Practical guidance for combination lipid-modifying therapy in high- and very-high-risk patients: A statement from a European Atherosclerosis Society Task Force.

BACKGROUND AND AIMS: 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. METHODS: Evidence-based review. RESULTS: 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. CONCLUSIONS: This guidance aims to improve real-world use of guideline-recommended combination lipid modifying treatment.

Safety of red yeast rice supplementation: A systematic review and meta-analysis of randomized controlled trials.

Recently, concerns regarding the safety of red yeast rice (RYR) have been raised after the publication of some case reports claiming toxicity. Since the previous meta-analyses on the effects of RYR were mainly focused on its efficacy to improve lipid profile and other cardiovascular parameters, we carried out a meta-analysis on safety data derived from the available randomized controlled clinical trials (RCTs). Primary outcomes were musculoskeletal disorders (MuD). Secondary outcomes were non-musculoskeletal adverse events (Non-MuD) and serious adverse events (SAE). Subgroups analyses were carried out considering the intervention (RYR alone or in association with other nutraceutical compounds), monacolin K administered daily dose (≤3, 3.1-5 or >5 mg/day), follow-up (>12 or ≤12 weeks), with statin therapy or statin-intolerance and type of control treatment (placebo or statin treatment). Data were pooled from 53 RCTs comprising 112 treatment arms, which included 8535 subjects, with 4437 in the RYR arm and 4303 in the control one. Monacolin K administration was not associated with increased risk of MuD (odds ratio (OR) = 0.94, 95% confidence interval (CI) 0.53,1.65). Moreover, we showed reduced risk of Non-MuD (OR = 0.59, 95%CI 0.50, 0.69) and SAE (OR = 0.54, 95%CI 0.46, 0.64) vs. control. Subgroups analyses confirmed the high tolerability profile of RYR. Furthermore, increasing daily doses of monacolin K were negatively associated with increasing risk of Non-MuD (slope: -0.10; 95%CI: -0.17, -0.03; two-tailed p < 0.01). Based on our data, RYR use as lipid-lowering dietary supplement seems to be overall tolerable and safe in a large kind of moderately hypercolesterolaemic subjects.

The Role of Nutraceuticals in Statin Intolerant Patients.

Statins are the most common drugs administered for patients with cardiovascular disease. However, due to statin-associated muscle symptoms, adherence to statin therapy is challenging in clinical practice. Certain nutraceuticals, such as red yeast rice, bergamot, berberine, artichoke, soluble fiber, and plant sterols and stanols alone or in combination with each other, as well as with ezetimibe, might be considered as an alternative or add-on therapy to statins, although there is still insufficient evidence available with respect to long-term safety and effectiveness on cardiovascular disease prevention and treatment. These nutraceuticals could exert significant lipid-lowering activity and might present multiple non-lipid-lowering actions, including improvement of endothelial dysfunction and arterial stiffness, as well as anti-inflammatory and antioxidative properties. The aim of this expert opinion paper is to provide the first attempt at recommendation on the management of statin intolerance through the use of nutraceuticals with particular attention on those with effective low-density lipoprotein cholesterol reduction.

A nutraceutical approach (Armolipid Plus) to reduce total and LDL cholesterol in individuals with mild to moderate dyslipidemia: Review of the clinical evidence.

Compelling evidence supports the effectiveness of the reduction of total and LDL cholesterol (TC and LDL-C) in primarily preventing cardiovascular events, within the framework of life-long prevention programs mainly consisting in lifestyle changes. Pharmacological treatment should be introduced when lifestyle changes, including use of nutraceuticals, have failed. ESC/EAS guidelines list a number of nutraceutical compounds and functional foods which have been individually studied in randomized, controlled clinical trials (RCTs). To date only a proprietary formulation of three naturally occurring substances with putative complementary lipid-lowering properties - red yeast rice, policosanol and berberine - combined with folic acid, astaxanthin, and coenzyme Q10 (Armolipid Plus®) has been extensively investigated in several RCTs, 7 of which were placebo-controlled, 2 were ezetimibe comparators and 4 were "real life" studies comparing diet and Armolipid Plus to diet alone. The trials included mostly patients with mild to moderate dyslipidemia, treated for 6-48 weeks. The trials also included special populations and patients in whom statins were contraindicated or who could not tolerate them. Armolipid Plus has proved to be able to achieve significant reductions in TC (11-21%) and in LDL-C (15-31%) levels, which is equivalent to expectations from low dose statins. In patients intolerant to statins, who do not achieve their therapeutic target with ezetimibe, Armolipid Plus can achieve a further 10% improvement in TC and LDL-C. The safety and tolerability of Armolipid Plus were excellent, thought likely due to the intentional combination of low doses of its active ingredients: low enough not to be associated with untoward effects, but high enough to exert therapeutic effects in combination with other complementary substances. Consequently, in the event of intolerance to statins, Armolipid Plus offers an effective alternative, which is devoid of the safety risks associated with synthetic pharmacological therapy. In conclusion Armolipid Plus, in addition to dietary measures, could be a rational choice for individuals with mild to moderate hyperlipidemia and for all dyslipidemic patients in whom statins are not indicated or who cannot tolerate them.

