Dyslipidemia has been globally recognized, for almost seven decades, as one of the most important risk factors for the development and complications of atherosclerotic cardiovascular disease (ASCVD) [...]

Fras Z.

Jug B.

Penson P. E.

Rizzo M.

English

Archivio istituzionale della ricerca - Università di Palermo

metabolitesHOHOHEditorialChallenges and Opportunities on Lipid Metabolism DisordersDiagnosis and Therapy: Novel Insights and Future PerspectiveZlatko Fras 1,2 , Borut Jug 1,2, Peter E. Penson 3,4 and Manfredi Rizzo 5,*Citation: Fras, Z.; Jug, B.; Penson,P.E.; Rizzo, M. Challenges andOpportunities on Lipid MetabolismDisorders Diagnosis and Therapy:Novel Insights and Future Perspective.Metabolites 2021, 11, 611. https://doi.org/10.3390/metabo11090611Received: 31 August 2021Accepted: 4 September 2021Published: 9 September 2021Publisher’s Note: MDPI stays neutralwith regard to jurisdictional claims inpublished maps and institutional affil-iations.Copyright: © 2021 by the authors.Licensee MDPI, Basel, Switzerland.This article is an open access articledistributed under the terms andconditions of the Creative CommonsAttribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).1 Centre for Preventive Cardiology, Department of Vascular Medicine, Division of Medicine,University Medical Centre Ljubljana, SI-1525 Ljubljana, Slovenia; zlatko.fras@kclj.si (Z.F.);borut.jug@kclj.si (B.J.)2 Chair of Internal Medicine, Medical Faculty, University of Ljubljana, SI-1000 Ljubljana, Slovenia3 School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool L3 3AF, UK;p.penson@ljmu.ac.uk4 Liverpool Centre for Cardiovascular Science, Liverpool L7 8TX, UK5 Department of Health Promotion, Mother and Child Care, Internal Medicine and MedicalSpecialties (Promise), University of Palermo, 90133 Palermo, Italy* Correspondence: manfredi.rizzo@unipa.it; Tel.: +39-(091)-655-2945Dyslipidemia has been globally recognized, for almost seven decades, as one of themost important risk factors for the development and complications of atheroscleroticcardiovascular disease (ASCVD) [1]. Clinical trials and large epidemiological studies haveprovided strong evidence for the magnitude of low-density lipoprotein cholesterol (LDL-C)lowering (primarily by statins), consistently predicting ASCVD risk reductions [1]. It hasbeen recently emphasized that patients at high cardiovascular risk, such as those withtype-2 diabetes, are mainly at risk of ASCVD [2]; therefore, the prevention and treatmentof the development and progression of atherosclerosis is still a major public health issuethat needs to be addressed properly.However, several questions still remain to be answered in relation to the comprehen-sive, higher-quality management of raised LDL-C levels. These include more consistent useof the highest possible doses of potent statins; easier prescription of combination therapies;faster and better identification of patients with dyslipidemia who would benefit fromalternative treatment strategies, such as PCSK9 inhibition; as well as issues relating to thediagnosis and effective management of statin intolerance and its subjective equivalents [3–8].In addition, researchers have not yet fully addressed the questions of when to start andhow aggressively to treat hypercholesterolemia in children, adolescents, and the elderly, aswell as whether to respond to the risk of ASCVD with statins in very-high- and high-riskpatients with normal/low LDL-C concentrations [1,9,10].Despite the unequivocal efficiency of statins, it remains to be determined to whatextent the residual ASCVD risk is related to dyslipidemia, especially in patients with lowLDL-C. Furthermore, questions remain as to the choice of the best possible management ofpatients with combined hyperlipidemia, moderate hypertriglyceridemia or atherogenicdyslipidemia [11]. We face these challenges in clinical practice in most patients withmetabolic syndrome and type-2 diabetes [12,13]. This is also linked to the fact that LDLparticles are very heterogenous, with different physico-chemical composition, metabolicbehavior, LDL-receptor affinity, susceptibility to oxidation and, ultimately, different athero-genic potential [14]. Small, dense LDL particles are responsible for the formation andprogression of atherosclerotic plaques, and have been recognized as an independent riskfactor for cardiovascular diseases, even independently of LDL concentrations [15].There is indeed increasing evidence suggesting that the quality (e.g., small denseparticles), and not only the quantity (e.g., plasma concentrations), of LDL is associated withcardiovascular risk [16]. Elevated levels of small, dense LDL particles are found in manycategories of patients at high cardiovascular risk [17–21] and are the key factors for the earlyMetabolites 2021, 11, 611. https://doi.org/10.3390/metabo11090611 https://www.mdpi.com/journal/metabolitesMetabolites 2021, 11, 611 2 of 4stages of atherosclerosis (subclinical) and endothelial dysfunction, which both amplify therisk of cardiovascular events [22]. Beyond statins [23], some novel