This European Atherosclerosis Society (EAS) Task Force provides practical guidance for combination therapy for elevated low-density lipoprotein cholesterol (LDL-C) and/or triglycerides (TG) in ...high-risk and very-high-risk patients.
Evidence-based review.
Statin-ezetimibe combination treatment is the first choice for managing elevated LDL-C and should be given upfront in very-high-risk patients with high LDL-C unlikely to reach goal with a statin, and in primary prevention familial hypercholesterolaemia patients. A proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor may be added if LDL-C levels remain high. In high and very-high-risk patients with mild to moderately elevated TG levels (>2.3 and < 5.6 mmol/L >200 and < 500 mg/dL) on a statin, treatment with either a fibrate or high-dose omega-3 fatty acids (icosapent ethyl) may be considered, weighing the benefit versus risks. Combination with fenofibrate may be considered for both macro- and microvascular benefits in patients with type 2 diabetes mellitus.
This guidance aims to improve real-world use of guideline-recommended combination lipid modifying treatment.
•This EAS Task Force gives practical guidance for combination lipid lowering therapy in high- and very-high-risk patients.•In patients unlikely to reach the LDL-C goal with a statin alone combination with ezetimibe is suggested as first choice.•A PCSK9 inhibitor may be added if LDL-C levels remain high.•For type 2 diabetes with high triglycerides on statin, fenofibrate may be considered for macro- and microvascular benefits.••High-dose icosapent ethyl may be also considered for high triglycerides on statin treatment, weighing benefit vs. risk.
To appraise the clinical and genetic evidence that low-density lipoproteins (LDLs) cause atherosclerotic cardiovascular disease (ASCVD).
We assessed whether the association between LDL and ASCVD ...fulfils the criteria for causality by evaluating the totality of evidence from genetic studies, prospective epidemiologic cohort studies, Mendelian randomization studies, and randomized trials of LDL-lowering therapies. In clinical studies, plasma LDL burden is usually estimated by determination of plasma LDL cholesterol level (LDL-C). Rare genetic mutations that cause reduced LDL receptor function lead to markedly higher LDL-C and a dose-dependent increase in the risk of ASCVD, whereas rare variants leading to lower LDL-C are associated with a correspondingly lower risk of ASCVD. Separate meta-analyses of over 200 prospective cohort studies, Mendelian randomization studies, and randomized trials including more than 2 million participants with over 20 million person-years of follow-up and over 150 000 cardiovascular events demonstrate a remarkably consistent dose-dependent log-linear association between the absolute magnitude of exposure of the vasculature to LDL-C and the risk of ASCVD; and this effect appears to increase with increasing duration of exposure to LDL-C. Both the naturally randomized genetic studies and the randomized intervention trials consistently demonstrate that any mechanism of lowering plasma LDL particle concentration should reduce the risk of ASCVD events proportional to the absolute reduction in LDL-C and the cumulative duration of exposure to lower LDL-C, provided that the achieved reduction in LDL-C is concordant with the reduction in LDL particle number and that there are no competing deleterious off-target effects.
Consistent evidence from numerous and multiple different types of clinical and genetic studies unequivocally establishes that LDL causes ASCVD.
Lipid risk factors for cardiovascular disease depend in part on lifestyle, but optimum control of lipids often demands additional measures. Low-density lipoprotein (LDL) doubtless contributes ...causally to atherosclerosis. Recent human genetic findings have substantiated a number of novel targets for lipid-lowering therapy including apolipoprotein C-III, angiopoietin-like protein 3 and 4, apolipoprotein V, and ATP citrate lyase. These discoveries coupled with advances in biotechnology development afford new avenues for management of LDL and other aspects of lipid risk. Beyond LDL, new treatments targeting triglyceride-rich lipoproteins and lipoprotein(a) have become available and have entered clinical development. Biological and RNA-directed agents have joined traditional small-molecule approaches, which themselves have undergone considerable refinement. Innovative targeting strategies have increased efficacy of some of these novel interventions and markedly improved their tolerability. Gene-editing approaches have appeared on the horizon of lipid management. This article reviews this progress offering insight into novel biological and therapeutic discoveries, and places them into a practical patient care perspective.
Abstract
Aims
To objectively appraise evidence for possible adverse effects of long-term statin therapy on glucose homeostasis, cognitive, renal and hepatic function, and risk for haemorrhagic stroke ...or cataract.
Methods and results
A literature search covering 2000–2017 was performed. The Panel critically appraised the data and agreed by consensus on the categorization of reported adverse effects. Randomized controlled trials (RCTs) and genetic studies show that statin therapy is associated with a modest increase in the risk of new-onset diabetes mellitus (about one per thousand patient-years), generally defined by laboratory findings (glycated haemoglobin ≥6.5); this risk is significantly higher in the metabolic syndrome or prediabetes. Statin treatment does not adversely affect cognitive function, even at very low levels of low-density lipoprotein cholesterol and is not associated with clinically significant deterioration of renal function, or development of cataract. Transient increases in liver enzymes occur in 0.5–2% of patients taking statins but are not clinically relevant; idiosyncratic liver injury due to statins is very rare and causality difficult to prove. The evidence base does not support an increased risk of haemorrhagic stroke in individuals without cerebrovascular disease; a small increase in risk was suggested by the Stroke Prevention by Aggressive Reduction of Cholesterol Levels study in subjects with prior stroke but has not been confirmed in the substantive evidence base of RCTs, cohort studies and case–control studies.
