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Cardiovascular disease (CVD) is a chronic non-communicable disease (NCD) and the predominant cause of morbidity and mortality worldwide. Substantial reductions in the CVD prevalence have been achieved in recent years by the attenuation of risk factors (particularly hypertension and dyslipidaemias) in primary and secondary prevention. Despite the remarkable success of lipid lowering treatments, and of statins in particular, in reducing the risk of CVD, there is still an unmet clinical need for the attainment of guideline lipid-targets in even 2/3 of patients. Bempedoic acid, the first in-class inhibitor of ATP-citrate lyase presents a new approach to lipid-lowering therapy. By reducing the endogenous production of cholesterol, upstream of the rate-limiting enzyme HMG-CoA-reductase, i.e., the target of statins, bempedoic acid reduces circulating plasma concentrations of low-density lipoprotein cholesterol (LDL-C), and major adverse CVD events (MACE). Bempedoic acid has the potential to contribute to the reduction of CVD risk not only as monotherapy, but even further as part of a lipid-lowering combination therapy with ezetimibe, reducing LDL-C cholesterol up to 40%. This position paper of the International Lipid Expert Panel (ILEP) summarises the recent evidence around the efficacy and safety of bempedoic acid and presents practical recommendations for its use, which complement the 'lower-is-better-for-longer' approach to lipid management, which is applied across international guidelines for the management of CVD risk. Practical evidence-based guidance is provided relating to the use of bempedoic acid in atherosclerotic CVD, familial hypercholesterolaemia, and statin intolerance. Although there are still no sufficient data avilable for the role of bempedoic acid in the primary prevention of CVD, its favourable effects on plasma glucose and inflammatory markers makes this drug a rational choice in the patient-centred care of specific groups of primary prevention., Competing Interests: Declaration of Competing Interest MB: speakers bureau: Amgen, Daiichi Sankyo, KRKA, Polpharma, Mylan/Viatris, Novartis, Novo-Nordisk, Pfizer, Sanofi-Aventis, Teva, Zentiva; consultant to Adamed, Amgen, Daiichi Sankyo, Esperion, NewAmsterdam, Novartis, Novo-Nordisk, Sanofi-Aventis; Grants from Amgen, Daiichi Sankyo, Mylan/Viatris, Sanofi and Valeant; CMDO at Longevity Group (Luxemburg); PEP owns four shares in AstraZeneca PLC and has received honoraria and/or travel reimbursement for events sponsored by AKCEA, Amgen, AMRYT; MF reports having received consulting fees and/or honoraria and delivering lectures for Abbott, Amarin, Amgen, AstraZeneca, Ajanta, Kowa, Merck and Co, Organon, Pfizer, Recordati, Sanofi/Regeneron, Servier, SMB, Ultragenyx and Viatris; GL: has given talks, attended conferences, received consultancy fees and participated in trials sponsored by Abbott Laboratories, Amgen, Astra-Zeneca, Berlin Chemie, Bayer, Boehringer Ingelheim, GlaxoSmithKline, Grindex, KRKA, MSD, Mylan, Novartis, Novo Nordisk, Pfizer, Sanofi, Servier Laboratories, Siemens Laboratories, Zentiva; PP; Grants from Akcea, Amgen. Scientific expert for: Amgen, Akcea, PRD Therapeutics; ŽR: has received honoraria from Novartis, Sanofi-Aventis and Swixx; MV has given talks, attended conferences, received consultancy fees and participated in trials sponsored by Amgen, Astra-Zeneca, Bayer, Boehringer Ingelheim, KRKA, MSD, Novartis, Novo Nordisk, Pfizer, Sanofi, Servier, Viatris, Zentiva; all other authors do not declare any conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Conflict of interest: M.B.: speakers bureau: Amgen, Daichii Sankyo, KRKA, Polpharma, Novartis, Pfizer, Sanofi, Teva, Viatris, Zentiva; consultant to: Adamed, Amgen, Daichii Sankyo, Esperion, NewAmsterdam, Novartis, Sanofi, Viatris; Grants from Amgen, Sanofi, and Viatris; CMO at Nomi Biotech Corporations; C.P.C. (2020–22): Research Grants from: Amgen, Better Therapeutics, Boehringer-Ingelheim (BI), Bristol-Myers Squibb (BMS), Daiichi Sankyo, Janssen, Merck, Novo Nordisk, Pfizer; Consulting fees from Aegerion/Amryt, Alnylam, Amarin, Amgen, Applied Therapeutics, Ascendia, BI, BMS, Eli Lilly, Janssen, Lexicon, Merck, Pfizer, Rhoshan, Sanofi; he serves on Data and Safety Monitoring Boards for the Veteran’s Administration, Applied Therapeutics and NovoNordisk; P.E.P.: owns four shares in AstraZeneca PLC and has received honoraria and/or travel reimbursement for events sponsored by AKCEA, Amgen, AMRYT, Link Medical, Mylan, Napp, Sanofi. No stocks, shares, and regular paid employment by a company with a stake in the content of the manuscript.

