Over the past decade, lipoprotein(a) Lp(a) made it to several consensus and guideline documents. This review aims to summarize the literature which underlies the various recommendations and compares ...recent European and North American consensus and guideline documents of the recent 3-4 years.
Multiple large epidemiological and genetic studies have provided strong evidence for a causal association between Lp(a) concentrations and atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis. There is a dose-dependent linear relationship between Lp(a) and ASCVD risk advocating to consider Lp(a) on a continuous scale rather than using thresholds. The best way to implement this in the clinic is by individualizing the Lp(a)-related risk using tools such as the 'Lp(a) risk calculator' ( http://www.lpaclinicalguidance.com ) that takes into account the Lp(a) level in the context of an individual's traditional risk factors and global risk for ASCVD. There is growing agreement across the guidelines regarding the clinical utility of measuring Lp(a) and more recent expert groups advocate for a general screening approach applied to all adults. As long as the cardiovascular outcomes trials for specific Lp(a)-lowering drugs are in progress, the current management of patients with high Lp(a) should focus on the comprehensive management of all other modifiable ASCVD risk factors which can be therapeutically addressed as per guideline recommendations.
Since the contribution of high Lp(a) concentrations to global ASCVD risk has been underestimated in the past, a clear recommendation to measure Lp(a) at least once in a person's lifetime is imperative. Recent expert consensus recommendations provide clinicians with direction on how to manage the excess risk associated with elevated Lp(a) concentration by comprehensive and individualized management of modifiable ASCVD risk factors while awaiting the results of clinical trials of Lp(a) targeted therapies.
Background
Intestinal microbiota have been found to be linked to cardiovascular disease via conversion of the dietary compounds choline and carnitine to the atherogenic metabolite TMAO ...(trimethylamine‐N‐oxide). Specifically, a vegan diet was associated with decreased plasma TMAO levels and nearly absent TMAO production on carnitine challenge.
Methods and Results
We performed a double‐blind randomized controlled pilot study in which 20 male metabolic syndrome patients were randomized to single lean vegan‐donor or autologous fecal microbiota transplantation. At baseline and 2 weeks thereafter, we determined the ability to produce TMAO from d6‐choline and d3‐carnitine (eg, labeled and unlabeled TMAO in plasma and 24‐hour urine after oral ingestion of 250 mg of both isotope‐labeled precursor nutrients), and fecal samples were collected for analysis of microbiota composition. 18F‐fluorodeoxyglucose positron emission tomography/computed tomography scans of the abdominal aorta, as well as ex vivo peripheral blood mononuclear cell cytokine production assays, were performed. At baseline, fecal microbiota composition differed significantly between vegans and metabolic syndrome patients. With vegan‐donor fecal microbiota transplantation, intestinal microbiota composition in metabolic syndrome patients, as monitored by global fecal microbial community structure, changed toward a vegan profile in some of the patients; however, no functional effects from vegan‐donor fecal microbiota transplantation were seen on TMAO production, abdominal aortic 18F‐fluorodeoxyglucose uptake, or ex vivo cytokine production from peripheral blood mononuclear cells.
Conclusions
Single lean vegan‐donor fecal microbiota transplantation in metabolic syndrome patients resulted in detectable changes in intestinal microbiota composition but failed to elicit changes in TMAO production capacity or parameters related to vascular inflammation.
Clinical Trial Registration
URL: http://www.trialregister.nl. Unique identifier: NTR 4338.
Aims
The aim of this study was to evaluate the low-density lipoprotein cholesterol lowering efficacy and safety of a bempedoic acid 180 mg and ezetimibe 10 mg fixed-dose combination in patients with ...hypercholesterolemia and a high risk of cardiovascular disease receiving maximally tolerated statin therapy.
Methods
This phase 3, double-blind clinical trial enrolled adult patients at high risk of cardiovascular disease due to atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or multiple cardiovascular disease risk factors. Patients were randomly assigned (2:2:2:1) to treatment with the fixed-dose combination, bempedoic acid 180 mg, ezetimibe 10 mg or placebo added to stable background statin therapy for 12 weeks. The primary efficacy endpoint was the percentage change from baseline to week 12 in low-density lipoprotein cholesterol.
Results
Among the 301 patients included in the primary analysis, the mean baseline low-density lipoprotein cholesterol level was 3.87 mmol/L (149.8 mg/dL). At week 12, the fixed-dose combination lowered low-density lipoprotein cholesterol (–36.2%) significantly more than placebo (1.8% (placebo-corrected difference –38.0%); P < 0.001), ezetimibe alone (–23.2%; P < 0.001) or bempedoic acid alone (–17.2%; P < 0.001). The fixed-dose combination lowered low-density lipoprotein cholesterol levels similarly across subgroups, including patients receiving high-intensity, other-intensity or no statin therapy. Improvements with the fixed-dose combination were also observed in secondary efficacy endpoints, including high-sensitivity C-reactive protein. In this trial, fixed-dose combination treatment had a generally similar safety profile compared with bempedoic acid, ezetimibe or placebo.
Conclusion
The bempedoic acid and ezetimibe fixed-dose combination significantly lowered low-density lipoprotein cholesterol versus placebo or other oral monotherapies and had a favourable safety profile when added to maximally tolerated statin therapy in patients with hypercholesterolemia and high cardiovascular disease risk.
