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AimsTo appraise the clinical and genetic evidence that low-density lipoproteins (LDLs) cause atherosclerotic cardiovascular disease (ASCVD).Methods and resultsWe 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.ConclusionConsistent evidence from numerous and multiple different types of clinical and genetic studies unequivocally establishes that LDL causes ASCVD.

Chronic low-degree inflammation is a hallmark of atherosclerotic cardiovascular (CV) disease. To assess the effect of lipid-lowering therapies on C-reactive protein (CRP), a biomarker of inflammation, we conducted a meta-analysis according to the PRISMA guidelines. Databases were searched from inception to July 2023. Inclusion criteria were: (i) randomized controlled trials (RCTs) in human, Phase II, III, or IV; (ii) English language; (iii) comparing the effect of lipid-lowering drugs vs. placebo; (iv) reporting the effects on CRP levels; (v) with intervention duration of more than 3 weeks; (vi) and sample size (for both intervention and control group) over than 100 subjects. The between-group (treatment-placebo) CRP absolute mean differences and 95% confidence intervals were calculated for each drug class separately. A total of 171 668 subjects from 53 RCTs were included. CRP levels (mg/L) were significantly decreased by statins [−0.65 (−0.87 to −0.43), bempedoic acid; −0.43 (−0.67 to −0.20), ezetimibe; −0.28 (−0.48 to −0.08)], and omega-3 fatty acids [omega3FAs, −0.27 (−0.52 to −0.01)]. CRP was reduced by −0.40 (−1.17 to 0.38) with fibrates, although not statistically significant. A slight increase of CRP concentration was observed for proprotein convertase subtilisin/kexin type 9 inhibitors [0.11 (0.07–0.14)] and cholesteryl-ester transfer protein inhibitors [0.10 (0.00–0.21)], the latter being not statistically significant. Meta-regression analysis did not show a significant correlation between changes in CRP and LDL cholesterol (LDL-C) or triglycerides. Statins, bempedoic acid, ezetimibe, and omega3FAs significantly reduce serum CRP concentration, independently of LDL-C reductions. The impact of this anti-inflammatory effect in terms of CV prevention needs further investigation. [ABSTRACT FROM AUTHOR]

The availability of pharmacological approaches able to effectively reduce circulating LDL cholesterol (LDL-C) has led to a substantial reduction in the risk of atherosclerosis-related cardiovascular disease (CVD). However, a residual cardiovascular (CV) risk persists in treated individuals with optimal levels of LDL-C. Additional risk factors beyond LDL-C are involved, and among these, elevated levels of triglycerides (TGs) and TG-rich lipoproteins are causally associated with an increased CV risk. Apolipoprotein C-III (apoC-III) is a key regulator of TG metabolism and hence circulating levels through several mechanisms including the inhibition of lipoprotein lipase activity and alterations in the affinity of apoC-III-containing lipoproteins for both the hepatic receptors involved in their removal and extracellular matrix in the arterial wall. Genetic studies have clarified the role of apoC-III in humans, establishing a causal link with CVD and showing that loss-of-function mutations in the APOC3 gene are associated with reduced TG levels and reduced risk of coronary heart disease. Currently available hypolipidaemic drugs can reduce TG levels, although to a limited extent. Substantial reductions in TG levels can be obtained with new drugs that target specifically apoC-III; these include two antisense oligonucleotides, one small interfering RNA and an antibody. [ABSTRACT FROM AUTHOR]

Adherence to the Mediterranean diet (MedDiet) is recommended for cardiovascular disease prevention. However, recent epidemiological studies report a shift toward lower adherence to MedDiet. We have conducted a prospective cohort study to evaluate changes in individual determinants of MedDiet adherence over time. Clinical information and MedDiet adherence score (MEDAS) were collected in 711 subjects (mean age 68 ± 10 years; 42% males), enrolled in the PLIC study (Progression of Intimal Atherosclerotic Lesions in Carotid arteries), during two visits conducted, on average, 4.5 years apart. MEDAS score worsening and improvements (absolute change, ΔMEDAS) and the variation in the proportion of subjects reporting to meet each MEDAS criteria were assessed. Overall, 34% of the subjects improved their MedDiet adherence (ΔMEDAS: +1.87 ± 1.13), by consuming more olive oil, legumes and fish and use of dishes seasoned with sofrito and 48% subjects worsened their MedDiet adherence (ΔMEDAS: −2.02 ± 1.14) by consuming less fruit, legumes, fish and nuts, with higher rates of worsening in women and subjects aged 50–65 years. Subjects who improved the score were more obese, had higher plasma glucose levels, and metabolic syndrome at the basal visit. In summary, we report an overall decrease in MedDiet adherence, evaluated during a timeframe heavily affected by the COVID-19 pandemic, underlining the need for better dietary interventions. [ABSTRACT FROM AUTHOR]

