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Background and Aims: Sodium glucose co-transporter 2 (SGLT2)-inhibitors were developed as glucose-lowering drugs. Surprisingly, SGLT2-inhibitors also reduced risk of cardiovascular disease. The impact of SGLT2-inhibitors on lipids and lipoproteins is unclear, but an effect might contribute to the observed lower cardiovascular risk. We conducted a meta-analysis to examine this, overall and by dose, ethnicity, and drug type., Methods: PubMed, EMBASE and Web of Science were searched for randomized controlled trials examining all available SGLT2-inhibitors. Studies with available lipid measurements were included. Quantitative data synthesis was performed using random and fixed effects models., Results: We identified 60 randomized trials, including 147,130 individuals. Overall, using random effects models, SGLT2-inhibitor treatment increased total cholesterol by 0.09 mmol/L (95% CI: 0.06, 0.13), low-density lipoprotein (LDL) cholesterol by 0.08 mmol/L (0.05, 0.10), and high-density lipoprotein (HDL) cholesterol by 0.06 mmol/L (0.05, 0.07), while it reduced triglycerides by 0.10 mmol/L (0.06, 0.14). Fixed effects estimates were similar but with smaller effect sizes for HDL cholesterol and triglycerides. For higher SGLT2-inhibitor doses, there was a nominally higher non-significant effect on lipids and lipoproteins. In Asian compared to non-Asian populations, a slightly larger increase in HDL cholesterol and a decrease in triglycerides were observed, but with similar results for total and LDL cholesterol. Treatment effects on lipids and lipoproteins were generally robust across different SGLT2-inhibitor drugs., Conclusion: In meta-analyses, SGLT2-inhibition increased total, LDL, and HDL cholesterol and decreased triglycerides. Effect sizes varied slightly by drug dose and ethnicity but were generally robust by drug type., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Børge Nordestgaard reports consultancies with Novo Nordisk. The other authors have no disclosures., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Atherosclerotic cardiovascular disease (ASCVD) is accelerated in people with diabetes. Dyslipidemia, hyperglycemia, oxidative stress, and inflammation play a role via a variety of mechanisms operative in the artery wall. In addition, some unique features predispose people with type 1 diabetes to accelerated atherosclerosis. Various organizations have created guidelines that provide advice regarding screening, risk assessment, and roadmaps for treatment to prevent ASCVD in diabetes. Management of dyslipidemia, especially with statins, has proven to be of immense benefit in the prevention of clinical CVD. However, since many patients fail to attain the low levels of low-density lipoproteins (LDL) recommended in these guidelines, supplemental therapy, such as the addition of ezetimibe, bempedoic acid or PCSK9 inhibitors, is often required to reach LDL goals. As a result, the upfront use of combination therapies, particularly a statin plus ezetimibe, is a rational initial approach. The addition to statins of drugs that specifically lower triglyceride levels has not proven beneficial, although the addition of icosapent-ethyl has been shown to be of value, likely by mechanisms independent of triglyceride lowering. Newer treatments in development, including apoC-III and ANGPTL3 inhibitors, seem promising in further reducing apoB-containing lipoproteins., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Atherosclerotic cardiovascular disease (ASCVD) represents the primary cause of mortality among patients with Type 2 Diabetes Mellitus (T2DM). In this population, High-Density Lipoprotein (HDL) particles exhibit abnormalities in number, composition, and function, culminating in diminished anti-atherosclerotic capabilities despite normal HDL cholesterol (HDL-C) concentrations. Hyperglycemic conditions contribute to these alterations in HDL kinetics, composition, and function, causing T2DM patients' HDL particles to exhibit decreased concentrations of diverse lipid species and proteins. Treatment of hyperglycemia has the potential to correct abnormal HDL particle attributes in T2DM; however, pharmacological interventions, including metformin and thiazolidinediones, yield inconsistent outcomes with respect to HDL-C concentrations and functionality. Despite numerous attempts with diverse drugs, pharmacologically augmenting HDL-C levels has not resulted in clinical benefits in mitigating ASCVD risk. In contrast, reducing Low Density Lipoprotein cholesterol (LDL-C) via statins and ezetimibe has demonstrated significant efficacy in curtailing CVD risk among T2DM individuals. Promising results have been observed in animal models and early-phase trials utilizing recombinant HDL and Lecitin Cholesterol Acyl Transferase (LCAT) -enhancing agents, but the evaluation of their efficacy and safety in large-scale clinical trials is ongoing. While aberrant HDL metabolism constitutes a prevalent aspect of dyslipidemia in T2DM, HDL cholesterol concentrations and composition no longer offer valuable insights for informing therapeutic decisions. Nevertheless, HDL metabolism remains a critical research area in T2DM, necessitating further investigation to elucidate the role of HDL particles in the development of diabetes-associated complications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background and Aims: Proper prescription and high adherence to intensive lipid lowering drugs (LLD) in patients with coronary heart disease (CHD) are crucial and strongly recommended. The aim of this study is to investigate long-term treatment patterns and adherence to LLD following hospitalization for a CHD event., Methods: Patients admitted to two Norwegian hospitals with a CHD event from 2011 to 2014 (N = 1094) attended clinical examination and completed a questionnaire, median 16 months later. Clinical data were linked to pharmacy dispensing data from 2010 to 2020. The proportions using high-intensity statin therapy (atorvastatin 40/80 mg or rosuvastatin 20/40 mg) and non-statin LLD after the CHD event were assessed. Adherence was evaluated by proportion of days covered (PDC) and gaps in treatment., Results: Median age at hospitalization was 63 (IQR 12) years, 21 % were female. Altogether, 1054 patients (96 %) were discharged with a statin prescription, while treatment was dispensed in 85 % within the following 90 days. During median 8 (SD 2.5) years follow-up, the proportion using high-intensity statin therapy ranged 62-68 %, whereas the use of ezetimibe increased from 4 to 26 %. PDC <0.8 was found in 22 % of statin users and 26 % of ezetimibe users. The proportions with a treatment gap exceeding 180 days were 22 % for statins and 28 % for ezetimibe. Smoking at hospitalization and negative affectivity were significantly associated with reduced statin adherence, regardless of adherence measure., Conclusions: In this long-term follow-up of patients with CHD, less than 70 % used high-intensity statin therapy with only small changes over time, and only 25 % used additional treatment with ezetimibe. We identified factors associated with reduced statin adherence that may be target for interventions., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:IE and CB are affiliated with Oslo Economics and have completed consultancy assignments outside the submitted work for several public and private institutions in recent years. HS is affiliated with Steno Diabetes Center Aarhus and has received consultancy fees from Novartis, Arla Foods AMBA, Bristol-Myers Squibb, Pfizer and Neumirna outside the submitted work. EH, ES and TD reports no conflicts of interest. SH has received lecture fees from Sanofi, Novartis, and Pfizer outside the submitted work. JM received lecture fees from Sanofi, Novartis, Boehringer Ingelheim, and Bayer outside the submitted work., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Dyslipidemia refers to unhealthy changes in blood lipid composition and is a risk factor for atherosclerotic cardiovascular diseases (ASCVD). Usually, low-density lipoprotein-cholesterol (LDL-C) is the primary goal for dyslipidemia management. However, non-high-density lipoprotein cholesterol (non-HDL-C) has gained attention as an alternative, reliable goal. It encompasses all plasma lipoproteins like LDL, triglyceride-rich lipoproteins (TRL), TRL-remnants, and lipoprotein a [Lp(a)] except high-density lipoproteins (HDL). In addition to LDL-C, several other constituents of non-HDL-C have been reported to be atherogenic, aiding the pathophysiology of atherosclerosis. They are acknowledged as contributors to residual ASCVD risk that exists in patients on statin therapy with controlled LDL-C levels. Therefore, non-HDL-C is now considered an independent risk factor or predictor for CVD. The popularity of non-HDL-C is attributed to its ease of estimation and non-dependency on fasting status. It is also better at predicting ASCVD risk in patients on statin therapy, and/or in those with obesity, diabetes, and metabolic disorders. In addition, large follow-up studies have reported that individuals with higher baseline non-HDL-C at a younger age (<45 years) were more prone to adverse CVD events at an older age, suggesting a predictive ability of non-HDL-C over the long term. Consequently, non-HDL-C is recommended as a secondary goal for dyslipidemia management by most international guidelines. Intriguingly, geographical patterns in recent epidemiological studies showed remarkably high non-HDL-C attributable mortality in high-risk countries. This review highlights the independent role of non-HDL-C in ASCVD pathogenesis and prognosis. In addition, the need for a country-specific approach to dyslipidemia management at the community/population level is discussed. Overall, non-HDL-C can become a co-primary or primary goal in dyslipidemia management., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Dyslipidemia is an important risk factor for coronary artery disease and stroke, and it has emerged as a major public health issue worldwide. Internet-based health management and intervention may offer a new approach to health management. This study was conducted to provide health guidance and education to people with dyslipidemia using an Internet health