Pooling and expanding registries of familial hypercholesterolaemia to assess gaps in care and improve disease management and outcomes: Rationale and design of the global EAS Familial Hypercholesterolaemia Studies Collaboration.

BACKGROUND: The potential for global collaborations to better inform public health policy regarding major non-communicable diseases has been successfully demonstrated by several large-scale international consortia. However, the true public health impact of familial hypercholesterolaemia (FH), a common genetic disorder associated with premature cardiovascular disease, is yet to be reliably ascertained using similar approaches. The European Atherosclerosis Society FH Studies Collaboration (EAS FHSC) is a new initiative of international stakeholders which will help establish a global FH registry to generate large-scale, robust data on the burden of FH worldwide. METHODS: The EAS FHSC will maximise the potential exploitation of currently available and future FH data (retrospective and prospective) by bringing together regional/national/international data sources with access to individuals with a clinical and/or genetic diagnosis of heterozygous or homozygous FH. A novel bespoke electronic platform and FH Data Warehouse will be developed to allow secure data sharing, validation, cleaning, pooling, harmonisation and analysis irrespective of the source or format. Standard statistical procedures will allow us to investigate cross-sectional associations, patterns of real-world practice, trends over time, and analyse risk and outcomes (e.g. cardiovascular outcomes, all-cause death), accounting for potential confounders and subgroup effects. CONCLUSIONS: The EAS FHSC represents an excellent opportunity to integrate individual efforts across the world to tackle the global burden of FH. The information garnered from the registry will help reduce gaps in knowledge, inform best practices, assist in clinical trials design, support clinical guidelines and policies development, and ultimately improve the care of FH patients.

Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment.

Familial hypercholesterolaemia (FH) is a common genetic cause of premature coronary heart disease (CHD). Globally, one baby is born with FH every minute. If diagnosed and treated early in childhood, individuals with FH can have normal life expectancy. This consensus paper aims to improve awareness of the need for early detection and management of FH children. Familial hypercholesterolaemia is diagnosed either on phenotypic criteria, i.e. an elevated low-density lipoprotein cholesterol (LDL-C) level plus a family history of elevated LDL-C, premature coronary artery disease and/or genetic diagnosis, or positive genetic testing. Childhood is the optimal period for discrimination between FH and non-FH using LDL-C screening. An LDL-C ≥5 mmol/L (190 mg/dL), or an LDL-C ≥4 mmol/L (160 mg/dL) with family history of premature CHD and/or high baseline cholesterol in one parent, make the phenotypic diagnosis. If a parent has a genetic defect, the LDL-C cut-off for the child is ≥3.5 mmol/L (130 mg/dL). We recommend cascade screening of families using a combined phenotypic and genotypic strategy. In children, testing is recommended from age 5 years, or earlier if homozygous FH is suspected. A healthy lifestyle and statin treatment (from age 8 to 10 years) are the cornerstones of management of heterozygous FH. Target LDL-C is <3.5 mmol/L (130 mg/dL) if >10 years, or ideally 50% reduction from baseline if 8-10 years, especially with very high LDL-C, elevated lipoprotein(a), a family history of premature CHD or other cardiovascular risk factors, balanced against the long-term risk of treatment side effects. Identifying FH early and optimally lowering LDL-C over the lifespan reduces cumulative LDL-C burden and offers health and socioeconomic benefits. To drive policy change for timely detection and management, we call for further studies in the young. Increased awareness, early identification, and optimal treatment from childhood are critical to adding decades of healthy life for children and adolescents with FH.

Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management.