Although adequate clinical management of patients with hypercholesterolemia without a history of known cardiovascular disease is essential for prevention, these subjects are often disregarded. Furthermore, the scientific literature on primary cardiovascular prevention is not as rich as that on secondary prevention; finally, physicians often lack adequate tools for the effective management of subjects in primary prevention and have to face some unsolved relevant issues. This document aims to discuss and review the evidence available on this topic and provide practical guidance. Available algorithms and risk charts represent the main tool for the assessment of cardiovascular risk in patients in primary prevention. The accuracy of such an estimate can be substantially improved considering the potential contribution of some additional risk factors (C-reactive protein, lipoprotein(a), family history of cardiovascular disease) and conditions (environmental pollution, sleep quality, socioeconomic status, educational level) whose impact on the cardiovascular risk has been better understood in recent years. The availability of non-invasive procedures to evaluate subclinical atherosclerosis may help to identify subjects needing an earlier intervention. Unveiling the presence of these conditions will improve cardiovascular risk estimation, granting a more appropriate intervention. The accurate assessment of cardiovascular risk in subjects in primary prevention with the use of algorithms and risk charts together with the evaluation of additional factors will allow physicians to approach each patient with personalized strategies, which should translate into an increased adherence to therapy and, as a consequence, a reduced cardiovascular risk. • Subjects in primary prevention with hypercholesterolemia are often not well managed. • Algorithms and risk charts are the main tool to assess cardiovascular risk in these. • Additional risk factors may impact the individual's cardiovascular risk. • Dietary approach, nutraceuticals, or drugs may be considered in primary prevention. • Achieving therapeutic goals increases adherence to therapy and reduces CV risk. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the effect of bempedoic acid on glycaemic and lipid variables in patients with hypercholesterolaemia. Methods: A patient‐level pooled analysis of four phase 3, randomized, double‐blind, placebo‐controlled trials evaluated changes in glycaemia, change from baseline in LDL‐C, and adverse events. Patients (N = 3621) on maximally tolerated statins were randomized 2:1 to oral bempedoic acid 180 mg or placebo once daily for 12 to 52 weeks with the results analysed by baseline glycaemic status (diabetes, prediabetes, or normoglycaemia). Results: The annual rate of new‐onset diabetes for bempedoic acid versus placebo in patients with normoglycaemia at baseline (n = 618) was 0.3% versus 0.8%, and for patients with prediabetes at baseline (n = 1868) it was 4.7% versus 5.9%. In patients with diabetes or prediabetes, bempedoic acid significantly (P <.0001) reduced HbA1c by −0.12% and −0.06%, respectively, and did not worsen fasting glucose versus placebo. Bempedoic acid significantly and consistently lowered LDL‐C levels versus placebo, regardless of baseline glycaemic status (placebo‐corrected difference range, −17.2% to −29.6%; P <.001 for each stratum). The safety of bempedoic acid was comparable with placebo and similar across glycaemic strata. Conclusions: Bempedoic acid significantly lowered LDL‐C across glycaemic strata and did not worsen glycaemic variables or increase the incidence of new‐onset diabetes versus placebo over a median follow‐up of 1 year. [ABSTRACT FROM AUTHOR]

