic acid offers a safe and effective oral therapeutic option for lipid lowering in patients who cannot tolerate statins. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 02988115.
The emergence of pathophysiological, epidemiologic, and genetic data strongly supports the causality for lipoprotein(a) Lp(a) in cardiovascular disease (CVD) and calcific aortic valve disease (CAVD). ...In parallel, novel Lp(a) lowering approaches have been developed that have re-invigorated clinical interest in Lp(a). Because Lp(a) is the most prevalent monogenetic lipid disorder globally, with prevalence of Lp(a) > 50 mg/dL estimated at >1.4 billion people, the rationale for diagnosing and managing Lp(a)-mediated risk is now stronger than ever. Patients with elevated Lp(a) are significantly under-diagnosed and the diagnosis is frequently made ad hoc rather than systematically. Elevated Lp(a) levels are associated with atherothrombotic risk and patients present with varied clinical phenotypes, ranging from stroke in pediatric age groups, to ST-segment elevation myocardial infarction in young males, to CAVD in elderly individuals. A new clinical care paradigm of a dedicated “Lp(a) Clinic” would serve to evaluate and manage such patients who have elevated Lp(a) as the pathophysiological etiology. Such a clinic would include multidisciplinary expertise in lipid metabolism, clinical cardiology, vascular medicine, valvular disease, thrombosis, and pediatric aspects of clinical care. This viewpoint argues for the rationale of an Lp(a) outpatient clinic where patients with elevated Lp(a) and their affected relatives can be referred, evaluated, managed and followed, to ultimately reduce Lp(a)-mediated CVD and CAVD risk.
•Lp(a) is a causal risk factor for cardiovascular disease (CVD) and calcific aortic valve disease.•Novel Lp(a) lowering approaches have re-invigorated clinical interest in Lp(a).•Elevated Lp(a) (>50 mg/dL) is estimated to be present in >1.4 billion people.•Patients with elevated Lp(a) are significantly under-diagnosed.•A rationale of an outpatient “Lp(a) clinic” is presented.
Lipoprotein(a) Lp(a) has risen to the level of an accepted cardiovascular disease risk factor, but final proof of causality awaits a randomized trial of Lp(a) lowering. Inhibiting apolipoprotein(a) ...production in the hepatocyte with ribonucleic acid therapeutics has emerged as an elegant and effective solution to reduce plasma Lp(a) levels. Phase 2 clinical trials have shown that the antisense oligonucleotide pelacarsen reduced mean Lp(a) levels by 80%, allowing 98% of subjects to reach on-treatment levels of <125 nmol/l (∼50 mg/dl). The phase 3 Lp(a)HORIZON (Assessing the Impact of Lipoprotein(a) Lowering With TQJ230 on Major Cardiovascular Events in Patients With CVD) outcomes trial is currently enrolling approximately 7,680 patients with history of myocardial infarction, ischemic stroke, and symptomatic peripheral arterial disease and controlled low-density lipoprotein cholesterol to pelacarsen versus placebo. The co-primary endpoints are major adverse cardiovascular events in subjects with Lp(a) >70 mg/dl and >90 mg/dl, in which either of the two being positive will lead to a successful trial. Additional ribonucleic acid-targeted therapies to lower Lp(a) are in preclinical and clinical development. The testing of the Lp(a) hypothesis will provide proof whether Lp(a)-mediated risk can be abolished by potent Lp(a) lowering.
In a 2-year clinical trial, the addition of ezetimibe to simvastatin had no effect on the progression of atherosclerosis, as measured by carotid-artery intima–media thickness, despite the additional ...lowering of levels of low-density lipoprotein cholesterol and C-reactive protein by ezetimibe when added to simvastatin. However, the study was not powered to assess clinical end points.
The addition of ezetimibe to simvastatin had no effect on the progression of atherosclerosis, as measured by carotid-artery intima–media thickness, despite the additional lowering of levels of low-density lipoprotein cholesterol and C-reactive protein.
A reduction in levels of low-density lipoprotein (LDL) cholesterol constitutes one of the cornerstones in the prevention of cardiovascular disease. In recent trials comparing various statins or the same statin at various doses, aggressive therapy to lower LDL cholesterol levels was associated with a reduction in rates of cardiovascular events.
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4
However, administration of the highest approved statin dose offers only limited additional lowering of LDL cholesterol at the expense of an increased incidence of side effects.
5
Therefore, novel compounds that further reduce LDL cholesterol levels when added to statin therapy are of interest. A recently introduced compound, ezetimibe, selectively . . .
Lipoprotein(a): the revenant Gencer, Baris; Kronenberg, Florian; Stroes, Erik S ...
European heart journal,
05/2017, Volume:
38, Issue:
20
Journal Article
Peer reviewed
Open access
In the mid-1990s, the days of lipoprotein(a) Lp(a) were numbered and many people would not have placed a bet on this lipid particle making it to the next century. However, genetic studies brought ...Lp(a) back to the front-stage after a Mendelian randomization approach used for the first time provided strong support for a causal role of high Lp(a) concentrations in cardiovascular disease and later also for aortic valve stenosis. This encouraged the use of therapeutic interventions to lower Lp(a) as well numerous drug developments, although these approaches mainly targeted LDL cholesterol, while the Lp(a)-lowering effect was only a 'side-effect'. Several drug developments did show a potent Lp(a)-lowering effect but did not make it to endpoint studies, mainly for safety reasons. Currently, three therapeutic approaches are either already in place or look highly promising: (i) lipid apheresis (specific or unspecific for Lp(a)) markedly decreases Lp(a) concentrations as well as cardiovascular endpoints; (ii) PCSK9 inhibitors which, besides lowering LDL cholesterol also decrease Lp(a) by roughly 30%; and (iii) antisense therapy targeting apolipoprotein(a) which has shown to specifically lower Lp(a) concentrations by up to 90% in phase 1 and 2 trials without influencing other lipids. Until the results of phase 3 outcome studies are available for antisense therapy, we will have to exercise patience, but with optimism since never before have we had the tools we have now to prove Koch's extrapolated postulate that lowering high Lp(a) concentrations might be protective against cardiovascular disease.
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