management platform and to assess the effectiveness of Internet health management and intervention in improving health-related behaviors and controlling blood lipids., Methods: Starting in 2013 (Baseline, N = 56,542), a Western longitudinal study in China was performed, and all interventional objects were provided with Internet health management. Health checkups were conducted annually, and questionnaires were administered every two years to analyze changes in health behaviors two years (2015) and four years (2017) following the intervention. In addition, factors affecting behavioral changes and lipid control were analyzed in the dyslipidemic population to understand the effectiveness and influencing factors of Internet health management on lipid control., Results: By guiding interventional objects through the Internet health management platform, the awareness rate of dyslipidemia increased from 19.1% in 2013 to 34.4% in 2017; and the control rate of dyslipidemia increased from 9.1% at baseline to 18.5%. Certain health-related behaviors that are beneficial to health (tobacco use, physical activity, and partial dietary) were gradually improved over the intervention time. For patients with dyslipidemia, triglyceride decreased from 2.90 mmol/L (2013) to 2.77 mmol/L (2017) as the years went by. Analysis of factors affecting lipid control showed that non-compliance with health instructions affected lipid control; in addition to these, being female (0.722, 95% CI: 0.546,0.954) was found to be a protective factor for effective lipid control., Conclusions: The basic Internet-based health management platform in this study appears to be moderately successful and is a valuable and feasible application. Tobacco, dietary, and physical activity interventions provided significant protection against dyslipidemia in patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background and Aims: We aimed to understand the impact of physicians' perception about LDL-cholesterol (LDLc) control on the management of patients with dyslipidemia in Spain., Methods: We performed a cross-sectional and multicenter study, in which 435 healthcare professionals participated in face-to-face meetings, collecting qualitative and quantitative information related to hypercholesterolemia management. Additionally, aggregated anonymized data of the last 10 patients with hypercholesterolemia attended by each physician were collected., Results: A total of 4,010 patients (8%, 13%, 16% and 61% with low, moderate, high, and very high cardiovascular [CV] risk) were included. Physicians' perception was that 62% of their patients attained LDLc goals (66%, 63%, 61% and 56%, for low, moderate, high and very high CV risk, respectively). However, when looking into the data only 31% (vs 62% p<0.01) of patients attained the LDLc goals (47%, 36%, 22% and 25%, respectively). Overall, 33% of patients were taking high intensity statins, 32% statin/ezetimibe, 21% low/moderate intensity statins and 4% PCSK9 inhibitors. These numbers were 38%, 45%, 8% and 6% for very high risk patients and 44%, 21%, 21% and 4% for high CV risk patients. In 32% of patients, a change in lipid lowering therapy was performed after the visit, mainly combining statins/ezetimibe (55%)., Conclusions: In Spain, most patients with dyslipidemia do not achieve the recommended LDLc goals because of an insufficient intensification of lipid lowering therapy. On the one hand, this is in part due to physicians misperception on preventive LDLc control and the need for repeated advice to patient, and, on the other, to the lack of patient adherence., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Juan Cosin-Sales: has received conference fees from Almirall, Amgen, Daiichi-Sankyo, Ferrer, MSD, Novartis, Organon, Rovi and Sanofi; has participated in advisory services for Almirall, Amgen, MSD and Sanofi; and has received research grants from Amgen, Ferrer, MSD and Sanofi. Raquel Campuzano: has received conference fees from Amgen, Daiichi-Sankyo, Ferrer, Mylan, MSD, Organon, Sanofi, Servier and Novartis; has participated in advisory services for Novartis, Amgen, Sanofi and Servier; and has received collaborations to scientific or research projects from Amgen, Daiichi-Sankyo, Ferrer, Organon, Servier and Novartis. José Luis Díaz: has received fees for presentations, advisory services or scientific collaborations from Amgen, Bayer, Boëringher, BMS, Lilly, MSD, Mylan, Novartis, Novo-Nordisk, Pfizer, Rovi, Rubió, Sanofi, Daiichi-Sankyo and Servier. Carlos Escobar: has received fees for conferences/advisory services from: Almirall, Amgen, Daiichi-Sankyo, Esteve, Ferrer, MSD, Novartis, Organon, Rovi, Sanofi, Servier and Viatris. María Rosa Fernández: has received fees for conferences from Amgen, Sanofi, Ferrer, Daiichi-Sankyo, Organon and Rovi; has participated in advisory services for Novartis, Amgen, Sanofi and Amarin. Juan José Gómez-Doblas: has received fees for conferences from Amgen, Sanofi, Daiichi-Sankyo, Organon and MSD; has participated in advisory services for Amgen, Sanofi and Amarin; and has received collaborations to scientific or research projects from Amgen, Sanofi, Ferrer and Daiichi-Sankyo. José María Mostaza: has participated in advisory services and/or conferences, or has carried out projects for Pfizer, Amarin, Ferrer, Sanofi, Amgen, Alter, Servier, Novartis and Daiichi-Sankyo. Juan Pedro-Botet: has received fees for conferences from Amarin, Amgen, Daiichi-Sankyo, Esteve, MSD, Sanofi and Viatris; and has participated in advisory services for Amarin, Amgen, Daiichi-Sankyo, Esteve, Ferrer, Sanofi and Viatris. Núria Plana: has received fees for conferences from Amgen, Sanofi, Daiichi-Sankyo Mylan and Alexion. Pedro Valdivielso: has received fees for conferences from Amgen, Sanofi, Ferrer, Amarin, Akcea, Sobi, MSD, Novartis and Daiichi-Sankyo; has participated in advisory services for Daiichi-Sankyo, Amgen, Sanofi, Akcea and Amarin; and has received research grants from Ferrer and Akcea., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background and Aims: The evidence that dyslipidemia is associated with hyperglycemia calls for an investigation of whether dyslipidemia, as well as lipid-modifying agents, could affect the subsequent development of diabetic retinopathy (DR). Therefore, we aimed to address these unanswered questions by utilizing Mendelian randomization (MR) analysis., Methods: Genetic variants were selected from the UK Biobank as instruments to serve as proxies for lipid traits [high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), apolipoprotein A-I (APOA-I) and apolipoprotein B (APOB)]. Univariable and multivariable MR analyses were performed to examine the associations of these lipid traits with DR and different levels of severity of DR. Based on the evidence for the effects of lipids on outcomes, we estimated the causal relevance of cholesteryl ester transfer protein (CETP) inhibitors in severe nonproliferative and proliferative DR using protein quantitative trait loci (pQTLs) and expression quantitative trait loci (eQTLs) as instruments., Results: Genetically determined HDL-C levels were inversely associated with the risk of severe nonproliferative DR (OR = 0.70, 95% CI = 0.52-0.94) and proliferative DR (OR = 0.90, 95% CI = 0.83-0.97) in the main analyses utilizing the inverse variance-weighted (IVW) MR method and a couple of sensitivity analyses. No association was noted between genetically proxied CETP inhibitors and DR., Conclusions: This MR study suggests the casual protective roles of HDL-C in severe nonproliferative DR and proliferative DR, which calls for further studies to confirm these findings. Current lipid-modifying agents acting on HDL-C may not reduce the risk of DR and new treatments are required in the future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background and Aims: We aimed to examine the longitudinal associations of total cholesterol (TC), non-high-density lipoprotein cholesterol (non-HDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride, and low-density lipoprotein cholesterol (LDL-C) with carotid-femoral pulse wave velocity (cfPWV) and carotid intima-media thickness (cIMT) progression., Methods: We studied 1779, 15-year-old participants from the Avon Longitudinal Study of Parents and Children, UK birth cohort, followed up for 9 years. Fasting TC, non-HDL-C, HDL-C, triglyceride, and LDL-C were measured at 15, 17, and 24 years and age-categorized as normal, elevated, and dyslipidemia based on National Heart, Lung, and Blood Institute lipid guidelines. cfPWV and cIMT were measured at 17 and 24 years. Associations were examined using linear mixed-effect models. To simulate the treatment of dyslipidemia we conducted temporal inverse allocation model analyses., Results: Among 1779 [49.9% female] participants, mean lipid levels and proportions at elevated or dyslipidemia categories increased from ages 15 through 24 years. Persistently elevated TC: effect estimate 0.026 mm; [95% CI 0.004 to 0.049; p = 0.024], elevated non-HDL-C, and elevated LDL-C were cumulatively associated with cIMT progression. Persistent borderline-low HDL-C: -0.027 mm; [-0.050 to -0.005; p = 0.019] and very-low HDL-C -0.035 mm; [-0.057 to -0.013; p = 0.002] levels were associated with cIMT progression. A temporal inverse allocation of elevated and dyslipidemic levels with normal lipid levels at age 17 years attenuated the associations of cumulative elevated TC, non-HDL-C, LDL-C, and low HDL-C with cIMT progression. Cumulative elevated lipids or dyslipidemia were not associated with cfPWV progression., Conclusions: Late adolescence is key to preventing, halting, and reversing dyslipidemic-related preclinical atherosclerosis progression, warranting universal lipid screening in the general pediatric population., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: The Apolipoprotein A5 (APOA5) rs662799 was significantly associated with blood lipid level at genome-wide significance level. Whether dynamic changes of adiposity influence the effect of lipid loci on long-term blood lipid profile remains unclear. We assessed interactions of 5-year body mass index (BMI) change and rs662799 genotypes with risk of incident dyslipidemia and longitudinal changes in serum lipids in a prospective cohort., Methods: We included 4329 