Statin-associated muscle symptoms (SAMS) are one of the principal reasons for statin non-adherence and/or discontinuation, contributing to adverse cardiovascular outcomes. This European Atherosclerosis Society (EAS) Consensus Panel overviews current understanding of the pathophysiology of statin-associated myopathy, and provides guidance for diagnosis and management of SAMS. Statin-associated myopathy, with significant elevation of serum creatine kinase (CK), is a rare but serious side effect of statins, affecting 1 per 1000 to 1 per 10 000 people on standard statin doses. Statin-associated muscle symptoms cover a broader range of clinical presentations, usually with normal or minimally elevated CK levels, with a prevalence of 7-29% in registries and observational studies. Preclinical studies show that statins decrease mitochondrial function, attenuate energy production, and alter muscle protein degradation, thereby providing a potential link between statins and muscle symptoms; controlled mechanistic and genetic studies in humans are necessary to further understanding. The Panel proposes to identify SAMS by symptoms typical of statin myalgia (i.e. muscle pain or aching) and their temporal association with discontinuation and response to repetitive statin re-challenge. In people with SAMS, the Panel recommends the use of a maximally tolerated statin dose combined with non-statin lipid-lowering therapies to attain recommended low-density lipoprotein cholesterol targets. The Panel recommends a structured work-up to identify individuals with clinically relevant SAMS generally to at least three different statins, so that they can be offered therapeutic regimens to satisfactorily address their cardiovascular risk. Further research into the underlying pathophysiological mechanisms may offer future therapeutic potential.

Residual macrovascular risk in 2013: what have we learned?

Cardiovascular disease poses a major challenge for the 21st century, exacerbated by the pandemics of obesity, metabolic syndrome and type 2 diabetes. While best standards of care, including high-dose statins, can ameliorate the risk of vascular complications, patients remain at high risk of cardiovascular events. The Residual Risk Reduction Initiative (R3i) has previously highlighted atherogenic dyslipidaemia, defined as the imbalance between proatherogenic triglyceride-rich apolipoprotein B-containing-lipoproteins and antiatherogenic apolipoprotein A-I-lipoproteins (as in high-density lipoprotein, HDL), as an important modifiable contributor to lipid-related residual cardiovascular risk, especially in insulin-resistant conditions. As part of its mission to improve awareness and clinical management of atherogenic dyslipidaemia, the R3i has identified three key priorities for action: i) to improve recognition of atherogenic dyslipidaemia in patients at high cardiometabolic risk with or without diabetes; ii) to improve implementation and adherence to guideline-based therapies; and iii) to improve therapeutic strategies for managing atherogenic dyslipidaemia. The R3i believes that monitoring of non-HDL cholesterol provides a simple, practical tool for treatment decisions regarding the management of lipid-related residual cardiovascular risk. Addition of a fibrate, niacin (North and South America), omega-3 fatty acids or ezetimibe are all options for combination with a statin to further reduce non-HDL cholesterol, although lacking in hard evidence for cardiovascular outcome benefits. Several emerging treatments may offer promise. These include the next generation peroxisome proliferator-activated receptorα agonists, cholesteryl ester transfer protein inhibitors and monoclonal antibody therapy targeting proprotein convertase subtilisin/kexin type 9. However, long-term outcomes and safety data are clearly needed. In conclusion, the R3i believes that ongoing trials with these novel treatments may help to define the optimal management of atherogenic dyslipidaemia to reduce the clinical and socioeconomic burden of residual cardiovascular risk.

[N-6 fatty acids and cardiovascular health: dietary intake recommendations]. / Acides gras oméga-6 et maladies cardiovasculaires: recommandations en matière d'apport alimentaire.

Omega-6 polyunsaturated fatty acids (n-6 PUFA) are well known for their critical role in many physiological functions and reduce risks of cardiovascular disease (CVD). However, some argue that excessive consumption of n-6 PUFA may lead to adverse effects on health and therefore recommend reducing dietary n-6 PUFA intake or fixing an upper limit. Epidemiological studies show that n-6 PUFA dietary intake significantly lowers blood LDL-cholesterol levels. In addition, n-6 PUFA intake lower several cardiovascular risk factors such as blood pressure, inflammatory markers, haemostatic parameters and obesity. Data from prospective cohort and interventional studies converge towards a specific protective role of dietary n-6 PUFA intake, in particular linoleic acid, against CVD. In regards to studies examined in this narrative review, recommendation for n-6 PUFA intake above 5%, and ideally about 10% of total energy appears justified for the prevention of ischemic heart disease.

Effect of low-fat, fermented milk enriched with plant sterols on serum lipid profile and oxidative stress in moderate hypercholesterolemia.

BACKGROUND: Plant sterol (PS)-enriched foods have been shown to reduce plasma LDL-cholesterol concentrations. In most studies, however, PSs were incorporated into food products of high fat content. OBJECTIVE: We examined the effect of daily consumption of PS-supplemented low-fat fermented milk (FM) on the plasma lipid profile and on systemic oxidative stress in hypercholesterolemic subjects. DESIGN: Hypercholesterolemic subjects (LDL-cholesterol concentrations >or=130 and

Intake of added oils and fats among middle-aged French adults: relationships with educational level and region of residence.