Conclusion
Long-term statin treatment is remarkably safe with a low risk of clinically relevant adverse effects as defined above; statin-associated muscle symptoms were discussed in a previous Consensus Statement. Importantly, the established cardiovascular benefits of statin therapy far outweigh the risk of adverse effects.
Mid-life, the years leading up to and following the menopause transition, in women is accompanied by a change in cardiometabolic risk factors, including increases in body weight, changes in body ...composition, a more insulin-resistant state, and a shift towards a more atherogenic dyslipidemia pattern. Cardiovascular disease (CVD) risk assessment should be performed continually throughout the lifespan, as risk is not stagnant and can change throughout the life course. However, mid-life is a particularly important time for a woman to be evaluated for CVD risk so that appropriate preventive strategies can be implemented. Along with assessing traditional risk factors, ascertainment of a reproductive history is an integral part of a comprehensive CVD risk assessment to recognize unique female-specific or female-predominant factors that modify a woman's risk. When there is uncertainty about CVD risk and the net benefit of preventive pharmacotherapy interventions (such as statins), measuring a coronary artery calcium score can help further refine risk and guide shared decision-making. Additionally, there should be heightened sensitivity around identifying signs and symptoms of ischemic heart disease in women, as these may present differently than in men. Ischemia from coronary microvascular disease and/or vasospasm may be present even without obstructive coronary artery disease and is associated with a heightened risk for major cardiovascular events and reduced quality of life. Therefore, correctly identifying CVD in women and implementing preventive and treatment therapies is paramount. Unfortunately, women are underrepresented in cardiovascular clinical trials, and more data are needed about how to best incorporate novel and emerging risk factors into CVD risk assessment. This review outlines an approach to CVD screening and risk assessment in women using several methods, focusing on the middle-aged population.
Atherosclerosis is initiated by functional changes in the endothelium accompanied by accumulation, oxidation, and glycation of LDL-cholesterol in the inner layer of the arterial wall and continues ...with the expression of adhesion molecules and release of chemoattractants. PCSK9 is a proprotein convertase that increases circulating LDL levels by directing hepatic LDL receptors into lysosomes for degradation. The effects of PCSK9 on hepatic LDL receptors and contribution to atherosclerosis via the induction of hyperlipidemia are well defined. Monoclonal PCSK9 antibodies that block the effects of PCSK9 on LDL receptors demonstrated beneficial results in cardiovascular outcome trials. In recent years, extrahepatic functions of PCSK9, particularly its direct effects on atherosclerotic plaques have received increasing attention. Experimental trials have revealed that PCSK9 plays a significant role in every step of atherosclerotic plaque formation. It contributes to foam cell formation by increasing the uptake of LDL by macrophages via scavenger receptors and inhibiting cholesterol efflux from macrophages. It induces the expression of inflammatory cytokines, adhesion molecules, and chemoattractants, thereby increasing monocyte recruitment, inflammatory cell adhesion, and inflammation at the atherosclerotic vascular wall. Moreover, low shear stress is associated with increased PCSK9 expression. PCSK9 may induce endothelial cell apoptosis and autophagy and stimulate the differentiation of smooth muscle cells from the contractile phenotype to synthetic phenotype. Increasing evidence indicates that PCSK9 is a molecular target in the development of novel approaches toward the prevention and treatment of atherosclerosis. This review focuses on the molecular roles of PCSK9 in atherosclerotic plaque formation.
JCL Roundtable: Global Think Tank on Lipoprotein(a) Maher, Lisa L.; Tokgözoğlu, S. Lale; Sanchez, Eduardo J. ...
Journal of clinical lipidology,
May-June 2021, 2021 May-Jun, 2021-05-00, 20210501, Letnik:
15, Številka:
3
Journal Article
Recenzirano
Lipoprotein(a) operates in causal pathways to promote atherosclerosis, arterial thrombosis, and aortic stenosis. It has been associated with rare cases of nonatherosclerotic arterial thrombotic ...stroke at any age. Inherited variation of lipoprotein(a) levels substantially increases cardiovascular risk in 20% of people worldwide. Recent progress in identifying the risk associated with lipoprotein(a) and in pursuing effective treatment has led to a recent Global Think Tank including representatives from the European Atherosclerosis Society, American Heart Association, Preventive Cardiovascular Nurses Association, National Lipid Association, and other groups. The need for standardized laboratory measurement in nanomoles per liter met with unanimous consensus. Atherosclerotic risk is linearly associated with plasma lipoprotein(a) levels, so that persons with the highest levels may have risk similar to other severe inherited lipoprotein disorders. Universal once-in-lifetime screening has been recommended by European and Canadian cardiovascular societies, but not by U.S. organizations. Current pharmacologic therapies are limited to 20-30% lowering of lipoprotein(a) levels, and no pharmacologic treatment for lowering lipoprotein(a) has yet been proven to reduce risk in a cardiovascular outcomes trial. Treatment for high-risk patients focuses on reducing low density lipoprotein cholesterol and other risk factors. New therapies targeting messenger RNA for apolipoprotein(a) can achieve 80-90% reduction of lipoprotein(a) levels. One such therapy using a liver-directed antisense oligonucleotide is currently being tested in a large cardiovascular outcomes trial. Increased recognition of lipoprotein(a)-associated risk and emergence of potentially effective therapy together lead to a mandate for a unified global effort on education, standardization, and clinical management.
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