anti-diabetic medicationshave shown favorable effects on the above mentioned patho-physiological alterations [24–26],and increasing evidence for effective cardiometabolic prevention are coming from incretin-based therapies [27]. Furthermore, the role of increased levels of lipoprotein (a) and thepotential clinical efficiency of the much more effective lowering of this lipoprotein isan increasingly challenging topic [28]. Additional topics of interest include the role ofemerging therapies for elevating concentrations of high-density lipoprotein cholesterol(HDL-C) and augmenting HDL particle functionality [29,30], as well as the modulation oflipoprotein-associated phospholipase A2 [31].Although the available options for pharmacologic interventions are fortunately ex-panding, further well-designed studies are needed to assess the clinical effectiveness andlong-term safety of any of these new pharmacological options. The majority of currentpreventive cardiology guidelines encompass numerous, increasingly evidence-supportedrecommendations on the way to approach the difficulties of poor compliance and ad-herence to long-term lipid-lowering therapy [2,12]. Furthermore, different aspects of thediagnosis and therapy of dyslipidemia are worthy of discussion in the era of contempo-rary medicine. In particular, one can highlight the so-called “4P” (predictive, preemptive,personalized, and participatory) approach, which primarily considers perspectives on themore efficient use of individual genetic information for both diagnostic and therapeuticpurposes. In general, a more personalized but comprehensive approach is required insteadof a “one-size-fits-all” intervention.Furthermore, during the current pandemic, particularly careful management of car-diometabolic risk is necessary, since diabetes, obesity and hypertension are associated withan increased risk of the most severe forms of COVID-19, and its associated mortality [32].In addition, cardiometabolic complications are increasing for many concomitant reasons,such as reduced physical activity, altered eating behaviors and a lack of access to healthcarefacilities for non-COVID patients [33]. In this context, the importance of managing lipidalterations and the role of statins during the COVID-19 pandemic has been recently dis-cussed [34,35]. In summary, with this Special Issue of Metabolites, it is our aim to criticallyreview the available evidence on some of the above-listed challenges and opportunities.We wish to provide the medical and scientific community with the best update on currentand novel lipid diagnostic tools, as well as on treatment options, in order to reduce theburden of ASCVD.Author Contributions: All authors have contributed equally to the present editorial and have readand agreed to the published version of the manuscript.Funding: The present work did not receive any funding.Conflicts of Interest: The authors declare that this article has been written independently. P.E.P. ownsfour shares in AstraZeneca PLC and has received honoraria and/or travel reimbursement for eventssponsored by AKCEA, Amgen, AMRYT, Link Medical, Mylan, Napp and Sanofi. M.R. is a full-timeProfessor of Internal Medicine at the University of Palermo, Italy; Editor in Chief of Metabolitessection Lipid Metabolism; and currently Medical Director in Novo Nordisk Eastern Europe; he hasgiven lectures, received honoraria and research support, and participated in conferences, advisoryboards, and clinical trials sponsored by many pharmaceutical companies, including Amgen, AstraZeneca, Boehringer Ingelheim, Kowa, Eli Lilly, Meda, Mylan, Merck Sharp & Dohme, Novo Nordisk,Novartis, Roche Diagnostics, Sanofi and Servier. None of the above-mentioned pharmaceuticalcompanies had any role in this article, which has been written independently, without any financialor professional help, and reflects only the opinion of the authors, without any role of the industry.Z.F. reports grants, has given talks, acted as a consultant of Amgen, Astra Zeneca, Bayer, BoehringerIngelheim, Krka Pharma, Novartis, Novo Nordisk, Pfizer, and Sanofi, all outside the submitted work.Metabolites 2021, 11, 611 3 of 4References1. Banach, M.; Penson, P.E.; Vrablik, M.; Bunc, M.; Dyrbus, K.; Fedacko, J.; Gaita, D.; Gierlotka, M.; Jarai, Z.; Magda, S.L.; et al.Optimal use of lipid-lowering therapy after acute coronary syndromes: A Position Paper endorsed by the International LipidExpert Panel (ILEP). Pharmacol. Res. 2021, 166, 105499. [CrossRef]2. Maranta, F.; Cianfanelli, L.; Rizzo, M.; Cianflone, D. Filling the gap between Guidelines and Real World in the cardiovascularapproach to the diabetic patients: The need for a call to action. 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Challenges and opportunities on lipid metabolism disorders diagnosis and therapy: Novel insights and future perspective

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Challenges and opportunities on lipid metabolism disorders diagnosis and therapy: Novel insights and future perspective

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