non-dyslipidemia participants aged ≥ 40 years at baseline from a well-defined community-based cohort and followed up for an average of 5 years. BMI and blood lipids were measured at baseline and follow-up., Results: The association of each rs662799 A-allele with risk of incident dyslipidemia was stronger along with the increase in BMI change level, with the odds ratios (OR) increasing from 1.03 in the lowest tertile of BMI change (< 0.02 kg/m 2 ) to 1.17 in the second (0.02-1.29), and 1.46 in the highest tertile (> 1.29) (p for interaction < 0.001). Associations of each 1-unit of BMI (kg/m 2 ) increase with incident dyslipidemia were more prominent in the AA carriers (OR = 1.50, 95%CI [1.26-1.80], p < 0.001), while much weaker in the GA (OR = 1.10) or GG carriers (OR = 1.09) (p for interaction  = 0.002). Similar results were found for the risk of incident higher triglycerides (TG) and lower high-density lipoprotein cholesterol (HDL-c), or the longitudinal changes in log 10 -TG (all p for interaction ≤ 0.02)., Conclusions: BMI changes significantly modulate rs662799 genetic contribution to dyslipidemia and long-term lipid profile, which provide new evidence for personalized clinical management of lipids according to individual genetic background., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Disorders of plasma lipids remain key risk factors for the development of atherosclerotic cardiovascular disease (ASCVD) in the Middle East and are estimated to increase more dramatically in the next decade than in any other global region except Africa. This statement is an update to the 2016 consensus clinical recommendations for the management of plasma lipid disorders in the Middle East, following the evaluation of newer cholesterol-lowering agents in randomised controlled cardiovascular outcome trials, as well as the publication of revised international guidelines., Methods: A multidisciplinary panel of regional experts was convened to update the consensus clinical recommendations for the management of plasma lipids in the Middle East. The recommendations constructed in 2016 were reviewed against emerging research since publication., Results: Newly developed Middle East ASCVD risk categories were established using the multiple risk group categories from the recently updated international guidelines and the epidemiological evidence from the Gulf Region. These consensus recommendations support a more intensive reduction of LDL-C across cardiovascular risk categories. Alongside low-density lipoprotein cholesterol, we recommend non-high-density lipoprotein cholesterol as a primary treatment target. Lifestyle modifications remain the first-line treatment recommendation for all patients. The first-line pharmacological treatment in patients with dyslipidaemia is statin therapy, with a number of second-line agents available. The selection of a second lipid-lowering agent for combination therapy with statin should be based on the lipid-lowering target of the patient. Guidance is also provided on the management of underlying conditions and special populations; of particular pertinence in the region are familial hypercholesterolaemia, diabetes and metabolic dyslipidaemia. New therapies have emerged from research that found positive outcomes in reducing low-density lipoprotein cholesterol levels. The initial results of these newly researched drugs strongly indicate their inclusion as future therapies in dyslipidaemia management in the Middle East., Conclusions: These updated consensus clinical recommendations provide practicing clinicians with comprehensive, region-specific guidance to improve the detection and management of plasma lipid disorders in patients in the Middle East., (Copyright © 2021. Published by Elsevier B.V.)

Background and Aims: Central and Eastern Europe (CEE) is a largely understudied region, despite having the highest cardiovascular disease mortality in Europe. This analysis aimed to assess the proportion of patients in CEE who achieved their LDL-C goals based on individual cardiovascular risk recommended by the 2016 and 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines., Methods: The DA VINCI study was a cross-sectional observational study of primary and secondary prevention patients receiving lipid-lowering therapy across Europe between June 2017 and November 2018., Results: In total, 2154 patients were enrolled from the Czech Republic (n = 509), Hungary (n = 319), Poland (n = 460), Romania (n = 259), Slovakia (n = 123) and Ukraine (n = 484). At LDL-C measurement, most patients were on either moderate- or high-intensity statin monotherapy (53% and 32%, respectively). Despite this, only 44% of patients achieved risk-based LDL-C goals recommended by the 2016 ESC/EAS guidelines, ranging from 21% in Ukraine to 50% in Hungary and Romania. Only 24% of patients overall achieved the risk-based LDL-C goals recommended by the 2019 ESC/EAS guidelines, ranging from 11% in Ukraine to 32% in Poland., Conclusions: Among patients receiving lipid-lowering therapy, more than half did not achieve their 2016 LDL-C goals. In one of the first comparative analyses evaluating 2019 risk-based goal attainment among countries in CEE, three-quarters of patients did not meet their 2019 LDL-C goals, highlighting a significant gap between guidelines and clinical practice for lipid management in CEE., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Dyslipidemias are common among patients with chronic kidney disease (CKD) and are a major risk factor for cardiovascular disease. This study aimed to investigate the association between early-stage CKD and new-onset dyslipidemia for each lipid profile., Methods: This nationwide longitudinal study included data from the Japan Specific Health Checkups (J-SHC) Study. New-onset dyslipidemia was indicated by hypertriglyceridemia (High-TG; ≥150 mg/dL), hyper-LDL cholesterolemia (High-LDL-C; ≥140 mg/dL), or hypo-HDL chelesterolemia (Low-HDL-C; <40 mg/dL) levels according to the guideline of Japan Atherosclerosis Society, or High-TG/HDL-C ratio (≥3.5) which was a good predictor of atherosclerosis. The incidence of new-onset dyslipidemia was compared between participants with and without CKD. Survival curves were used to analyze the incidence of each dyslipidemia., Results: Of 289,462 participants with a median follow-up period of 3 years, the incidence of High-TG, High-LDL-C, Low-HDL-C, and High-TG/HDL-C ratios were 64.4/1000 person-years, 83.1/1000 person-years, 14.5/1000 person-years, and 39.6/1000 person-years, respectively. The adjusted hazard ratios (95% confidence intervals) for High-TG, High-LDL-C, Low-HDL-C, and High-TG/HDL-C ratio were 1.09 (1.05-1.13), 0.99 (0.95-1.04), 1.12 (1.05-1.18), and 1.14 (1.09-1.18), respectively, in CKD participants as compared to non-CKD participants. Decreased eGFR and presence of proteinuria were independently associated with higher risks for new-onset of High-TG, Low-HDL-C, and High-TG/HDL-C ratios., Conclusions: CKD was associated with a higher risk of new-onset High-TG, Low-HDL-C, and High-TG/HDL-C ratios, but not High-LDL-C, in the general population. These CKD-specific lipid abnormalities may explain the residual risk for CKD-related cardiovascular disease., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Apolipoprotein E (apoE) is a major apolipoprotein involved in lipoprotein metabolism. It is a polymorphic protein and different isoforms are associated with variations in lipid and lipoprotein levels and thus cardiovascular risk. The isoform apoE4 is associated with an increase in LDL-cholesterol levels and thus a higher cardiovascular risk compared to apoE3. Whereas, apoE2 is associated with a mild decrease in LDL-cholesterol levels. In the presence of other risk factors, apoE2 homozygotes could develop type III hyperlipoproteinemia (familial dysbetalipoproteinemia or FD), an atherogenic disorder characterized by an accumulation of remnants of triglyceride-rich lipoproteins. Several rare APOE gene variants were reported in different types of dyslipidemias including FD, familial combined hyperlipidemia (FCH), lipoprotein glomerulopathy and bona fide autosomal dominant hypercholesterolemia (ADH). ADH is characterized by elevated LDL-cholesterol levels leading to coronary heart disease, and due to molecular alterations in three main genes: LDLR, APOB and PCSK9. The identification of the APOE-p.Leu167del variant as the causative molecular element in two different ADH families, paved the way to considering APOE as a candidate gene for ADH. Due to non mendelian interacting factors, common genetic and environmental factors and perhaps epigenetics, clinical presentation of lipid disorders associated with APOE variants often strongly overlap. More studies are needed to determine the spectrum of APOE implication in each of the diseases, notably ADH, in order to improve clinical and genetic diagnosis, prognosis and patient management. The purpose of this review is to comment on these APOE variants and on the molecular and clinical overlaps between dyslipidemias., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Aims: Familial dysbetalipoproteinemia (FD), characterized by remnant lipoprotein accumulation and premature cardiovascular disease, occurs in homozygous carriers of the APOE ε2 allele, but genetic predisposition alone does not suffice for the clinical phenotype. Cross-sectional studies suggest that a second metabolic hit - notably adiposity or insulin resistance - is required, but the association between these risk factors and development of FD has not been studied prospectively., Methods: For this study, we evaluated 18,987 subjects from two large prospective Dutch population-based cohorts (PREVEND and Rotterdam Study) of whom 118 were homozygous APOE ε2 carriers. Of these, 69 subjects were available for prospective analyses. Dyslipidemia - likely to be FD - was defined as fasting triglyceride (TG) levels >3 mmol/L in untreated subjects or use of lipid lowering medication. The effect of weight, body mass index (BMI), waist circumference, type 2 diabetes mellitus and non-TG metabolic syndrome on development of dyslipidemia was investigated., Results: Eleven of the 69 ε2ε2 subjects (16%) developed dyslipidemia - likely FD - during follow-up. Age-, sex- and cohort-adjusted risk factors for the