Objective: In primary hypercholesterolemia many people treated with statins do not reach their plasma LDL-C goals and are at increased risk of cardiovascular disease (CVD). This study aimed to evaluate efficacy and safety of a new fixed-dose combination (FDC) formulation of rosuvastatin/ezetimibe (R/E) in this population. Methods: This was a multicenter, multinational, randomized, double-blind, double-dummy, active-controlled, parallel-arm study of FDC R/E in people with primary hypercholesterolemia at very high risk (VHR) or high risk (HR) of CVD, inadequately controlled with 20 mg or 10 mg stable daily dose of rosuvastatin or equipotent dose of another statin. The primary objective was to demonstrate superiority of FDC R/E versus rosuvastatin monotherapy uptitrated to 40 mg (R40) or 20 mg (R20) in reduction of LDL-C after 6 weeks. Results: Randomized VHR participants (n = 244) were treated with R40, R40/E10, or R20/E10; randomized HR participants (n = 208) received R10/E10 or R20. In VHR participants, superiority of R40/E10 and R20/E10 versus R40 was demonstrated on LDL-C percent change from baseline to Week 6 with least squares mean differences (LSMD) of −19.66% (95% CI: −29.48% to −9.84%; P <.001) and −12.28% (95% CI: −22.12% to −2.44%; P =.015), respectively. In HR participants, superiority of R10/E10 over R20 was not demonstrated (LSMD −5.20%; 95% CI: −15.18% to 4.78%; P =.306), despite clinically relevant LDL-C reduction with R10/E10. No unexpected safety findings were reported. Conclusions: The results from this study suggest that R/E FDCs improve LDL-C reduction and goal achievement in people with primary hypercholesterolemia inadequately controlled with statins and at VHR/HR of CVD. [ABSTRACT FROM AUTHOR]

The widespread use of statins has largely improved the treatment of hypercholesterolemia, but many patients still fail to achieve the LDL-C targets recommended by guidelines. Furthermore, some patients continue to present a very high cardiovascular (CV) risk or even an extreme risk despite being well treated, mainly due to the presence of co-morbidities such as diabetes or peripheral artery disease, which significantly increase their global CV risk. For these very high CV risk patients, the most recent European guidelines have reviewed the LDL-C goals and recommend an LDL-C reduction of at least 50% and a goal of <55 mg/dL or even <40 mg/dL. Recent clinical trials have shown that patient stratification based on the presence or absence of atherothrombotic risk factors may represent a valuable tool to identify patients at extremely high CV risk who may benefit more from an aggressive LDL-C-lowering approach. In these patients it may be appropriate to aim for the lowest LDL-C level, independently of recommended goals, with all the available pharmacological approaches. Image 1 • A high proportion of patients with stable CAD presents an extreme CV risk. • The lowest LDL-C level is mandatory with all the available approaches. • The identification of FH patients is a critical issue. • Poor adherence to therapy is common in the daily practice. • Increasing the knowledge of a long-term therapy benefit may increase adherence. [ABSTRACT FROM AUTHOR]

A large number of cardiovascular events are not prevented by current therapeutic regimens. In search for additional, innovative strategies, immune cells have been recognized as key players contributing to atherosclerotic plaque progression and destabilization. Particularly the role of innate immune cells is of major interest, following the recent paradigm shift that innate immunity, long considered to be incapable of learning, does exhibit immunological memory mediated via epigenetic reprogramming. Compelling evidence shows that atherosclerotic risk factors promote immune cell migration by pre-activation of circulating innate immune cells. Innate immune cell activation via metabolic and epigenetic reprogramming perpetuates a systemic low-grade inflammatory state in cardiovascular disease (CVD) that is also common in other chronic inflammatory disorders. This opens a new therapeutic area in which metabolic or epigenetic modulation of innate immune cells may result in decreased systemic chronic inflammation, alleviating CVD, and its co-morbidities. [ABSTRACT FROM AUTHOR]

High-density lipoproteins (HDL) are a target for drug development because of their proposed anti-atherogenic properties. In this review, we will briefly discuss the currently established drugs for increasing HDL-C, namely niacin and fibrates, and some of their limitations. Next, we will focus on novel alternative therapies that are currently being developed for raising HDL-C, such as CETP inhibitors. Finally, we will conclude with a review of novel drugs that are being developed for modulating the function of HDL based on HDL mimetics. Gaps in our knowledge and the challenges that will have to be overcome for these new HDL based therapies will also be discussed. [ABSTRACT FROM AUTHOR]