Trial Registration
ClinicalTrials.gov identifier: NCT03337308.
Lipoprotein(a) Lp(a), a distinct lipoprotein class, has become a major focus for cardiovascular research. This review is written in light of the recent guideline and consensus statements on Lp(a) and ...focuses on 1) the causal association between Lp(a) and cardiovascular outcomes, 2) the potential mechanisms by which elevated Lp(a) contributes to cardiovascular diseases, 3) the metabolic insights on the production and clearance of Lp(a) and 4) the current and future therapeutic approaches to lower Lp(a) concentrations. The concentrations of Lp(a) are under strict genetic control. There exists a continuous relationship between the Lp(a) concentrations and risk for various endpoints of atherosclerotic cardiovascular disease (ASCVD). One in five people in the Caucasian population is considered to have increased Lp(a) concentrations; the prevalence of elevated Lp(a) is even higher in black populations. This makes Lp(a) a cardiovascular risk factor of major public health relevance. Besides the association between Lp(a) and myocardial infarction, the relationship with aortic valve stenosis has become a major focus of research during the last decade. Genetic studies provided strong support for a causal association between Lp(a) and cardiovascular outcomes: carriers of genetic variants associated with lifelong increased Lp(a) concentration are significantly more frequent in patients with ASCVD. This has triggered the development of drugs that can specifically lower Lp(a) concentrations: mRNA-targeting therapies such as anti-sense oligonucleotide (ASO) therapies and short interfering RNA (siRNA) therapies have opened new avenues to lower Lp(a) concentrations more than 95%. Ongoing Phase II and III clinical trials of these compounds are discussed in this review.
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Inflammation is a key feature of atherosclerosis and a target for therapy. Statins have potent anti-inflammatory properties but these cannot be fully exploited with oral statin therapy due to low ...systemic bioavailability. Here we present an injectable reconstituted high-density lipoprotein (rHDL) nanoparticle carrier vehicle that delivers statins to atherosclerotic plaques. We demonstrate the anti-inflammatory effect of statin-rHDL in vitro and show that this effect is mediated through the inhibition of the mevalonate pathway. We also apply statin-rHDL nanoparticles in vivo in an apolipoprotein E-knockout mouse model of atherosclerosis and show that they accumulate in atherosclerotic lesions in which they directly affect plaque macrophages. Finally, we demonstrate that a 3-month low-dose statin-rHDL treatment regimen inhibits plaque inflammation progression, while a 1-week high-dose regimen markedly decreases inflammation in advanced atherosclerotic plaques. Statin-rHDL represents a novel potent atherosclerosis nanotherapy that directly affects plaque inflammation.
C-reactive protein is postulated to embody an index that can reflect cardiovascular risk and can be used to independently predict major cardiovascular events and mortality. On the other hand, ...credible experimental data have become available that demonstrate the abundant presence of C-reactive protein in atherosclerotic lesions and, moreover, identify C-reactive protein as an initiator of several pathogenic pathways that can cause atherogenic changes. Consequently, there has been a paradigm shift in which C-reactive protein is no longer regarded as merely an indicator of cardiovascular risk, but increasingly considered a direct partaker in the pathogenesis of atherosclerotic cardiovascular disease. These data underscore the need to explore risk-reducing interventions that selectively inhibit C-reactive protein activity as a novel strategy to prevent clinical manifestations of atherosclerosis.
This study was designed to assess the relationship of high-density-lipoprotein cholesterol (HDL-C), HDL particle size, and apolipoprotein A-I (apoA-I) with the occurrence of coronary artery disease ...(CAD), with a focus on the effect of very high values of these parameters.
High plasma levels of HDL-C and apoA-I are inversely related to the risk of CAD. However, recent data suggest that this relationship does not hold true for very high HDL-C levels, particularly when a preponderance of large HDL particles is observed.
We conducted a post-hoc analysis of 2 prospective studies: the IDEAL (Incremental Decrease in End Points through Aggressive Lipid Lowering; n = 8,888) trial comparing the efficacy of high-dose to usual-dose statin treatment for the secondary prevention of cardiovascular events, and the EPIC (European Prospective Investigation into Cancer and Nutrition)-Norfolk case-control study, including apparently healthy individuals who did (cases, n = 858) or did not (control patients, n = 1,491) develop CAD during follow-up. In IDEAL, only HDL-C and apoA-I were available; in EPIC-Norfolk, nuclear magnetic resonance spectroscopy-determined HDL particle sizes were also available.
In the IDEAL study, higher HDL-C proved a significant major cardiac event risk factor following adjustment for age, gender, smoking, apoA-I, and apoB. A similar association was observed for HDL particle size in EPIC-Norfolk. Increased risk estimates were particularly present in the high ends of the distributions. In contrast, apoA-I remained negatively associated across the major part of its distribution in both studies.
When apoA-I and apoB are kept constant, HDL-C and HDL particle size may confer risk at very high values. This does not hold true for very high levels of apoA-I at fixed levels of HDL-C and apoB. These findings may have important consequences for assessment and treatment of CAD risk.
This meta-analysis of three clinical trials assessed the effect of triglyceride-lowering pharmacologic therapy on the risk of acute pancreatitis in patients with severe hypertriglyceridemia.
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