development of FD were BMI (OR 1.19; 95%CI 1.04-1.39), waist circumference (OR 1.26 95%CI 1.01-1.61) and presence of non-TG metabolic syndrome (OR 4.39; 95%CI 1.04-18.4) at baseline. Change in adiposity during follow-up was not associated with development of dyslipidemia., Conclusions: Adiposity increases the risk of developing an FD-like lipid phenotype in homozygous APOE ε2 subjects. These results stress the importance of healthy body weight in subjects at risk of developing FD., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Elevated low-density lipoprotein cholesterol (LDL-C) is a principally modifiable cause of atherosclerotic cardiovascular disease; accordingly, recent European and US multisociety dyslipidaemia guidelines emphasise the importance of lowering LDL-C to reduce cardiovascular risk. This review provides perspectives on established and emerging agents that reduce LDL-C to help providers synthesize the abundance of new evidence related to prevention of cardiovascular disease. We provide hypothetical cases of patients with different cardiovascular risk factors and medical histories to illustrate application of current lipid-lowering guidelines in various clinical settings. As a core focus of preventive therapy, both European and US lipid management guidelines emphasise the importance of identifying patients at very high cardiovascular risk and treating to achieve LDL-C levels as low as possible, with European guidelines setting a goal of <1.4 mmol/L (<55 mg/dL) in patients with very high-risk cardiovascular disease. The proprotein convertase subtilisin/kexin type 9 inhibitors are now included in the guidelines and may fulfil an important unmet need for very high-risk patients who are not able to achieve LDL-C goals with conventional agents. The recently approved bempedoic acid and other promising agents under development will add to the armamentarium of lipid-lowering drugs available for clinicians to help patients meet their treatment goals., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Aims: Shift work is common worldwide and linked to deleterious cardiovascular effects that might be underlined by dyslipidemia. The aim of this systematic review and meta-analysis is to determine the impact of shiftwork on dyslipidemia., Methods: Searching in PubMed, Cochrane Library, Science Direct and Embase databases without language restriction on 15 February 2020, included studies that describe blood lipids levels or a risk measure in shift workers compared with fixed-day workers (controls). Differences by study-level characteristics were estimated using stratified meta-analysis by type of shift work, and meta-regression to examine relations between dyslipidemia and demographic, lifestyle and work characteristics. Estimates were pooled using random-effect meta-analysis., Results: We included a total of 66 articles, representing 197,063 workers. Shift work globally increased the levels of triglycerides (overall SMD = 0.09; 95CI 0.05 to 0.13; p < 0.001), and globally decreased the levels of c-HDL (-0.08; 95CI -0.12 to -0.03; p = 0.001). Permanent night shift workers were an at-risk type of shift for dyslipidemia with significantly higher blood levels of total cholesterol (0.22; 95CI 0.01 to 0.42; p = 0.043) and triglycerides (0.18; 0.03 to 0.33; p = 0.017), and significantly lower blood levels of c-HDL (-0.16; 95CI -0.32 to 0.00; p = 0.05). Permanent night shift workers were more at-risk for total cholesterol than rotating 3 × 8 shift workers (Coefficient 0.22; 95CI 0.01 to 0.42; p = 0.038) and rotating 2 × 12 shift workers (0.24; 0.02 to 0.46; p = 0.037), and more at-risk for triglycerides than rotating day shift workers (0.21; 95CI 0.03 to 0.38; p = 0.023). Results were non-significant for c-LDL, nor depending on type of shifts., Conclusions: Shift work, and particularly permanent night shift, is associated with dyslipidaemia via elevated total cholesterol and triglycerides, and reduced HDL-cholesterol. Our current study provides a practical and valuable strengthening of the evidence-base required for preventive health initiatives and workplace reform., (Copyright © 2020. Published by Elsevier B.V.)

Background and Aims: We aimed to investigate potential eligibility for proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors in patients with coronary artery disease and dyslipidaemia according to patient characteristics and variable criteria., Methods: We prospectively enrolled 2000 patients (acute coronary syndrome = 407, chronic coronary artery disease inpatients = 1087, outpatient Lipid's clinic = 506). To calculate PCSK-9 inhibitors real-world eligibility, a proprietary adjustable software was developed, which stores data and patient characteristics and can determine eligibility depending on different criteria. We tested four scenarios with different LDL thresholds according to ESC/EAS 2016 and 2019 Guidelines, 2017 American College of Cardiology Expert Consensus, and National criteria., Results: The eligible percentage was 18.85%, 9.75%, 8.55% and 2.15%, in the total population for the four classifications, respectively, and it varied according to clinical status. The increase toward more recent guidelines was mostly attributed to the increasing number of coronary patients who become eligible as our criteria become stricter., Conclusions: For the first time, a realistic estimation of PCSK-9 eligibility is provided via an adjustable predictive model in a population of 2000 patients with acute coronary syndrome, chronic coronary artery disease and dyslipidaemia. This can be a valuable tool for the incorporation of PCSK-9 inhibitors in health care systems., Competing Interests: Declaration of competing interest Dr Vlachopoulos and Dr Richter have received research grants and honoraria from Amgen, Elpen, Mylan, MSD, Sanofi and Servier outside the submitted work. Dr Skoumas has received research grants and honoraria from Amgen, Sanofi, MSD, and Elpen and Dr Tousoulis has received research grants and honoraria from Amgen, Pfizer, MSD, Boehringer Ingelheim, and Sanofi outside the submitted work. Dr Dima and Dr Soulis have received a research grant for the submitted work. The other the authors have nothing to disclose., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background and Aims: Cohort studies found blood lipid traits were associated with the risk of chronic kidney disease (CKD). We aimed to investigate whether blood lipid traits were causally associated with the risk of CKD in the Chinese., Methods: 15,244 participants without kidney disease and cancer from the Dongfeng-Tongji cohort were recruited in 2008-2010 in Shiyan City, China. Blood total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), and triglyceride (TG) levels were measured. 5251 participants had genotype data and were included in the Mendelian randomization analysis. Incident CKD was defined as estimated glomerular filtration rate <60 ml/min per 1.73 m 2 in 2013. Logistic regression and Mendelian randomization methods were used to estimate the observed and causal associations of blood lipid traits with incident CKD., Results: Various blood lipid traits were associated with CKD risk, and the odds ratios (95% confidence intervals) for incident CKD comparing the extreme quartiles were 1.45 (1.24-1.70) for TG, 1.26 (1.08-1.46) for nonHDL-c, 2.21 (1.91-2.57) for TC:HDL-c ratio, 2.14 (1.83-2.51) for TG:HDL-c ratio, and 0.47 (0.40-0.55) for HDL-c. The Mendelian randomization analysis indicated that 1 mmol/l increase in the genetic predicted blood TG level was associated with a 5% (95% confidence interval, 0-10%) higher risk of CKD., Conclusions: Although blood levels of HDL-c, TG, nonHDL-c, TC:HDL-c ratio, and TG:HDL-c ratio were observed to be associated with incident CKD, the Mendelian randomization analysis provided genetic evidence to support causal relation for blood TG level only., Competing Interests: Declaration of competing interest The authors declared they do not have anything to disclose regarding conflict of interest with respect to this manuscript., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background and Aims: The aim of the study was to estimate trends and differences in cardiovascular disease (CVD) risk factor prevalence among middle-aged men and women based on the data from the Lithuanian High Cardiovascular Risk (LitHiR) primary prevention program between 2009 and 2018., Methods: A community-based cross-sectional study included men aged 40-54 years and women aged 50-64 years without overt CVD. Nationally representative data comprised 110,370 Lithuanian adults (42.4% men and 57.6% women) examined in the period 2009-2018. Prevalences of major CVD risk factors, such as dyslipidaemia, arterial hypertension, diabetes mellitus, obesity, metabolic syndrome and smoking, were assessed., Results: The study showed a significant drop in the prevalence of dyslipidaemia and TC levels among men (p = 0.030 and p < 0.001) and no significant change among women (p = 0.594 and p = 0.799). The prevalence of AH significantly decreased in both gender groups (p < 0.001 in women and p < 0.001 in men). Obesity rates declined among women while it remained constant among men (p < 0.001 and p = 0.100 respectively). There was a significant decline among women and a significant increase among men in the prevalence of metabolic syndrome (p < 0.001 and p = 0.016 respectively). The prevalence of diabetes increased until 2013, after which it started decreasing in the whole group (p = 0.005). The study showed a significant increase in the percentage of smoking women (p < 0.001), although the number of smoking men remained much higher (about 40%) (p < 0.001)., Conclusions: In our observational study, we have documented a high prevalence of all CVD risk factors in 2009 with a slight decrease during the period in most prevalence rates, except in dyslipidaemia and smoking levels., Competing Interests: Declaration of competing interest The authors declared they do not have anything to disclose regarding conflict of interest with respect to this manuscript., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Competing Interests: Declaration of competing interest The author declared she does not have anything to disclose regarding conflict of interest with respect to this manuscript.