Dyslipidemias and atherosclerosis play a pivotal role in cardiovascular risk and disease. Although some pathophysiological mechanisms underlying these conditions have been unveiled, several knowledge gaps still remain. Experimental models, both in vitro and in vivo , have been instrumental to our better understanding of such complex processes. The latter have often been based on rodent species, either wild-type or, in several instances, genetically modified. In this context, the zebrafish may represent an additional very useful in vivo experimental model for dyslipidemia and atherosclerosis. Interestingly, the lipid metabolism of zebrafish shares several features with that present in humans, recapitulating some molecular features and pathophysiological aspects in a better way than that of rodents. The zebrafish model may be of help to address questions related to exposome factors as well as to genetic features, aiming to dissect selected aspects of the more complex scenario observed in humans. Indeed, exposome-related dyslipidemia/atherosclerosis research in zebrafish may target different scientific questions, related to nutrition, microbiota, temperature, light exposure at the larval stage, exposure to chemicals and epigenetic consequences of such external factors. Addressing genetic features related to dyslipidemia/atherosclerosis using the zebrafish model is already a reality and active research is now ongoing in this promising area. Novel technologies (gene and genome editing) may help to identify new candidate genes involved in dyslipidemia and dyslipidemia-related diseases. Based on these considerations, the zebrafish experimental model appears highly suitable for the study of exposome factors, genes and molecules involved in the development of atherosclerosis-related disease as well as for the validation of novel potential treatment options. • Experimental models to study dyslipidemias and atherosclerosis are relevant tools • Rodent species (wild-type/genetically modified) have been used over time • Zebrafish represents another very useful recently-developed experimental model • Lipid metabolism of zebrafish shares several features with that present in humans • Gene/genome editing in zebrafish may help to identify new candidate genes associated to dyslipidemia-related diseases [ABSTRACT FROM AUTHOR]

Even at low-density lipoprotein cholesterol (LDL-C) goal, patients with cardiometabolic abnormalities remain at high risk of cardiovascular events. This paper aims (i) to critically appraise evidence for elevated levels of triglyceride-rich lipoproteins (TRLs) and low levels of high-density lipoprotein cholesterol (HDL-C) as cardiovascular risk factors, and (ii) to advise on therapeutic strategies for management. Current evidence supports a causal association between elevated TRL and their remnants, low HDL-C, and cardiovascular risk. This interpretation is based on mechanistic and genetic studies for TRL and remnants, together with the epidemiological data suggestive of the association for circulating triglycerides and cardiovascular disease. For HDL, epidemiological, mechanistic, and clinical intervention data are consistent with the view that low HDL-C contributes to elevated cardiovascular risk; genetic evidence is unclear however, potentially reflecting the complexity of HDL metabolism. The Panel believes that therapeutic targeting of elevated triglycerides (≥1.7 mmol/L or 150 mg/dL), a marker of TRL and their remnants, and/or low HDL-C (<1.0 mmol/L or 40 mg/dL) may provide further benefit. The first step should be lifestyle interventions together with consideration of compliance with pharmacotherapy and secondary causes of dyslipidaemia. If inadequately corrected, adding niacin or a fibrate, or intensifying LDL-C lowering therapy may be considered. Treatment decisions regarding statin combination therapy should take into account relevant safety concerns, i.e. the risk of elevation of blood glucose, uric acid or liver enzymes with niacin, and myopathy, increased serum creatinine and cholelithiasis with fibrates. These recommendations will facilitate reduction in the substantial cardiovascular risk that persists in patients with cardiometabolic abnormalities at LDL-C goal. [ABSTRACT FROM PUBLISHER]

Genetics and environmental and lifestyle factors deeply affect cardiovascular diseases, with atherosclerosis as the etiopathological factor (ACVD) and their early recognition can significantly contribute to an efficient prevention and treatment of the disease. Due to the vast number of these factors, only the novel "omic" approaches are surmised. In addition to genomics, which extended the effective therapeutic potential for complex and rarer diseases, the use of "omics" presents a step-forward that can be harnessed for more accurate ACVD prediction and risk assessment in larger populations. The analysis of these data by artificial intelligence (AI)/machine learning (ML) strategies makes is possible to decipher the large amount of data that derives from such techniques, in order to provide an unbiased assessment of pathophysiological correlations and to develop a better understanding of the molecular background of ACVD. The predictive models implementing data from these "omics", are based on consolidated AI best practices for classical ML and deep learning paradigms that employ methods (e.g., Integrative Network Fusion method, using an AI/ML supervised strategy and cross-validation) to validate the reproducibility of the results. Here, we highlight the proposed integrated approach for the prediction and diagnosis of ACVD with the presentation of the key elements of a joint scientific project of the University of Milan and the Almazov National Medical Research Centre. [ABSTRACT FROM AUTHOR]