Aims: Statin intolerance (SI) represents a significant public health problem for which precise estimates of prevalence are needed. Statin intolerance remains an important clinical challenge, and it is associated with an increased risk of cardiovascular events. This meta-analysis estimates the overall prevalence of SI, the prevalence according to different diagnostic criteria and in different disease settings, and identifies possible risk factors/conditions that might increase the risk of SI., Methods and Results: We searched several databases up to 31 May 2021, for studies that reported the prevalence of SI. The primary endpoint was overall prevalence and prevalence according to a range of diagnostic criteria [National Lipid Association (NLA), International Lipid Expert Panel (ILEP), and European Atherosclerosis Society (EAS)] and in different disease settings. The secondary endpoint was to identify possible risk factors for SI. A random-effects model was applied to estimate the overall pooled prevalence. A total of 176 studies [112 randomized controlled trials (RCTs); 64 cohort studies] with 4 143 517 patients were ultimately included in the analysis. The overall prevalence of SI was 9.1% (95% confidence interval 8.0-10%). The prevalence was similar when defined using NLA, ILEP, and EAS criteria [7.0% (6.0-8.0%), 6.7% (5.0-8.0%), 5.9% (4.0-7.0%), respectively]. The prevalence of SI in RCTs was significantly lower compared with cohort studies [4.9% (4.0-6.0%) vs. 17% (14-19%)]. The prevalence of SI in studies including both primary and secondary prevention patients was much higher than when primary or secondary prevention patients were analysed separately [18% (14-21%), 8.2% (6.0-10%), 9.1% (6.0-11%), respectively]. Statin lipid solubility did not affect the prevalence of SI [4.0% (2.0-5.0%) vs. 5.0% (4.0-6.0%)]. Age [odds ratio (OR) 1.33, P = 0.04], female gender (OR 1.47, P = 0.007), Asian and Black race (P < 0.05 for both), obesity (OR 1.30, P = 0.02), diabetes mellitus (OR 1.26, P = 0.02), hypothyroidism (OR 1.37, P = 0.01), chronic liver, and renal failure (P < 0.05 for both) were significantly associated with SI in the meta-regression model. Antiarrhythmic agents, calcium channel blockers, alcohol use, and increased statin dose were also associated with a higher risk of SI., Conclusion: Based on the present analysis of >4 million patients, the prevalence of SI is low when diagnosed according to international definitions. These results support the concept that the prevalence of complete SI might often be overestimated and highlight the need for the careful assessment of patients with potential symptoms related to SI., Competing Interests: Conflict of interest: P.E.P. has received honoraria and/or travel reimbursement for events sponsored by AKCEA, Amgen, AMRYT, Link Medical, Mylan, Napp, Sanofi; D.P.M. has given talks, acted as a consultant, or attended conferences sponsored by Amgen and Novo Nordisk; P.P.T.: speaker for Amgen, Esperion, Merck, Novo Nordisk; consultant to Amarin, Amgen, Kowa, Merck, Resverlogix, and Theravance; Ž.R. has given talks sponsored by Sanofi-Aventis and Novartis; M.B.: speakers bureau: Amgen, Herbapol, Kogen, KRKA, Polpharma, Mylan/Viatris, Novartis, Novo Nordisk, Sanofi-Aventis, Teva, Zentiva; consultant to Abbott Vascular, Amgen, Daichii Sankyo, Esperion, FreiaPharmaceuticals, Novartis, Polfarmex, Sanofi-Aventis; Grants from Amgen, Mylan/Viatris, Sanofi, and Valeant; CMO at Nomi Biotech Corporation; all other authors have no conflict of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Statin intolerance is a clinical syndrome whereby adverse effects (AEs) associated with statin therapy [most commonly statin-associated muscle symptoms (SAMS)] result in the discontinuation of therapy and consequently increase the risk of adverse cardiovascular outcomes. However, complete statin intolerance occurs in only a small minority of treated patients (estimated prevalence of only 3-5%). Many perceived AEs are misattributed (e.g. physical musculoskeletal injury and inflammatory myopathies), and subjective symptoms occur as a result of the fact that