Lipoprotein(a), Lp(a), is a modified atherogenic low-density lipoprotein particle that contains apolipoprotein(a). Its levels are highly heritable and variable in the population. This consensus statement by HEART UK is based on the evidence that Lp(a) is an independent cardiovascular disease (CVD) risk factor, provides recommendations for its measurement in clinical practice and reviews current and emerging therapeutic strategies to reduce CVD risk. Ten statements summarise the most salient points for practitioners and patients with high Lp(a). HEART UK recommends that Lp(a) is measured in adults as follows: 1) those with a personal or family history of premature atherosclerotic CVD; 2) those with first-degree relatives who have Lp(a) levels >200 nmol/l; 3) patients with familial hypercholesterolemia; 4) patients with calcific aortic valve stenosis and 5) those with borderline (but <15%) 10-year risk of a cardiovascular event. The management of patients with raised Lp(a) levels should include: 1) reducing overall atherosclerotic risk; 2) controlling dyslipidemia with a desirable non-HDL-cholesterol level of <100 mg/dl (2.5 mmol/l) and 3) consideration of lipoprotein apheresis., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Guidelines recommend high-intensity statins for patients with atherosclerotic cardiovascular disease (ASCVD). Subgroups with comorbidities that increase cardiovascular risk, such as diabetes mellitus (DM), chronic kidney disease (CKD) or polyvascular disease (PoVD), may derive greater absolute benefit from addition of non-statin therapies. We assessed the relationship between lower low-density lipoprotein cholesterol (LDL-C) and major adverse cardiovascular events (MACE) risk reduction during alirocumab phase III ODYSSEY trials among these subgroups., Methods: Patient data were pooled from nine trials comparing alirocumab with control (placebo/ezetimibe), predominantly on background maximally tolerated statin. Patients with baseline ASCVD were stratified into subgroups with DM, CKD or PoVD, or without comorbidities, and between-group relative and absolute benefits were compared., Results: Among 3505 patients with ASCVD, 1573 had no comorbidities, 981 had DM, 660 had CKD and 943 had PoVD, with overlap between comorbidities; mean baseline LDL-C levels were 119 (ASCVD overall), 123, 117, 114 and 113 mg/dL, respectively. Overall, each 39 mg/dL lower on-study LDL-C was associated with a 25% lower MACE risk, hazard ratio 0.75 (95% confidence interval, 0.62-0.90, p = 0.0023), with a similar lower risk observed in each very high-risk subgroup (DM, CKD or PoVD; 30-35%) but not in the subgroup without these comorbidities (9%). Absolute benefits were greater for very high-risk subgroups; lowering LDL-C from 120 to 40 mg/dL would result in 2.76-4.35 fewer MACE/100 patient-years versus 0.3 for no comorbidities., Conclusions: Among patients with ASCVD and mean baseline LDL-C >100 mg/dL, patients with DM, CKD or PoVD appeared to derive greater absolute cardiovascular benefits from further LDL-C reduction than those without., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Dyslipidemia is a major risk factor for cardiovascular disease, the leading cause of preventable death worldwide. As a result, a full understanding of the factors influencing dyslipidemia is urgently necessary. Bile acids have been recognized as regulators of lipid metabolism, and neutral sterols may influence serum lipid levels. Therefore, this analysis was conducted to better understand the relationship between bile acids, neutral sterols, and dyslipidemia., Methods: We examined cross-sectional associations between selected fecal metabolites and serum lipids or markers of dyslipidemia in 1387 participants of the KORA FF4 study using linear and logistic regression models., Results: We found positive associations between fecal bile acids and serum high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-c), total cholesterol, triglycerides and markers of dyslipidemia, though associations were seen most consistently with triglycerides and hypertriglyceridemia. We also found positive associations between fecal cholesterol and serum LDL-c, total cholesterol, triglycerides, hypertriglyceridemia and high serum total cholesterol, though only associations with triglycerides or hypertriglyceridemia remained significant after applying the Bonferroni correction. Unexpectedly, several fecal plant sterols were positively associated with serum lipids and the associated markers of dyslipidemia. However, many of these associations were no longer statistically significant after adjusting for multiple testing., Conclusions: Our results provide insight into the role that bile acids may play in the development or progression of dyslipidemia. However, further confirmation of these results is warranted. Longitudinal and experimental studies are necessary to clarify the mechanisms behind these associations and to determine causality., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Dyslipidemia is a major risk factor for atherosclerotic cardiovascular disease (ASCVD). As key regulators of lipoprotein metabolism, apolipoproteins (apos) are discussed as vascular risk factors. This study aimed to analyze associations of major plasma apos with coronary artery disease (CAD), peripheral artery disease (PAD) and carotid artery plaque (CAP) to elucidate their diagnostic potential in risk assessment., Methods: ApoA-I, apoA-II, apoA-IV, apoB-100, apoC-I, apoC-III, apoE, and apoJ were simultaneously quantified in 3 μL EDTA-plasma by LC-MS/MS in a case-control subgroup of the Leipziger LIFE-Heart Study (N = 911). Confounder analysis with demographic, clinical covariates and serum lipids, cardiac, inflammatory, and hepatic markers were performed. Apos were associated with CAD, CAP, and PAD in a multivariate regression model., Results: Fasting and statin therapy showed strongest effects on apo concentrations. Inverse correlations of HDL-related apos A-I, A-II, A-IV, and C-I were observed for troponin T and interleukin 6. Concentrations of apos A-II, B-100, C-I, and E were decreased under statin therapy. After adjustment for influencing factors and related lipids, only apoB-100 (odds ratio per one SD [OR], 1.39; 95% confidence interval [CI], 1.05-1.84) was independently associated with CAD while apoA-IV (OR, 0.74; 95% CI 0.58-0.95) indicated PAD. ApoB-100 (OR, 1.55; 95% CI, 1.18-2.04), apoC-III (OR, 1.30; 95% CI, 1.06-1.58), and apoE (OR, 1.34; 95% CI, 1.13-1.58) were associated with CAP., Conclusions: Triglyceride rich lipoproteins (TRLs) associated apos A-IV, B-100, C-III, and E are independently associated with stable ASCVD, providing further evidence for a potential role of TRLs in atherogenesis., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Intracranial atherosclerosis (ICAS) is a predictable and preventable condition, but existing evidence concerning its risk factors has not been quantitatively assessed. The aim of this meta-analysis is to identify the non-modifiable and modifiable risk factors for ICAS., Methods: PubMed and EMBASE were searched (1995-May 15, 2018) for cross-sectional and longitudinal studies exploring risk factors for ICAS. The risk estimates and 95% confidence intervals (CIs) in multivariate analysis were aggregated using random-effect models., Results: Thirty-four studies comprising 59,736 subjects met the inclusion criteria for the systematic review involving thirty-one risk or protective factors. Seven factors were associated with ICAS, as suggested by the meta-analysis, including advanced age (odds ratio (OR) 1.05, 95% CI 1.03-1.08), metabolic syndrome (OR 2.13, 95% CI 1.35-3.37), diabetes mellitus (OR 1.98, 95% CI 1.69-2.31), hypertension (OR 1.97, 95% CI 1.69-2.31), dyslipidemia (OR 1.29, 95% CI 1.04-1.59), high levels of low-density lipoprotein cholesterol (OR 1.06, 95% CI 1.00-1.12) and high levels of apolipoprotein A1 (OR 0.34, 95% CI 0.15-0.75). The subgroup analysis for study populations indicated advanced age, metabolic syndrome, diabetes mellitus and hypertension as an elevated risk of ICAS among community subjects and stroke patients; according to the subgroup analysis for ethnicity, similar associations remained in Asians, but only metabolic syndrome and diabetes mellitus were correlated with ICAS in Caucasians., Conclusions: Individuals with advanced age, metabolic syndrome, diabetes mellitus, hypertension and dyslipidemia might have a higher risk of ICAS, whereas high levels of apolipoprotein A1 might protect against ICAS., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Aims: Considerable attention is given nowadays to the presence of cardiovascular diseases risk factors in children. The current blood lipid classification system for Chinese children was based on the United States National Cholesterol Education Program (NCEP) cutpoints, which did not take the age, gender and race differences into consideration. This study aimed to develop gender- and age-specific lipid cutpoints for dyslipidemia screening in Chinese children and compare the ability of new cutpoints and NCEP pediatric cutpoints to predict obesity and unfavorable blood pressure (BP) levels., Methods: Data were obtained from a nationwide multicenter cross-sectional study: The China Child and Adolescent Cardiovascular Health Study, comprising 12,875 Chinese children aged 6-18 years. We calculated cutpoints for abnormal levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) that were linked to Chinese adult abnormal lipid thresholds using the General Additive Model for Location Scale and Shape method., Results: Borderline-high and high cutpoints (TC, LDL-C and TG) as well as low cutpoints (HDL-C) were developed to classify the abnormal blood lipid levels in Chinese children. Better performance for prediction of obesity, elevated BP, and