Over the years, the relationship between high-density lipoprotein (HDL) and atherosclerosis, initially highlighted by the Framingham study, has been revealed to be extremely complex, due to the multiple HDL functions involved in atheroprotection. Among them, HDL cholesterol efflux capacity (CEC), the ability of HDL to promote cell cholesterol efflux from cells, has emerged as a better predictor of cardiovascular (CV) risk compared to merely plasma HDL-cholesterol (HDL-C) levels. HDL CEC is impaired in many genetic and pathological conditions associated to high CV risk such as dyslipidemia, chronic kidney disease, diabetes, inflammatory and autoimmune diseases, endocrine disorders, etc. The present review describes the current knowledge on HDL CEC modifications in these conditions, focusing on the most recent human studies and on genetic and pathophysiologic aspects. In addition, the most relevant strategies possibly modulating HDL CEC, including lifestyle modifications, as well as nutraceutical and pharmacological interventions, will be discussed. The objective of this review is to help understanding whether, from the current evidence, HDL CEC may be considered as a valid biomarker of CV risk and a potential pharmacological target for novel therapeutic approaches. [ABSTRACT FROM AUTHOR]

Abstract: Background: Although omega-3 fatty acids have well documented properties which would reduce the cardiovascular (CV) disease risk, the evidence from randomized controlled trials (RCTs) remains inconclusive. We performed a meta-analysis of the available RCTs for investigating the CV preventive effect of administrating at least 1 gram/day, and for at least 1 year, omega-3 fatty acid supplements to patients with existing CV disease. Methods: RCTs published up to March 2013 were searched from PubMed, EMBASE, and the Cochrane Library. Two of us independently reviewed and selected eligible trials. Results: Of 360 articles retrieved, 11 randomized, double-blind, placebo controlled trials fulfilling inclusion criteria, overall involving 15,348 patients with a history of CV disease, were considered in the final analyses. No statistically significant association was observed for all-cause mortality (RR, 0.89; 95% CI, 0.78 to 1.02) and stroke (RR, 1.31; 95% CI, 0.90 to 1.90). Conversely, statistically significant protective effects were observed for cardiac death (RR, 0.68; 95% CI, 0.56 to 0.83), sudden death (RR, 0.67; 95% CI, 0.52 to 0.87), and myocardial infarction (RR, 0.75; 95% CI, 0.63 to 0.88). Conclusion: Overall, our results supply evidence that long-term effect of high dose omega-3 fatty acid supplementation may be beneficial for the onset of cardiac death, sudden death and myocardial infarction among patients with a history of cardiovascular disease. [Copyright &y& Elsevier]

The availability of efficient lipid-lowering drugs has substantially reduced the incidence and mortality for cardiovascular disease (CVD). Despite that, CVD still represents a major cause of death and disability; efforts are thus required to prevent this disease, since reducing the established CV risk factors may slow or prevent the onset of cardiovascular events. Current guidelines recommend a healthier lifestyle for all CV risk categories, as it may have a beneficial impact on several risk factors; in individuals with a low-to-moderate hypercholesterolemia, which are not eligible for a pharmacological approach and are not far from the cholesterol target recommended for their risk category, functional foods or nutraceuticals may be considered as supplement to reduce their CV risk status. Of note, counseling and lifestyle intervention in people at moderate CV risk represents a major issue for both preventing a further risk increase and reducing the need for drugs. Studies on general populations have clearly indicated that lifestyle interventions translate into a clinical benefit, with reduction of the incidence of myocardial infarction and the risk of developing type 2 diabetes. Image 1 • Current guidelines recommend a healthier lifestyle for all CV risk categories. • Functional foods or nutraceuticals may be used in lower CV risk individuals. • Lifestyle intervention in people at moderate CV risk can reduce the need for drugs. • Lifestyle interventions translate into a clinical benefit in the general population. [ABSTRACT FROM AUTHOR]