patients expect them to do so when taking medicines (the nocebo/drucebo effect)-what might be truth even for over 50% of all patients with muscle weakness/pain. Clear guidance is necessary to enable the optimal management of plasma in real-world clinical practice in patients who experience subjective AEs. In this Position Paper of the International Lipid Expert Panel (ILEP), we present a step-by-step patient-centred approach to the identification and management of SAMS with a particular focus on strategies to prevent and manage the nocebo/drucebo effect and to improve long-term compliance with lipid-lowering therapy., (© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Myocarditis refers to the clinical and histological characteristics of a diverse range of inflammatory cellular pathophysiological conditions which result in cardiac dysfunction. Myocarditis is a major cause of mortality in individuals less than 40 years of age and accounts for approximately 20% of cardiovascular disease (CVD) events. Myocarditis contributes to dilated cardiomyopathy in 30% of patients and can progress to cardiac arrest, which has a poor prognosis of <40% survival over 10 years. Myocarditis has also been documented after infection with SARS-CoV-2. The most commonly used lipid-lowering therapies, HMG-CoA reductase inhibitors (statins), decrease CVD-related morbidity and mortality. In addition to their lipid-lowering effects, increasing evidence supports the existence of several additional beneficial, 'pleiotropic' effects of statins. Recently, several studies have indicated that statins may attenuate myocarditis. Statins modify the lipid oxidation, inflammation, immunomodulation, and endothelial activity of the pathophysiology and have been recommended as adjuvant treatment. In this review, we focus on the mechanisms of action of statins and their effects on myocarditis, SARS-CoV-2 and CVD., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Atherosclerosis, a chronic progressive inflammatory condition characterized by the formation of lipid-laden lesions in arterial walls, is associated with substantial morbidity (including ischaemic stroke and myocardial infarction) and mortality. Risk factors for atherosclerosis are well understood and can be ameliorated by evidence-based and guideline-directed pharmaceutical agents (e.g. the reduction of circulating concentrations of low-density lipoprotein cholesterol by statins). Additionally, many natural products (usually food derivatives) and 'nutraceuticals' (pharmaceutical formulations prepared from components of foods) have been shown to have favourable effects on risk factors for atherosclerotic cardiovascular disease. This literature review summarises the evidence for anti-atherogenic natural compounds. The article focuses on agents which are discussed in international guidelines and are supported by extensive high-quality randomized-controlled trial (RCT) data. We focus on micronutrients (compounds present in food in small quantities) and nutraceuticals, in particular, phytosterols, polyunsaturated ω-3 fatty acids and red-yeast rice. We conclude that the 'nutraceutical approach' (identify the active ingredients in natural products; produce high-quality products according to Good Manufacturing Practice guidelines; evaluate them in long-term outcomes trials) is the mechanism by which the domains of natural product research and evidence-based medicine can move closer together., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Competing Interests: Declaration of competing interest MB has served on the speakers bureau of Abbott/Mylan, Abbott Vascular, Actavis, Akcea, Amgen, Biofarm, KRKA, MSD, Sanofi-Aventis, Servier and Valeant, and has served as a consultant to Abbott Vascular, Akcea, Amgen, Daichii Sankyo, Esperion, Lilly, MSD, Resverlogix, Sanofi-Aventis; Grants from Sanofi and Valeant; GFW has received honoraria for lectures and advisory boards for Sanofi, Regeneron, Kowa, and Amgen; PEP owns four shares in Astra Zeneca PLC and has received travel/speaker's fees from Amgen Inc. The other authors have no competing interests to declare.