hypertension were found with the proposed cutpoints in comparison with the NCEP pediatric cutpoints (AUC for obesity: 0.612 vs. 0.597, p = 0.017; AUC for elevated BP: 0.529 vs. 0.521, p = 0.017; AUC for hypertension: 0.536 vs. 0.527, p = 0.016)., Conclusions: The gender- and age-specific cutpoints should improve the accuracy of dyslipidemia screening in China and be more reasonable in practice., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Aims: Research on the biologic activities of HDL, such as cholesterol efflux capacity and HDL composition, has allowed the understanding of the effect of interventions directed to improve cardiovascular risk. Previously, statin therapy has shown conflicting results about its effects on cholesterol efflux capacity of HDL; the underlying mechanisms are unclear but studies with positive effects are associated with an increase of HDL-cholesterol levels. We investigated if 10 weeks of atorvastatin therapy changes HDL efflux capacity and the chemical composition of its subpopulations., Methods: In a before-after design basis, HDL-cholesterol levels, chemical composition and cholesterol efflux capacity from HDL subpopulations isolated by isophynic ultracentrifugation were assessed in plasma samples from 60 patients with type 2 diabetes mellito (T2DM) at baseline and after 10 weeks of treatment with 20 mg atorvastatin. Cholesterol efflux was measured from human THP-1 cells using large, light HDL2b and small, dense 3c subpopulations as well as total HDL as acceptors. Changes of cholesterol efflux and chemical composition of HDL after treatment were analyzed. Correlations among variables potentially involved in cholesterol efflux were evaluated., Results: A significant decrease of 4% in HDL-cholesterol levels was observed from 47 (42-54) to 45 (39-56) mg/dL, p = 0.02. Cholesterol efflux from total-HDL and HDL2b and 3c subfractions was maintained unchanged after treatment. The total mass of HDL remained unaffected, except for the HDL3a subpopulation accounted for by a significant increase in total protein content. No significant correlations for variables previously known to be associated with cholesterol efflux were found in our study., Conclusions: Short therapy of 10 weeks with 20 mg of atorvastatin does not modify the cholesterol efflux capacity neither the total mass of HDL2b, HDL3c and total HDL. The discrepancy with previous reports may be due to the selective effects among different classes of statins or differences in the approaches to measure cellular cholesterol efflux., (Copyright © 2018. Published by Elsevier B.V.)

Background and Aims: Alirocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9, significantly reduces low-density lipoprotein cholesterol (LDL-C). We evaluated the efficacy and safety of alirocumab in individuals with type 2 diabetes mellitus (T2DM) with versus without mixed dyslipidaemia (MDL, defined as baseline LDL-C ≥70 mg/dL [1.8 mmol/L] and triglycerides ≥150 mg/dL [1.7 mmol/L])., Methods: Data from 812 individuals with T2DM, from the placebo-controlled, 78-week, Phase 3 ODYSSEY LONG TERM trial of alirocumab 150 mg every 2 weeks (Q2W), on a background of maximally tolerated statins ± other lipid-lowering therapies, were pooled according to MDL status. Efficacy endpoints included percentage change from baseline to Week 24 in calculated LDL-C and other lipids/lipoproteins., Results: In individuals with T2DM who received alirocumab 150 mg Q2W, mean LDL-C changes from baseline to Week 24 were -62.6% (vs. -6.0% with placebo) in those with MDL and -56.1% (vs. 5.6%) in those without MDL, with no significant between-group difference (p-interaction = 0.0842). Risk-based LDL-C goals (<70 [1.8 mmol/L] or <100 mg/dL [2.6 mmol/L]) were achieved by 69.1% and 72.4% of alirocumab-treated individuals with and without MDL, respectively. Mean reductions in non-high-density lipoprotein cholesterol (49.2% and 47.8%) and apolipoprotein B (50.2% and 49.1%) with alirocumab were also similar in those with and without MDL, respectively. Treatment-emergent adverse event rates were comparable between alirocumab-treated individuals with T2DM, with and without MDL., Conclusions: Reductions in LDL-C and other lipids with alirocumab, as well as safety and tolerability, were comparable between individuals with T2DM and with versus without MDL., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Low-density lipoprotein-cholesterol (LDL-C) is a well-accepted causal risk factor for athero-thrombotic cardiovascular disease, as demonstrated in large epidemiological studies, including Mendelian randomization data. Several randomized controlled trials and meta-analyzes have shown that lipid lowering therapies, such as statins and more recently the non-statin agents ezetimibe and Proprotein Convertase Subtilisin Kexin type 9 (PCSK9) monoclonal antibodies (mAb), reduce cardiovascular events across a broad range of baseline LDL-C levels. Over time, the recommended target for LDL-C has become more stringent, moving from 2.6 mmol/l to 1.8 mmol/l in very high-risk patients. It is currently recommended to start high intensity statin treatment immediately after acute coronary syndromes (ACS) to maximally and rapidly reduce LDL-C. The novel treatment options enable the achievement of very low LDL-C levels below 1 mmol/l, with no reported safety issues, in particular with regard to neurocognitive events. However, current evidence supports the use of PCSK9 mAb treatment in ACS patients only after an initial 2-3 month run-up treatment adaptation period with maximally tolerated statin. The use of PCSK9 mAb immediately in the acute phase of ACS (<1 month) remains to be studied. Some data suggest that circulating PCSK9 increases coronary plaque vulnerability, inflammation as well as platelet aggregation in the acute phase of ACS, potentially justifying earlier PSCK9 mAb treatment initiation. As the use of novel treatment combinations in ACS is further explored to widen the perspectives of a more personalized approach for the management of ACS based on individual patient risk profile and baseline LDL-C values, their relative cost-effectiveness will also need to be assessed., (Copyright © 2018. Published by Elsevier B.V.)

Background and Aims: Prognosis variations in patients discharged after an acute coronary syndrome (ACS) according to the professionals involved has not been clearly outlined. The aim of our study was to assess the impact on a specific outpatient clinic (SOC)., Methods: We included all consecutive patients admitted for an ACS in a single center. We performed a propensity score matching with all patients discharged from hospital according to whether they were referred to the SOC or not., Results: From the 1822 patients discharged, 260 couples of well-balanced ACS patients were obtained after propensity score matching. Median follow-up was 43.3 months and cardiovascular mortality rate was 10.4%, all-cause mortality was 13.9% and any MACE 38.2%. Patients attended the SOC had significantly lower rates at all three endpoints. Multivariate analysis results showed how the follow-up in the SOC was associated with significantly lower risk at all endpoints. SOC patients also had significantly lower rate at hospital readmissions and the multivariate analysis identified a negative association between the first cardiovascular readmission and SOC (sHR: 0.26 95%CI 0.18-0.367; p < 0.01). Mean LDLc levels at the time of ACS admission was 99.0 (36.7) mg/dl and no difference was observed in patients referred to SOC vs. non-referred. Patients followed at the SOC achieved significantly lower LDLc and higher percentage of LDLc <70 mg/dl (56.7% vs. 36.7%; p < 0.01). SOC follow-up was associated with 44% higher probability of final LDLc <70 mg/dl., Conclusions: An SOC for ACS patients was independently associated with higher LDLc control and long-term survival., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Aims: Mechanisms for the association between iron stores and risk factors for diabetes and cardiovascular disease, such as metabolic syndrome (MetS) and its components, are still not clear. We evaluated the associations between ferritin levels, MetS and its individual components, and potential role of confounding, in a meta-analysis., Methods: We searched articles in MEDLINE and EMBASE until February 14th, 2018. There were two approaches: meta-analysis of 1) cross-sectional and longitudinal studies and 2) only cross-sectional studies. Meta-regressions were conducted to identify sources of heterogeneity in the associations of ferritin with MetS and its individual components., Results: Information from 26 studies (5 prospective) was systematically reviewed and 21 studies were meta-analysed. The pooled OR for MetS by increased ferritin was 1.78 (95%CI: 1.60-1.97) in the meta-analysis 1, and 1.70 (95%CI: 1.49-1.95) in the meta-analysis 2. The pooled association was weaker in studies adjusted for hepatic injury markers (meta-regression coefficient (95% CI): -0.34 (-0.60,-0.09) p = 0.008) and body mass index (BMI) (meta-regression coefficient (95% CI): -0.27 (-0.53,-0.01) p = 0.039). Among MetS components, the pooled association with increased ferritin was strongest with high triglycerides [OR (95%CI): 1.96 (1.65-2.32)] and high glucose levels [OR 95%CI: 1.60 (1.40-1.82)]. Higher cut-off points used to define high ferritin concentrations were more strongly associated with high triglycerides [meta-regression coefficient (95% CI): 0.22 (0.03, 0.041), p = 0.023]., Conclusions: High triglycerides and glucose are the components more strongly associated with ferritin. Hepatic injury and BMI appear to influence the ferritin-MetS association, and a threshold effect of high ferritin concentration on the ferritin-high triglycerides association was observed., (Copyright © 2018. Published by Elsevier B.V.)