To estimate the prevalence of cardiovascular (CV) disease and CV risk factors among Polish patients. A nationwide cross-sectional study, LIPIDOGRAM2015, was carried out in Poland in the 4th quarter of 2015 and 1st and 2nd quarters of 2016; 438 primary care physicians enrolled 13,724 adult patients that sought medical care in primary health care practices. Nearly 19% of men and approximately 12% of women had cardiovascular disease (CVD). Over 60% of the recruited patients had hypertension (HTN), >80% had dyslipidaemia and <15% of patients were diagnosed with diabetes (DM). All of these disorders were more frequent in men. In 80% of patients the waist circumference exceed norm for the European population. Less than half of the patients were current smokers or had smoked in the past. Patients with CVD had significantly higher blood pressure and glucose levels but lower low density lipoprotein-cholesterol level. The prevalence of CVD and CV risk factors among patients in Poland is high. CVD is more common in men than in women. The most common CV risk factors are excess waist circumference, dyslipidaemia and HTN. Family physicians should conduct activities to prevent, diagnose early and treat CVD in the primary health care population. Image 1 • LIPIDOGRAM2015 is a nationwide cross-sectional study on the prevalence of CVD and CV risk factors in Poland. • The most common CV risk factors are excess waist circumference, dyslipidaemia and HTN. • Among primary care patients, CVD was present in 19% of men and 12% of women. [ABSTRACT FROM AUTHOR]

Evinacumab, an angiopoietin-like protein 3 monoclonal antibody, reduced low-density lipoprotein cholesterol (LDL-C) significantly in a Phase 2 study of patients with homozygous familial hypercholesterolemia. In this double-blind, placebo-controlled Phase 1 study, we compared safety, tolerability, pharmacokinetics, and pharmacodynamics of evinacumab between healthy Japanese and Caucasian adults. Subjects with LDL-C ≥2.6 and <4.1 mmol/L were enrolled to one of four dose cohorts: evinacumab subcutaneous (SC) 300 mg single dose, SC 300 mg once weekly for eight doses, intravenous (IV) 5 mg/kg, or IV 15 mg/kg once every 4 weeks for two doses. Each cohort comprised 24 subjects (12 Japanese; 12 Caucasian), randomized (3:1) to receive evinacumab or placebo within each ethnic group with a 24-week follow-up. The safety profile of evinacumab (IV and SC) in both ethnicities was comparable with placebo, with no serious or severe treatment-emergent adverse events. Pharmacokinetic profiles were comparable between Japanese and Caucasian subjects across IV and SC groups. Mean calculated LDL-C decreased from baseline with both IV doses, beginning on day 3 up to week 8. Triglyceride changes observed with evinacumab IV were rapid (seen by day 2) and sustained up to week 8. Evinacumab SC doses also reduced LDL-C and triglyceride levels, although lower doses induced smaller changes. Evinacumab (IV and SC) reduced other lipids, including apolipoprotein B, versus placebo. In both ethnicities, evinacumab (IV and SC) was generally well tolerated, exhibiting comparable pharmacokinetic profiles. Dose-related reductions in LDL-C and triglycerides were observed with evinacumab in both ethnic groups. Image 1 • The effects of evinacumab were compared between Japanese and Caucasian subjects. • Evinacumab exhibited a safety profile comparable to placebo in both ethnicities. • Evinacumab decreased LDL-C and triglyceride levels in both ethnicities. • Identical evinacumab doses are appropriate in both ethnicities due to similar PK/PD. • Evinacumab may help address the unmet need for LDL-C-lowering therapies in homozygous familial hypercholesterolemia (HoFH). [ABSTRACT FROM AUTHOR]