Purpose of Review: We aimed to summarize recent guidelines, position papers, and high-quality clinical research relating the use of nutraceuticals in the management of individuals at high risk of atherosclerotic cardiovascular disease., Recent Findings: It is essential that individuals at high risk of cardiovascular disease receive guideline-directed evidence-based therapies to reduce their risk of morbidity and mortality from cardiovascular events. Compared with conventional therapeutics, nutraceuticals have undergone relatively little investigation in randomized controlled trials. Thus, recommendations for nutraceuticals in international guidelines are rare, and nutraceuticals should not be used preferentially in place of statins. Nevertheless, recent position papers from the International Lipid Expert Panel and clinical evidence from studies of triglyceride reduction by polyunsaturated fatty acid administration demonstrate that nutraceuticals do have an important role in optimizing therapy in individuals at high risk of cardiovascular disease. Roles for nutraceuticals include as follows: (1) managing residual risk associated with lipids other than low-density lipoprotein cholesterol (LDL-C); (2) managing non-lipid-mediated residual risk; (3) optimizing LDL-C treatment in statin intolerance; (4) optimizing LCL-C treatment when add-on therapies for statins are not available; (5) as adjuncts to lifestyle for individuals at high lifetime risk of atherosclerotic cardiovascular disease (ASCVD). The strength of evidence for each of these applications is variable. In addition to guideline-directed therapeutics, nutraceuticals may have roles in optimizing preventative therapy and targeting residual risk in individuals at high risk of ASCVD. Application of Good Manufacturing Practice and randomized controlled trials when producing and evaluating nutraceuticals will expand the armoury of evidence-based agents for the prevention of ASCVD.

Statins beside their main effect on reducing the progression of cardiovascular disease through pharmacological inhibition of the endogenous cholesterol synthesis, have additional pleiotropic effects including antiinflammatory effects mediated through the induction of suppressor regulatory T cells (Tregs). Statin-induced expansion of Tregs reduces chronic inflammation and may have beneficial effects in autoimmune diseases. However, statins could represent a double-edged sword in immunomodulation. Drugs that act by increasing the concentration of Tregs could enhance the risk of cancers, particularly in the elderly and may have adverse effects in neurodegenerative disorders and infectious diseases. In the present paper, we review the experimental studies that evaluate the effects of statins on Treg cells in autoimmune and inflammatory diseases and we discuss potential therapeutic applications of statins in this setting., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The 'placebo effect' and 'nocebo effect' are phenomena whereby beneficial (placebo) or adverse (nocebo) effects result from the expectation that an inert substance will relieve or cause a particular symptom. These terms are often inappropriately applied to effects experienced on drug therapy. Quantifying the magnitude of placebo and nocebo effects in clinical trials is problematic because it requires a 'no treatment' arm. To overcome the difficulties associated with measuring the nocebo effect, and the fact that its definition refers to inert compounds, rather than drugs, we introduce the concept of 'drucebo' (a combination of DRUg and plaCEBO or noCEBO) to relate to beneficial or adverse effects of a drug, which result from expectation and are not pharmacologically caused by the drug. As an initial application of the concept, we have estimated the contribution of the drucebo effect to statin discontinuation and statin-induced muscle symptoms by performing a systematic review of randomized controlled trial of statin therapy., Methods: This preferred reporting items for systematic reviews and meta-analysis-compliant systematic review was prospectively registered in PROSPERO (CRD42017082700). We searched PubMed and Cochrane Central from inception until 3 January 2018 using a search strategy designed to detect studies including the concepts (Statins AND Placebo AND muscle pain). We included studies that allowed us to quantify the drucebo effect for adverse muscle symptoms of statins by (i) comparing reported rates of muscle symptoms in blinded and unblinded phases of randomized controlled trials and (ii) comparing rates of muscle symptoms at baseline and during blinded therapy in trials that included patients with objectively confirmed statin intolerance at baseline. Extraction was performed by two researchers with disagreements settled by a third reviewer., Results: Five studies allowed the estimation of the drucebo effect. All trials demonstrated an excess of side effects under open-label conditions. The contribution of the drucebo effect to statin-associated muscle pain ranged between 38% and 78%. The heterogeneity of study methods, outcomes, and reporting did not allow for quantitative synthesis (meta-analysis) of the results., Conclusions: The drucebo effect may be useful in evaluating the safety and efficacy of medicines. Diagnosis of the drucebo effect in patients presenting with statin intolerance will allow restoration of life-prolonging lipid-lowering therapy. Our study was limited by heterogeneity of included studies and lack of access to individual patient data. Further studies are necessary to better understand risk factors for and clinical management of the drucebo effect., (© 2018 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.)