Background and Aims: The latest guidelines from the American Association of Clinical Endocrinologists (AACE) and the American College of Endocrinology (ACE) proposed a new "extreme-risk" category of patients, for whom a low-density lipoprotein cholesterol (LDL-C) level <55 mg/dL (1.4 mmol/L) is advised. We aimed to identify the proportion of patients with stable coronary artery disease (CAD), who are at extreme cardiovascular (CV) risk, and explore how achievable is the new LDL-C goal., Methods: We enrolled 1629 consecutive patients ≤80 years with stable CAD. Fasting lipids were determined and patients having probable or definite heterozygous familial hypercholesterolaemia (HeFH) were identified using the Dutch Lipid Clinic Network algorithm., Results: The prevalence of risk factors/characteristics suggesting an extreme CV risk were as follows: 32% diabetes mellitus, 33% premature CAD and 9.2% HeFH. In total, 895 (55%) patients had at least one of those risk factors/characteristics and formed the extreme CV risk category. Among patients at extreme risk, 87% were on lipid-lowering therapy, of whom 20.3% had LDL-C <70 mg/dL (1.8 mmol/L) and only 5.3% had LDL-C <55 mg/dL., Conclusions: More than half of all patients with stable CAD are at extreme CV risk and very few (∼5%) achieve LDL-C levels <55 mg/dL. Using maximally-tolerated high-intensity statin combined with ezetimibe, if necessary, is imperative to bridge the treatment gap, while in selected cases the addition of PCSK9 inhibitors will be required., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Aims: Non-LDL dyslipidemia (NLD) confers cardiovascular risk, and prevalence rates appear to be high in elderly populations. Small cohorts have identified several lifestyle, anthropometric, and medical factors associated with NLD. We aimed to assess sex- and age-specific prevalence of NLD in a contemporary population cohort (n = 167 729), and to identify independent determinants of NLD, focusing on lifestyle, anthropometric, and medical factors., Methods: The prevalence of NLD was assessed per 10-year age intervals in adults without cardiovascular disease not using lipid-modifying drugs from the Dutch LifeLines cohort. NLD was defined as low HDL-cholesterol or high triglycerides or high remnant cholesterol as per guideline cut-off values. Multivariable regression was used to identify factors independently associated with NLD. Determinants included age, smoking, alcohol use, physical activity, diet, BMI, diabetes mellitus (DM), chronic kidney disease, and in women, menopausal state and oral contraceptive use., Results: NLD occurred in 15-19% of women and 13-30% of men in this cohort, with the highest prevalence of 30% in 35-55 year old men. In most age groups, the prevalence in women was lower than in men. Obesity (both sexes: Odds ratio (OR) 5.3, 95% confidence interval (95%CI) 5.0-5.7), current smoking (men: OR 1.8, 95%CI 1.7-1.9; women OR 2.2, 95%CI 2.1-2.3), and DM (men: OR 2.2, 95%CI 1.8-2.6; women: OR 2.7, 95%CI 2.3-3.1) were strongly associated with NLD., Conclusions: NLD already occurs frequently at an early age. Modifiable lifestyle choices, obesity, and DM were strong determinants of NLD. Public health efforts could substantially contribute to decrease NLD., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Aims: The prevalence and correlates of subclinical atherosclerosis when low-density lipoprotein cholesterol (LDL-C) levels are low remain unclear. Therefore, we examined the association of cardiovascular risk factors and subclinical atherosclerosis among individuals with untreated LDL-C <70 mg/dL., Methods: We included participants from the Multi-Ethnic Study of Atherosclerosis (MESA) and the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) cohorts. To optimize accuracy, LDL-C was calculated by the validated Martin/Hopkins equation that uses an adjustable factor for the ratio of triglycerides to very low-density lipoprotein cholesterol. We defined subclinical atherosclerosis as a coronary artery calcium (CAC) score >0 in the combined cohort or common carotid intima media thickness (cIMT) in the 4 th quartile, using cohort-specific cIMT distributions at baseline. Logistic regression models examined the cross-sectional associations of cardiovascular risk factors and subclinical atherosclerosis., Results: Among 9411 participants not on lipid lowering therapy, 263 (3%) had LDL-C <70 mg/dL (MESA: 206, ELSA: 57). Mean age in this population was 58 (SD 12) years, with 43% men, and 41% Black. The prevalence of CAC >0 in those with untreated LDL-C<70 mg/dL was 30%, and 18% were in 4th quartile of cIMT. In demographically adjusted models, only ever smoking was significantly associated with both CAC and cIMT. Similar results were obtained in risk factor-adjusted models (smoking: OR, 2.29; 95% CI, 1.10-4.80 and OR, 3.44; 95% CI, 1.41-8.37 for CAC and cIMT, respectively)., Conclusions: Among middle-aged to older individuals with untreated LDL-C <70 mg/dL, subclinical atherosclerosis remains moderately common and is associated with cigarette smoking., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Aims: Non-high-density lipoprotein cholesterol (non-HDL-C) goals are defined as 30 mg/dL (0.78 mmol/L) higher than the respective low-density lipoprotein cholesterol (LDL-C) goals. This definition, however, do not consider the population distribution of non-HDL-C, which could represent a more appropriate individual goal when both markers are discordant. The aim of this study is to establish non-HDL-C goals at the same population percentiles of LDL-C., Methods: Non-HDL-C values were assigned at the same percentiles correspondent to the LDL-C treatment goals for 14,837 participants from the Longitudinal Study of Adult Health (ELSA-Brasil) with triglycerides levels ≤ 400 mg/dL (4.52 mmol/L). We also assessed the frequency of reclassification, defined as the number of subjects with LDL-C levels in the recommended therapeutic category, but with non-HDL-C levels above or below the category., Results: The non-HDL-C values, based on correspondent LDL-C population percentiles, were 92 (2.38), 122 (3.16), 156 (4.04), 191 (4.95), and 223 mg/dL (5.78 mmol/L). Among participants with LDL-C <70 mg/dL (1.81 mmol/L), 22.8% were reclassified in a higher category according to the guidelines-based non-HDL-C cut-off and 30.1% according to the population percentile-based cut-off; 25.6% and 64.1%, respectively, if triglycerides concurrently 150-199 mg/dL (1.69-2.25 mmol/L)., Conclusions: Our results demonstrated that non-HDL-C percentiles-based goals were up to 8 mg/dL (0.21 mmol/L) lower than the guidelines recommended goal and had a profound impact on the reclassification of participants, notably when LDL-C was <100 mg/dL (2.56 mmol/L), the treatment goal for high risk patients. Therefore, non-HDL-C goals should be changed for reduction of residual risk., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Aims: We aimed to examine the effect of serum sitosterol, a cholesterol absorption marker, on clinical outcomes in acute coronary syndrome patients with dyslipidaemia., Methods: This is a sub-analysis of the HIJ-PROPER trial that assesses the effect of aggressive low-density lipoprotein cholesterol (LDL-C) lowering treatment with pitavastatin + ezetimibe in 1734 acute coronary syndrome (ACS) patients with dyslipidaemia. Patients were divided into two groups based on sitosterol level at enrolment (cut-off value was 2.2 μg/mL; a median of baseline sitosterol level), and clinical outcomes were examined., Results: The mean LDL-C level after 3 years in the low sitosterol group was 84.8 ± 20.1 mg/dL with pitavastatin-monotherapy and 64.6 ± 20.3 mg/dL with pitavastatin + ezetimibe, while corresponding values in the high sitosterol group were 91.0 ± 22.9 mg/dL and 71.1 ± 23.3 mg/dL, respectively. In the high sitosterol group, the Kaplan-Meier event rate for the primary endpoint at 3 years was 26.0% in the pitavastatin + ezetimibe group, as compared with 34.3% in the pitavastatin-monotherapy group (hazard ratio, 0.71; 95% confidence interval, 0.56-0.91; p = 0.006, p-value for interaction = 0.010). However, in the low sitosterol group, there was no significant reduction of the primary endpoint by pitavastatin + ezetimibe therapy., Conclusions: Aggressive lipid-lowering treatment with ezetimibe had a positive effect on clinical outcomes in the high sitosterol subset of ACS patients with dyslipidaemia, but not in the low sitosterol subset. This effect was independent of LDL-C reduction and suggests that sitosterol measurement on admission in ACS patients might contribute to a "personalised" lipid-lowering approach., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Lipoprotein (a) (Lp(a)) is a cholesterol-rich lipoprotein known since 