This narrative review aims to discuss the more relevant evidence on the role of linoleic acid (LA), a n-6 essential fatty acid that constitutes the predominant proportion of dietary polyunsaturated fatty acids (PUFA), in cardiovascular health. Although LA can be metabolized into Arachidonic Acid (AA), a 20 carbon PUFA which is the precursor of eicosanoids, including some with proinflammatory or prothrombotic-vasoconstrictor action, the large majority of experimental and clinical studies have assessed the potential benefit of increasing dietary intake of LA. Overall, data from clinical studies and meta-analyses suggest an association between high dietary intakes or tissue levels of n-6 PUFA, and specifically LA, and the improvement of cardiovascular risk (mainly of the plasma lipid profile), as well as long-term glycaemic control and insulin resistance. Most observational data show that elevated/increased dietary intake or tissue levels of LA is associated with a reduced incidence of cardiovascular diseases (mainly coronary artery diseases) and of new onset metabolic syndrome or type 2 diabetes. The effects of LA (or n-6 PUFA) in other physio-pathological areas are less clear. High quality clinical trials are needed to assess both the actual amplitude and the underlying mechanisms of the health effects related to dietary intake of this essential fatty acid. Image 1 • Linoleic acid (LA) is an essential18-carbon n-6 polyunsaturated fatty acid. • An adequate dietary supply of LA is crucial for human health. • LA intakes/blood levels are inversely correlated with cardiovascular disease risk. • LA intakes should be increased in most western countries. [ABSTRACT FROM AUTHOR]

Statins are highly effective for preventing cardiovascular events by reducing low-density lipoprotein cholesterol (LDL-C). However, many patients taking statins report muscle-related symptoms that prevent the use of guideline recommended doses. Patients with reported intolerance to statins have a high risk of cardiovascular events. Clinical strategies that optimize cardiovascular risk reduction through LDL-C lowering need to be applied in patients experiencing intolerable side effects that they attribute to statins. In this paper, the authors review definitions of statin intolerance, propose algorithms to better define statin intolerance, and describe approaches to optimize cardiovascular risk reduction among individuals reporting statin-associated muscle symptoms. [ABSTRACT FROM AUTHOR]

Background and aims Statin-associated muscle symptoms (SAMS) frequently cause statin non-adherence, switching and discontinuation, contributing to adverse cardiovascular (CV) outcomes. Therefore, the management of SAMS is key in the effective treatment of patients with cardiovascular disease (CVD), through achievement of maximum-tolerated statin dosing and other practical aspects. The aim of this article is to provide practical, focused advice for healthcare professionals on the management of patients with SAMS. Methods An expert working group combined current evidence, published guidelines and experiences surrounding a number of topics concerning SAMS to provide recommendations on how to best assess and manage this condition and reach the highest tolerated dose of statin for each individual patient. Results The group collaborated to provide guidance on definitions in the SAMS field, psychological issues, re-challenging and switching treatments, as well as interpretation of current guidelines and optimal treatment of SAMS in different patient populations. An algorithm was developed to guide the management of patients with SAMS. In addition, the expert working group considered some of the more complex scenarios in a series of frequently asked questions and suggested answers. Conclusions The expert working group gave recommendations for healthcare professionals on the management of SAMS but highlighted the importance of tailoring the treatment approach to each individual patient. Evidence supporting the role of nutraceuticals and complementary therapies, such as vitamin D, was lacking, however the majority of the group favoured combination therapy with ezetimibe and the addition of PCSK9 inhibitors in high-risk patients. [ABSTRACT FROM AUTHOR]

Abstract: We estimated the need to use low-efficacy statins or high-efficacy statins or drug combinations to bring high- or very-high cardiovascular risk subjects to their LDL-c target, in a sample representative of the Italian adult population and according to the principles of reimbursement of hypercholesterolemic drugs currently used in Italy. The results allow us concluding that among high or very high cardiovascular risk patients about three patients out of five should be prescribed high-efficacy statins or drug combinations. The other two prescriptions might take into account lower-efficacy statins. If we also compute the values of HDL-c in these subjects – the large majority of which stands below the optimal values as suggested by International guidelines – we bring forward the need either to select specific statins able to increase the levels of these protective lipoproteins or to consider combination therapies of statins with fibrates or nicotinic acid. Our data might conceivably be applied to other low-cardiovascular risk countries and should be taken into account when defining the proportion of drugs with different efficacy and cost in the everyday clinical practice. [Copyright &y& Elsevier]