OBJECTIVE: To describe the relative contribution of 10 created food groups to total fat intake in middle-aged subjects. The relationship of added oil and fat intake with region of residence and educational level was also assessed. DESIGN: Cross-sectional study. SUBJECTS/SETTING: Participants of the French Supplémentation en Vitamines et Minéraux Antioxydants study who completed at least six 24-hour dietary records after inclusion into the study (N=6,572). RESULTS: Added oils and fats were the main source of total fat intake. Animal fat and margarine intakes showed a significant inverse association with educational level, whereas oils with monounsaturated fatty acids (MUFA) were positively associated with education level. Animal fat intake was significantly higher in the western and northern parts of France (54.2% and 50.4%) and lower in the Mediterranean Coast (39.0%). A significant inverse gradient was found with oils with polyunsaturated fatty acids or MUFA in the southwest and the Mediterranean Coast compared with the northern part of France. CONCLUSIONS: We showed a north to south gradient for animal fat intake and the opposite for oils with MUFA and polyunsaturated fatty acid in France. This gradient parallels the known disparities for cardiovascular mortality in this country. This should contribute to adapting dietary guidelines for dietary change in a public health perspective.

Magnitude of HDL cholesterol variation after high-dose atorvastatin is genetically determined at the LDL receptor locus in patients with homozygous familial hypercholesterolemia.

OBJECTIVE: The combination of LDL apheresis with high doses of a potent hepatic hydroxymethylglutaryl coenzyme A reductase inhibitor, such as atorvastatin, has been the best therapy available for the prevention of cardiovascular disease in patients with homozygous familial hypercholesterolemia (HFH). However, some concerns have been made about the effect of atorvastatin on HDL cholesterol levels in these patients. METHODS AND RESULTS: HDL cholesterol levels were determined bimonthly over the course of 2 years of treatment with high-dose atorvastatin in genotypically defined HFH patients either receptor-defective (n=6) or receptor-negative (n=6) under long-term treatment with LDL apheresis. We additionally stratified the atorvastatin effect on HDL cholesterol according to the genotype as an indicator of residual in vivo LDL receptor activity. Our findings indicate that (1) an early and transitory reduction of plasma HDL cholesterol levels occurs during the first 4 weeks of atorvastatin treatment; (2) the degree of the transient HDL reduction is higher in receptor-negative than in receptor-defective patients (-21+/-11 versus -10+/-4%; P=0.01); and (3) after long-term treatment, HDL cholesterol concentration remains higher in receptor-defective than receptor-negative patients (P=0.026). CONCLUSIONS: The present study reveals that HDL cholesterol reduction after high-dose atorvastatin is an early and transient event in HFH patients which magnitude depends on the presence of a residual LDL-R activity.

Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia.

BACKGROUND: Patients with homozygous familial hypercholesterolemia (HoFH) have a high incidence of cardiovascular morbidity and mortality from premature atherosclerosis, and the efficacy of pharmacological therapy has been limited. We evaluated the efficacy, safety, and tolerability of ezetimibe, a novel cholesterol absorption inhibitor, in a multicenter, double-blind, randomized trial of HoFH patients receiving atorvastatin or simvastatin. Methods and Results- Fifty patients with a diagnosis of HoFH on the National Cholesterol Education Program Step 1 or stricter diet and taking open-label atorvastatin 40 mg/d or simvastatin 40 mg/d (statin-40) with (n=25) or without (n=25) concomitant LDL apheresis were randomized to 1 of 3 double-blind treatments: atorvastatin or simvastatin 80 mg/d (statin-80, n=17); ezetimibe 10 mg/d plus atorvastatin or simvastatin 40 mg/d (n=16); or ezetimibe 10 mg/d plus atorvastatin or simvastatin 80 mg/d (n=17) for 12 weeks. The primary end point was mean percentage change in LDL cholesterol (LDL-C) from statin-40 baseline to the end point for patients receiving statins alone (statin-80) versus patients receiving ezetimibe plus atorvastatin or simvastatin at either dose (ezetimibe plus statin-40/80). Ezetimibe plus statin-40/80 significantly reduced LDL-C levels compared with statin-80 (-20.7% versus -6.7%, P=0.007). In the high-dose statin cohorts, ezetimibe plus statin-80 reduced LDL-C by an additional 20.5% (P=0.0001) versus statin-80. Similar significant reductions in LDL-C concentrations were observed for patients with genotype-confirmed HoFH (n=35). Ezetimibe was safe and well tolerated. CONCLUSIONS: Ezetimibe coadministered with atorvastatin or simvastatin in patients with HoFH produced clinically important LDL-C reductions compared with best current therapy. Ezetimibe provides a new, complementary pharmacological approach for this high-risk population.