1963. In spite of extensive research on Lp(a), there are still numerous gaps in our knowledge relating to its function, biosynthesis and catabolism. One reason for this might be that apo(a), the characteristic glycoprotein of Lp(a), is expressed only in primates. Results from experiments using transgenic animals therefore may need verification in humans. Studies on Lp(a) are also handicapped by the great number of isoforms of apo(a) and the heterogeneity of apo(a)-containing fractions in plasma. Quantification of Lp(a) in the clinical laboratory for a long time has not been standardized. Starting from its discovery, reports accumulated that Lp(a) contributed to the risk of cardiovascular disease (CVD), myocardial infarction (MI) and stroke. Early reports were based on case control studies but in the last decades a great deal of prospective studies have been published that highlight the increased risk for CVD and MI in patients with elevated Lp(a). Final answers to the question of whether Lp(a) is ready for wider clinical use will come from intervention studies with novel selective Lp(a) lowering medications that are currently underway. This article expounds arguments for and against this proposition from currently available data., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Aims: Meta-analyses of randomised controlled trials (RCTs) have suggested a possible benefit of statin treatment on the risk of venous thromboembolism (VTE), with potential differences by type and dose of statins. We aimed to assess differences among statins and to investigate the relationship between risk of VTE and reduction of LDL-cholesterol (LDL-c) levels., Methods: We electronically searched, through November 29, 2017, RCTs comparing a statin with either placebo or another statin treatment, including 100 or more adult participants, and lasting at least 24 weeks. Data on first VTE events and LDL-c was analysed with a network meta-analysis and a meta-regression., Results: Thirty RCTs (159,058 participants; 1431 events) were included, with 28 reporting LDL-c data. Network meta-analysis indicated a larger benefit for rosuvastatin compared to placebo and other statins; 50% of the effect of statins on VTE risk reduction, however, was explained by their different potencies in lowering LDL-c. The risk reduction in VTE was proportional to LDL-c decrease (37% relative lower risk per each 1 mmol/L reduction in LDL-c), without an apparent threshold. A reduction of 1 mmol/L in LDL-c would translate in 37 less VTE events per year in 100,000 people in UK, corresponding to 3162 prevented episodes per year in people between 50 and 59 years., Conclusions: In RCTs with statin treatment, the reduction of VTE risk was only partially related to LDL-c reduction and the benefit was larger than that observed for atherothrombotic risk. Further RCTs are warranted to clarify the relationship between statin, lipid modifications, and VTE risk., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Aims: Statin utilization and lipid goal achievement were estimated in a large sample of Italian patients at high/very-high cardiovascular (CV) risk., Methods: Patients aged ≥18 years with a valid low-density lipoprotein cholesterol (LDL-C) measurement in 2015 were selected from the IMS Health Real World Data database; non-high-density lipoprotein cholesterol (non-HDL-C) was assessed in those with available total cholesterol measurements. Index dates were defined as the last valid lipid measurement in 2015. Patients were hierarchically classified into mutually exclusive risk categories: heterozygous familial hypercholesterolemia (primary and secondary prevention), atherosclerotic CV disease (including recent acute coronary syndrome [ACS], chronic coronary heart disease, stroke, and peripheral arterial disease), and diabetes mellitus (DM) alone. Statin and non-statin lipid-modifying therapy (LMT) use, and European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guideline-recommended goal attainment, were assessed., Results: Among 66,158 patients meeting selection criteria, the overall rate of LMT prescriptions was 53.3%, including 7.7% on high-intensity statin therapy. Statin use was highest for recent ACS and lowest for DM alone. LDL-C goal attainment was 16.0% for <1.8 mmol/l and 45.0% for <2.5 mmol/l; 24.3% reached non-HDL-C <2.6 mmol/l and 52.2% were at <3.3 mmol/l. Goal achievement was greatest with high-intensity statin use., Conclusions: Statin use in this cohort was consistent with previous reports in Italian patients at high/very-high CV risk, and low relative to statin use in other European countries. The low rate of ESC/EAS lipid goal attainment observed was consistent with outcomes of other European studies., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: The association between cholesterol and stroke has been inconsistent. This study aimed to examine the association between total cholesterol (TC) and mortality from total stroke and stroke subtypes., Methods: 503,340 Korean adults aged 40-80 years without a history of heart disease or stroke participated in routine health examinations in 2002 and 2003, and were followed up until 2013. Adjusted hazard ratios (HRs) for stroke (I60-I69) mortality were calculated., Results: Nonlinear associations for total stroke (U-curve) and hemorrhagic stroke (L-curve), especially intracerebral hemorrhage (ICH), but a linear association for ischemic stroke, were found. In the range <200 mg/dL, TC was inversely associated with stroke mortality (HR per 39 mg/dL [1 mmol/L] increase = 0.88 [95% CI = 0.80-0.95]), mainly due to hemorrhagic stroke (HR = 0.78 [0.68-0.90]), especially ICH (HR = 0.72 [0.62-0.85]). In the upper range (200-349 mg/dL), TC was positively associated with stroke mortality (HR = 1.09 [1.01-1.16]); ICH and subarachnoid hemorrhage mortality showed no inverse association. The associations were generally similar in middle-aged (40-64 years) and elderly (≥65 years) adults and, in the upper range, each 1 mmol/L (39 mg/dL) higher TC was associated with 11% higher mortality from stroke (95% CI = 2%-21%) in the elderly. Both middle-aged (39%) and elderly (23%) adults had higher ischemic stroke mortality associated with TC ≥240 mg/dL, compare to <200 mg/dL., Conclusions: TC level around 200 mg/dL was associated with the lowest risk of overall stroke in the elderly and middle-aged adults. No stroke subtype including ICH, was inversely associated with TC in the range ≥200 mg/dL., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Despite recent therapeutic advances, there is an unmet need in cardiovascular disease prevention. Clinical trials and meta-analyses have established that LDL-C lowering, particularly by statin therapy, reduces the progression of coronary atherosclerosis and the risk of coronary events. Insufficient LDL-C reduction and high residual risk in a significant proportion of statin-treated patients signify that additional therapies are required to deliver more effective coronary care. Pharmacological inhibition of cholesterol absorption (with ezetimibe) and PCSK9 activity (with evolocumab or alirocumab) provides potentially useful approaches for the therapeutic modulation of LDL-C metabolism in statin-treated patients. In recent trials, combination strategies involving a statin and non-statin agent (ezetimibe or evolocumab) have been shown to promote coronary atherosclerosis regression and improve cardiovascular outcomes in patients with moderate-to-high cardiovascular risk. This review summarizes recent evidence on the effects of dual lipid-lowering therapy on coronary atherosclerosis., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Aims: Mild endogenous elevation of unconjugated bilirubin (UCB) as seen in Gilbert's syndrome (GS), might mitigate cardiovascular disease (CVD) risk factors including overweight/obesity. This study aimed to determine whether hyperbilirubinaemia is linked to improved anthropometric data and lipid profile., Methods: Our study considered GS and age-/gender-matched healthy controls (n = 248). Additionally, obese female type 2 diabetic patients (DM2) (n = 26) were included as a "disease control group"., Results: BMI, hip circumference (HC), and lipid profile were significantly lower in GS. UCB was inversely correlated with BMI (p <0 .001), HC as well as with fat mass (FM) and lipid variables (p < 0.05). Moreover, DM2 patients had significantly lower UCB compared to GS and healthy controls. Older GS subjects (≥35 years) had significantly reduced anthropometric data and improved lipid profile., Conclusions: Our results propose that the health promoting potential of mild hyperbilirubinaemia may extend to protection from age-related weight gain and dyslipidaemia., (Copyright © 2017 Elsevier B.V. All rights reserved.)