Background: Previous studies have reported that statin use was associated with reductions in cardiovascular morbidity and mortality among patients with dyslipidemia, even without established cardiovascular disease. However, inadequate adherence may reduce statins'' protective effects. Objective: The aim of this work was to investigate whether an association exists between statin adherence when used as primary prevention and risk of subsequent ischemic heart disease (IHD). Methods: People aged ≥18 years who were residents of Italy's Lombardy region and were newly treated with statins in 2002 to 2003 were assessed as part of a retrospective analysis of data from a health services database. Patients who were hospitalized for IHD during this period were identified with hospital discharge information from a health-services database; IHD-related hospitalizations were identified by International Classification of Diseases, Ninth Revision, Clinical Modification, codes for acute myocardial infarction (410), acute and subacute forms of IHD (411), and/or codes concerning coronary revascularization (36.0–36.9). Four groups of patients were excluded: those with ≥1 lipid-lowering drug within 2 years before the index prescription (to limit the sample to treatment initiators); those who had been hospitalized for cardiovascular disease or had used medications for IHD or heart failure within 2 years before the index date (to limit the study to primary prevention); those who did not have ≥1 year of follow-up; and those who received only 1 dispensation of a statin during the first year after the index prescription. Follow-up continued until hospitalization for IHD or any other cardiovascular cause, death from any cause, emigration, or the end of the study period (June 30, 2007). The proportion of days covered (PDC) by therapy with statins was the exposure variable; it served as a proxy for adherence. PDC (and therefore adherence) was categorized as very low (≤25%), low (26%–50%), intermediate (51%–75%), or high (≥75%) coverage. A proportional hazards model was fitted to estimate hazard ratio (HR) and 95% CIs for the association between time-dependent categories of PDC and time of IHD hospitalization, after correcting for covariates. Results: A group of 90,832 patients was included; during follow-up, 1480 patients experienced a hospitalization for IHD. After the Cox proportional hazards model was adjusted for age, sex, type of statin dispensed at index prescription, current use of other selected drugs (ie, antidiabetics, antihypertensives, digitalis or organic nitrates, or other cardiac medications), Charlson comorbidity index, and whether or not a given patient switched statins, those with low, intermediate, or high statin coverage had HR (95% CI) values of 0.85 (0.72–0.98), 0.82 (0.71–0.95), and 0.81 (0.71–0.94), respectively, compared with patients with very low coverage. Conclusions: In these Italian subjects without a history of cardiovascular disease, low, intermediate, and high levels of adherence to statin pharmaco-therapy were associated with lower risk of nonfatal IHD compared with those who had very low (≤25%) adherence. However, these findings have several limitations, such as the use of database information (rather than medical records), the assumption that PDC accurately represented actual adherence, and confounding (ie, unmeasured factors related to PDC or to adherence may have influenced clinical outcomes). [Copyright &y& Elsevier]

Aim: To provide information on the balance between the cardiovascular (CV) benefit and the diabetogenic harm of statin therapy in the current clinical practice.Methods: All the 115,939 residents (older than 50 years) in the Italian Lombardy Region newly treated with statins between 2003 and 2005, were followed from the first statin prescription until 2012 to identify those experiencing a macrovascular complication and those with at least one sign suggestive of new onset diabetes. The proportion of days of follow-up covered by statin prescriptions measured adherence with statins. Hazard ratio, and relative 95% confidence interval (CI), for the two considered outcomes associated with statin adherence, were separately estimated (proportional hazard models). Number needed to treat (NNT) and number needed to harm (NNH), i.e., number of individuals who must be treated with statins in order to prevent a macrovascular complication, or to generate a new onset diabetes, respectively, were calculated to evaluate the balance between CV benefit and diabetogenic harm of statin therapy.Results: Compared to those at very low adherence with statins, patients at high adherence showed a significant reduction of macrovascular risk (28%, 95% CI: 23%-33%) and a greater risk of developing diabetic condition (67%, 50%-86%). In the whole cohort, the NNT was 26, whereas the NNH 65. NNT was lower than NNH also in all considered strata of age, gender, clinical profile.Conclusions: This large cohort investigation provides real-world evidence that the balance between CV benefit and diabetogenic harm of statin therapy is largely favourable to treatment benefits. [ABSTRACT FROM AUTHOR]